# The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2



## sekio

This is the place to discuss the various chemical and biological implications of novel and well-known drugs that don't deserve their own thread.

Previous Thread


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## pharmakos

i've read pihkal about 4 times over, and sometimes when i do my crazy ass brainstorming i imagine that i am bouncing ideas off of sasha.   tonight i was thinking about how some ligands can bind permanently to receptors.  (here, i am assuming that full agonists tend to bind permanently more often than partial agonists, idk for sure if that is true or not).  

i had an idea, that it might be possible to get "permanently" bound ligands off the receptor by introducing a second drug that is a competitive *partial *agonist at that receptor but with a much greater binding affinity than the primary drug in this example.  might be rare to find such a molecule, and idk if it is even possible for a drug to have both of those properties, but i feel it is worth pondering over nonetheless.

at first i looked at the problem like sasha would.  i wouldn't want to waste time in the laboratory with rats and petri dishes, i would jump straight to self-administered in vivo testing to test such a thing if i thought "permanent" binding had happened to me.  in this case, the most immediate means of telling if your experiment had the desired result would be by monitoring your own consciousness as the drug progresses in its action, _of course_.  however, that is far from conclusive.  you might be able to monitor your urine and excrement as a means to determine if the experiment was a success or not, but that would be messy.  (and no matter what, hopefully you will never actually find yourself in this situation!)

i then had a thought, and asked sasha, "wait, in this case would it actually be much quicker and easier to radiolabel some ligands and test the theory in vitro?"

then i had the thought "god dammit i shouldn't be able to ask a question like that, i haven't even taken organic chemistry yet, i wish i was in school right now." lol   they told me at the last minute this fall that i needed to pay for my own classes this semester, since i dropped out of my last semester there.  soooo i won't be starting up again until the winter, not that i was very far yet.

[/insomnia]

[insomniaedit]perhaps would be most effective with multiple administrations, and you may need other methods to induce metabolism or excretion while the bounced pseudo-permanent agonist was in extracellular space.  maybe plasmaphersis would be the best choice at this stage (sort of like treating bromism)?  once its kicked off the receptor though there would only be a small window of opportunity to get it out of the subject somehow before the second drug is metabolised.

this might be some phizer level pharmacology/biochemistry here i realize   discovering just the right antidote drug would take quite a bit of work i am sure.  as a matter of principal, though, i refuse to believe that anything can be _absolutely _*permanently* bound to a receptor.  heh  [/inso..


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## 23536

I think if something covalently bonds to a receptor, that receptor is destroyed.  It's the same principle as irreversible MAOIs.


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## pharmakos

^^^ guess i should do more reading and less thinking


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## MattPsy

If something is a suicide substrate (like a covalently binding agonist) then eventually receptor internalization will occur (and the receptor is replaced eventually). However until internalization occurs signal transduction can usually still take place so the effect of an irreversible agonist is not that of an antagonist, effectively, because the receptor population is not immediately destroyed.


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## pharmakos

very interesting.

it would be possible for a receptor to have a covalently bound ligand that is bound in such a position/conformation that another ligand could still bind to the receptor, no?  since two molecules can bind to two completely different sites on the same receptor.

also, what if you could use a covalently binding agonist to your advantage in some way?  for one example, perhaps the covalently bound ligand could allow an entirely new type of ligand to bind to the receptor, a ligand that could not have bound to the receptor before.  creating new avenues for signal transduction in that way.

take nature's receptor design and improve upon it somehow


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## MattPsy

For the former, that would be called an irreversible allosteric modulator.


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## Steps

Does anyone know the affinities on 5-HT, DAT, and NET for
Dextro, Levo, and Racemic Methamphetamine/Amphetamine


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## sekio

Have you looked here? I haven't seen a figure for racemic meth/amphetamine.


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## ebola?

Could there be (given methodologies for in vitro binding and release assays)?  Would the mean between the d and l isomers provide a rough indication?

ebola


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## pharmakos

ebola? said:


> Could there be (given methodologies for in vitro binding and release assays)?  Would the mean between the d and l isomers provide a rough indication?
> 
> ebola



i was thinking that as well.  i don't think a simple mean will do it though, it looks like the numbers change exponentially as potency drops.  but yeah i am pretty sure that there has to be some kind of a direct correlation between R and the individual values for D and L.


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## vortex30

Ah, here is a good place to pose this question. I wanted ADD answers to most likely a BDD question. I'm currently wrapping up day 3 of opiate withdrawal. Nothing too terrible but probably on par with the worst I have experienced before. As far as I've always been aware, your classic opiate painkillers (oxycodone and hydromorphone in particular for my use) are not toxic in the slightest, and that the health dangers occur with complications related to IV use, overdose and addiction. Well I have IVed a little, never overdosed and have on and off had some light dependencies but nothing major. But the withdrawals I get don't feel 'benign'. Very achey, bones are crackily, neck is stiff, headache, etc. Now, is this 'bad' for me? What is going on in my body that is causing these symptoms? Is it simply downregulation of mu-opioid receptors coupled with a lack of endorphins that is balancing, or are there some toxic processes to it as well? It feels awfully gross and toxic, but withdrawal can be tricky and the mind is a powerful thing.

In addition same question but now posed to benzodiazepine/GABAergic withdrawal, assuming it is not to the point of having a seizure, again just mild-moderate withdrawal. Feels god-awful, but is it all in the mind or are there toxic processes occurring? 

Thanks!


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## sekio

> But the withdrawals I get don't feel 'benign'.


 That's why they're withdrawals.

You'll make it.


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## shir

*comt*

i asked on a different thread about comt inhibitors
this is my original post:


> Hi
> Is anyone knows what comt enzymes tend to degrade more: dopamine, norepinephrine, epinephrine? And in what ratio?
> Thanks



Epsilon Alpha said:


> http://pharmrev.aspetjournals.org/content/51/4/593.full.pdf
> Page 596 will have your answers, please post questions like this in the Big and Bangin' thread.
> 
> But its sort of a 1/1.5 DA/NE affinity ratio.



now, thanks Epsilon, if i'm not wrong the arcticle said that COMT tends to dergade NE 1.5 times then DA, but also tend to degrade much more L-DOPA that eventually if i will take COMT inhibitors it will increase more of my dopamine then noradrenaline? or i'm wrong? sorry, my english just not so good, i just would like to know if i will take comt inhibitors like "entacapone" what it will increase more eventually NE or DA and in what ratio


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## pharmakos

opiates cover up your every day aches and pains.  these aches/pains are bound to feel WORSE than baseline after a period of opiate use/abuse.  just the natural course of things.


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## vortex30

sekio said:


> That's why they're withdrawals.
> 
> You'll make it.



Touche good sir. Indeed I'm feeling much better today, been through this many times, but I've always just wondered what is going on in there. Of course withdrawal tends to take the form of the opposite effect to what the effect of the drug is, so pain killer will lead to pain...But my real question, to make this ADD material, is what is going on to cause these symptoms? Any toxic processes occurring or merely the balancing out of mu receptor down-regulation plus decreased production of endorphins (and naturally, lack of opiates)? I did feel a lot better this morning though (4 full days from last dose) and even went for a 20 minute run and light work out after which was painful, but made me feel a lot better.



thenightwatch said:


> opiates cover up your every day aches and pains.  these aches/pains are bound to feel WORSE than baseline after a period of opiate use/abuse.  just the natural course of things.



Ah, so this is sort of a glimpse into what I'm in for in the future, perhaps 30-40+ years down the line? (I'm 21) I did describe myself as feeling like an 80 year old man to my buddy, haha. This makes sense, but I'm surprised I have pain in so many areas...!


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## Cydroxy

vortex30 said:


> Ah, here is a good place to pose this question. I wanted ADD answers to most likely a BDD question. I'm currently wrapping up day 3 of opiate withdrawal. Nothing too terrible but probably on par with the worst I have experienced before. As far as I've always been aware, your classic opiate painkillers (oxycodone and hydromorphone in particular for my use) are not toxic in the slightest, and that the health dangers occur with complications related to IV use, overdose and addiction. Well I have IVed a little, never overdosed and have on and off had some light dependencies but nothing major. But the withdrawals I get don't feel 'benign'. Very achey, bones are crackily, neck is stiff, headache, etc. Now, is this 'bad' for me? What is going on in my body that is causing these symptoms? Is it simply downregulation of mu-opioid receptors coupled with a lack of endorphins that is balancing, or are there some toxic processes to it as well? It feels awfully gross and toxic, but withdrawal can be tricky and the mind is a powerful thing.
> 
> In addition same question but now posed to benzodiazepine/GABAergic withdrawal, assuming it is not to the point of having a seizure, again just mild-moderate withdrawal. Feels god-awful, but is it all in the mind or are there toxic processes occurring?
> 
> Thanks!



Have you studied much into the Kappa Opiod Receptor? It is the receptor that deals directly with opiate dependence and some of the withdrawal symptoms associated with that. It has been some time sense the last time I studied it but I believe there are several scientific journals that state that as you continue your use of opiate agonist, the K Opiate receptor grows. And as the K receptor grows, so does the tolerance to opiates and with that increase also comes how bad the withdrawal symptoms are.

Little bit of interesting knowledge about the K receptor, there are 2 well known drugs that activate this receptor - Ibogaine and Salvia Divinorum. Of those two, Ibogaine actually has been scientifically proven to cause shrinkage to the receptor, but at the expense of a earth shattering visual experience. BUT it is used very successfully to alleviate the addictive symptoms and withdrawals of Opiates, in particular heroin. It also is has been shown to drop opiate tolerance as well. There are clinics world wide called Ibogaine clinics and they specialize in the treatment of addiction.

The problem with ibogaine though is that it is not always an easy one to get your hands on, plus a 24 hour spiritual journey is prob not exactly what you are looking for. Now salvia on the other hand only last upwards of 30 min or so (3-4 hours if you hold the plant in your mouth for 30 min- but it taste like you are eating grass).

I spent the better part of more then 10 hours trying to discover if salvia may have some of the same anti addictive properties as ibogaine in that they both hit the same receptor in similar ways. I did find an article about it being used in one case study of a woman with a hard to treat case of depression using it to fully relive symptoms. But there has never really been a study on salvia's ability to relive opiate withdrawal symptoms. My good friend and I joke all the time that maybe its time to bust into some salvia to drop our opiate tolerance.

Thats my 2 cents. Sorry I did not post any links to scientific articles or journals, I did not want to spend 2 or 3 hours tracking down all the papers I have read. Most of it can be found in pub med through articles linked on wiki about these subjects.


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## ebola?

I think that you need citations.  A good bit of this sounds unsubstantiated.  In particularly, receptors don't "grow" or shrink.  Rather, populations of receptors may be upregulated or downregulated (among other fates, under varying biochemical conditions).

ebola


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## MattPsy

I once used a mixed mu-kappa agonist (caused horrific hallucinations only slightly above the recreational mu effect dose-range which lasted for a good 45mins to 1.5 hours) for a decent while and was badly dependent on it. I will inform you that it did not make the material in question any less addictive or physical-dependency forming. It did not prevent the development of tolerance, either - well, for the mu effects anyway - the kappa effects seemed to always require the same amount of material. You can probably see what happens here.

Good riddance.


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## sekio

Icky, was it one of the azocine drugs?


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## MattPsy

Nope- you have PM.


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## Epsilon Alpha

shir said:


> now, thanks Epsilon, if i'm not wrong the arcticle said that COMT tends to dergade NE 1.5 times then DA, but also tend to degrade much more L-DOPA that eventually if i will take COMT inhibitors it will increase more of my dopamine then noradrenaline? or i'm wrong? sorry, my english just not so good, i just would like to know if i will take comt inhibitors like "entacapone" what it will increase more eventually NE or DA and in what ratio



Well L-DOPA is the precursor for NE as well, it kind of goes like this:
L-DOPA---(DOPA decarboxylase)----->Dopamine-----(Dopamine Beta hydroxylase)----->NE

I really can't say what would happen as far as total effects go though, stuff gets complicated fast with the whole autoreceptor, tonic/phasic levels, and where the COMT has its greatest effects. Off the top of my head I recall some COMT inhibitors having nasty side effects due to peripheral issues or some sort of other effect, but I recall orange urine was a side effect for one of them.

Also, we really are lacking in studies that display their effects in healthy individuals, or even ADHD for that matter.


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## Amu

Epsilon Alpha said:


> Well L-DOPA is the precursor for NE as well, it kind of goes like this:
> L-DOPA---(DOPA decarboxylase)----->Dopamine-----(Dopamine Beta hydroxylase)----->NE
> 
> I really can't say what would happen as far as total effects go though, stuff gets complicated fast with the whole autoreceptor, tonic/phasic levels, and where the COMT has its greatest effects. Off the top of my head I recall some COMT inhibitors having nasty side effects due to peripheral issues or some sort of other effect, but I recall orange urine was a side effect for one of them.
> 
> Also, we really are lacking in studies that display their effects in healthy individuals, or even ADHD for that matter.



Wouldn't COMT inhibitors have to cross the BBB to increase DA/NE levels directly? Tolcapone does this and is hepatoxic. Entacapone will not cross BBB and isn't hepatoxic but will just increase L-DOPA, which is going to give those nasty side effects (and I guess L-DOPA would cross the BBB, which it sucks at, and increase CNS DA/NE). Theoretically, tolcapone would work for ADHD, as it would target COMT which is most abundant in the prefrontal cortex. It's interesting though, that most MAO-A/B inhibitors have been shown to not improve ADHD, and some of them do not even amplify DA/NE transporter inhibitors, cocaine was found to not be affected, for example. "Moreover, these findings suggest that adverse consequences related to altered catecholamine transmission would not occur if patients taking phenelzine, a non-selective MAO inhibitor, relapsed and used cocaine."[1] Not cut in stone, but the pharmacology of phenelzine, tranylcypromine, etc... is very complicated, the latter causing a whole host of changes recently elaborated upon.[2]

1 - http://www.ncbi.nlm.nih.gov/pubmed/11245920
2 - http://www.ncbi.nlm.nih.gov/pubmed/16927039


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## SNR

I have a question. I have seen "XX could prevent XX molecule from being metabolized by MAO. " 

What are these methods in molecular design that prevent a molecule from being metabolized by MAO and how do they work? 

~snr


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## Amu

SNR said:


> I have a question. I have seen "XX could prevent XX molecule from being metabolized by MAO. "
> 
> What are these methods in molecular design that prevent a molecule from being metabolized by MAO and how do they work?
> 
> ~snr



SNR: XX in that case would be something like the molecule Phenelzine, which binds to the MAO enzyme sites and thus prevents any other molecule from binding to the MAO enzyme, so for example dopamine cannot be broken down by MAO because 80% of MAO enzymes have phenelzine bonded to the MAO enzymes. Are you asking how to DESIGN a molecule that forms a bond to the MAO enzyme?


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## SNR

I'm not talking about an MAOI at all. 
I'm talking about how to, for example, prevent a substituted phenethylamine molecule from being quickly metabolized by MAO.


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## Epsilon Alpha

SNR said:


> I'm not talking about an MAOI at all.
> I'm talking about how to, for example, prevent a substituted phenethylamine molecule from being quickly metabolized by MAO.



Pretty much need a MAO-B inhibitor brah, so pretty much a PEA with a highly reactive group tacked onto it somewhere preferably towards the N. Or are you asking for stuff to make it less likely to be broken down by MAO? If so an alpha carbon is your best bet, so pretty much an amphetamine is the answer to that (points out retarded duration difference of DOX vs 2C-X)

You could maybe tack on a giant chain substitution on it like MPH, but I really don't think that's where you want to go with this. Same with making it conformationally constrained shit pretty much becomes really different then.


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## psood0nym

I love 4-AcO/ho-DPT but find it is difficult to get into a solution for IMing. How do I easily and conveniently get 4-AcO-DPT fumarate into a solution suitable for intramuscular injection? Alternatively, if I just leave it in sterile water for a few days will that eventually do the trick?


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## Iodjini_dk

How about dissolving it in propylene glycol? It will dissolve many compounds which are insoluble in water. However I would expect the fumarate to be quite water soluble. Maybe its contaminated with something that should not be injected in the first place?


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## Epsilon Alpha

Injecting non-quality controlled chemicals really isn't something I'd support. But, warmed sterile saline might be your best option if the stuff dissolves easily which might require some pH tweaking. Pull up some pKa data on it or some closely related compounds and see what it says, might have to add a acid or alkali to it. Buuuuut...
HARM REDUCTION BRAH!


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## psood0nym

Thanks for the replies. If I give propylene glycol a shot and it works I'll post back, thanks. I was just hoping someone knew an IMable acid or other product that worked based on some special property of 4-ho-DPT fumerate that caused it to have poor water solubility. I've had 4-AcO-DPT and 4-ho-DPT from ostensibly three sources. It's possible they were all from the same source, but well, there you have it. In any case I've specifically asked for other than the fumerate because of the solubility problems, and was told that the labs were having difficulty keeping it stable in other forms. Shulgin also noted the difficulty in synthesizing 4-ho-DPT in general, so I don't really doubt it. One person in the Big and Dandy thread says it's specifically _because it's the fumerate form_ that it has solubility problems, if that tells you anything.

Anyways, I've tried adding acetic acid, citric acid, and just as an experiment, DMSO -- all with extensive heating. None of them made it water soluble. One person reported success with huge volumes of water, but injecting large volumes is a pain. If it's an impurity that's not dissolving than the impurity makes up a lot of the total weight, yet my insufflated dosage for effects is about what you'd expect for the given oral dosage guidelines (plus the reported success with large volumes of water discounts the impurity theory, too). Oral seems like a waste, and insufflation blows (rectal requires more than insufflation, and so also seems a bit wasteful). IM DPT is the best, and I think it would be for 4-ho-DPT, too, which is why I'm trying to figure it out. 

I tried the pKa table but I'm not really super sure what would make a good corollary for 4-ho/AcO-DPT fumerate. 4-AcO-DMT fumerate is water soluble so...


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## sekio

Have you tried adding a small amount of some other water soluble acid (citric? hydrochloric?) and boiling the fuck out of it? I think the issue is that the hydroxytryptamine fumarate salts are just not very soluble and they need a better counterion to go into sol'n nicely.


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## psood0nym

sekio said:


> Have you tried adding a small amount of some other water soluble acid (citric? hydrochloric?) and boiling the fuck out of it? I think the issue is that the hydroxytryptamine fumarate salts are just not very soluble and they need a better counterion to go into sol'n nicely.


I tried heating with both acetic acid and citric acid monohydrate, but did not exactly boil the fuck out of them. I mostly just heated them to pretty hot for about 10 minutes, where the vial got foggy from evaporating water. I suppose I could bust out the hot plate and properly boil the mL or so of water I plan to IM for maybe five minutes to see if that works, thanks. I shattered the bottom of a borosilicate vial using a frying pan recently (I think it was just way too hot too fast), and microwaving makes the water leap out of small vials, so I've resisted vigorous boiling. Both 4-ho-DMT and 4-AcO-DMT fumerate (pretty sure the ho was fumerate at least) have no trouble going into solution in my experience, BTW, but it's worth a shot nevertheless. I will post back if it works (within a few weeks I think).


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## sekio

Acquire some test tubes or boiling tubes and get a good butane torch lighter. Grab some tongs, add water and your compound and go wild.

I have had success with putting DPT HCl into sol'n by this exact method.


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## psood0nym

^Sounds like a plan, thanks.  DPT HCl is a bit of a pain to get into solution, but FYI I've gotten it into solution at 50 mg per mL simply putting the vial on top of my toaster oven and letting the heat from one or two "toasts" get it into solution, without even adding acid. But whatever works. 4-ho-DPT fumerate is MUCH more resistant.


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## Mr Blonde

Epsilon Alpha said:


> Injecting non-quality controlled chemicals really isn't something I'd support. But, warmed sterile saline might be your best option if the stuff dissolves easily which might require some pH tweaking. Pull up some pKa data on it or some closely related compounds and see what it says, might have to add a acid or alkali to it. Buuuuut...
> HARM REDUCTION BRAH!



This reminded me of something... I've been using chemicalize.org to get calculations on pKa, log d and other data on various compounds. Is this site considered fairly reliable? I've only just started using it recently, and it seems good so far.


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## nuke

psood0nym said:


> T...
> 
> I tried the pKa table but I'm not really super sure what would make a good corollary for 4-ho/AcO-DPT fumerate. 4-AcO-DMT fumerate is water soluble so...



Another thing to try I would guess is a urea and sucrose solution, something like 5%-10% urea and then isotonic concentrations of sucrose with blood...  There are old studies in glaucoma patients of 30% urea and 10% sucrose as well, so it's probably safe.


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## greyback

thenightwatch said:


> i've read pihkal about 4 times over, and sometimes when i do my crazy ass brainstorming i imagine that i am bouncing ideas off of sasha.   tonight i was thinking about how some ligands can bind permanently to receptors.  (here, i am assuming that full agonists tend to bind permanently more often than partial agonists, idk for sure if that is true or not).
> 
> i had an idea, that it might be possible to get "permanently" bound ligands off the receptor by introducing a second drug that is a competitive *partial *agonist at that receptor but with a much greater binding affinity than the primary drug in this example.  might be rare to find such a molecule, and idk if it is even possible for a drug to have both of those properties, but i feel it is worth pondering over nonetheless.
> 
> at first i looked at the problem like sasha would.  i wouldn't want to waste time in the laboratory with rats and petri dishes, i would jump straight to self-administered in vivo testing to test such a thing if i thought "permanent" binding had happened to me.  in this case, the most immediate means of telling if your experiment had the desired result would be by monitoring your own consciousness as the drug progresses in its action, _of course_.  however, that is far from conclusive.  you might be able to monitor your urine and excrement as a means to determine if the experiment was a success or not, but that would be messy.  (and no matter what, hopefully you will never actually find yourself in this situation!)
> 
> i then had a thought, and asked sasha, "wait, in this case would it actually be much quicker and easier to radiolabel some ligands and test the theory in vitro?"
> 
> then i had the thought "god dammit i shouldn't be able to ask a question like that, i haven't even taken organic chemistry yet, i wish i was in school right now." lol   they told me at the last minute this fall that i needed to pay for my own classes this semester, since i dropped out of my last semester there.  soooo i won't be starting up again until the winter, not that i was very far yet.
> 
> [/insomnia]
> 
> [insomniaedit]perhaps would be most effective with multiple administrations, and you may need other methods to induce metabolism or excretion while the bounced pseudo-permanent agonist was in extracellular space.  maybe plasmaphersis would be the best choice at this stage (sort of like treating bromism)?  once its kicked off the receptor though there would only be a small window of opportunity to get it out of the subject somehow before the second drug is metabolised.
> 
> this might be some phizer level pharmacology/biochemistry here i realize   discovering just the right antidote drug would take quite a bit of work i am sure.  as a matter of principal, though, i refuse to believe that anything can be _absolutely _*permanently* bound to a receptor.  heh  [/inso..



Drugs that permanently bind to receptors is something you do not want to happen. There is a famous case involving this guy Barry Kidston who synthesized a pain killer MPPP but a slight alteration in his procedure resulted in an impurity 
of MPTP. Why would this be so bad? Because after injecting his batch, the MPTP permanently bound to his dopamine receptors and gave the 23 year parkinson's like symptoms; in fact, because of his misfortune we figured out the dopamine mechanism of parkinson's.

Remember, your neurons don't always want to be active because the resulting neurotoxins eventually destroy the neurons you wanted to keep "on" forever.


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## skillet

MPTP doesn't work like that, it's metabolised into MPP+ in the brain, gets taken up by dopaminergic neurons, and kills them. 

GPCR's are in a constant flux of being internalised and degraded, and synthesised and transported to the membrane, so though it's possible to permanently attach something to a particular receptor, that receptor doesn't actually last that long.


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## sekio

"Permanently binding" ligands are no worse than normal, ultra-potent ones. The receptor eventually gets internalised and destroyed.


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## ebola?

What types of affinities are necessary for us to consider 'conventional' binding equivalent to formation of covalent bonds?

ebola


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## Dysphoric

Does anyone have sources claiming MDMA to be less dangerous than Cannabis? I've heard it before, but I'd like some reliable sources if possible...

Also I'd just like some MDMA studies showing how harmless it really is in moderate doses, or just sources in general saying "good" stuff about MDMA. 

Please and thank you!


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## Amu

Dysphoric said:


> Does anyone have sources claiming MDMA to be less dangerous than Cannabis? I've heard it before, but I'd like some reliable sources if possible...
> 
> Also I'd just like some MDMA studies showing how harmless it really is in moderate doses, or just sources in general saying "good" stuff about MDMA.
> 
> Please and thank you!



Do note that most of the studies on users are regarding "E" which usually has DA-releasing stimulants which increase the neurotoxicity (and perhaps even enhance the magic of the trip). Most sources regarding the good stuff about MDMA talk about it's potential therapeutic properties, but I'm not aware of any human studies that test say 25-100 mg of pure MDMA on a regular basis and do a thorough examination of long-term side effects. Erowid's neurotoxicity articles state MDMA neurotoxicity is mostly observed at 100mg+ doses, and they reference that to certain studies.

Also, unless said cannabis doses cause psychosis or intense anxiety causing psychological trauma, or an unusually potent effect on short-term memory for specific individuals, I doubt a study on reasonable MDMA vs. reasonable cannabis use would conclude MDMA being less dangerous overall. It would be less dangerous when MDMA's pro-social and entactogen qualities are beneficial for PTSD/autism patients, but not overall.


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## Indole

Dysphoric said:


> Does anyone have sources claiming MDMA to be less dangerous than Cannabis? I've heard it before, but I'd like some reliable sources if possible...
> 
> Also I'd just like some MDMA studies showing how harmless it really is in moderate doses, or just sources in general saying "good" stuff about MDMA.
> 
> Please and thank you!



 I would be VERY surprised if you were able to find any sources claiming MDMA to be less neurotoxic than cannabis. I say this because of the wealth of information regarding MDMA's neurotoxic effects and lack thereof for cannabis. Also, from personal experience I can say that daily, habitual cannabis usage leads to negligible effects on cognition and psychological performance, while the same can most certainly not be said about MDMA. 

If you like, I can PM you several articles that examine the toxicity of MDMA when I am back home with my stash of articles in a few days.


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## airsh0w

What makes D2-like receptors dysphoric and D1-like receptors euphoric? Does it have to do with cAMP and PKA? How can phosphorylation create a subjective experience through information feedback?


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## ebola?

dysphoric said:
			
		

> Does anyone have sources claiming MDMA to be less dangerous than Cannabis? I've heard it before, but I'd like some reliable sources if possible...



Who are you hearing this from?  AFAIK, this has no basis in any research.



			
				airshow said:
			
		

> What makes D2-like receptors dysphoric and D1-like receptors euphoric?



Er...it doesn't make much pharmacological sense to call a specific receptor euphoric or dysphoric.  D2-like receptors are more localized to the nucleus accumbens, so I would have expected specific direct agonists for d2-like receptors to more reliably elicit subjective ratings of 'liking' the drug.  However, none of these agonists make for good recreational compounds.

ebola


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## Dysphoric

ebola? said:


> Who are you hearing this from?  AFAIK, this has no basis in any research.
> 
> 
> 
> Er...it doesn't make much pharmacological sense to call a specific receptor euphoric or dysphoric.  D2-like receptors are more localized to the nucleus accumbens, so I would have expected specific direct agonists for d2-like receptors to more reliably elicit subjective ratings of 'liking' the drug.  However, none of these agonists make for good recreational compounds.
> 
> ebola



BBC covered this and said that MDMA in moderate use was less dangerous than Cannabis use. Cannabis isn't harmless, that's for sure.


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## airsh0w

Does tolerance have a limit?


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## ebola?

dysphoric said:
			
		

> BBC covered this and said that MDMA in moderate use was less dangerous than Cannabis use. Cannabis isn't harmless, that's for sure.



Did the comparison presented argue that moderate use of MDMA is less dangerous than use of cannabis at the same frequency?  If so, that's freaking weird.

ebola


----------



## sekio

> Does tolerance have a limit?


Does Santa have a beard? Depends which tolerance.


----------



## airsh0w

Thanks for dodging my question with a obvious yet unproven possibility and reducing its validity with an appeal to ridicule.8)


----------



## sekio

You'll have to be a lot more specific. Tolerance to the analgesic effects of opioids, tolerance to psychedelics, tolerance to dopaminergic drugs, etc... are all seperate things.


----------



## airsh0w

Ok I think I have my answer to that. How about?

What is 5-HT7s role in memory and learning and perhaps LTP?


----------



## ebola?

That is a completely separate question from the time course and eventual outcome of tolerance accrual for various ligands agonizing or antagonizing various receptors.

ebola


----------



## pharmakos

i haven't actually seen the BBC episode in question, but i believe i have read the study it was based on.  the study also included the social, legal, family, and financial impacts of being a user of each drug.  with those factors included i can see how marijuana could be considered more dangerous.  still sorta a crapshoot though =p  i guess i'd have to look at the study again/watch the show.


----------



## ebola?

Moderate use of MDMA is what, once a month or less frequent?  I don't see how toking once a month could have worse auxiliary consequences...

ebola


----------



## Dysphoric

Well, I quit smoking cigarettes. My question is, is how long does it take for my brain to balance itself after quitting Nicotine? I still want to smoke and keep it as a social thing (I did well for about a year and then got too cocky and started smoking everyday which soon led to a year long dependency [2-3 cigs a day]), but when is it safe to smoke again?  What I'm asking is, is how long until my brain doesn't want or need it anymore and kind of forget about it? 

I'm on my 15th day now, BTW. 

Another question is, will my Dopamine receptors be more sensitized after cessation? I heard it causes a lot of desensitization to D2 receptors? If so, will I feel my Desoxyn a lot more now? I've also been off of that for a year now.

Last question. Does Nicotine or anything in the Tobacco help protect against certain neurotoxicity from Meth/Amps because of its MAO properties? I also heard this.


----------



## SerotonergicHaze

I would speculate that Tobacco should have neuroprotective effects due to the MAO-A inhibiting effects from memory Harmine is the compound responsible.

I had an issue of social smoking becoming a habit, and decided to abstain. It's been about 21 days so far and even though I was a very light smoker (3-4 a night) I still have the occasional craving, but felt "normal" after a few days.

I don't think you'll ever be able to look at a cigarette in the eyes of a non smoker for a very long time, but I would speculate based on my own experiences your nicotinic acetylcholine receptors and MAO-A levels should be normal in around a week. If anyone can contribute some real information it would be wonderful!


----------



## Dysphoric

SerotonergicHaze said:


> I would speculate that Tobacco should have neuroprotective effects due to the MAO-A inhibiting effects from memory Harmine is the compound responsible.
> 
> I had an issue of social smoking becoming a habit, and decided to abstain. It's been about 21 days so far and even though I was a very light smoker (3-4 a night) I still have the occasional craving, but felt "normal" after a few days.
> 
> I don't think you'll ever be able to look at a cigarette in the eyes of a non smoker for a very long time, but I would speculate based on my own experiences your nicotinic acetylcholine receptors and MAO-A levels should be normal in around a week. If anyone can contribute some real information it would be wonderful!


 
Thanks for the reply! 

But do you know anything about cessation from Nicotine and Dopamine? That's my last question I want answered. I heard Nicotine does a fair share of down-regulation (Desensitization) on Dopamine receptors. Is this true? If so, how long until they're "Up-regulated" or Sensitized again?


----------



## ebola?

> I would speculate that Tobacco should have neuroprotective effects due to the MAO-A inhibiting effects from memory Harmine is the compound responsible.



Tobacco actually partially inhibits MAO-B, and it is unknown how.

ebola


----------



## Dysphoric

ebola? said:


> Tobacco actually partially inhibits MAO-B, and it is unknown how.
> 
> ebola


 
So... Would it still be somewhat neuroprotective when used with Meth/Amps?


----------



## ebola?

Not by much.  Inhibition of MAO-B is only partial, and inhaling burn plants is a good way to ingest oxidative species.

ebola


----------



## Dysphoric

Can you answer my other two questions? I feel like you might be able to give me an answer.


----------



## SerotonergicHaze

ebola, Tobacco is indeed a MAO-A inhibitor

_Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine._
source: http://www.pnas.org/content/93/24/14065.abstract

The MAO inhibition effect appears to be from  beta-carbolines 
http://biopsychiatry.com/maoi-smoke.htm


----------



## drugs

Is it known how escitalopram can stop/reduce the (subjective)effects of mdma? Especially in long term users of escitalopram? 

I realize that it most likely is related with the SSRI action of escitalopram, but what is the exact mechanism that causes this?


----------



## Epsilon Alpha

Blockade of the SERT and downregulation of several receptors responsible for the "high"is the bulk of it. Not sure how much detail you want, but you can find a few detailed reports of receptor changes online.


----------



## pharmakos

is it possible to "fool" a GC/MS, LC/MS, etc test to make it look like an impure sample is actually 99.9% pure?


----------



## Amu

thenightwatch said:


> is it possible to "fool" a GC/MS, LC/MS, etc test to make it look like an impure sample is actually 99.9% pure?



Yes, by sending you a GC/MS done on a pure sample


----------



## pharmakos

^^^ lol that is definitely one possibility.

is it possible to use a substance with a similar peak to mask the presence of a second substance that is also present?  or any other way to fool the test?  got a friend that is sitting on two UR-144 samples that are both supposedly 99% pure, but he claims one is way less potent than the other...


----------



## ebola?

> ebola, Tobacco is indeed a MAO-A inhibitor
> 
> Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine.
> source: http://www.pnas.org/content/93/24/14065.abstract
> 
> The MAO inhibition effect appears to be from beta-carbolines
> http://biopsychiatry.com/maoi-smoke.htm



I stand corrected.  Interesting stuff.

ebola


----------



## Iodjini_dk

thenightwatch said:


> ^^^ lol that is definitely one possibility.
> 
> is it possible to use a substance with a similar peak to mask the presence of a second substance that is also present?  or any other way to fool the test?  got a friend that is sitting on two UR-144 samples that are both supposedly 99% pure, but he claims one is way less potent than the other...



If the eluent strenght is set way too high, all compounds in the sample could elute in the same peak. Also if the impurity has the same retention time as the desired compound they will both elute in one peak.

Anyways, you cant really use the vendor's analysis for anything. You have no way of knowing that its legit.


----------



## pharmakos

Iodjini_dk said:


> If the eluent strenght is set way too high, all compounds in the sample could elute in the same peak. Also if the impurity has the same retention time as the desired compound they will both elute in one peak.
> 
> Anyways, you cant really use the vendor's analysis for anything. You have no way of knowing that its legit.



one of the samples was independently tested.

the more potent one was the one that was independently verified.  the less potent one is the one with the vendor crying up and down in the thread that his stuff must be 99.9% pure.

i think i've heard enough lol, thanks guys 

the stuff that was third party tested was originally sold as JTE-907 btw.  the trip reports made a lot more sense once the lab results came back.  glad i stayed away from that one until it got lab confirmed.... UR-144 did end up being pretty nice though.


----------



## Epsilon Alpha

More of a journal request/ quick summery request but does anyone have information on the expression and function of the purported CB3 receptor?
Been dying to do some reading on it, but I've been focusing more on my studies lately.

Also, +1 internets if anyone can give me specific mechanisms for amphetamine induced inflammation of nerve fibers/CNS tissues; Yet another thing I wish I had more time for.


----------



## Indole

Can anyone shed any light on the dream supressant properties of cannabis? Any journal articles, or studies would be greatly appreciated.


----------



## skillet

Hmm, no! A quick look suggests endocannabinoids increase the duration of REM sleep, and CB1 inverse agonists reduce the duration. Though cannabis or oral THC apparently also decrease the duration. I can't find much more than that.



Epsilon Alpha said:


> More of a journal request/ quick summery request but does anyone have information on the expression and function of the purported CB3 receptor?
> Been dying to do some reading on it, but I've been focusing more on my studies lately.



What's CB3? GPR55 or something?


----------



## Epsilon Alpha

Yeah GPR55 and 18 are really close to being reclassified, and it wouldn't shock me to find even more of them.


----------



## Dysphoric

I've been reading that Phenylalanine is a neurotoxin. Is this true? I can't seem to find any information proving this, at least from reliable sources.


----------



## pharmakos

there should be an  ADD social

i know it might not hit 40 pages ever but still =p


----------



## Lombergerh

Is it possible to get effects from Cerebrolysin intranasal usage?


----------



## Epsilon Alpha

Dysphoric said:


> I've been reading that Phenylalanine is a neurotoxin. Is this true? I can't seem to find any information proving this, at least from reliable sources.



If you have metabolic issues like phenylketonuria then yes, but you'd effectively have to only eat L-phenylalanine for weeks on end if you don't before it would cause significant damage. Its going to saturate the large neutral amino acid transporter far before it reaches that level.


----------



## Vader

The transesterification of cocaine to cocaethylene gets talked about a lot, but does it happen at the other ester group as well, replacing the benzyl group with an ethyl?


----------



## Iodjini_dk

Probably. But to a much lesser extent Id guess. The benzoyl ester is far more bulky and thus resistant to hydrolysis and enzymatic clevage than the methyl ester.


----------



## Amu

Is it possible memantine as an uncompetitive low-affinity NMDA antagonist (that doesn't interfere with regular levels of glutamate agonism) could possibly block or reduce the effects of a partial NMDA receptor agonist like D-Cycloserine? I doubt it, I wanted to read what you folks think. Also, has anyone ever found memantine to block the beneficial recreational/theraputic effects of common psychoactive drugs, in specific speed, LSD, ketamine, GHB, Opiates, MDMA?


----------



## Dysphoric

How much exactly does your heart rate increase on Meth/Amps?

1.) Lets say a fairly healthy individual took 40mgs of Adderall, how much would their heart rate go up? 
2.) And now I want to know what the difference would be if instead they would take Desoxyn at around 20-30mgs, how much of increase? 

I would assume Adderall (d-l Amphetamine) is slightly more Cardio-toxic, correct?

I'm curious because that is one thing that gives me anxiety when it comes to drugs, is fast BPM (tachycardia) I have a prescription for Desoxyn, but I've hardly touched it and now that I've started college I want to start taking here and there, around 20-30 mgs. I can handle an increase in BPM, I just don't like too fast, obviously. 

Also, I've talked to most of my friends that I've let try Desoxyn before and they said it hardly raised their BPM (vs Adderall), so would Desoxyn hardly touch my BPM at around 20-30mgs?

Also, I'm referring to Oral dosing.


----------



## DroneLore

Anyone know of any drugs (they don't even need to cross the BBB, just any sort of medically useful molecule) that is hypervalent?

How likely is it that our carbon-based biological equipment would be able to interact with them?


----------



## 23536

DroneLore said:


> Anyone know of any drugs (they don't even need to cross the BBB, just any sort of medically useful molecule) that is hypervalent?



Many sulfur- or phosphorous-containing compounds, like say topiramate, in which the sulfur atom has ten twelve valence electrons:






Organophosphates are also hypervalent.

Now how about any hypovalent biologically-active molecules?  Organoborides?


----------



## ebola?

Why don't we yet have a selective dopamine releasing agent?  Is this an accident of the array of ligands we're discovered, or is there something about the relevant pharmacology that makes developing such difficult?  I would hazard a guess that it's the former, as we have selective releasers of norepinephrine and serotonin...

ebola


----------



## Epsilon Alpha

Well the problem with DAT is how freaking similar it is to NET, in the PFC there aren't even any DAT transporters; NET is responsible for DA uptake there.
Not to mention how DAT is pretty much identical to NET downstream, NE is effectively a slightly more polar version of DA so making a selective releasing agent with traditional SAR pretty much requires making one of those "oily binds to anything amines".

I can go into more detail if you want man.
Peace
-EA


----------



## ebola?

> Well the problem with DAT is how freaking similar it is to NET



Okay.  But we have multiple releasing agents which are selective for NET over DAT...



> in the PFC there aren't even any DAT transporters; NET is responsible for DA uptake there.



But yes, we'd need to concede that efflux at NETs entails significant inhibition of reuptake of DA.



> Not to mention how DAT is pretty much identical to NET downstream



I don't think that I understand this point.  At what point in signaling is the function of DA transporters similar to that of NE transporters?  If we're talking about efflux rather than mere transport of the endogenous ligand, does this trend hold?

ebola


----------



## Epsilon Alpha

ebola? said:


> I don't think that I understand this point.  At what point in signaling is the function of DA transporters similar to that of NE transporters?  If we're talking about efflux rather than mere transport of the endogenous ligand, does this trend hold?
> 
> ebola


 
Well to my understanding most of the selectivity is conferred by the brain simply having more NE stores and NET transporters, so to reach half maximal activity you need far lower releasing agent concentrations for NE than DA. This is from my pharmacology prof, so it might not follow current research as far as it was the leading theory some years ago.

edit: What I meant for that was catecholamines all share very similar transport/synthesis pathways, so its very difficult to cause selective DA efflux without NE efflux. Though, without a double there are agents more selective for DA vs NE than others. However, as far as agents which bind to random receptors to elicit DA release without NE release then there's a lot of promise for "selective DA releasers"


----------



## ebola?

EA said:
			
		

> Well to my understanding most of the selectivity is conferred by the brain simply having more NE stores and NET transporters, so to reach half maximal activity you need far lower releasing agent concentrations for NE than DA. This is from my pharmacology prof, so it might not follow current research as far as it was the leading theory some years ago.



Ah.  Right.  But if you look at the binding affinities themselves, we have agents where the ki for DAT is 2-3 orders of magnitude larger than the ki for NET.  Even in an environment where NET and DAT densities are similar, these agents would remain selective for NET.  So my question is, why don't we have ligands where the pattern of affinities and efficacies is reversed?



> What I meant for that was catecholamines all share very similar transport/synthesis pathways, so its very difficult to cause selective DA efflux without NE efflux.



Gotcha.  Yes, here I concur, given (as you note) the role of DA uptake by NET in the pfc and downstream metabolism of DA to NE.  However, there are numerous downstream processes where selective efflux at DAT would have vastly different consequences than selective efflux at NET.



> Though, without a double there are agents more selective for DA vs NE than others.



However, we don't yet have agents that are selective for DA per se; every known DA releaser actually has a stronger effect at NE.

ebola


----------



## Repulse

Surfing the digital realms of the internet I found an odd analog, that looks like a arylcyclohexamine analog with a structure best described as being 'in-between' that of Ketamine and Methoxetamine.

It looks like this:
http://f69.myupload.dk/getfile/1122584H-qYXQ3B (click the link) 



Chemsketch printed the assumed IUPAC name below, _2-(3-methoxyphenyl)-2-(methylamino)cyclohexanone_

After researching a little bit, I have yet to find any data on this. 
The site that held it touted it as an "NMDA receptor antagonist and dopamine reuptake inhibitor", which sounds plausible looking at it's close relatives, but hardly verifiable unless there's some hard data to rely on.

It got me curious - so, does anyone recognize this? 
I'm dying for some data and/or SAR 


For reference: 

Ketamine structure:
http://f69.myupload.dk/getfile/1TskcL3i_

Methoxetamine structure: 
https://upload.wikimedia.org/wikipedia/commons/thumb/0/03/Methoxetamine.png/285px-Methoxetamine.png


Thanks


----------



## ebola?

This could also be thought of as the 2-keto analogue of 3-meo-pce.

(3-meo-pce thread in PD)

ebola


----------



## Vader

ebola?, EA, this is a really interesting conversation, I'm sure I'm not the only person who can't participate but is loving lurking, keep up the good work


----------



## Epsilon Alpha

ebola? said:


> Ah.  Right.  But if you look at the binding affinities themselves, we have agents where the ki for DAT is 2-3 orders of magnitude larger than the ki for NET.  Even in an environment where NET and DAT densities are similar, these agents would remain selective for NET.  So my question is, why don't we have ligands where the pattern of affinities and efficacies is reversed?
> 
> 
> 
> Gotcha.  Yes, here I concur, given (as you note) the role of DA uptake by NET in the pfc and downstream metabolism of DA to NE.  However, there are numerous downstream processes where selective efflux at DAT would have vastly different consequences than selective efflux at NET.
> 
> 
> 
> However, we don't yet have agents that are selective for DA per se; every known DA releaser actually has a stronger effect at NE.
> 
> ebola


So this is during a coffee break before a lab so bear with:

Well most of the problem comes from the fact that using traditional SAR, as things become more selective for DAT vs NET it also starts to bind to other things, for example meth vs regular amp. DAT just loves those oily mofo's.

But what I was getting at is the PKC mediated releasing action really isn't that different for NE vs DA, so using the traditional amphetamine MOA isn't ever really going to give you a greater DA/NE ratio. However, for reuptake inhibitors or things that bind to things like 5ht3 or NAChR there is a strong possibility for making a "selective" indirect DA agonist.

I'll post more when I have more time.


----------



## Repulse

ebola? said:


> This could also be thought of as the 2-keto analogue of 3-meo-pce.
> 
> (3-meo-pce thread in PD)
> 
> ebola


 
Wouldn't it be "2-keto-3-MeO-PCE" with a methylamine rather than ethylamine? 
At this point, the nomenclature becomes almost as lengthy as the IUPAC name!


----------



## ebola?

My mistake.
...


			
				EA said:
			
		

> Well most of the problem comes from the fact that using traditional SAR, as things become more selective for DAT vs NET it also starts to bind to other things, for example meth vs regular amp. DAT just loves those oily mofo's.



Ah.  This was the piece of the puzzle that I was missing.  Still, to my knowledge, we don't even have a DA releaser that is promiscuous at other sites but with negligible affinity for NET.



> But what I was getting at is the PKC mediated releasing action really isn't that different for NE vs DA, so using the traditional amphetamine MOA isn't ever really going to give you a greater DA/NE ratio.



Aha!  Another piece of the puzzle that I didn't understand.  So amphetamine-like efflux is achieved by the exogenous ligand inducing PKC to phosphorylate the transporter (by binding to PKC, changing its conformational form?).  Okay, so if this mechanism is fundamentally similar whether we're talking about DAT or NET, why do releasers have any selectivity at all?  Are there different isoforms of PKC present proximate to different transporters?

ebola


----------



## Epsilon Alpha

ebola? said:


> My mistake.
> Aha!  Another piece of the puzzle that I didn't understand.  So amphetamine-like efflux is achieved by the exogenous ligand inducing PKC to phosphorylate the transporter (by binding to PKC, changing its conformational form?).  Okay, so if this mechanism is fundamentally similar whether we're talking about DAT or NET, *why do releasers have any selectivity at all?  Are there different isoforms of PKC present proximate to different transporters?*
> 
> ebola



An excellent question! Part of the answer comes back to the fact that there is just more NE than DA in the brain period, but I don't know about isoforms I might check it out if I ever see the other side of midterm mountain =/

But, as far as transporter reversal goes there is a ton of evidence implicating PKC as well as many other receptors. But, PKC is what finally phosphorylates the transporter.


----------



## Captain.Heroin

Dysphoric said:


> How much exactly does your heart rate increase on Meth/Amps?



Dose dependent.  Conservative dosages will barely effect it, higher dosages causing concerns of heart failure.


----------



## Cloudy

thenightwatch said:


> one of the samples was independently tested.
> 
> the more potent one was the one that was independently verified.  the less potent one is the one with the vendor crying up and down in the thread that his stuff must be 99.9% pure.
> 
> i think i've heard enough lol, thanks guys
> 
> the stuff that was third party tested was originally sold as JTE-907 btw.  the trip reports made a lot more sense once the lab results came back.  glad i stayed away from that one until it got lab confirmed.... UR-144 did end up being pretty nice though.



Do you have a report of the UR-144 any where, or can you describe you're experience I'm getting some in this week and really struggling to find much info


----------



## pharmakos

UR-144 feels like low mids... stony body buzz, sedating, gives the munchies hardcore, but nothing too "WHOA" mentally (though there is a bit of a head high).  UR-144 is "creeper" as well


----------



## TheAppleCore

Hey, I'm just wondering.

What would ketamine be titled in the PCP / 3-MeO-PCP / 3-MeO-2-Oxo-PCE / etc. nomenclature?


----------



## ebola?

Ketamine contains neither the PCP nor the PCE skeleton (it contains a methylamino group rather than an ethylamino group, and of course only 2 ring-systems), so this nomenclature doesn't really work for it.


----------



## Vader

But if one were determined to refer to it in such terms, 2-chloro-2'-oxo-PCM would be as good as it gets.


----------



## Vader

When a carboxylic acid reacts with an amine, why is it that a covalent bond is formed and not an ionic one?


----------



## Transform

In short, the difference in electronegativity is not high enough.

There is a degree of ionic bonding and covalent bonding in every bond, but the difference in electronegativity governs which is dominant and therefore which we call it.

Carbon doesn't form ionic bonds often at all, except in combination with a few metals, and these are unstable.

As a guide, the closer two atoms are in the periodic table, the more covalent their bond will be.


----------



## Repulse

I recently had a taste of 2-(3-methoxyphenyl)-2-(methylamino)cyclohexanone which I talked about on the previous page.
(Methoxetamine with a methylated amine - one could call it N-methyl-methoxetamine for the lack of a better name)


----------



## sekio

re:N-methyl-methoxetamine - I remember reading that secondary amines are the way to go for ArCHAs - viz. phencyclamine (mild) vs eticyclidine (strong) vs dieticyclidine (weak, really a prodrug for eticyclidine) - making a tertiary amine gratly decreases activity (except it seems in the case of a pyrrolidine or piperidine subst).


----------



## Vader

I think repulse was talking about N-methylnormethoxetamine, not the tertiary amine.


----------



## sekio

Oh, whoops.

I still want to see N-ethyl-norketamine.

Or etoxadrol!


----------



## bluedom

Excuse me for dusting off some old threads but I felt this was interesting.  Are there any covalent binding agonists that bind to a receptor in a reversible fashion, i.e., the covalent bond is broken before the receptor is internalised? It'd definitely be possible to design proteins with this property to specific ligands. But the cost of making and breaking covalent bonds (entropic vs. enthalpic) may make this a rare mechanism in nature given that the noncovalent solution works (what is fraction of covalent binding agonists relative to all agonists?). 




MattPsy said:


> If something is a suicide substrate (like a covalently binding agonist) then eventually receptor internalization will occur (and the receptor is replaced eventually). However until internalization occurs signal transduction can usually still take place so the effect of an irreversible agonist is not that of an antagonist, effectively, because the receptor population is not immediately destroyed.


----------



## bluedom

I think you hit the nail on the head: traditional SAR isn't good enough to identify/design a ligand with the selectivity you want. If it is boiling down to hydrophobic vs. polar, i.e., hydrophobicity is obscuring the signal in picking/designing a ligand that is selective for DAT but not for NET, then it needs to be controlled for.   Doing it with the current best computational docking methods would be more accurate and selective.  How about computationally screening every known human ingestible compound against both DAT and NET and identify ones that have high affinity for DAT and low affinity for NET,? Someone's already doing this it looks like.

So I take it that the original point was to design a SDRI (or SIDRI - for the indirect kind)? I agree you could work on NAChR instead of DAT.  In fact, it'd be interesting to examine what happens with DA vs. NE with all the current NaChR agonists available. (As an aside I hadn't pondered this, but NaChR is similar to GABA A so it's possible to see how a GABA modulator can also effect DA levels.)

Another way to be to have a ligand that decreases the number of DATs expressed or translated either directly or indirectly.   This probably will have effects you don't want too so it's a messy way of doing it (though it gets around the oily ligand problem).  But is this that different from a DRI that works by indirectly internalising DAT?

And then you can create a leaky channel like AMPH does and make DAT go from symporter to antiporter.

There are reports of compounds in animal models and preclinical studies that have higher selectivity to DAT compared to NET or SERT.

I would turn the question back on the OP.  What can you do to take a ligand that binds both DAT and NET and modify to make it selective to DAT and nonselective to NET? (I'm asking from a atomic interaction perspective---when you look at the structures of DAT and NET and the binding sites, what can you distinguish?)

--

Another way to think about this is in terms of modulating currents upstream of the dopamine release. Dopamine gets released based on a particular voltage signal the neuron it is in receives (I'm not a neurobiologist so please excuse me if I'm not being technically correct and I would appreciate it).   The amount of modulators immediately upstream of DAT is in the order of tens of thousands. Apparently it has been shown that the rate and direction for DAT itself is totally dependent on the Na gradient which is controlled by a Na+/Ka+ ATPase. It's probably not a good idea to directly mess with this sodium pump (unless there's a specific isoform that controls the DAT gradient) but there's probably things upstream that let you control this pump indirectly.

--

This is a good idea BTW. Whoever can design a SDRI may contribute a lot to this world in many ways. I concur with EA; there are a lot of ways to accomplish this.



Epsilon Alpha said:


> So this is during a coffee break before a lab so bear with:
> 
> Well most of the problem comes from the fact that using traditional SAR, as things become more selective for DAT vs NET it also starts to bind to other things, for example meth vs regular amp. DAT just loves those oily mofo's.
> 
> But what I was getting at is the PKC mediated releasing action really isn't that different for NE vs DA, so using the traditional amphetamine MOA isn't ever really going to give you a greater DA/NE ratio. However, for reuptake inhibitors or things that bind to things like 5ht3 or NAChR there is a strong possibility for making a "selective" indirect DA agonist.
> 
> I'll post more when I have more time.


----------



## atrollappears

ebola? said:


> Aha!  Another piece of the puzzle that I didn't understand.  So amphetamine-like efflux is achieved by the exogenous ligand inducing PKC to phosphorylate the transporter (by binding to PKC, changing its conformational form?).  Okay, so if this mechanism is fundamentally similar whether we're talking about DAT or NET, why do releasers have any selectivity at all?  Are there different isoforms of PKC present proximate to different transporters?
> 
> ebola



I don't see why "DAT and NET are similar" leads to "no selectivity at all can be achieved by those transporters." These graphs seem to imply different transporter affinities for the different amphetamines, since they're graphs of transporter uptake activity. I don't think that by the methodology used in the study would be confounded by release, since the transporters were studied in intestinal cells which I assume wouldn't don't express PKC. As you'd expect, meth has a much higher relative inhibitory ability at DAT over NET as compared to amp.
I don't know to what extent you can extrapolate from inhibitory efficacy to general affinity for the transporter, because I assume the extent to which they act as substrates rather than inhibitors varies. But in any case the way that each agent acts on DAT as compared to NET does very between the individual amphetamines.
http://www.biomedcentral.com/1471-2210/6/6/figure/F1
Full study:
http://www.biomedcentral.com/1471-2210/6/6


----------



## ebola?

Ah.  Very good study.  So it looks like various other factors affect the ability of amphetamines to phosphorylate the receptor.  So theoretically, one could manipulate them to engender a very high degree of selectivity.

ebola


----------



## Epsilon Alpha

You guys interested in making a thread out of the NE/DA efflux ratios topic?
Also, its PKC-beta that's responsible in neurons, not sure if its expressed significantly in GI cells.


----------



## bluedom

Yep, with a focus on SDRIs?



Epsilon Alpha said:


> You guys interested in making a thread out of the NE/DA efflux ratios topic?
> Also, its PKC-beta that's responsible in neurons, not sure if its expressed significantly in GI cells.


----------



## ebola?

Er...it's actually releasers where the topic becomes interesting; we've already developed highly selective DARIs.

ebola


----------



## bluedom

If you have selective DARIs then what is the need for the releasers? 



ebola? said:


> Er...it's actually releasers where the topic becomes interesting; we've already developed highly selective DARIs.
> 
> ebola


----------



## Epsilon Alpha

bluedom said:


> If you have selective DARIs then what is the need for the releasers?


There's no actual "need" for them in the market, but its interesting as sin to discuss and who knows where the conversation will turn. Someone post the OP and I'll get around to the new thread by Sunday.


----------



## atrollappears

Epsilon Alpha said:


> Also, its PKC-beta that's responsible in neurons, not sure if its expressed significantly in GI cells.



From skimming wikipedia, it doesn't look like they do.



bluedom said:


> If you have selective DARIs then what is the need for the releasers?



There's no guarantee that they'll act as similarly as NDRIs and NDRAs, between which there are already big enough differences that one might want to use one instead of the other 
Just speculating, since alpha 1 receptor activation increases basal dopamine release IIRC then maybe selective DRIs have a low ceiling of efficacy which DRAs might not have.


----------



## ebola?

> If you have selective DARIs then what is the need for the releasers?



Monoamine releasers feel really different from reuptake inhibitors.

ebola


----------



## bluedom

Is that really a general comment and true for all monoamines?  What serotonine releasers are there? I guess MDMA could be classified as one. It is probably more analogous to amphetamines than to cocaine which is somewhat analogous to an SSRI though cocaine's action is rather immediate. 

And suppose we could agree they feel different, then would you say that the releases are "better" than MORIs or worse? I'd say cocaine is "better" subjectively than amphetamines, and even better for your health than amphetamines.

I think a separate thread discussing this issue (what EA proposed) would be interesting. 

(I'm currently in the process of designing/finding such compounds for the record.)



ebola? said:


> Monoamine releasers feel really different from reuptake inhibitors.
> 
> ebola


----------



## bluedom

But then they're not selective to dopamine (I guess we're using the terms "selective" and "specific" interchangeably), so they won't be a selective/specific DRI if they also act as NDRIs...



atrollappears said:


> There's no guarantee that they'll act as similarly as NDRIs and NDRAs, between which there are already big enough differences that one might want to use one instead of the other
> Just speculating, since alpha 1 receptor activation increases basal dopamine release IIRC then maybe selective DRIs have a low ceiling of efficacy which DRAs might not have.


----------



## Vader

> Monoamine releasers feel really different from reuptake inhibitors.


I'm not entirely sure I agree, to me mephedrone feels more similar to cocaine than MDPV does.


----------



## Enix150

^Don't meph and MDPV do both? I agree mephedrone is more like cocaine than MDPV, but it's also more like MDPV than cocaine is... It's like a spectrum with meph in the middle? I just wish we could fill in all the blank space. If we determined affinities for some of these RC's, then we could get some real rational design going on.


----------



## TheAppleCore

Quick question...

With regard to theoretical aMT-related neurotoxicity, nuke said:



			
				nuke said:
			
		

> I'm guessing that the problems are similar to MDMA, in that many of the metabolites of monoamines under high temperature conditions and with high levels of oxidants do to the breakdown of monoamines are going to be excessively toxic.



So, here nuke is referring to endogenous monoamines such as the serotonin, dopamine, and norepinephrine released by aMT. Wouldn't the body metabolize exogenous monoamines like psychedelic tryptamines and phenethylamines in much the same way, resulting in similar or identical toxic metabolites, though? If the metabolites of monoamines are "excessively toxic" under high temperature conditions, then wouldn't something like psilocybin also be neurotoxic, if taken at an outdoor festival on a very hot day, for example?


----------



## Epsilon Alpha

My guess is that a bit dependent on dosage (things like MDMA are easily >100mg), and the fact most hallucinogens don't cause massive monoamine release.
*Massive* doses of 5HT2A agonists are toxic according to some studies though.


----------



## TheAppleCore

^ Hmm. When you take a reasonable dose of magic mushrooms, I'm guessing you're probably getting something on the order of 20-40 mg active tryptamine alkaloids. If the metabolites of a standard dose of mushrooms are not substantially neurotoxic, but metabolites of endogenous SE, DA, & noradrenaline released by MDMA *are* neurotoxic -- and your theory holds true -- then the quantity of monoamines released by MDMA would have to be on another order of magnitude entirely, above the few dozen milligrams of tryptamine that you ingest when you take mushrooms. Perhaps hundreds of milligrams of SE, DA, and noradrenaline combined.

If we can verify whether or not this assumption is correct, then we could be enlightened...


----------



## sekio

To the best of my knwoledge, the metabolites of serotonin/dopamine/NE/adrenaline are basically non-toxic. The issue is e.g. oxygen and peroxide radicals being generated when monoamine oxidase processes the compound. I personally think this is only an issue where there is an abnormally high concentration of monoamines.

It has been said that having the pair of hydroxyl groups increases toxicity because it can redox cycle to an ortho-quinone and back again. But neither dopamine, norepinephrine, adrenaline, or even alpha-methyldopamine or O-methyldopamine are actually neurotoxic. 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine (a mouthful indeed) was found to be toxic, however, and is a metabolite of alpha-methyldopamine (and also MDMA).

No major metabolites of the monoamine neurotransmitters are toxic in normal concentrations. (substituted phenylacetate/indole-3-acetic acid)


----------



## atrollappears

sekio said:


> I personally think this is only an issue where there is an abnormally high concentration of monoamines.



Monoamine-depleted animals still show neurotoxic damage, as long as their temperatures are raised as they would be if they were not monoamine depleted.


----------



## sekio

Oh, interesting. So perhaps it's entirely thermal.


----------



## Epsilon Alpha

Maybe *ques dramatic music* its partly mediated by heat sensitive ion channels!
Someone draft up a decent OP for the NE/DA releasers topic! Pwwwweeeeeaaaase?


----------



## ebola?

Vader said:
			
		

> I'm not entirely sure I agree [that releasers feel vastly different from reuptake inhibitors], to me mephedrone feels more similar to cocaine than MDPV does.



Well, cocaine and mephedrone have relatively balanced activity at all three monoamines, with a skew toward dopamine and NE, and both have a similarly brief duration of action.  MDPV is highly selective for DA and NE, with a skew toward activity at NE, with a much longer duration of action, with a slower rise to peak plasma levels.  In short, other similarities between cocaine and mephedrone supersede their distinction as releaser versus reuptake inhibitor.  Also, many others find MDPV more similar to coke than mephedrone (I find all 3 pretty different from one another).



			
				Enix said:
			
		

> Don't meph and MDPV do both?



All effective releasers also act as reuptake inhibitors (as if a transporter is reversed, it cannot take up the endogenous ligand).



> If we determined affinities for some of these RC's, then we could get some real rational design going on.



The affinities for coke and MDPV are known, and we have some measures of efficacy for mephedrone (though not ec50s).  The thing is, reasoning about SAR for psychoactives is in its infancy, so true 'rational drug design' is presently a dream.

ebola


----------



## bluedom

Do all effective releasers work by reversing the transporter? (In a general biological sense this is not true since you can have release by lysis also but I'm asking about neurons; some drugs do seem to produce some effects by partial lysis/rupture/making holes even in neurons.)

SAR for all drugs is in its infancy (I have high standards). After all, we only have the static structures of 80,550 (as of now) proteins from a universe of proteins and all the conformations they can adopt; let alone how drugs bind to those proteins.

Some people are being clever about this. Check out the 2010 NIH Director's Pioneer Awardees (and in general all of them since 2005). There are few awardees who're exploring neuronal circuits using optogenetics and few doing a lot of structure-based in silico drug discovery.



ebola? said:


> All effective releasers also act as reuptake inhibitors (as if a transporter is reversed, it cannot take up the endogenous ligand).
> 
> The affinities for coke and MDPV are known, and we have some measures of efficacy for mephedrone (though not ec50s).  The thing is, reasoning about SAR for psychoactives is in its infancy, so true 'rational drug design' is presently a dream.
> 
> ebola


----------



## atrollappears

sekio said:


> Oh, interesting. So perhaps it's entirely thermal.





Epsilon Alpha said:


> Maybe *ques dramatic music* its partly mediated by heat sensitive ion channels!
> Someone draft up a decent OP for the NE/DA releasers topic! Pwwwweeeeeaaaase?



I remember reading that heat inhibits the function of glutathione peroxidase (or some antioxidant enzyme). Don't remember if it was a reliable source though.


----------



## pharmakos

randomly stumbled across this really cool looking drug:






http://en.wikipedia.org/wiki/HZ-2

highly selective kappa opiod agonist

sorta looks like a frog imo


----------



## sekio

Pretty. You should post it in the "symmetrical molecules" thread too


----------



## Vader

If one were trying to form a 2C-X freebase, would using NaOH lead to the possibility of nucleophilic substitution at the 4-position, destroying the compound?
EDIT: Now that I think about it, if one were to dissolve, say, 2C-I HCl in water, the chloride anion would dissociate. Could this then act as a nucleophile, leading to formation of 2C-C? Excuse my poor chemistry, but hey, that's what this thread is for!


----------



## sn23

No such reactions would occur. The donor substituents inactivate the ring for nucleophilic substitution. Plus hydroxide and halogenides aren't reactive enough.


----------



## Amu

bluedom said:


> Do all effective releasers work by reversing the transporter? (In a general biological sense this is not true since you can have release by lysis also but I'm asking about neurons; some drugs do seem to produce some effects by partial lysis/rupture/making holes even in neurons.).



Dextromethamphetamine can cross the cell membrane (due to lipophilicity) directly in the absence of a transporter and induce release


----------



## LeLouche

Figured I'd post this here.

Is there any harm to keeping CYP3A4 inhibited for long periods of time? Not taking into account the pharmaceutical drugs it metabolizes


----------



## Transform

Vader said:


> If one were trying to form a 2C-X freebase, would using NaOH lead to the possibility of nucleophilic substitution at the 4-position, destroying the compound?
> EDIT: Now that I think about it, if one were to dissolve, say, 2C-I HCl in water, the chloride anion would dissociate. Could this then act as a nucleophile, leading to formation of 2C-C? Excuse my poor chemistry, but hey, that's what this thread is for!



Further, I've tried this with 2C-E and 2C-B and have been successful vaporising them,


----------



## Vader

I presume (well, I'm pretty sure) that such reactions can happen (after all, Shulgin used 2C-B as a precursor for the series), but I guess asking about under what conditions they might occur is verging on synthesis discussion. Ah, well, I'll just hit the books.

What's the logic behind the "25x-NBOMe" naming (the 25 bit, specifically)? I thought it might be the position of the methoxyl groups, but that seems odd, and those probably aren't the right numbers for those positions on those molecules. Anyway, should I be saying "two five x" or "twentyfive x"?


----------



## Astavats

It's the positions of methoxy substitutions as there is also 24-NBMeO, -NB, and -NBOH in this paper for the 2,4-dimethoxy counterparts.


----------



## nuke

Amu said:


> Dextromethamphetamine can cross the cell membrane (due to lipophilicity) directly in the absence of a transporter and induce release


 
Unlikely.. It's charged at pH = 7 and also fairly large. Amphetamine uses a saturatable transporter to cross the bbb.
springerlink.com/content/g038l05313406571/

Probably the reason why beta-hydroxylated amphetamines do not cause severe intoxication is due to poor transport through the bbb, but that's a personal hypothesis.  There has also been suppositions that the enhanced activity of meth compared to amp is due to enhanced lipophilicity, but i'm not sure i buy it as the pka for the amine in meth is higher (--> more likely to be charged at pH=7).


----------



## sn23

Vader said:


> I presume (well, I'm pretty sure) that such reactions can happen (after all, Shulgin used 2C-B as a precursor for the series), but I guess asking about under what conditions they might occur is verging on synthesis discussion. Ah, well, I'll just hit the books.



Yes, let's just say that either more reactive halogen compounds or more special conditions are needed for such aromatic halogen substitutions to happen.

I assumed you meant aqueous solutions. Freebasing with molten NaOH might be another story.


----------



## bluedom

My guess is that it's just the monamine depletion that leads to breaking the neural circuitry that causes damage (like an atrophy). If you think of the monamine signal as a wire in a circuit (which is a complex feedback system) then when the wire is cut the ends are damaged and/or perhaps it's just rewiring to a new circuit. 



sekio said:


> Oh, interesting. So perhaps it's entirely thermal.


----------



## Steps

In response to an earlier post

Dopamine Reuptake Inhibitors have a tendency to produce anxiogenesis, paranoia, uncomfortable physical stimulation, diaphoresis, and such in me

Whereas Dopamine Releasing Agents have a tendency to produce anxiolysis, paranoia relief, physical stimulation that isn't uncomfortable, and diaphoresis only on the comedown

P.S., what would this do? Its kinda... a double methamphetamine


----------



## sekio

"doubled up" methamphetamines are too bulky to bind to transporters effectively.


----------



## Steps

sekio said:


> "doubled up" methamphetamines are too bulky to bind to transporters effectively.



I dont think youve ever replied to me on AIM

anywho, eh, a nitro meth of some sorts maybe?


----------



## ebola?

Where would you want the nitrogen substitution?  Ring-nitrogentation at the 4 position can be useful with psychedelic SAR (yet not particularly well plotted out in terms of receptor affinities), but n-methylation of phenethylamines tends to abolish psychedelic activity.  nitrogenation elsewhere needs further explanation.

ebola


----------



## Steps

Can someone explain why 4-MAR isn't neurotoxic?


----------



## sekio

It would be expected to have a similar neurotoxicity to amphetamine, but less than methamphetamine.

The aminorexes have not been investigated too much due to unwanted 5HT2B agonism at heart valves (c.f. fenfluramine & the Fen Phen crisis).even though at first glance it seems they are "miracle stimulants".


----------



## Steps

sekio said:


> It would be expected to have a similar neurotoxicity to amphetamine, but less than methamphetamine.
> 
> The aminorexes have not been investigated too much due to unwanted 5HT2B agonism at heart valves (c.f. fenfluramine & the Fen Phen crisis).even though at first glance it seems they are "miracle stimulants".



But, I've been reading up, and so far studies can't show any evidence of neurotoxicity, the only studies that did had to use doses high enough to kill half of the animals and make them have convulsions to cause any downregulation or neurotoxicity


----------



## IBDResearch

*Can anyone read a few NMR results for me?*

I recently got a few results back from the lab. I however can not read NMR results. The person who usually doe this for me is not available. 

This is what the lab wrote along with the results and all four are within one PDF. I am going to try and upload the PDF which is password protected here but if it doesn't upload I will upload it using some hosting website. http://www.pdfhost.net/index.php?Action=Download&File=ea91c1835bf297450a895704bbdf0a8f The password is: 1q47iwrt7 
This is the description of each one. 
A2012.0001 is AH7921
B2012.0001 is 2cB-fly.
M2012.0005 is 4-meo-pcp hcl
D2012.0001 is desoxypipradrol 

Thanks so much!


----------



## Epsilon Alpha

Steps said:


> But, I've been reading up, and so far studies can't show any evidence of neurotoxicity, the only studies that did had to use doses high enough to kill half of the animals and make them have convulsions to cause any downregulation or neurotoxicity



My theory is that they lack a toxic metabolite or binding site that is responsible for amphetamine related toxicities, like NAChR or any of the random mGluR's amphetamines seem to love binding to.


----------



## skillet

IBDResearch said:


> I recently got a few results back from the lab. I however can not read NMR results. The person who usually doe this for me is not available.
> 
> This is what the lab wrote along with the results and all four are within one PDF. I am going to try and upload the PDF which is password protected here but if it doesn't upload I will upload it using some hosting website. http://www.pdfhost.net/index.php?Action=Download&File=ea91c1835bf297450a895704bbdf0a8f The password is: 1q47iwrt7
> This is the description of each one.
> A2012.0001 is AH7921
> B2012.0001 is 2cB-fly.
> M2012.0005 is 4-meo-pcp hcl
> D2012.0001 is desoxypipradrol
> 
> Thanks so much!



The 4-MeO-PCP looks ok, maybe 50-60% pure judging by the integration between 2.2-0.9ppm. The rest are just wrong. Desoxypipradol should have a huge 10H mess around 7ppm rather than a 1-2H doublet. AH-7921 is missing an aromatic proton, and the peak at 5.2ppm shouldn't be there. 2CB-FLY I think is actually 2C-E...

Edit: D2012.0001 could be 2C-iP.


----------



## DroopyEyedKoala

skillet said:


> The 4-MeO-PCP looks ok, maybe 50-60% pure judging by the integration between 2.2-0.9ppm. The rest are just wrong. Desoxypipradol should have a huge 10H mess around 7ppm rather than a 1-2H doublet. AH-7921 is missing an aromatic proton, and the peak at 5.2ppm shouldn't be there. 2CB-FLY I think is actually 2C-E...
> 
> Edit: D2012.0001 could be 2C-iP.



That's not sounding good... Anyone have a second opinion or is this the general consensus?


----------



## atrollappears

Epsilon Alpha said:


> or any of the random mGluR's amphetamines seem to love binding to.



What?? Amphetamines bind to mGluRs?



nuke said:


> the pka for the amine in meth is higher (--> more likely to be charged at pH=7).



Oooh interesting. Perhaps this explains some of its potency.


----------



## Hyperthesis

IBDResearch said:


> I recently got a few results back from the lab. I however can not read NMR results. The person who usually doe this for me is not available.
> 
> This is what the lab wrote along with the results and all four are within one PDF. I am going to try and upload the PDF which is password protected here but if it doesn't upload I will upload it using some hosting website. http://www.pdfhost.net/index.php?Act...895704bbdf0a8f The password is: 1q47iwrt7
> This is the description of each one.



*Skillet* already summed it up nicely.
However, there came a question for a second opinion. Here it goes:



			
				IBDResearch said:
			
		

> A2012.0001 is AH7921


...definitely not! AH-7921 contains a 1,3,4-trisubstituted phenyl-ring, but the spectrum rather indicates a para-substituted aromatic moiety. The resolution of the scan in the high-field (1-4 ppm) is too bad and thus lends only to speculation. And whatever that material actually is - at least it isn't pure. Impurity-peaks can be seen eg. at 1.15/1.17, ~2.3, 2.8 and 5.1 ppm. I'd think that the broad singlets at 9.2 and 9.9 ppm are not supposed to be there, too, judging from their integrals.



			
				IBDResearch said:
			
		

> B2012.0001 is 2cB-fly


For sure not 2C-B-FLY, the two signals around 6.8 ppm just don't fit. But the guess towards 2C-E sounds actually not like the worst idea...



			
				IBDResearch said:
			
		

> M2012.0005 is 4-meo-pcp hcl


Maaaaybe... The aromatic range suggests a para-positioned phenyl-ring, but that's it so far. Apart from this does the spectrum invite for the wildest speculation. Without further analysis (13C-NMR, DEPT135, IR, *MS*!!!) I wouldn't go out on a limb and confirm that this is 4-MeO-PCP. Assuming for a second that the material is actually what it was supposed to be then the purity is around 60% or less. 



			
				IBDResearch said:
			
		

> D2012.0001 is desoxypipradrol


Nope. Skillet beats me to it: It looks indeed very much like (reasonably pure) 2C-iP; traces of solvents can be seen at ca. 1.25 and 2.1 ppm.


----------



## skillet

Hyperthesis said:


> Apart from this does the spectrum invite for the wildest speculation. Without further analysis (13C-NMR, DEPT135, IR, *MS*!!!) I wouldn't go out on a limb and confirm that this is 4-MeO-PCP. Assuming for a second that the material is actually what it was supposed to be then the purity is around 60% or less.



I don't know about wild speculation, it's a pretty close match to the NMR of definite 4-MeO-PCP, and some of the 4-MeO-PCP spectra posted here. I haven't seen a spectrum run in DMSO before, admittedly, but it's pretty likely to be 4-MeO-PCP. But yeah, taking something that impure and with such a high required dose isn't a great idea anyway.



Mr Smokes Blunts. said:


> I got 2 NMR's done on what is supposed to be N-ethyl-  norketamine:



The peak at 10ppm is the NH2+, it disappears after shaking with D2O due to exchange with deuterium. It looks ok I think - the integrals are right and the shifts are about what I'd expect. I don't have a reference to be able to say for sure though. And it's got some ether and ethyl acetate in it by the looks of it but otherwise looks fairly pure.


----------



## red beard

I found this paper that demonstrated inhibition of CYP2D6 and CYP3A4 enzymes by kratom.

Does anyone know how to compare the concentrations of extract used in the paper to plain leaf dosages?  I'm wondering at what dose this sort of inhibition becomes relevant.


----------



## AlphaMethylPhenyl

Can someone please relate the intricate psychopharmacology of the Kavalactones? This is wickedly elementary compared to what yall discussing, but so far I've heard of GABA-A, MAOI-B, NRI, SRI, and Na+ (similar to lithium) action. Verification and elaboration please!

And does Risperidone actually increase levels of Serotonin in small doses (.5mg and under)?. And does it somehow enable normal dopamine release instead of merely suppressing it?

Thanks


----------



## Epsilon Alpha

atrollappears said:


> What?? Amphetamines bind to mGluRs?


Its not really clear right now, but mGluR's are intimately tied into its mechanism of action, it does however have some weird binding affinity to NAChR's ala bupropion


----------



## Lombergerh

My question is not exactly about chemistry and pharmacology, but more about diseases, i hope somebody can show me derection for digging or may be even answer to this question.
So, there are so many neruodegenerative diseases such as Hantingnton, Alzheimer e.t.c they are all impair your cogntive process, brain functioning, reaction time e.t.c
But are there any disease that actually can improve some of your cognitive processes? May be memory, ability to focus, reaction time, abstract or logical thinking e.t.c?


----------



## Lombergerh

Lombergerh said:


> My question is not exactly about chemistry and pharmacology, but more about diseases, i hope somebody can show me derection for digging or may be even answer to this question.
> So, there are so many neruodegenerative diseases such as Hantingnton, Alzheimer e.t.c they are all impair your cogntive process, brain functioning, reaction time e.t.c
> But are there any disease that actually can improve some of your cognitive processes? May be memory, ability to focus, reaction time, abstract or logical thinking e.t.c?



Also i didn't mean that these disease would have only good effects, they might be killing you but give some benefits while doing it) Or imapir one cognitive function but improve another - acting in this way.


----------



## Vader

Hypomanic individuals can appear be higher-functioning than normal, though I'm not sure that mania constitutes a disease in the sense that you are using that term.


----------



## Lombergerh

Vader said:


> Hypomanic individuals can appear be higher-functioning than normal, though I'm not sure that mania constitutes a disease in the sense that you are using that term.


Yes, it's also suitable in this situation, i mean not only disease but disorders in general, mental and physical.


----------



## ebola?

vader said:
			
		

> Hypomanic individuals can appear be higher-functioning than normal, though I'm not sure that mania constitutes a disease in the sense that you are using that term.



Indeed.  There's a reason that unipolar hypomaniacs tend not to seek treatment for any "disorder".

ebola


----------



## pharmakos

generally speaking though, if an individual did have a "condition" that improved mental function we probably wouldn't even notice it. (unless there were negative symptoms that went along with it)


----------



## Vader

Can't believe I didn't think of Savant syndrome.


----------



## pharmakos

a friend recently overdosed on vicodin and xanax, slipped into a coma, and eventually died in the hospital

i had a thought that maybe giving him a *low* dose of vicodin and xanax together might bring him out of his coma.... maybe sorta like reminding his brain what he was last doing before he "fell asleep"...

is there any science anywhere that would support an idea like this?  i know i heard a story once of Zolpidem bringing someone out of a really long coma

the doctors ended up waking him up from his coma for a minute using a shot of adrenaline... so he could say goodbye and people could say goodbye to him.... he died soon after... this seemed almost inhumane to me.... he was probably so confused suddenly waking up from adrenaline and finding himself in the ER...  but i also had the thought that maybe if they coadministered vicodin and xanax with the adrenaline then maybe his body would have been able to handle the stress from the adrenaline and maybe nursed back to health

IDFK.  it all sucks.  i didn't know the kid very well though.


----------



## Vader

Don't think "hair of the dog" really works for respiratory depression. Someone might drop some science, but it doesn't sound likely. My condolences, I'm sorry for your loss.


----------



## pharmakos

he did have quite the tolerance.  my thought was that a low dose would be closer to baseline for him than total sobriety.  

tbh my theory doesn't seem very likely to me either, but worth consideration at least.


----------



## sekio

Coma is certainly a mysterious and unpredicatble thing, but if it was induced by a sedative drug overdose there is probably large amounts of brain tissue in bad shape from oxygen starvation. I don't think drugs just spontaneously cause comas - generally they result from aspiration of vomit or lack of oxygen.

The zolpidem thing was serendipitous, I don't think the same effects on comatose people have been reproduced with other drugs.

Sorry for your loss.


----------



## pharmakos

are there any drug therapies for coma that are intended to increase oxygen levels in the brain?


----------



## sekio

Given the drugs involved I would expect this to be a fairly textbook case of drug induced respiratory depression. The coma itself was likely caused because your friend stopped breathing while unconcious. 
By the time coma has occured, brain tissue is almost always already dead and re-oxygenation will do nothing. Unless someone would have found him earlier to provide e.g. rescue breathing or an antidote, there is essentially no therapy for large-scale brain damage.

I had read somewhere that ketamine increased cerebellar blood flow some large amount. That said, I don't expect administering ketamine to a braindead patient will bring them back, or even help at all.

I think you should try to accept the facts, and take solace that your friend was feeling no pain when he passed on. There's nothing you really could have done.


----------



## pharmakos

thenightwatch said:


> are there any drug therapies for coma that are intended to increase oxygen levels in the brain?



^^ was purely out of curiosity



sekio said:


> I think you should try to accept the facts



i think that's pretty rude of you

honestly i only met the dude once, i'm not going on like this out of some crazy grief stricken rage or something



sekio said:


> there is essentially no therapy for large-scale brain damage.



and there never will be if every conversation like this is stifled


----------



## pharmakos

though


----------



## sibirianfox

There's also the Kratom plant that would join Iboga and Salvia.

It has been used for centuries to alleviate opiate withdrawals in Asia.

From what I understood, Kratom could lead to opiate dependency if used for prolonged periods and in heavy amounts.
But if sparingly and only during withdrawals, it would NOT be a substitute.

As for "...plus a 24 hour spiritual journey is prob not exactly what you are looking for...", I have to disagree. From testimonials I've stumbled upon, the spiritual journey is what allows the addict to address the root of his addiction. As in "why do I kill myself when I could enjoy life and its wonders".
The physiological processes are yet poorly understood. Ibogaine, more specifically its main metabolite-noribogaine-"reset" the brain in terms of opiate tolerance. In terms of withdrawal alleviation, the best analogy I found was "your worst flu is transformed into a bad cold".
Ibogaine treatments are done mostly in the "shadows", so outside of medical community, often by ex-junkies or even worth, users with a "doctor-complex". 
Ibogaine experience is very subjective from what I've read, and very dose-dependent. Under-dose the patient and he'll leave the experience with expectations shattered. Which could be a sad thing since for many addicts Ibogaine becomes the last line of defense, last hope.


----------



## sibirianfox

Sorry...
I just joined and was trying to reply to somebody's post...
For some reason in my response above, the person's quote is not listed.
I'm not sure what I did wrong. I cliqued on "Post quick reply". 
Should it be "go advanced" if I want the quotes to show?
Tnx!


----------



## yoyoman

> the doctors ended up waking him up from his coma for a minute using a shot of adrenaline... so he could say goodbye and people could say goodbye to him.... he died soon after... this seemed almost inhumane to me.... he was probably so confused suddenly waking up from adrenaline and finding himself in the ER... but i also had the thought that maybe if they coadministered vicodin and xanax with the adrenaline then maybe his body would have been able to handle the stress from the adrenaline and maybe nursed back to health




Why wouldn't they try methamphetamine or at least racemic amphetamine?  That's the first thing that would pop into my mind if someone is slipping into a coma or is in one.  IV amphetamines, meth being safer on the body you could crank the dose up pretty high (long half life, but whats the harm if it doesn't work).

I just don't get why they'd shoot him with adrenalin its like taking ephedrine to study everyday.


----------



## Epsilon Alpha

yoyoman said:


> Why wouldn't they try methamphetamine or at least racemic amphetamine?  That's the first thing that would pop into my mind if someone is slipping into a coma or is in one.  IV amphetamines, meth being safer on the body you could crank the dose up pretty high (long half life, but whats the harm if it doesn't work).
> 
> I just don't get why they'd shoot him with adrenalin its like taking ephedrine to study everyday.



I think they've trailed it, this source (sketchy as hell) makes it sound like it works for some cases of mild damage.
http://www.comawakening.com/coma.html


----------



## Cloudy

sekio said:


> Given the drugs involved I would expect this to be a fairly textbook case of drug induced respiratory depression. The coma itself was likely caused because your friend stopped breathing while unconcious.
> By the time coma has occured, brain tissue is almost always already dead and re-oxygenation will do nothing. Unless someone would have found him earlier to provide e.g. rescue breathing or an antidote, there is essentially no therapy for large-scale brain damage.
> 
> I had read somewhere that ketamine increased cerebellar blood flow some large amount. That said, I don't expect administering ketamine to a braindead patient will bring them back, or even help at all.
> 
> I think you should try to accept the facts, and take solace that your friend was feeling no pain when he passed on. There's nothing you really could have done.


And if ketamine or some other nada-antagonist was used they have to be used at a specific interval for a very short amount of time or the prolonged antagonism would result in a flood of glutamate post antagonism resulting in further brain damage.  One of e problems with the studies involving ketamine and traumatic head injuries are poor procedures involving the administration of ketamine.  I could pull up articles from my computer (on my iPad right now) if people were interested in further looks at this topic (ketamine for brain trama)



Epsilon Alpha said:


> I think they've trailed it, this source (sketchy as hell) makes it sound like it works for some cases of mild damage.
> http://www.comawakening.com/coma.html



I think some people put to much faith in episodes of house md were mircles happen all the time from experimental treatments


----------



## Cloudy

thenightwatch said:


> ^^ was purely out of curiosity
> 
> 
> 
> i think that's pretty rude of you
> 
> honestly i only met the dude once, i'm not going on like this out of some crazy grief stricken rage or something
> 
> 
> 
> and there never will be if every conversation like this is stifled


You are posting on a web forum to individuals who most likely don't have the capability to preform the research or have the time to come up with your hopes and dreams in a few lines of text to satisfy you (no offense to the professionals in ADD), you're not addressing a bunch of professional medical doctors or researchers who are working on tasks like this.  I don't know what type of answer you are expecting to get.  You can do reading on your own to find many of the expiremental processes being used like hyperthermia, various drugs prevent different stages of cell death, etc.  but your most likely going to find articles showing no mircle therapy out there not showing the level of success for the desired results you'd like to see.  Most experiments I've read have not had much success and still need years of research or in the case of some promising leads like ketamine, poor procedures in more realistic applications of the drug/combination of drugs with keteamine has slowed down the prospect of using ketamine in these type of situations due to poor results.  Like I said a lot of the articles published using ketamine as a way to prevent further brain damage as well as induce synaptogenesis/neurogenesis show the opposite of the desired/expected response.  Of course intiatially the nmda-antagonism slows cell death but in the higher phases of studies I've read the use of ketamine using their designed procedures caused further cell death making revival impossible.  The timing of infusion as well as quantity administered needs to be done at a specific time pre/during/immediately (need to re read to articles to better explain the timing issue) after the traumatic injury took place.  The infusion then needs to be halted to prevent a cascade of glutamate via a rebound effect produced by prolonged nmda-antagonism further speeding up apoptosis/cell death by the influx of Ca^2, Stimulating nitric oxide synthase leading to the production free radical ONOO- resulting further cascades of negative effects that produce further free radicals causing detrimental effects on the mitochondria within the cells as well as continue to increase the influx of Ca^2 and ONOO- along with many other damaging processes I'm not 100% knowledgable of.  

When using ketamine for other therapies like inducing LTP the timing of administration is also important because like with trying to treat a tramautic brain injury, extended non competitive antagonism can cause the opposite of the desired effect to occur resulting in LTD, and all the lovely side-effects you see with dissociative abuses (poor memory retention/formation, Difficulty concentrating, inability to Learn new associated behaviors, difficulty with language/communication, Delusional thoughts, etc all easily seen when you read through the countless mxe threads).  However if the administration and doses infused are dosed at certain time intervals LTP can be seen and ones ability to retain previously learned knowledge is increased, along with other potential benefits (reduction in stress/synaptogensis, potential therapeutic potentials in depression, forms of anxiety, OCD, and potentially others). 

Sorry I kinda went one rant With the last paragraph as I find it very interesting and good to know for users "trying" to get the benefits from ketamine or other dissocitives like MXE as I feel to many like to pretend they are doing something positive to their brain where they are actually over using and doing the opposite.  Sure different benefits like the anti-d qualities may still be seen with abusive dosing but interns of LTP or cognitive abilities I'd say not.  End rant


----------



## pharmakos

thanks cloudy



> I don't know what type of answer you are expecting to get.



i wasn't upset at any of the responses other than the "i think you should quit asking these questions and try to come to terms with your grief"

really had already put my grief behind me a few weeks ago

and questions are always okay imo, stifling questions in ADD is pretty contrary to the goal of the place i'd say


----------



## nAON

thenightwatch said:


> are there any drug therapies for coma that are intended to increase oxygen levels in the brain?




Look into Piracetam, apparently it's shown to help in decreasing negative effects of hypoxia in stroke victims.


----------



## Jktm

Sorry if this isn't even Pseudo-ADD material, but was curious as to what types of drugs/chemicals could be used to combat endogenous obesity from an extremely slow metabolism? I'm currently taking 75mg of IR phentermine daily and am eating around 1000 calories/day, but weight-loss comes slowly and has long plateaus that arise quickly once weight-loss has resumed, so I'm pretty sure it's not my appetite that is the issue. I know we aren't supposed to ask individualized questions such as this in ADD (or at least make your own thread for one), but I figured that there's probably many other people with this issue, so maybe it won't be a big deal.


----------



## sekio

There aren't very many drugs that raise metabolic rate in a "safe" way.

Two or three of the ones that come to me off the top of my head are D-methamphetamine, MDA/MDMA/Fenfluramine, and 2,4-dinitrophenol.

Meth is neurotoxic, the MDx and fenfluramines are likely cardiotoxic with long term use, and 2,4-dinitrophenol can cause all sorts of stupid side effects like caracts at a young age.

There is also the option of steroid therapy, but I am not very well-read into that book.


----------



## Epsilon Alpha

Jktm said:


> Sorry if this isn't even Pseudo-ADD material, but was curious as to what types of drugs/chemicals could be used to combat endogenous obesity from an extremely slow metabolism? I'm currently taking 75mg of IR phentermine daily and am eating around 1000 calories/day, but weight-loss comes slowly and has long plateaus that arise quickly once weight-loss has resumed, so I'm pretty sure it's not my appetite that is the issue. I know we aren't supposed to ask individualized questions such as this in ADD (or at least make your own thread for one), but I figured that there's probably many other people with this issue, so maybe it won't be a big deal.



It may be worth having your thyroid checked if your metabolism is that slow. If you come out with a low T3/T4 level you might want to talk to your doctor about supplementation.

Then there's steroids... Yeah it's a path I wouldn't recommend due to side effects, but that's beside the point.


----------



## sekio

Thyrioid and testosterone level tests are probably a good idea to have done by a Dr. - those are two big factors.


----------



## Jktm

I am a CPP so so the testosterone is definitely a possibility...I just wish my doc didn't charge extra for those labs... *sigh*

Thanks for the info guys...


----------



## m060mm

Epsilon Alpha said:


> this source (sketchy as hell)
> http://www.comawakening.com/coma.html



For truth.

I'm pretty sure he's a copypasta. The lack of organization and nonsequitor presentation.. and that background makes me nauseous after reading just a few lines.



Jktm said:


> Sorry if this isn't even Pseudo-ADD material, but was curious as to what types of drugs/chemicals could be used to combat endogenous obesity from an extremely slow metabolism? I'm currently taking 75mg of IR phentermine daily and am eating around 1000 calories/day, but weight-loss comes slowly and has long plateaus that arise quickly once weight-loss has resumed, so I'm pretty sure it's not my appetite that is the issue. I know we aren't supposed to ask individualized questions such as this in ADD (or at least make your own thread for one), but I figured that there's probably many other people with this issue, so maybe it won't be a big deal.




These guys' suggestions so far are pretty spot on. This is an endocrine disorder; treating the obesity itself, while beneficial to your overall health, is not the solution.

+1 to T3/T4, +1 to a whole HTPA axis assessment. Decline the MRI unless they really can't find anything with exhaustive blood work. (I'm considering cost, which you mentioned.) Insist on testing E2 early; you're giving me the impression that you have above average body fat. Even if you can control estrogen while you wait for conclusive results, it will help with your weight loss efforts and likely a lot of other side effects if it's in fact out of range. (Range being 10-30ng/dL; don't let them tell you 50-60 is ok.)

Congrats on being disciplined enough to stick to 1000/day but with all due, that is too low. Just my opinion after dealing with various comorbid conditions. I don't know your situation. I've had clients lose 100+ in a matter of six to nine months (no gimmicks so my numbers aren't jaw dropping) and keep it off. I'd say about 20% of them were hitting plateaus because they weren't eating enough. You need to build muscle to burn fat, look better and increase your basal metabolic rate, which is a factor many seem to underestimate.

Obviously you should consult your doctor before changing anything, but I think there are a few points worth discussing.

Best of luck!

edit: I went on the assumption that by CPP you meant precocious puberty. That's why I'm guessing your estrogen (or rather, T:E ratio) is off.


----------



## Jktm

CPP is Chronic Pain Patient lol...my bad...I was thinking my testosterone could have decreased from opioids...

And my sex/age is being questioned...20 year old dude lol...my brain is desensitized to estrogen lol...


----------



## doppelgänger1

Jktm said:


> Sorry if this isn't even Pseudo-ADD material, but was curious as to what types of drugs/chemicals could be used to combat endogenous obesity from an extremely slow metabolism? I'm currently taking 75mg of IR phentermine daily and am eating around 1000 calories/day, but weight-loss comes slowly and has long plateaus that arise quickly once weight-loss has resumed, so I'm pretty sure it's not my appetite that is the issue.


Too low calories intake will result in lower t3-bloodlevels and therfore lower calorie consumption. I don't know exactly, but 1000kcal sounds like to low to me.


----------



## Jktm

Another question from the pharmacology hopeful lol...

Does higher peak plasma concentrations of drugs necessitate increased receptor saturation (e.g. Would donating a pint of whole blood (or a unit of plasma for that matter) result in better response to pain medications)? I donate every 8 weeks regardless, but was wondering if taking the same dose of a medication after donating result in a stonger response than a dose taken a few hours before getting drained.


----------



## sekio

Not neccesarily.

If memory serves, decreasing blood volume will primarily affect drugs by decreasing the amount of water availiable for it to partition into, and decreasing e.g. albumin binding. (non-target binding) But dontaing a pint of 2 of blood won't really change gross parameters of drug efficacy and metabolism.

I would wager that a lot of the perceptible changes when yoiur blood is drained simply come from a loss of blood pressure & decrease in blood sugar. They're probably offset pretty easily by drinking some juice and waiting a little while. (hence why juice and cookies are a staple of blood drives)


----------



## Jktm

why is phentermine not an amphetamine? is it because the methyl group is on the second carbon as opposed to the amine?

I just notice the only difference in nomenclature between it an methampetamine is the placement of the methyl group...


----------



## sekio

Phentermine could be considered an amphetamine, it is alpha,alpha-dimethyl-phenethylamine,

The problem is, the alpha-carbon is a chiral center in amphetamine, and if it's in the wrong place it won't work... explaining phentermines (and L-amphetamine's) decreased potency.


----------



## Jktm

Ah, so it's that methyl group that fucks it up...

thanks for all the answers man...


----------



## Thorns Have Roses

Why is it we assume 3-methoxymorhpinan does nothing to contribute to the recreational effects of DXM, aside from the fact it has local anesthetic effects (DXM>MEM>DXO)? My gut tells me that it's a real player in the experience (probably an undesirable one), but I couldn't really find any info to support that.


----------



## Lombergerh

Is it possible to "reset" the brain receptors?
I don't need to lowering tolerance to any drug, i heavly abused Prozak and DOx and feel somewhat uncomfortable(my life literally goes down i feel much more anixious, a little dumber, and totaly lazier.
Also can Prozak or 5HT2-agonists impare my cognitive functions?


----------



## sekio

@ lombergh, no there is no easy way to "reset" your "receptors".


----------



## pharmakos

Lombergerh said:


> Is it possible to "reset" the brain receptors?
> I don't need to lowering tolerance to any drug, i heavly abused Prozak and DOx and feel somewhat uncomfortable(my life literally goes down i feel much more anixious, a little dumber, and totaly lazier.
> Also can Prozak or 5HT2-agonists impare my cognitive functions?



its not exactly "resetting your receptors," but you should look into St. John's Wort


----------



## SONN

I just found alpha-propyl-mescaline on some obscure RC website.

I wish there was more exploration of alpha-ethyl-phenethylamines or alpha-propyl-phenethylamines, it doesn't make sense to me that all of the worthwhile phenethylamines with an alpha group are methylated.

maybe even alpha-allyl-phenethylamine? I'm quite curious about the possibilities.


----------



## Astavats

SONN said:


> I wish there was more exploration of alpha-ethyl-phenethylamines or alpha-propyl-phenethylamines, it doesn't make sense to me that all of the worthwhile phenethylamines with an alpha group are methylated.



"APM" or α-propyl-mescaline has been made before along with some other extended alkyl chain friends (see this and this) though it is expected to be inactive.



			
				PiHKAL said:
			
		

> But since the first of these, AEM, was not active, there was no enthusiasm for tasting anything higher. This family was never published; why publish presumably inactive and thus uninteresting material?


----------



## SONN

^idk, man.

_Presumably_ inactive.

I just find it hard to believe there aren't ANY active phenethylamines with an alpha-alkyl group that isn't a methyl.


----------



## pharmakos

^^ there's gotta be some gems in the higher alpha-alkyl analogues.  active ones will probably be fewer and farther between, but there has to be some imo.


----------



## sekio

There are active phenethylamines with "long" alkyl chains, look into the prolintanes.

Unfortunately most of them are monoamine transport inhibitors versus serotonin 5ht2 agonists.


----------



## Tussmann

*Cool Abstract for NMDA antagonist users*

Clin Drug Investig. 2012 Aug 1;32(8):e1-e15. doi: 10.2165/11633850-000000000-00000.
A Study of Potential Pharmacokinetic and Pharmacodynamic Interactions between Dextromethorphan/Quinidine and Memantine in Healthy Volunteers.
Pope LE, Schoedel KA, Bartlett C, Sellers EM.
Source
Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA.

Abstract
Background and Objective: Dextromethorphan/quinidine (DMQ) is the first agent indicated for the treatment of pseudobulbar affect. Dextromethorphan, the active ingredient, is a low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. This study evaluated the potential for a drug-drug interaction (DDI) of DMQ with memantine, which is also an NMDA receptor antagonist. Methods: This open-label, randomized, parallel-group study enrolled healthy adults who were randomized into one of two treatment groups. Group 1 subjects were administered memantine at a starting dose of 5 mg once daily, which was titrated over a 3-week period to a dose of 10 mg twice daily (every 12 hours) and continued for another 11 days to attain steady state; DMQ 30 mg (dextromethorphan 30 mg/quinidine 30 mg) every 12 hours was then added for a further 8 days. Group 2 subjects received DMQ 30 mg every 12 hours for 8 days to attain steady state; memantine was then added, titrated on the same schedule as in group 1, and continued at 10 mg every 12 hours for an additional 11 days. Pharmacokinetic blood sampling was performed to assess the primary endpoints of the 90% confidence intervals (CIs) for the geometric mean ratios of the areas under the plasma concentration-time curves (AUCs) for memantine, dextromethorphan, dextrorphan - the dextromethorphan metabolite - and quinidine during concomitant therapy versus monotherapy. Safety/tolerability and pharmacodynamic variables were also assessed. Results: A total of 52 subjects were randomized. In both group 1 (n = 23) and group 2 (n = 29), the 90% CIs for the ratios of the AUCs during concomitant therapy versus monotherapy were within the predefined range to indicate similarity (0.8-1.25) for memantine, dextromethorphan and dextrorphan, indicating no pharmacokinetic DDI. The 90% CI for the AUC ratio for quinidine was slightly above the predefined range; however, the mean AUC increased by only 25%. In both groups, incidence of adverse events was similar, and pharmacodynamic variables were either similar or slightly improved with DMQ added to memantine and memantine added to DMQ, compared to monotherapy with either agent. *Conclusion: Minimal pharmacokinetic and pharmacodynamic interactions were observed between memantine and DMQ, suggesting they can be coadministered without dose adjustment.*



I might start using a combination of the two instead of ordering bulk shipments of memantine from overseas. For all of you interested in practical drug-tolerance prevention, this is good news.


----------



## pharmakos

these are from the big & dandy 4-fa thread, thought it might get a better answer here




ScruffyNerfHerder said:


> There have been concerns raised about the possible side effects of the floluorine in 4-fa (skeletal warping), but it has been speculated that the body would be unable to break the fluorine free and the compound would be excreted chemically unchanged. Would there be a method of urine analysis that could confirm this?





hansdegans said:


> This is exactly what I would like to know also. Had it last weekend and it was one of the best experiences so far. Without all the negative side effects. I would like to add what the chemical reaction is when consumed with alcohol? Nobody seems to bother about this, but the fluorine is bad when its released in your body. Maybe it can not be released by only consuming 4-fa it self, but what if you add alcohol?
> 
> I'm thinking of doing this more often on parties, but I would like to make it to an age of 60 at least also . Nobody with a science/chemical degree that can research some pee? I think we've read enough "This is how I feel with 4fa" comments, its time for some real results.



in particular, the question about adding alcohol piqued my interest


----------



## sekio

Fluorines attached to carbons don't just magically fly off - they're bonded on there tighter than hydrogens. Yes, this means that metabolism is blocked at the 4-position*. No, this isn't a bad thing. No, this doesn't irreverably bind enzymes. No, this won't result in "free fluorine". No, this does not paralell the heavier haloamphetamines. No, this is not indicative of any more toxicity than amphetamine itself.

_* amphetamine is hydroxylated at the 4-position by some liver enzymes as a minor metabolic route. 4-hydroxamphetamine is considered a nasty body load and is not thought to contribute to the positive f/x_

Essentially the only thing that liberates fluorine from organic compounds is *fire.* Don't burn your 4-FA and you won't have to worry about HF exposure.

"Fluorine is bad when released in your body" -true, but in high concentrations. A dose of 4-FA doesn't have an appreciable amount of fluorine in it, compared to toothpaste.

Amphetamines do not "react" with alcohol, though consumption of large amounts of alcohol will change pharmacokinetics in a non-specific, unpredictable way by interefering with pH and enzymatic metabolism.



---

The major routes for fluorine toxicity are:
1. Metabolism of fluoroalkanes to *toxic fluoroacetate*. This only happens for even numbered n-fluorinated straight chain alkanes. (It was a possible concern of AM-2201, but that has an ODD number of carbons in the chain).
2. Ionic fluoride salt poisoning (This is what happens if you eat too much toothpaste)

Ring-fluorinated compounds like flurbiprofen, escitalopram et cetera (there are thousands) do not pose a threat for fluorine exposure


----------



## King Kong

I just start playing with autodock vina and I am looking for theoretical structure of serotonin receptors and transporters.
You know where I could find this kind of PDB files? I found several scientific paper speaking about their model, but I was unable to find the PDB model... which is a pity!

(Also... Do you know a good forum about computational chemistry?)

Thanks in advance!


----------



## TheAppleCore

Can anyone estimate how long until MXE is fully metabolized / excreted? I want to know how long after MXE use I can safely take ayahuasca (and it seems that there is good reason to be wary of MXE + MAOIs).


----------



## Jktm

Is there anyway of comparing phentermine's potency as a stimulant (while it's not a true amphetamine, it is still a sympatomimetic amine stimulant) to that of amphetamine/methamphetamine and is there a conversion for potency between amp and m-amp?


----------



## Epsilon Alpha

Jktm said:


> Is there anyway of comparing phentermine's potency as a stimulant (while it's not a true amphetamine, it is still a sympatomimetic amine stimulant) to that of amphetamine/methamphetamine and is there a conversion for potency between amp and m-amp?



Well you could look at the monoamine efflux ratios and EC50's.


----------



## ebola?

Honestly, it simply does something different from the more desirable classical stimulants (with phentermine's increased selectivity for NE over dopamine), so drawing up some conversion factor to derive straightforward potency-equivalence simply isn't viable.

ebola


----------



## Epsilon Alpha

How so? I was under the impression it was just a reuptake inhibitor or releaser


----------



## ebola?

Yes, but we have to answer the question, "potency in doing what?"  This will have a very different answer depending on a compound's particular selectivity for one monoamine over others.  You could compare with d-amp's EC50s as a monoamine releaser (assuming similar pharmacokinetics...which is somewhat sound), but dopaminergic effects seem to matter a great deal.

ebola


----------



## JackiesBabyy

*What's the physiological cause of benzo/alcohol withdrawal?*

Like how the cause of opiate withdrawal is mainly the rebound pain caused by the mu receptors not being constantly activated + lots of NE in your system causing the anxiety/sweating/diarrhea, stimulant WDs are caused by dopamine and (and serotonin for MDMA and 4-FA, anyway) depletion destroying your ability to feel pleasure (and derealization/depression caused by 5-HT depletion). How does a lack of GABA cause deadly siezures, DTs and the other symptoms of benzo/alcohol WD?


----------



## daytryptr

Your body down-regulates how much gaba it needs to make naturally since when benzo's bind to the gaba receptor they enhance the potency/efficacy of natural gaba at doing its job. Less gaba is needed to inhibit while the benzos are acting, and when you discontinue use you are left with a gaba down-regulation that takes a while to return to normal levels. Gaba being the chief inhibitory neurotransmitter in the brain, when heavily down-regulated and abrubtly discontinued can lead to over-activity causing withdrawals, all the way from rebound anxiety to grand mal seizures, and possibly death.

from wiki-



> http://en.wikipedia.org/wiki/Benzodiazepine_withdrawal_syndrome
> Benzodiazepines potentiate the action of the neurotransmitter GABA. When this potentiation is sustained by long-term use, neuroadaptations occur which result in decreased GABA activity and increased excitability of the glutamate system. When benzodiazepines are stopped, these neuroadaptations are "unmasked", leading to excitability of the nervous system and the appearance of withdrawal symptoms. Increased glutamate excitatory activity during withdrawal is believed to result in kindling phenomena.[82] Those who have a prior history of withdrawing from benzodiazepines are found to be less likely to succeed the next time around.[83] Repeated benzodiazepines withdrawals, like with alcohol withdrawal, may lead to sensitization or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse.


----------



## sekio

In BZD/Barb/alcohol W/D, your GABA-A receptores are insufficiently activated to endogenous GABA. Benzos/barbs (and to some extent alcohol) all make GABA-A receptors *more sensitive* to GABA and so when they are used for a long time your body decreases production. When you withdraw your body's levels of GABA won't be enough to activate receptors properly.

GABA-A is a mian inhibitory neurotransmitter (stops seizures etc and other silly brain activity) so you could see why this would be bad


----------



## JackiesBabyy

sekio said:


> In BZD/Barb/alcohol W/D, your GABA-A receptores are insufficiently activated to endogenous GABA. Benzos/barbs (and to some extent alcohol) all make GABA-A receptors *more sensitive* to GABA and so when they are used for a long time your body decreases production. When you withdraw your body's levels of GABA won't be enough to activate receptors properly.
> 
> GABA-A is a mian inhibitory neurotransmitter (stops seizures etc and other silly brain activity) so you could see why this would be bad



Oh, also, how do the seizures KILL you? The only time I've heard of seizures killing epileptic people is when they happen while the person is driving, crossing a street, or something else dangerous. 

And, how about GABA-B? What is that for?


----------



## sekio

The seizures kill you from exhaustion, aspiration of vomit, or respiratory collapse. Or of course from injuries 2nd to it.

GABA-B is a mostly unrelated subclass of receptors that bind GABA as well, but they don't have effects like "classical" sedatives (benzos/barbs) - although they are inhibitory when activated - and lack a benzodiazepine/barbiturate binding site. Example of agonists: phenibut, baclofen.


----------



## DexterMeth

There's no cross-tolerance with GABA-A and B agonists, correct?


----------



## sekio

Not with the classical ones, no


----------



## AlphaMethylPhenyl

Can you clarify "respiratory collapse"?

I fair amount of people who die from seizure have bitten off their tongue and choked on it too, just adding.

Phenibut does activate GABA-A at high doses from what I can recall.


----------



## sekio

"respiratory collapse" = insufficient coordinated muscle motion to effect breathing


----------



## Anoymator

Anybody know why pregabalin at high doses yields some heavy closed eye visuals? This effect has been reported a few times and it tends to be of a movie-like nature in that you can see how themes develop.


----------



## Transform

GHB does something similar for me. They are typically quite colourful, and if they progress past neon RGB static then they're quite realistic. They only come very close to the knockout dose though.


----------



## Anoymator

Transform said:


> GHB does something similar for me. They are typically quite colourful, and if they progress past neon RGB static then they're quite realistic. They only come very close to the knockout dose though.



It must be something else than the purported GABA analogue property of pregabalin, right? Last I read on pregabalin, it is still not 100% on how it works but I read up on it long time ago. Would love an educated opinion from you guys. I actually decided to try a high dose with no tolerance (500mgs) and 4 hours into the trip I was watching an actual movie (from the CEVs) though I could only hold it for 30-40 mins before I was going into full sleep. NO OEVs though.

I am wondering what sub-receptors and other receptors yield CEVs aside from the typical 5HT sub-receptors.


----------



## pharmakos

the only CEV i ever got from pregabalin was i shut my eyes and i was magically transported to a beach at night time =p  was quite vivd


----------



## Renz Envy

How can one speed up the process of adapting to a natural GABA level post continuous benzo use?

Also

How do the GABA-B receptors effect dopamine?


----------



## Anoymator

thenightwatch said:


> the only CEV i ever got from pregabalin was i shut my eyes and i was magically transported to a beach at night time =p  was quite vivd



LOL. What I got was some stuff similar to static noise on TV which in minutes progressed to objects morphing into other objects (the fuck??) and then it looked like I was watching all of this from a theatre. If I moved my eyes when they were closed, the objects would transform automatically, which makes me think if these CEVs are due to the eye movement which may be caused as one drifts into full sleep (no idea, just suggesting??).

Ive read other people comparing it to ketamine and to me it feels like the CEVs I'd get from a low dose of mushrooms.


----------



## ebola?

sekio said:
			
		

> Not with the classical ones, no



Does this then suggest as a corollary that tolerance to GABA-agonists (be they allosteric modulators at GABAA or B) is mediated nearly exclusively via receptor downregulation, and not downregulation of the endogenous synthesis of GABA?

ebola


----------



## c0rt3x

*Endorphine Reuptake Inhibitors*

Are there any known Endorphine Reuptake Inhibitors already?


----------



## Nagelfar

From my understanding the mu-G-coupled protein receptor doesn't have the same transporter re-uptake pump system like the monoamines (dopamine, serotonin, norepinephrine) do.


----------



## sekio

There are definitely chemicals that prevent the breakdown of engogenous opioids, not sure how effective they are in man though


----------



## Hammilton

Why'd you delete my post from this thread when you moved it?


----------



## sekio

I didn't. If you posted during the time it got merged your post has probably floated into the void. (Apologies for that)


----------



## JackiesBabyy

*DXM Afterglow...Is this possibly why it happens?*

Some people say they feel nice rather than hung over after a DXM trip. Well, it's known that NMDA antagonism upregulates dopamine receptors. So could the increase in dopamine receptors possibly be why many people feel nice after the trip? Most people who claim to get hangovers are either regular users or took a massive dose.


----------



## Moe-D

I had a terrible hangover from DXM..  
It was my first time and I liked the actual high, but the day after was horrible.. Including headaches, chill's and anxiety.
The dose was around 300mg if I remember right.. Havent tried it again..... YET


----------



## JackiesBabyy

Moe-D said:


> I had a terrible hangover from DXM..
> It was my first time and I liked the actual high, but the day after was horrible.. Including headaches, chill's and anxiety.
> The dose was around 300mg if I remember right.. Havent tried it again..... YET



I'm the opposite. I took 350-400mg my first time and the high was terrible, lots of nausea in the beginning and there was zero euphoria, the dissociation was just uncomfortable(although synthetic weed's dissociation was euphoric to me), and I just felt retarded.

The afterglow was nice and relaxing, conversely.


----------



## Gaz_hmmmm

*Amphetamine without Cortisol Release, How Would It Be Different?*

I was wondering if there was an amphetamine that didn't release cortisol how would its effects be different from standard amphetamine that releases cortisol?

The things I can think of are that it probably wouldn't lead to as much weight loss, maybe less immune system problems (This is from recreational dosing!) and maybe less memory enhancement as I know cortisol plays a part in memory function ( http://www.ncbi.nlm.nih.gov/books/NBK3907/ ).

I can't really think of much else at the moment.


----------



## sekio

I always thought that the cortisol release of amphetamine is caused by downstream activation of dopamine receptors - i.e. amphetamine itself doesn't release cortisol, dopaminergics in general do


----------



## Anoymator

Anoymator said:


> Anybody know why pregabalin at high doses yields some heavy closed eye visuals? This effect has been reported a few times and it tends to be of a movie-like nature in that you can see how themes develop.



Awww yes. Here comes the lyrical train again.

Mafaka, I am seeing a freaking movie when I close my eyes. Black and white, oldschool Charles Chaplin style. I even get subliminal messages in the movie, random words.

For the love of Snoopy, any one know the MOA for the CEVs? I tried asking Charles Chaplin; he said it's NMDA antagonism but then I told him that pregabalin is not known to modulate the NMDA receptor so he shrugged his shoulders, winked at me and evaporated.

Edit: Serious question, with open eyes I feel stoned but it is when I close my eyes that the show begins in seconds.

2nd edit: he also told me it's Charlie, not Charles. You've got to be kidding me.


----------



## pharmakos

maybe there's some downstream effect on glutamate levels?


----------



## Epsilon Alpha

Anoymator said:


> Awww yes. Here comes the lyrical train again.
> 
> Mafaka, I am seeing a freaking movie when I close my eyes. Black and white, oldschool Charles Chaplin style. I even get subliminal messages in the movie, random words.
> 
> For the love of Snoopy, any one know the MOA for the CEVs? I tried asking Charles Chaplin; he said it's NMDA antagonism but then I told him that pregabalin is not known to modulate the NMDA receptor so he shrugged his shoulders, winked at me and evaporated.
> 
> Edit: Serious question, with open eyes I feel stoned but it is when I close my eyes that the show begins in seconds.
> 
> 2nd edit: he also told me it's Charlie, not Charles. You've got to be kidding me.



Well it really changes sleep architecture, particularly enhancing slow wave sleep, so I would hazard a guess it's a "pipe dream" like phenomenon. Perhaps it knocks your neuronal activity down into REM mode?


----------



## Anoymator

Epsilon Alpha said:


> Well it really changes sleep architecture, particularly enhancing slow wave sleep, so I would hazard a guess it's a "pipe dream" like phenomenon. Perhaps it knocks your neuronal activity down into REM mode?



Thanks for replying guys. Sorry for the post last night, was utterly fucked on 500mgs of pregabalin. I'm using it to wean down from a high tramadol use and it is helping. It knocked my ass out even after 6 hours of having ingested it, even though without the pregabalin I'd be withdrawing hardcore from the tramadol. Love this drug, only thing is that it has caused me to have clots so I always inject a fast anticoagulant if im going to use high doses.

The CEVS are very real and sometimes even too violent as they are moving too fast. I was chilling out with Charlie Chaplin and it felt like I was drifting into sleep, then I opened my eyes and everything faded and I just felt stoned. I really do think there is something going with REM sleep because while I am conscious, I can only hold the CEVs for 40 mins before passing out.

I like the glutamate theory, how would that cause CEVs? How about what Chaplin told me (LOL)? Would you advanced folks think pregabalin could cause some activation in the NDMA receptor at all? I would not be the first one to report that high doses of pregabalin feel like ketamine.

I really hope that a trend of abusing pregabalin to get CEVs is not started as the drug is fairly easy to get and it will be going generic in 2013, but the drug is worth the occasional use to get some wicked CEVs and feel stoned for 8 hours.


----------



## pharmakos

Anoymator said:


> I like the glutamate theory, how would that cause CEVs?



if you didn't realize, the NMDA receptor is a glutamate receptor.


----------



## Anoymator

thenightwatch said:


> if you didn't realize, the NMDA receptor is a glutamate receptor.



I am not advanced (just curious in terms of drug pharmacology) and while I am aware that they are both interrelated, I don't know how the glutamate theory would explain the CEVs caused by pregabalin as for all I know this drug is not known to interact with this receptor (but then, I could easily be wrong). If you know the modus operandi, by all means, enlighten me.

Pregabalin seems to be a drug which is still not fully known as to how it works which makes me even more curious to know any suspected actions which could yield this notable side effect (I always get CEVs at high doses and so do others, but the drug is very expensive hence the online user experience reports are not plenty).


----------



## pharmakos

i'm not really too advanced either.  this is from the wikipedia entry on pregabalin, tho: 



> Pregabalin decreases the release of neurotransmitters including glutamate, noradrenaline, substance P and calcitonin gene-related peptide.



not QUITE the same as NMDA antagonism.  but close?  like i said, i'm not too advanced either.


----------



## NeuroPsyence

*Would 5-HT1d agonism affect NMDA-antagonist neurotoxicity?*

...


----------



## sekio

What neurotoxic properties of NMDA antagonists / DRIs are you talking about? To my knowledge, they're not. (no Olney's Lesions in primates, ketamine as an antidepressant that promotes neuron growth, many trials of NMDA antagonists for stroke neuroprotection, NDRI drugs being comparatively very safe  to releasing agents, etc)

Many 5-HT agonistic compounds are cerebral vasoconstrictors, but it's not always bad wrt neurotoxicity. It would however increase b.p. and hence stroke risk if used regularly.


----------



## NeuroPsyence

I was under the impression that the documented impairment of memory and cognitive function in regular users of ketamine implies neurotoxicity, even of the specific mechanism is not understood. Also there have been a couple studies that have suggested mechanisms whereby ketamine can cause adverse effects on the CNS. I've linked to two of them below.

http://www.ncbi.nlm.nih.gov/pubmed/17418473

http://www.ncbi.nlm.nih.gov/pubmed/7976530


----------



## pharmakos

sekio said:


> ketamine as an antidepressant that promotes neuron growth, many trials of NMDA antagonists for stroke neuroprotection



recreational sized doses are a different story i think


----------



## Anoymator

What do you all think could be the reason why a good % of people *report an instant mood lift with tramadol?* Tramadol (as opposed to O-desmethyltramadol) is a very weak opioid so this mood lift can't be fully attributed (if at all) to opiate receptor activity. I have read many reporting this effect about 20-30 minutes after ingestion of doses between 150- 300mgs and in one single dose (not spaced out to maximise the opiate effect).


----------



## vortex30

Anoymator said:


> What do you all think could be the reason why a good % of people *report an instant mood lift with tramadol?* Tramadol (as opposed to O-desmethyltramadol) is a very weak opioid so this mood lift can't be fully attributed (if at all) to opiate receptor activity. I have read many reporting this effect about 20-30 minutes after ingestion of doses between 150- 300mgs and in one single dose (not spaced out to maximise the opiate effect).



Probably because Tramadol is also an SNRI.


----------



## Anoymator

vortex30 said:


> Probably because Tramadol is also an SNRI.



Yes but, as far as I am concerned, SNRIs take weeks to yield the mood lift, not 20 minutes, plus the mood lift from tramadol is irrespective of having taken it other times. Likewise, the reported mood effect of SNRIs seems to be more towards a stabilized "no-highs & no-lows" effect which is not same as that of tramadol.


----------



## amanitadine

Tramadol is a SRA as well


----------



## asecin

*natural pain killer saliva*

http://en.wikipedia.org/wiki/Opiorphin


this seems quite interesting. anyone ever heard or read about this ? i wonder if there are any developments on this. 

by any developments i actually mean; Therapeutic application of opiorphin in humans would require modifying the molecule to avoid its rapid degradation in the intestine and its poor penetration of the blood–brain barrier.

any clue you chemist junkies


----------



## sekio

This topic comes up all the time (modifying things to cross BBB that would not cross otherwise).

The consensus is no, it's not something that is going to happen. It can be done with things like polysorbate nanoparticles and direct brain infusions, because otherwise "deactivating" the BBB, or protein metabolism in the gut is a bad plan.

There are literally 100s of peptides active at mu/delta opioid receptors. You can find them in meat, cheese, milk, grains, plants, even humans. But none of them are particularly active when administered exogenously because they are transported out of BBB like loperamide. (viz. nobody uses IV endorphin). In addition the peptides may have activity at sites other than mu-OR that we don;t know yet.

I expect that just like most "biologic" drugs that peptidergic opiods won't really go far. I remember there was a designer peptide that crossed BBB for sale  some years back - trials were not exactly what I would call promising as it seemed to me it never produced "typical" effects of an opioid, nor reinforcing behaviour.

Please keep posts like this in the B&B thread


----------



## TheAppleCore

Is there any reason to believe that DXM would share the same negative effects on the urinary tract as ketamine and MXE?


----------



## sekio

Damage to the urinary tract is not something that is "common" with ketamine IMO (probably an incidence of one in five hundred, weighted towards heavy users, * i bet there is a genetic component). I personally think some of people induce nocebo in themselves... & of course ketamine can cause schizophrenoid reactions so that doesn't help.

I have never heard of DXM induced urinary tract damage. Nor have I heard of it with MXE, except again in high doses.


----------



## TheAppleCore

Thanks for the reply. 

I sometimes question whether or not I'm imagining things, but it seems like too great of a coincidence that I happen to notice substantially increased urination frequency in conjunction with weekly / bi-weekly MXE use. Along with a number of other folks on these forums. So now of course I am desperately trying to find a kinder substitute...  Tisk... what an alluring high.


----------



## sekio

Diuresis is not neccesarily a sign of damage. Look at caffeine - if you use it infrequently it will increase urine output in some people spectacularly. Nobody worries about caffeine induced bladder damage! On the contrary, urinating a lot means your body is flushing the drug from your system.

Ketamine is documented as being a diuretic, I would expect MXE is too.


----------



## TheAppleCore

^ Interesting. Although I still notice the effect now, and it has been weeks since any MXE use.


----------



## amanitadine

^ I found methoxetamine to be a terrible diuretic,to the point of it being virtually prohibitive.  FWIW, Ketamine does a similar thing to me,  but in a much gentler fashion. "MXE" ( as much as I hate to type that, but I'm tired of spelling it out  ) felt downright nasty in this regard. Ketamine and it's  bladder issues  really seems to vary, I went through a period years ago of prolonged outrageous consumption and never had any bladder pains or such, just temporarily increased output. Yet some people run into issues  much easier. . .who knows.. The jury is still out on this one, (in terms of cause and effect, not the existence of, which is now widely recognized) according to the literature. The norketamine metabolite has been much bandied about bluelight over the years, but this seems to only be conjecture.

Caffeine also isn't the  extreme diuretic most assume it is. IIRC it isn't much of one until large amounts are consumed, like >4-500 mg. But the example still works


----------



## AlphaMethylPhenyl

diuretics thus are healthy in their own right


----------



## amanitadine

Explain? That is a very simple statement about a complex subject. Sure, they are often prescribed (some types) and can decrease the risk of strokes, high blood pressure, heart attacks, etc. But there is a documented link between diuresis and an increased risk of diabetes, which can also cause the aforementioned HBP and heart attacks,  among other things. So how are they healthy in their own right? It's not that simple. . .


----------



## AlphaMethylPhenyl

nothing is

I was referencing the obvious


----------



## sekio

I thought that misuse of diuretics was also a cause of electrolyte imbalances of all sorts as well.

In the short term diuresis is probably not of concern; but long term diuretic therapy, esp. with "selective" diuretics like furosemide is not going to be healthy for everyone


----------



## JackiesBabyy

*Q about mu opioid agonism, tramadol/tapentadol/NRI opiates, and norepinephrine.*

Tramadol and tapentadol are both NRIs(tramadol is an SSRI too but that doesn't matter here), therfore they both increase norepinephrine concentrations in the brain. Well, I remember reading one of the effects of mu-opioid agonism is that it DECREASES norepinephrine and one of the causes of opiate withdrawal is too much norepinephrine. So....shouldn't this make tramadol WDs less intense than other opiates rather than worse like many people say? And shouldn't taking tramadol when withdrawing make the WDs worse due to it increasing NE? Or am I totally off base here? 

And another semi-related question. Since tramadol is a serotonin releasing agent(yes, it's a releasing agent, not JUST a reuptake inhibitor) as well, and mu-opioid agonism also increases dopamine, how come tramadol isn't empathogenic(or is it? I've never had it so I can't say.) like MDMA, which also releases serotonin and dopamine?


----------



## sekio

Given that norepinephrine antagonists (anti-adrenergics like clonidine) are used for w/d from opioids, I see where you're coming from. But I would be more inclined to think of Tramadol as a SNRI plus opioid. Do _you _think SNRI withdrawal, plus opioid withdrawal, would cancel each other out?

Remember, "drug X increases monoamine Y" is pretty meaningless. _Where_ does the increase happen, and under _what circumstances_?


----------



## JackiesBabyy

sekio said:


> Given that norepinephrine antagonists (anti-adrenergics like clonidine) are used for w/d from opioids, I see where you're coming from. But I would be more inclined to think of Tramadol as a SNRI plus opioid. Do _you _think SNRI withdrawal, plus opioid withdrawal, would cancel each other out?
> 
> Remember, "drug X increases monoamine Y" is pretty meaningless. _Where_ does the increase happen, and under _what circumstances_?



Well as for the 2nd part of my post, since both MDMA and tramadol are considered "serotonin releasing agents" I'd assume they both released it in the same way albiet at different intensities.


----------



## AlphaMethylPhenyl

They're not very structurally related. I can pretty much guarantee they release in different regions. Sekio is trying to tell you that just because two drugs both release a neurotransmitter, doesn't mean the effects will be the same.


----------



## Lombergerh

SSRI damage - is there anything?
I wonder why so many people dislike SSRI and blame it for having bad impact on your health?
Is it true, especially i wnat to know about fluoxetine. Can it ruin your serotonin or other neruomediators metabolism permanently?


----------



## ebola?

> Well as for the 2nd part of my post, since both MDMA and tramadol are considered "serotonin releasing agents" I'd assume they both released it in the same way albiet at different intensities.



Not only would expect the compounds to be differently selective for anatomical region, but tramadol's mechanism of transporter reversal might simply be a bit different, given that a prior study found its efficacy as a releaser to be subject to clear 'ceiling effects'.

ebola


----------



## AlphaMethylPhenyl

I don't think SSRIs are that bad. Many people are upset that they offer little/no recreational potential.
Its definitely possible. How long or at what intensity of usage this happens is hard to say


----------



## JackiesBabyy

Ho-Chi-Minh said:


> I don't think SSRIs are that bad. Many people are upset that they offer little/no recreational potential.
> Its definitely possible. How long or at what intensity of usage this happens is hard to say



A lot of people are resentful or afraid of them due to the sexual side effects that can be extreme and last a long time in some.


----------



## gladiolus

*anorgasmia on ssri's: the relevant 5HT subtype responsible?*

I'm confused, I've been reading for hours about how the main suspected culprit is 5HT1a increased activation caused by ssri's, which causes incresed prolactin synthesis, but then again I read that a good treatment for sexual dysfunction in ssri use are 5HT1a agonists!
Obviously both can't be true.
And if there really is (and probably is) a particular 5HT subtype that reduces sexual feelings and response when either: a) subject to serotonin reuptake inhibition or b) the subsequent downgrading or upgrading of receptor types in response to this, then:

can we design an antagonist at that receptor or even a reverse agonist? What subtype? Hmmmm.....and in normal people, would a reverse agonist at this subtype act as a pro-sexual aphrodesiac?


----------



## Renz Envy

*4-alpha 3-phenylbutyric acid(phenibut) into a salt*

I got side tracked and ended up in the dusty old section of bluelight. One of the members gave an experience about having converted phenibut into a salt from an acid, thus decreasing some pain from intranasal administration and apparently strengthening the oral administration



> I woke up on the street, at the time I didn't give it a second thought - it's a very good anxiolytic indeed!) - absolutely zero recollection of the events in between. I found by changing it from it's acidic form to a sodium salt you can increase oral bioavailability quite significantly, and it tastes much less nasty as a salt so it's easier to mix into a drink.


  The Phenibut Thread

It would be in my best interest to know how one would one go about doing this conversion?


----------



## sekio

Textbook acid neutralisation. Add 22.2% by weight of sodium hydroxide (1 molar equivalent to phenibut - preferably add the lye in solution) and mix it really well, then remove the water by evaporation.

Or use your favourite alkali to bring a solution of phenibut to neutrality (ph 6.0-8.0) where it exist as a zwitterionic, doubly-charged form and is very water soluble. One could use sodium bicarbonate if you were hurtin'.


----------



## Renz Envy

Thanks,

I'll try sodium hydroxide and see how it works.


----------



## pharmakos

do psilocybe mushrooms contain any "plain" n,n-DMT?  anyone have any papers?


----------



## sekio

If they do, there's not any more than parts per thousand.


----------



## pharmakos

isn't the theory that DMT is the immediate metabolic precursor to psilocybin in mushrooms?  if so then is all the DMT very rapidly converted to 4-ho and 4-po?

my immediate thought was that there must not be much DMT, if any.  but then i got to wondering and i think maybe there is more in there, and perhaps it accounts some what for the increased effects of "shroomahuasca".   

hoping for a paper rather than guesses tho.


----------



## Epsilon Alpha

That awkward moment when you find your lab supervisor browsing bluelight ADD...
Hi Alan!


----------



## sekio

nice. at least you're among friends.


----------



## pharmakos

that wouldn't be awkward at all hahaha.  i would be stoked.  :D


----------



## Sturnam

Epsilon Alpha said:


> That awkward moment when you find your lab supervisor browsing bluelight ADD...
> Hi Alan!



ITT: EA finds out that his lab supervisor is vektor


----------



## pharmakos

from the 25I-NBOMe wikipedia article:



> It is also believed to be the drug that caused a fatal overdose of a teen in East Grand Forks, Minnesota in June 2012, after a "hobby chemist" friend had converted 2C-I that he had purchased online, into the much more potent 25I-NBOMe.



that's not even possible, is it?  here's the link given as a reference for that portion: http://www.inforum.com/event/article/id/365948/publisher_ID/1/


----------



## skillet

It's definitely possible, but the article doesn't mention 2C-I. I think it's more likely he was just buying 25I and laying sheets.


----------



## sekio

The lay-man is not going to do the conversion from 2C-x to 25x. Too much work.


----------



## pharmakos

i was fairly sure, just wanted to double check.  gonna edit that bit out of the wiki article to prevent the spread of misinformation.


----------



## ebola?

To what extent should we attribute d-amphetamine's propensity to increase synaptic dopamine to reversal of DAT versus activity at VMAT2?  What about for norepinephrine?

ebola


----------



## Epsilon Alpha

ebola? said:


> To what extent should we attribute d-amphetamine's propensity to increase synaptic dopamine to reversal of DAT versus activity at VMAT2?  What about for norepinephrine?
> 
> ebola



You need both for synaptic dopamine to increase significantly, VMAT2 reversal ups cystolic dopamine and DAT reversal results in an efflux of cystolic dopamine. The same should go for norepinepherine.


----------



## ebola?

Are there known dopamine releasers with low affinity for VMAT2?

ebola


----------



## hjalmar

*(±)-1-(1,2-Diphenylethyl)piperidine maleate (lefetamine analog and NMDA antagonist)*

I just noticed [insert major biopharm company here] offers it on its site






What immediately catched my eye is that this compound is a lefetamine analog (piperidine instead of dimethylamino-group) and next to that it is offered as a racemic mixture (lefetamine being the l-isomere of 1,2-Diphenyl-1-dimethylaminoethane is the active one, the d-isomere not being very active but about of similar toxicity).

My obvious question is, what is known about the activity of this compound?
Tocris states:


> Biological Activity
> High affinity antagonist at the ion channel on the NMDA receptor.



but the only paper that mentions it is:



> Ragawski (1993) Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. TiPS 14 325. PMID: 7504360.



which I cannot immediately locate... maybe at the pharmaceutical departement of the local uni, let's hope.

EDIT: and there's this paper, should be easier available:

http://www.ncbi.nlm.nih.gov/pubmed/19345586



> *NMDA receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)piperidine enantiomers and of related compounds.*
> 
> *Bioorg Med Chem. 2009 *May 1;17(9):3456-62. Epub 2009 Mar 19
> Berger ML, Schweifer A, Rebernik P, Hammerschmidt F.
> 
> Source
> Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna, Austria. michael.berger@meduniwien.ac.at
> 
> Abstract
> We resolved 1,2-diphenylethylamine (DPEA) into its (S)- and (R)-enantiomer and used them as precursors for synthesis of (S)- and (R)-1-(1,2-diphenylethyl)piperidine, flexible homeomorphs of the NMDA channel blocker MK-801. We also describe the synthesis of the dicyclohexyl analogues of DPEA. These and related compounds were tested as inhibitors of [(3)H]MK-801 binding to rat brain membranes. Stereospecificity ranged between factors of 0.5 and 50. Some blockers exhibited stereospecific sensitivity to the modulator spermine. Our results may help to elucidate in more detail the NMDA channel pharmacophore.



It can be found online here:
http://cbr.meduniwien.ac.at/fileadmin/db_files/pub_art_185.pdf

Note on page 3458:


> Incorporation of the nitrogen atom of the primary amino group of (S)-5a into a piperidine ring resulted in the highly potent NMDA receptor channel blocker (S)-6, ﬁve times more potent than (S)-5a, with comparable stereoselectivity (factor 49)


----------



## naughtynicknails

You're not allowed to source or even discuss vendors on this site 

You should delete the first part of your post.

Welcome to Bluelight


----------



## Vader

Haha, I think that you can talk about Tocris and Sigma, the cat might be out of the bag there  Of course, I might be wrong, I don't mod this forum, but I imagine it's OK.


----------



## cannibalsnail

On a similair note:

http://en.wikipedia.org/wiki/Dexoxadrol

http://en.wikipedia.org/wiki/Etoxadrol

Potential new, non aryl-cyclohexamine dissociatives. However some worrying reports are on the page: "In the brain, etoxadrol slows down the synthesis of serotonin to 50-60% of control rates and speeds up the rate of dopamine synthesis by up to 200% of the normal rate 4–6 hours after intravenous administration". I'm unclear on what in the structure causes this but at a guess the Dioxy ring ring looks suspect: The MD ring in MDMA inhibits Tryptophan Hydroxylase and the Dopamine synthesis would be caused by a blockade of Autoreceptors on the surface membrane of Dopamine neurones. 

Alternatively:

http://en.wikipedia.org/wiki/Dextrallorphan

http://en.wikipedia.org/wiki/Dextrorphan

Analogues of these could hold potential. However I think the sheer number of possible ring substitutions would make it a fumble in the dark to find anything with real activity. Maybe Acetoxy-DXO?


----------



## JackiesBabyy

*How, in detail, does serotonin release cause empathy?*

From what I can find apparently 5-HT1a being activated releases oxytocin which causes empathogenic effects. But is there more to it than that? I think you need dopamine release along with 5-HT release to cause empathy, but then why doesn't a dopamine releaser + a 5-HT1a agonist drug cause empathy? Or a dopamine releaser + an SSRI? (I know SRAs aren't SSRIs but they seemingly have the both end result, more serotonin available to bind to the receptors.)

Semi-related question, are there any selective SRAs out there? If so, what are the effects? I did read something interesting about cocaine still being reinforcing in lab mice with no dopamine transporters (cocaine is an serotonin-NE-dopamine reuptake inhibitor, and those rats still found it reinforcing with no dopamine transporter to inhibit, but this doesn't quite answer my question as it's a reuptake inhibitor and not a releasing agent).


----------



## sekio

MDAI is considered to be a "selective serotonin releasing agent".

I think the effects you are referring to come from the broad downstream activation of serotonin receptors.

There is no one receptor that produces "empathy" in the brain, however. As you probably realize, selective 5-HT1a agonists aren't considered to be abusable or euphoric per se.



> I'm unclear on what in the structure causes this but at a guess the Dioxy ring ring looks suspect: The MD ring in MDMA inhibits [..]



That's some pretty interesting thinking. I don't think chemistry works that way, or Cialis (which has methylenedioxy ring on it) would be just as damaging.

It's not the structural motifs in the chemical that decide its activity; its how those motifs interact with the drug's targets that matter. The MD ring on MDMA just makes the molecule look "enough" like serotonin that it binds 10x better than "normal" amphetamine. If you put it anywhere else it doesn't work half as well.

Etoxadrol has been high on my list of "promising dissociatives". It's potent (a "recreational" dose would be likely 0.25-0.5 mg/kg), relatively long-lasting, (probably) orally bioavailiable, and most importantly it's self administered in monkeys. Not to mention its a nice painkiller etc, and any drug that has trials stopped due to hallucinations and nightmares is obviously pretty effective as a psychotropic. (Dex and etoxadrol were developed as intravenous anesthetics.)


----------



## Vader

> most importantly it's self administered in monkeys


Always a good sign...


> trials stopped due to hallucinations and nightmares


Shut up and take my money.


----------



## pharmakos

Vader said:


> Haha, I think that you can talk about Tocris and Sigma, the cat might be out of the bag there  Of course, I might be wrong, I don't mod this forum, but I imagine it's OK.



you'd have to be pretty rich and desperate to order your drugs from Sigma.  the markups are ridiculous there.

please edit if this price discussion isn't allowed, but.... a single dose of MDA from Sigma-Aldrich would cost about $1000.  for a single dose.  lolol.


----------



## hjalmar

naughtynicknails said:


> You're not allowed to source or even discuss vendors on this site
> 
> You should delete the first part of your post.
> 
> Welcome to Bluelight



I thought that rule only applied to RC vendors, not the major players on the field who only deliver to legit companies after going through your life history.


----------



## Epsilon Alpha

hjalmar said:


> I thought that rule only applied to RC vendors, not the major players on the field who only deliver to legit companies after going through your life history.



Yep, these guys are ok to post!
Now where did I put my $500 kilo of NaCl from Sigma...


----------



## naughtynicknails

hjalmar said:


> I thought that rule only applied to RC vendors, not the major players on the field who only deliver to legit companies after going through your life history.



Aye I was unfamiliar with that site when i posted..

Ignore me


----------



## amanitadine

Continuing off topic, sigma, and later sigma Aldrich, as well as dudes like Acros, fisher, etc, used to be so much more accessible. Never an issue opening accounts in the early and  mid 90's. Always a good source (back then) for tryptamines, ketamine, and VERY occasionally phenethylamines, including some very rare psi 2-C's, which WERE outrageously priced. But yeah, reagents, glass, you name it, were easy as cake up until the late 90's. Oh my how things have changed.. . 


There has been considerable interest in etoxadrol amongst a few for a spell. I have yet to hear of any bonafide rogue trials. . . .


----------



## doppelgänger1

Is 4-fa metabolized in the same way and ratios as plain amphetamine, just without 4'-hydroxylation, which according to wikipedia is minor anyway?


----------



## hjalmar

Let's say someone got ahold of about a gram of racemic 1,2-diphenyl-1-dimethylaminoethane hydrochloride (of confirmed identity, no vendors of questionable morals involved). If I understand correctly from the sparse information I've seen, the dextro-isomer counteracts the opioid affinity of the levo-isomer (lefetamine) somewhat. The compound is supposed to be a stimulant and act at least partly as an NMDA antagonist (from which I suppose dissociative action?)

I'm a good chemist but not that well versed in pharmacology. What would be a reasonable dosage level to try this compound, and I find it hard to picture the kind of effect it would give?

Also, racemic 1,2-diphenyl-1-piperidinoethane can be obtained, but is there any information towards the active dosage, duration and what to expect of activity in humans? I'm afraid the only experience with a dissociative I've had was a single 600mg dose of DXM, which was a bit too potent and long-lasting to my taste?


----------



## sekio

Judging from the structure and related compounds (lefetamine), I suggest titrating up to 10-30mg slowly?


----------



## cannibalsnail

Standard safe procedure is:

~1mg on skin surface - wait 24 hours
~0.1mg orally - wait 24 hours
~0.1mg sublingualed - wait 24 hours
~0.5mg orally - wait 24 hours
~1mg orally - wait 24 hours

Then progress in 1mg increments orally or nasally every few hours until activity is reached.


----------



## iPandaN

*Lisdexamphetamine (Vyvanse) Metabolite Hydroxyamphetamine and Lower Dopamine Levels*

Not a Pharm major by any means, but pharmaceuticals is something that interests me greatly, I am currently an 11th grader, but plan to go onto pharmacy school. I do know quite a bit though. Anyways that's all the background info that's really necessary.

I read long ago about the metabolism of lisdexamphetamine (I take 60 mgs). It gets metabolized into D-Amphetamine in the body, and then roughly 95% of the D-Amphetamine is metabolized into phenylacetone, then to benzoic acid, and then finally hippuric acid. The other 5% gets converted into p-Hydroxyamphetamine,while although a minor metabolite, may have significant physiological effects as it is an analogue of norepinephrine. 

"Although p-hydroxyamphetamine is a minor metabolite (~5% of the dose), it may have significant physiological effects as a norepinephrine analogue"
From: http://en.wikipedia.org/wiki/Dextroamphetamine

Coming across this next bit of inforation made me start to do some digging.

Hydroxyamphetamine is known to bind to the TAAR-1 receptors in humans, and as I read here : "Activation of rat TAAR1 expressed in HEK293 cells assessed as accumulation of [3H]cAMP after 1 hr by competitive binding assay "

source: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=635290#aDescription

Does this have the same effect in humans with increased cAMP levels? I was wondering if this could be the cause of what i will later discuss.

I have read that increased cyclic adenosine monophosphate reduce your dopamine levels. "Another side-effect of high cAMP levels, is decreased dopamine activity and increased prolactin levels. "
source: http://voices.yahoo.com/negative-effects-high-cyclic-amp-levels-11299662.html

Although this is not the most scholarly of sources, I do believe that they wouldn't misrepresent conclusions of tests/experiments.

My step-brother is prescribed Vyvanse and Paroxetine, and I found out he was put on Paroxetine (SSRI) after being put onto Vyvanse. Paroxetine inhibits cytochrome P450 2D6 (CYP2D6), which does not allow any of the D-amphetamine to be metabolized into Hydroxyamphetamine. Could the Hydroxyamphetamine have caused (through increased cAMP levels) lower dopamine levels while there was still a buildup of cAMP before the effects of the Hydroxyamphetamine go away, and thus contributed to some depression-like symptoms? I do know that CNS stimulants/amphetamines usually cause higher dopamine levels (which are generally naturally lower in people with ADHD), but is the deficit caused by the hydroxyamphetamine enough to offset the gain in dopamine caused by Dextroamphetamine. Could this be a reason why he developed minor depression like symptoms or his already current symptoms (I don't know which was the case) worsened or did not improve after starting vyvanse? Or could this have been perscribed in response to anxiety onset by the Hydroxyamphetamine? Could Paroxetine then be considered as a booster such as Intuniv (guanfacine) to increase the duration of the drug and lower anxiety/other adverse affects? Any input would be greatly appreciated as I am very curious!


----------



## sekio

Hydroxyamphetamine does not cause "lower dopamine levels", you are reading much too far into this...

the effects of elevated cAMP are too broad... its one of the well studie intracellular messengers. i think only *chronically high* levels of camp cause dopamine downregulation. (not acute stimulant effects)

and you forget that amphetamine itself is a ligand for the TAAR.... really amphetamine has the same effects as hydroxy-amphetamine, it is just more polar and lacks the same degree of central effects as it cannot cross the blood brain barrier so effectively.


----------



## iPandaN

I figured as much, for a medicine that inefficient, wouldn't do much good. But sill on this topic, would this cause the vyvanse to last slightly longer, due to it having to all be metabolized one way, where the rate of metabolization would be slightly lower. Also do you anything about the facilitation of L-Lysine removal, by reflux in a very basic solution? Then one could neutralize the solution (say NaOH and HCl) and end up with salt, d-amp, and L-Lysine. Then one could boil off the water, then put


----------



## iPandaN

*edit*

I figured as much, for a medicine that inefficient, wouldn't do much good. But sill on this topic, would this cause the vyvanse to last slightly longer, due to it having to all be metabolized one way, where the rate of metabolization would be slightly lower?

       Also do you know anything about the facilitation of L-Lysine removal, by reflux in a very basic solution? I vaguely remember hearing something about it. Just thinking here, but if it's possible, then one could neutralize the solution (say NaOH and HCl) and end up with salt, d-amp, and L-Lysine. Then one could evaporate/ boil off the water, then put the dry contents in acetone and remove insolubles and repeat process. This would leave you with pure L-Lysine and Dextroamphetamine? Just curious for educational purposes, I've seen a lot of people discussing trypsin as a method. For one that could obtain such chemicals this would be a simple alternative.


----------



## cook

How would non-anxious person feel GABAa inverse agonist? Would it be identical to benzodiazepine withdrawal?


----------



## Jktm

Is it possible to estimate how long diphenhydramine inhibits the CYP2D6 liver enzyme? Just wondering because I'm really itching from some tramadol, but don't want to take it and miss out on my pain relief.


----------



## sekio

If you've already taken the Tramadol, taking diphenhydramine won't do anything w.r.t enzyme inhibition as the tram will be moving through your liver before the diph hits it.
Diphenhydramine is a relatively weak inhibitopr of cyp2d6 anyway, unless you are taking multi-hundred milligram doses  it should not be a concern.


----------



## pharmakos

^^ he was worried about whether or not his next dose of tramadol would still work.   jktm is recovering from a pretty bad accident.

that said, tramadol doesn't do jack for my pains =p


----------



## ungelesene_bettlek

*3D structure of LSD*

I just draw the four stereoisomers of LSD with MarvinSketch and used its "Clean 3D" option to get three-dimensional models. is this supposed to give realistic results? because if this is the case, I found something I cannot understand: when viewed edge-on, the (5R,8R)-isomer (i.e. good (+)-LSD) seems to be the most flat, while the (5S,8S)-isomer ((-)-LSD) is much more off the plane shape. but shouldn't the two be just mirror images of one another? and if so, shouldn't they be completely similar in flatness...?

btw, the (5S,8R)-isomer ((-)-iso-LSD) is pretty much as off-flat as the (5S,8S)-isomer, while the (5R,8S)-isomer ((+)-iso-LSD) is somewhere in between.

here are some pictures to make more clear what I mean; all of them are taken from the pyrrole side of the indole substructre:




(5R,8R)-LSD






(5S,8S)-LSD






(5S,8R)-LSD






(5R,8S)-LSD


----------



## sekio

MarvinSketch should have a MM2 look alike for generating optimised 3d models that are more or less the energy-minimised conformations. (how the molecules appear in nature)

The planarity of d-LSD is well known and is one of the reasons that it activates the 5-HT2a receptor so well.


----------



## skillet

You still have to be careful, it'll only find the local energy minimum. If you draw, say, a boat cyclohexane and minimise it, you'll get the optimum geometry for a boat cyclohexane (local minimum), not a chair cyclohexane (global minimum).


----------



## Ziiirp

*Dangers of Hydrolysis*

Hey there,

I am not sure, whether this is advanced enough, guess not. My question is, if a non-toxic substance can become a toxic one, if a hydrogen ion is added, or if it just degrades. Then I am confused by the term "degradation". Does it simply mean, the amount of untransformed molecules decreases (meaning the transformed ones are completely useless), or does it mean, that one molecule just is getting less potent in the pharmacological sense, when a hydrogen ion is added ?

Use case :

You have a stable, non-toxic hcl. Put it into Water, let it stand in the dark for 2 years and take it. Could it be dangerous ?

Thanks for the input !


----------



## Transform

It depends entirely on the properties of the individual molecule. To my knowledge, there are no common recreational drugs which become dangerous after being stored in water for a long time, only inactive.

Usually water molecules will "degrade" the compound one molecule at a time until there are no longer enough left to have any effect on the body.

Some molecules are unaffected by water, others will burst into flames when they get wet.


----------



## Epsilon Alpha

Ziiirp said:


> Hey there,
> 
> I am not sure, whether this is advanced enough, guess not. My question is, if a non-toxic substance can become a toxic one, if a hydrogen ion is added, or if it just degrades. Then I am confused by the term "degradation". Does it simply mean, the amount of untransformed molecules decreases (meaning the transformed ones are completely useless), or does it mean, that one molecule just is getting less potent in the pharmacological sense, when a hydrogen ion is added ?
> 
> Use case :
> 
> You have a stable, non-toxic hcl. Put it into Water, let it stand in the dark for 2 years and take it. Could it be dangerous ?
> 
> Thanks for the input !



Moved to the Big and Bangin' thread.

Its very hard to say based on the information that its a HCl salt only, the compound, type of water, type of container, storage environment, and How often it has been opened all play giant roles. Degredation generally refers to a irreversible reaction of the compound in question, adding hydrogen ions can do that depending on the compound in question though it often requires a certain pH to occur significantly.


----------



## sekio

Most drugs are stable in water almost indefinitely, it's things like high acidity (low pH), UV radiation, and dissolved oxygen/etc that are usually detrimental to the drug.
In those cases the drug molecule is usually transformed/rearranged to another molecule that does not share activity at the same binding sites.

Usually adding hydrogen ions to basic nitrogens is an easily reversible process that does not effect potency.


----------



## babylonboy

My main concern with water would be bacterial growth, good ol vodka treats you right.


----------



## laCster

*modafinil pharmocology*

can someone please explain what does 





> "_Modafinil's substantial, but incomplete, independence from both monoaminergic systems and those of the orexin peptides has proven baffling with respect to the better understood mechanisms of stimulants such as cocaine. Alternative mechanisms of action that have been proposed include the activation of glutamatergic circuits while inhibiting GABAergic neurotransmission.[17][18] Enhanced electrotonic coupling by enhancing the effectiveness of direct gap junctions between neurons has also been suggested by several studies. Most neurons are separated by synapses, and communication between cells is accomplished via release and diffusion of neurotransmitters. However, some neurons are directly connected to one another via gap junctions, and it is proposed that modafinil influences the effectiveness of these connections. Urbano et al. determined that modafinil increased activity via this mechanism in the thalamocortical loop, which is critical in organizing sensory input and modulating global brain activity.[19] Administration of the gap junction blocker mefloquine abolished this effect, providing good evidence that this result was a consequence of improved electrical coupling. Further research by the same group also noted the capacity of the calmodulin kinase II (CaMKII) inhibitor, KN-93, to abolish modafinil's enhancement of electrotonic coupling. They came to the conclusion that modafinil's effect is mediated, at least in part, by a CaMKII-dependent exocytosis of gap junctions between GABAergicinterneurons and possibly even glutamatergic pyramidal cells. Additionally, Garcia-Rill et al. discovered that modafinil has pro electrotonic effects on specific populations of neurons in two sites in the reticular activating system. These sites, the subcoeruleus nucleus and the pedunculopontine nucleus, are thought to enhance arousal via cholinergic inputs to the thalamus.[20]
> Looking more closely at electrotonic coupling, gap junctions permit the diffusion of current across linked cells and result in higher resistance to action potential induction since excitatory post-synaptic potentials must to diffuse across a greater membrane area. This means, however, that when action potentials do arise in coupled cell populations, the entire populations tend to fire in a synchronized manner.[21] Thus enhanced electrotonic coupling results in lower tonic activity of the coupled cells while increasing rhythmicity. Agreeing with data implicating catecholaminergic mechanisms, modafinil increases phasic activity in the locus coeruleus (the source for CNS norepinephrine) while reducing tonic activity with respect to interconnections with the prefrontal cortex.[22] This implies an increased signal-to-noise ratio in the circuits connecting the two regions. Greater neuronal coupling theoretically could enhance gamma band rhythmicity, a potential explanation for modafinil's nootropic effects.[23] Modafinil's beneficial effects on working memory and motor networks are suggestive of heightened gamma band activity.[23]_" mean??



i dont understand how modafinil works on the CNS, like increasing dopamine, but how does it do this? 

ALSO

because modafinil induces 3A4 enzymes, will it increase the amount of bup --> norbup?? please help me... 

some of you ADD'ers are really smart, and i'd like learn some of your knowledge 

mainly concerned with mondafinil + bup and how modafinil works, like will modafinil prove more effective than bupropion for depression/studying??

thanks


----------



## Jktm

would white grapefruit juice exacerbate apap toxicity? i was a bit recklesswith my vicodin dosing yesterday and drank wgfj with it. any constructive input is apprecited.


----------



## sekio

> i dont understand how modafinil works on the CNS, like increasing dopamine, but how does it do this?



To put it simply: we don't know. We do know that modafinil acts in multiple unique ways to promote wakefulness and alertness and is not e.g. just a dopamine reuptake inhibitor. 


> would white grapefruit juice exacerbate apap toxicity


It should not but if you are concerned at all about APAP toxicity go see a doctor.


----------



## SONN

so on a scale of 1/10 how bad is cocaine for you?? I'm talking less than a quarter of a gram. I know that mixing it with alcohol is incredibly toxic.


----------



## sekio

Mixing it with alcohol is actually not very much more toxic because cocaethylene is not formed in huge amounts. But there is an additive effect definitely

Pharmaceutical cocaine can be very taxing on the heart/cardiovascular system and is apparently much stronger than people consider it to be, with ~60mg being a balls to the wall overdose.

It is impossible to rate harm on a scale from 1 to 10 because most people will respond variably. But in the gransd scheme of things, there are better drugs to consume than cocaine. The short duration and fiendish nature can be a real problem for some.


----------



## babylonboy

Is this really an ADD question? Seems more like BDD. What does "on a scale of 1 to 10" mean? C'mon guy, try and be at least a little rigorous and academic in this forum.


----------



## ugly

Academic.

That's a good word

for this forum.

i
luv
it


----------



## SONN

yea I was just hoping for a rather simplified reason or mechanism of action that would sum up why it is bad for you. I know it has some toxic metabolites and it causes lots of dopamine to linger in the synapses. Where does the dopamine go from there though? is the 'clean up' of all the extra dopamine a very taxing and toxic process?

I understand it's bad because it's addicting that's kind of a no brainer..

but I know that MDMA has the totally neurotoxic metabolite caused by glutamate's reaction with alpha-methyl-dopamine (which I heard causes pretty brutal amounts of free radicals and can even cleave off cell dendrites), I was wondering if there is anything similar happening with cocaine.


----------



## sekio

The metabolites of cocaine are not toxic AFAIK. 

The excessive dopamine in the synapse is normally destroyed by MAOI or COMT. Normally DRIs do not cause direct cell damage, only mild oxidative stress. Cocaine is particularly bad because it is a potent vasoconstrictor (increasing blood pressure, reducing blood flow) & interferes with electrical conductuivity in the heart.


----------



## nuke

sekio said:


> Most drugs are stable in water almost indefinitely, it's things like high acidity (low pH), UV radiation, and dissolved oxygen/etc that are usually detrimental to the drug.
> In those cases the drug molecule is usually transformed/rearranged to another molecule that does not share activity at the same binding sites.
> 
> Usually adding hydrogen ions to basic nitrogens is an easily reversible process that does not effect potency.



True, but the hydrochloride salts of most compounds tend to be fairly acidic (hence why plugging salts/freebases in water isn't recommended -- primary and secondary amines are especially bad in my experience).  If the person bothers to make a pH 7 buffer and freezes the solution at -20C between uses, most compounds will stay active for a long time.


----------



## ebola?




----------



## sekio

I lol'd


----------



## Renz Envy

Interference with the conductivity of the heart is the #1 issue I have with cocaine. The sodium channel blocking properties make it so that overdoses are no joke. Anyone admitted to an ER for a stimulant overdose will be given more attention if it is cocaine related.

I find this bothersome as I have read "anti-drug" type journals in which relate amphetamines and cocaine as both being closely related as far as heart damage/risk goes.

Never understood why it can't be easily explained as: Amphetamines are bad news for the brain, Cocaine is bad news for the heart.


----------



## SONN

do you think there is anyway to preload on supplements to prevent the heart problems or keep your heart healthier? would any vasodilator work??

do you think Arginine and Lysine would help? do you think pot would increase or decrease heart related risks? or is there anything I could utilize to prevent some of the health risks? I preload a LOT when I'm gonna take MDMA and I have a feeling it's pretty effective in preventing some of the neurotoxicity, and I'd like to have a similar type of regimen with Cocaine.


----------



## 5HToInfinity

For cocaine i'd suggest Quercertin, Magnesium, Acetyl-L-Carnitine, Arginine, Lysine, Ubiquinol. Also Clonidine for comedowns.


----------



## sekio

> do you think there is anyway to preload on supplements to prevent the heart problems or keep your heart healthier?



no, not really (aside from limiting cocaine use). Cocaine actually intereferes with the circuit that 'keeps pace' in the heart due to its anesthetic effect - and common anesthetic cuts like procaine, lidocaine, benzocaine all enhance toxicity.

Trying to counteract cocaines vasoconstriction with lysine/arginine is a pipe dream. Good luck.


----------



## SONN

I haven't really felt any vasoconstriction from it like I sometimes do from psyches/stimulants yet.

I totally do limit my cocaine use, it's far too expensive and impure around here usually so i've only actually tried it on 4 occasions, two of which being tiny bumps given to me in live music settings. Each time it's seemed like a far superior stimulant than most others i've tried. I hate most of the popular ones personally so I was really banking on a way to make this at least FEEL like a safer/healthier experience, but i suppose it twas just a mere pipe dream


----------



## amanitadine

Look into _why_ the phenyltropanes were developed and you will have the vast majority of your answer. Aside from the obvious. Google, a miracle.


----------



## sekio

Unfortunately that god damn carbomethoxy group on the tropane has to ruin everyone's fun. (unless you want to use cocaine as a feedstock- your yields will blow dog dick) Hence the development of methylphenidate


----------



## Jktm

Does benzphetamine have any function itself or does it's mechanism of action rely solely on it's hepatic conversion to amp/m-amp?

Also, would one be able to provide an estimation of equivalent dosage to d-amp?


----------



## ebola?

I'd be surprised if the compound itself were active...that's a REALLY bulky substitution.

ebola


----------



## sekio

I would not be suprised if N-benzyl-methamphetamine had activity at someside receptors. But generally tertiary amine phenethylamines don't bind well to much!

If you had plain old N-benzylamphetamine (secondary amine) I bet it would bind to some of the targets NBOMes hit.


----------



## cook

I have a question about liquid measurement. Let's say I want to measure single micrograms of a substance, and the substance is in a solution. At what point am I going to get poor results even if I calculate&measure the volume  of liquid perfectly? I'm thinking there has to be a lower limit where there are too few molecules of a substance and randomness starts causing troubles. Is this true or are the molecules somehow evenly spread in a solution now matter how few of them?


----------



## Jabberwocky

I've been thinking of something lately and was hoping the talent around here could tell me if i'm barking up the wrong tree...

Two words: nicotinic antagonists.  A chemical that's capable of fully inhibiting the effects of cigarettes; *not* a replacement or maintenance-patch, but a full-on antagonist that'd make smoking cigarettes wholly unsatisfying (much like naloxone for opiates)

Is there anything that makes that impossible/impractical from a pharm/neurochem perspective?  I cannot say i'm too familiar w/ nicotinic receptors adn whatnot, so the idea may be flawed for obvious reasons that i'm just not seeing.
/otherwise, this one is one you, RC developers.  Think there's a market for cannabinoids and stims?  A pill that crushes cigarettes/nicorette/etc would be fire, and a true public service at that.


----------



## amanitadine

Buproprion is a nicotinic acetylcholine  receptor antagonist iIRC.

Chantix is a partial agonist. That may make you kill yourself. But hey, cigarettes will kill you too.

I quit a 20 year cig habit with a quality e-cig, without even trying. It's just a better vehicle for delivery of nicotine. Nicotine is a great drug. Cigarettes are not. For me, at least, not any more.


----------



## Jabberwocky

^yes it's the cholinergic aspect that i'm suspecting would make a naloxone-equivalent impractical... can you imagine the impact a full-blown antagonist could have??  FDA approval is major PITA, but through similar markets as RC's, with word of mouth of it actually making it pointless to smoke cigs, this could be a revolution lol.

and yes nicotine is a fantastic chemical, with cigarettes more than negating it :/  Nicotine's not only "enjoyable" but also helps cognition AND is a performance enhancer for endurnace activities!  I endorse it like i do caffeine, although tobacco/smoking as a delivery system is absurd and needs to end [says the kid languishing at a couple a day while on patches  ]


----------



## sekio

I think nicotinic ACh transmission is responsible for too much to be totally knocked down with an antagonist.

Notable nAChR antagonists in my head are e.g. DXM and ketamine. Not exactly fucntional drugs.\

(and I know people who quit smoking with Chantix rather successfully. The suicide risk thing I believe comes from discontinuing nicotine!)


----------



## 5HToInfinity

Whoa, wait, nicotinic antagonists? Wouldn't blocking nACh receptors result in muscle paralysis or something? After all, that's how Curare works..


----------



## sekio

Yeah, hence why nobody has made Narcan for Nicotine. Losing the ability to breathe of your own volition is certainly one way to stop smoking.


----------



## Jabberwocky

^sadly, i was expecting something along those lines.  
/thanks, i guess.


----------



## Transform

Cook: In a 1ug/ml solution of 25I, for example, there are 2.571821e+19 molecules per ml. It's not an issue on any scale that we will ever be using.


----------



## cook

Transform said:


> Cook: In a 1ug/ml solution of 25I, for example, there are 2.571821e+19 molecules per ml. It's not an issue on any scale that we will ever be using.



Ok thanks for that, so it seems that any known psychoactive substance can be reliable dosed this way if the calculations and measurements are correct.


----------



## Incunabula

Can some one explain to me, in very few words, what a ligand is? And yes, I did read the wikipedia page, but it's too advanced.


----------



## Transform

In this context it is a molecule which binds to a receptor and in doing so causes a pharmacological response.


----------



## pharmakos

ligands can be broken down into agonists or antagonists.  possibly several other things, but i can't think of them at the moment.


----------



## cannibalsnail

A ligand in pharmacology terms is a molecule that binds to a protein. The 3 types of ligands are:

Agonists: activate the proteins function.

Antagonists: blocks the protein function.

Allosteric modulators: Alter the function of the protein by binding somewhere other than the active site.

There are multiple subtypes of each of these but thats the basics of what a ligand is.


----------



## Jktm

I have a question or two about exceeding max solubility of a drug in a syringe.

For example, if one were to make a super saturated solution of aqueous morphine sulfate by mixing 200mg morphine so4 into .9ml  of water and sucked it up into a 1cc syringe, would all or most of the precipitated out morphine make it into the bloodstream upon pushing down the plunger, or would the crystalline precipitant simply stay in the syringe? I know upon registering, this would introduce blood into the syringe and allow more of the morphine to dissolve, but I'm not sure of the solubility of morphine in blood, and surely the 140+mg of undissolved morphine wouldn't dissolve into the new water/blood solution.

Another question I have regarding this is, would the precipitant morphine still "work" upon entering the bloodstream, and also, would giving the super-saturated mixture a good shake before registering and plunging help to allow more of the precipitant to enter the blood or would it still pool near the bottom of the syringe/in the needle and possibly clog it?

If anyone could shed some light on this for me it would be greatly appreciated.


----------



## sekio

> would all or most of the precipitated out morphine make it into the bloodstream upon pushing down the plunger



yes, it will be a suspension of solid in water. the excess blood volume will dissole the morphine solid (in theory). of course the crystalline matter may clog the needle or do otherwise untoward things, which is why suspensions are not injected...

just get a bigger syringe


----------



## Jktm

would the crystalline matter still work if it made it into the bloodstream?

also, if the needle is large enough (27g) is it possible that it wouldn't get clogged?

one other question, if the crystalline matter did make it into the bloodstream, would it do any damage as it's not in an aqueous solution?


----------



## Jabberwocky

the majority of it would be active yes (think of the most crude-approach: rubbing crushed pills into a gaping wound.  blood is a liquid and more than capable of getting water-soluble compounds from a solid)
(edit: unsure if 'majority', or 'same as if it were fully dissolved'; i'm not seeing the "point of loss", once in the blood there shouldn't be any reason it all dissolves)

re the needle it's possible, it's just a function of particle size, needle gauge, etc etc.

i can imagine there's some potential concerns if it's undissolved (ie, if it needs to become aqueous in the blood(from solid-susp. in your rig), how would you know it was fully-dissolved in blood b4 it was being pumped through your heart?  blood is very thick, and you use filters because you certainly don't want solids getting into your bloodstream and being pumped around.  If you're depending upon the blood to dissolve a suspended solid, that's obviously very very risky ansd foolish)

mainlining is fun, in large part, because it allows efficiency achieved by removing your body's natural filters.  you're talking about approaches where you're removing the accepted standards/safeties of safe-IV'ing.  i hope these q's are more theoretical for you, surely you see how dumb it is to play around w/ compounds directly into blood/body w/ liver and other organs processing 1st; removing safeties like filtration or suitable fluid volume (and leaving product undissolved) is foolish at best.


----------



## SONN

Does anyone know anything about 4-acetoxy-tryptamine? has this ever even been made? what about 5-methoxy-tryptamine? Does the book version of tihkal differ a lot from the erowid online resource one? I'd really like to read more about the effects of tryptamines that aren't dialkylated, and tryptamines with an acetoxy group.


----------



## pharmakos

http://en.wikipedia.org/wiki/5-Methoxytryptamine


----------



## SONN

^ you obviously have very little faith in me if you think I didn't first at least check wikipedia. I was wondering more about the subjective effects of tryptamines that are inactive orally and already are produced by the body, and if 4-aco-tryptamine (acetoxamine?) is something that can actually exist.


----------



## sekio

> if 4-aco-tryptamine (acetoxamine?) is something that can actually exist.



yes. naturally produced? probably not

I think shulgin pretty much established that anything less than a N,N dialkylated tryptamine is basically no fun, maybe N-mono-alkyl substituents would work if they are real bulky - like tert butyl maybe.


----------



## pharmakos

SONN said:


> ^ you obviously have very little faith in me if you think I didn't first at least check wikipedia.



you asked if it had ever been made *shrugs*


----------



## The Plague

*General Chemistry Discussion*

Hey there, I'm looking for some information on predicting receptor binding based on the chemical structure of the molecule.

First of all, is this discussion allowed on Bluelight?
Second, where is the appropriate forum for it?

I've seen a lot of posts talking about the binding affinities of certain chemicals and they said that particular moieties would facilitate binding at certain receptors.
What theory is this based on? Is there a general guideline or is it basically instinct, acquired by working in or studying organic chemistry?


----------



## sekio

> I've seen a lot of posts talking about the binding affinities of certain chemicals and they said that particular moieties would facilitate binding at certain receptors.
> What theory is this based on?



Best guesses and logical inferences, usually.


----------



## endotropic

This is called a structure activity relationship (SAR) analysis.  Unless this is your profession, the best way to go about this is to find all (or a good proportion) of the compounds that bind at a certain receptor, "line them up" in some logical way so that common elements overlap, then compare the differences in structure and look for things like, an acetyl group at the 4 position always made the compound more potent than similar structure with a methyl at that position.  

There are whole books filled with theories on how to do this more accurately, but in practice it's never perfect and there will always be surprises.


----------



## cannibalsnail

The more I learn about SAR, the more I realise its complete luck. N-Ethyl-Norketamine should have been more potent and longer than Ketamine but otherwise identical. Instead it was shorter, weaker and caused significantly greater nasal damage.


----------



## Limpet_Chicken

Of course, product quality of vendor wares can vary wildly. Was this a verified, and cleaned up sample of N-ethyl-norketamine?


----------



## Incunabula

Limpet_Chicken said:


> Of course, product quality of vendor wares can vary wildly. Was this a verified, and cleaned up sample of N-ethyl-norketamine?


I'm absolutely sure that at least one vendor carries the real deal.

I don't understand why there hasn't been more talk of isomers in regards to  NENK. I think that pure pharm-grade ketamine varies a lot, and I thought that it was generally agreed that this was due to different ratios of the 2 isomers..........


----------



## cannibalsnail

Racemic ketamine is still active and doesn't burn anywhere near as much nasally.


----------



## sekio

> I thought that it was generally agreed that this was due to different ratios of the 2 isomers..........



Probably not, as synthesis does not make "unbalanced mixtures". If you make ketamine, you make 50/50 R/S, or S-only. 
Either way it is easy to tell the isomeric purity of your K (or any drug) by using a polarimeter.


----------



## Solipsis

Exactly, synthesis is balanced - when S-only is made there is R-only as waste, which is not dumped. It merely follows black-market paths, together with illegally siphoned off ketamine of other forms. The demand for R is just much more unstable and lower.

The reason we are talking about ketamine is that it is special since both isomers have activity although different activity. With most other drugs there is only one active form, or there is only one form where the activity is beneficial. With amphetamine for example, the dextro form feels more cleanly mental while the levo isomer is more physical and disregarded in psychiatry. In rare cases there is one active isomer of a drug while the other is toxic in a sense e.g. thalidomide.

Isomers have different symmetric orientation which is important for the way the compound fits into receptors like a key into a lock.


----------



## sekio

> when S-only is made there is R-only as waste



Only if you're making esketamine from racemic by e.g. crystallisation or chiral chromatography. With e.g. chiral ligands it would be in theory possible to make 100% esketamine if done correctly.

I would assume in an industrial setting the arketamine that is "waste" is simply oxidatively deaminated and reaminated, a la amphetamine, so you convert the 100% R isomer to a mix of 50/50 R/S and seperate again, and again etc. 

I also know that in the flavour and fragrance industry as well as medicine, chirality is important, and people will get up in your shit if you suddenly start changing the enatiomeric blend. I have a hard time believing that commercial ketamine for anethesia is as wildly variable as some people claim. It is really not that difficult to do your own testing to see if the K is racemic or not. You need a tube for the sample, a ruler, a protractor (angle measuring thing), a (preferably low pressure sodium) lightbulb, and 2 polarisers. Dissolve some K in water, record concentration, put it in the tube & measure the path length of light through the sample. Line up the two polarisers so they are transparent (not opaque) and mark them along the edge at the same spot. Now fix one polariser to the front of the tube, ont to the back. Shine light through the back and view it from the front. Rotate the front polariser til you find the point where the light is brightest. Measure the angle between the marks on the 2 polarisers. Then work out the specific rotation [alpha] by dividing the measured angle by the [path length in decimeters, times the sample concentration (or density)]. If [alpha] = 0, you have racemic ketamine, if it is negative it is esketamine and should always be a certain value. Look it up in the Merck index.


----------



## Solipsis

You may be right but apparently there is enough money to be made to extend corruption so far that R-ketamine is still made by labs in the India-Pakistan region and I'm not sure what people get up in whose shit at that point. I *used to* know importers of the stuff and found the isomers to be different enough not to need analysis and furthermore reconfirmed it all later with other batches. Results were consistent for me, not the inconsistence you get after you ask random people about their subjective experience with vials of different brands. That is liquid, I was talking crystal.

Although the last I heard before I broke off with those people was that R was getting increasingly difficult to get. In fact I was traded for some of my =< 1g sample of R to remind a guy what it was like.
Sorry if that talk isn't all that scientific.

I'm antsy for more chem discussion.


----------



## issokay

*Is Chantix an opiate antagonist?*

I have a prescription for hydrocodone 10/325 and I just started taking Chantix. The Hydrocodone (Norco) no longer seems to be working. I would like to know if Chantix is, in fact an opiate antagonist, & how long after I stop taking Chantix will the opiate antagonist effect go away?
Thanks,
—Issokay


----------



## Incunabula

sekio said:


> Probably not, as synthesis does not make "unbalanced mixtures". If you make ketamine, you make 50/50 R/S, or S-only.
> Either way it is easy to tell the isomeric purity of your K (or any drug) by using a polarimeter.


So much for that theory then, it could have explained why Adder, and freinds, experiences with NENK was so different from others, and why SAR was so off...... 

I still don't get why changing the n-methyl to n-ethyl gives such a crappy version of K.


----------



## amanitadine

Yes, SAR is an educated guess. Much better with modeling than in shulgins days, but still a guess. And adders document is fiction.

Parke Davis chose n-methyl for a reason. There was a guy at the hive with a bunch of the old documents, most just documenting chemical characteristics, but some with animal study info. Those fuckers ran through hundreds if not thousands of variations of the arylcyclohexylamine skeleton. My how I wish I could find him now. That was fascinating stuff, and back when other skeletons held my attention more, and I was still working.

Last I checked there was one commercial producer of pharmaceutical (in vials) of S-ketamine. And they charge royally for it, due to the extra work involved. And like Sekio said, the R is likely deaminated/aminated/ separated ad infinitum. I have never bought into the hullabaloo of vials with varying ratios of S-R.  I don't know why pharmaceutical preparations of ketamine in vials vary like they do. I've tried literally dozens and dozens of preparations of such around the world, and  some do seem quite different, maybe eye of beholder, maybe shit quality control, and maybe adulterants like xylazine, etc. Who knows. But I doubt it is the ratio of isomers, just doesn't make sense for several reasons. Powder ketamine, all bets are off.

First time I tried S-ketamine I ordered it from SA or Acros, and the had a bright red "NEW!" star next to it. Hahaha. Never tried R- ketamine.

Okay, way off topic 

Oh and yes chirality in perfumery is fascinating stuff. . .


----------



## sekio

> There was a guy at the hive with a bunch of the old documents, most just documenting chemical characteristics, but some with animal study info.



Shit, I'd pay money to get my hands on that

Given the total lack of anyone actually doing analysis beyond bioassay I still doubt that most of what is sold as NENK/2-MeO-K is probably not as advertised. I would love to be proven wrong though, just not by someone insistig their source is "reliable".


----------



## sekio

Chantix is not an opioid antagonist, it is a nicotinic acetylcholine partial agonist.


----------



## issokay

Well I called a pharmacist earlier and they said the same thing. It is the only factor that has changed since my meds haven't been working at all.


----------



## specialrelativity

*stick*.


----------



## Limpet_Chicken

Your saying Adder made those TRs all up?


----------



## amanitadine

That's what I'm saying. And others, working in this field, have agreed. It's all SAR prediction, all the expected analogs are covered,  ( and shit like BTCP and bromado?! come on) and some of this is some pretty difficult chemistry. The details are ambiguous, and sound like educated guesses, and the several of the reports are in total contrast to actual tests with these compounds. His report came at the beginning of the ACH hype, was later edited to include some additional compounds after MXE went big time, and he claims to have worked with fentanyl analogues, etc. It doesn't add up. Basic chem knowledge plus some basic SAR guesses, and an obvious study of beagles work have led several to conclude this work is fiction. Plus, the guy is like 21 and was claiming to do this shit as teenager. Not buying it, for a million reasons. Interesting read at the time, until reading between the lines made it obvious it was a fake.


----------



## Incunabula

sekio said:


> Given the total lack of anyone actually doing analysis beyond bioassay I still doubt that most of what is sold as NENK/2-MeO-K is probably not as advertised. I would love to be proven wrong though, just not by someone insistig their source is "reliable".



Posted by Transform in the NENK big and dandy http://i.imgur.com/qKYQZ.png

I agree that the RC scene is sordid, but there's a few good vendors out there. Some of them even care about the products they sell, and have independent testing done.


----------



## RenaeMathers

There are free online databases with lists of binding affinities for certain compounds. I'm not sure if they'll help, but I'm researching a similar thing at the moment and I have them bookmarked in case they come in handy later.
PDSP K1 Database - Drug affinities
Binding DB - Binding affinities


----------



## pharmakos

why does my Captain Morgan turn slushy in the freezer while other similarly concentrated liquors remain liquid?

either the spice/sugar content changes its freezing point in some way, or its not as strong as the manufacturer claims.


----------



## sekio

How cold is your freezer? And is this 80 or 151 proof?

Maybe you are fractionally crystallizing the water out(!).


----------



## pharmakos

this is the 70 proof captain morgan

i cbf to do a proper reading on the temperature of the freezer, but i cranked the freezer dial down (or up who knows with freezers) a couple months ago and the same thing is happening.


----------



## sekio

Well, 70 proof is only ~35% ethanol.
Still your freezer would have to be negative 25 C to freeze it solid... [ref]

Lucky for you thermodynamics says that you can partially freeze a solution to do a freeze distillation, or fractional crystallisation (good for defatting soup). You're probably just making a Slushie-type mix of ice suspended in higher-proof alcohol.


----------



## pharmakos

there's two types of captain morgan in my freezer... traditional caramel-colored captain morgan, and captain morgan "silver".  the caramel colored stuff gets quite a bit slushier than the silver, but the silver does display a bit of crystallization.

as of yet i haven't had a sample that remained controlled for a long enough period to determine whether or not volume changes over time due to strictly environmental factors.


----------



## Genetic Freak

Solipsis said:


> Exactly, synthesis is balanced - when S-only is made there is R-only as waste, which is not dumped. It merely follows black-market paths, together with illegally siphoned off ketamine of other forms. The demand for R is just much more unstable and lower.
> 
> The reason we are talking about ketamine is that it is special since both isomers have activity although different activity. With most other drugs there is only one active form, or there is only one form where the activity is beneficial. With amphetamine for example, the dextro form feels more cleanly mental while the levo isomer is more physical and disregarded in psychiatry. In rare cases there is one active isomer of a drug while the other is toxic in a sense e.g. thalidomide.
> 
> Isomers have different symmetric orientation which is important for the way the compound fits into receptors like a key into a lock.




I wondered do isomeric values apply to the production of synthetic testosterone..? 

I had read somewhere there will be a D and an L form - mirror images of each other. Which I believe only one of the forms will work in the human body (the D if I remember correctly).

If I understand correctly it depends how the testosterone is synthetically produced. Usually Cholesterol is used as the raw material. It's extracted from plants and purified, and then treated with chemical reactions in a series of steps to produce testosterone (and other hormones).

Only one form of Cholesterol is found in nature, so whichever enantiomer is in nature, will be the starting point for the synthetic production of testosterone. 

Can anyone confirm this...

Cheers in advance...


----------



## sekio

Testosterone has 6 chiral centres, so there are in theory 64 possible isomers.

Realistically, only the one isomer of testosterone is biologically active I think, and that's the one derived from cholesterol.
(In your body, testosterone is derived from cholsetrol by enzymes.)

Many drugs have specific chirality or are specifically racemic... for instance, if you buy citalopram it will NEVER be 75% R-citalopram and 25% S-citalopram, always 50/50, unless explicitly compounded by a pharmacy that way.

Some natural drugs like e.g. morphine are also :always" one isomer. Nobody ever sees the "unnatural" enantiomer of morphine in prescribing usage.


----------



## Genetic Freak

sekio said:


> Testosterone has 6 chiral centres, so there are in theory 64 possible isomers.
> 
> *Realistically, only the one isomer of testosterone is biologically active I think, and that's the one derived from cholesterol*.
> (In your body, testosterone is derived from cholesterol by enzymes.)
> 
> Many drugs have specific chirality or are specifically racemic... for instance, if you buy citalopram it will NEVER be 75% R-citalopram and 25% S-citalopram, always 50/50, unless explicitly compounded by a pharmacy that way.
> 
> Some natural drugs like e.g. morphine are also :always" one isomer. Nobody ever sees the "unnatural" enantiomer of morphine in prescribing usage.



Can I conclude the end product of synthetically produced testosterone would only contain the one biologically active isomer....


----------



## sekio

Yes, I don't think that people would waste their time making the "inactive" isomer.


----------



## DroneLore

*Where does the water go after IVing?*

Ideally the compound of choice passes the blood brain barrier, but where does the water go? Jerry Stahl writes of having swollen limbs due to excess fluid from shooting dope. Can this really happen?


----------



## sekio

The water goes into your bloodstream, almost as if you'd drank it.

You would have to inject a *lot* of fluid to get swollen limbs, as water is removed from your circulation via the kidneys into the urine almost continouously. More likely swelling is from severe histamine release (from acute administration of opioids) or blockage of small veins/arteries by particulate matter, or it may just be that his kidneys were fucked to the point where he retained fluids.


----------



## Ligaturd

I have had saline drips at the hospital, constant drips for days at a time and my body gets rid of it normally. (distributes it where needed and the excess gets processed through the kidneys/bladder)


----------



## AlphaMethylPhenyl

same here


----------



## Epsilon Alpha

IV'ing doesn't get past the blood brain barrier, it gets past first pass metabolism however.
Merging with big and dandy thread.


----------



## SONN

I have a rather complicated series of questions.

So, I'm pretty sure a ligand's primary effects are determined by the weight and shape of the molecule fitting into the receptor (correct me if I'm wrong at any point in this por favor)

But what about the actual metabolism of the ligand? My (limited) understanding is that after it's rocked your brain for whatever period of time it obviously goes through some sort of chemical reaction and you end up peeing/pooping out all of the metabolites, except for when some of the ligand remains unchanged after traveling all the way back through your body/digestive tract-- is this the case or did the unchanged ligand not make it to your brain, meaning it ultimately didn't get you high?

I recently watched a video where shulgin talked about how DOB is metabolized and that after first pass metabolism it goes to the lungs for a period of time, THEN the brain. I am under the impression that there are a LOT of enzymes in your lungs that can potentially move around methyl groups and do all sorts of crazy stuff like that, is this true? AND is this because lots of ligands have parts that are oxidized/hydrolyzed off by enzymes in the lungs?

and do you think this has anything to do with the bronchodilating effects of some phenethylamine compounds?

I'm under the impression that the main reason MDA is more neurotoxic than MDMA is because MDA is easier metabolized into Alpha-methyl-dopamine because the N-methyl group doesn't need to be metabolized off. Does this mean that almost any amphetamine can metabolize into alpha-methyl-dopamine? and would that mean that normal alpha-methyl-phenethylamine is probably one of the worst because it's just one chemical reaction away?

even more questions... according to the history section of this wikipedia article there are proteolytic bacteria in the large bowel producing phenols, indoles, and ammonia which to my knowledge are very related to phenethylamine and tryptamine. Shulgin experimented in vitro with myristicin and ammonia and discovered that MDA could be synthesized in vitro by a culture of lamb's bowel cells IIRC. Seeing that there are soooo many strains of different bacteria (good and bad) possibly metabolizing things in slightly different ways is there a possibility that by ingesting these novel compounds with all these bulky/irregular substitutions that there are metabolites going through the bowels causing the synthesis of other compounds that we don't know about? and would these compounds be active or would they just be on their way out of the body meaning it doesn't matter anyways?

Obviously I could be wayy wayy off so I thought I'd come here for answers to all these elaborate questions.

I'm also very tired so i'll check back in the morning to see if any part of this post just doesn't make sense.


----------



## sekio

Most ligands are eventually metabolised, but usually to less active compounds. In this day and age we can do wonderful things like get mass spectra of metabolites from blood.
Generally psychoactive amphetamine/tryptamine type drugs are active and their metabolites are not.


----------



## SONN

so the likelihood of ammonia adding a really active methyl group onto the end of a metabolite is either very unlikely or entirely unknown?


----------



## sekio

> reason MDA is more neurotoxic than MDMA is because MDA is easier metabolized into Alpha-methyl-dopamine


Not sure about that. MDA is also more potent than MDMA as a monoamine transporter ligand. (more efficacious releaster of monoamines)



> Does this mean that almost any amphetamine can metabolize into alpha-methyl-dopamine? and would that mean that normal alpha-methyl-phenethylamine is probably one of the worst because it's just one chemical reaction away?


No, and no. Well, okay, the cheater answer is 'yes, if you find the right combination of enzymes'. Fortunately for us humans, only a small portion amphetamine is only converted to 4-hydroxyamphetamine, and there it stops. There are no common enzymes that add a pair of hydroxyl groups onto an aromatic ring at once, it is almost always done stepwise. In the synthesis of dopamine, phenylalanine is converted to tyrosine and finally then to L-DOPA by two seperate enzymes. (The latter enzyme does not work well on amphetamines, nor phenethylamine... only amino acids I believe)



> so the likelihood of ammonia adding a really active methyl group onto the end of a metabolite is either very unlikely



Ammonia can't add any methyl groups anywhere. It is nitrogen and hydrogen, a methyl group is carbon and hydrogen.

If you are talking about the metabolism of compounds like safrole and myrsticin to MDA/TMA, it has never been observed to any significant extent in man. Sure lamb bowel cells might do it but it's not going to be any more than a trace...


----------



## SONN

^lol yea I assumed I was wayyy off with at least one aspect of that. I've heard that Amphetamine is neurotoxic while Ritalin is not, could you elaborate on this a little for me?


----------



## illustrious junk

Hey peeps, first time poster here. Here's a question that's been bothering me:

Is there a correlation between how painful a substance is to snort, and how corrosive/damaging it is to the lining of the nose? I was sniffing ethylphenidate all day yesterday and, as anyone who's tried it will attest, it stings like a mother (worse than meth even) and feels corrosive as f*ck - is it reasonable to assume that a given amount of ethylphen or meth will do more damage to the septum than the same amount of a drug that hardly stings at all, like ketamine or mdpv?

Or am I being oversimplistic? Any thoughts appreciated. 

muchas gracias!


----------



## sekio

Generally pain is indicative of damage, but not always directly correlated.


----------



## illustrious junk

Cheers sekio! Pretty much what I suspected.


----------



## AlphaMethylPhenyl

whats a catchetolamine?


----------



## sekio

Cachetol, aka pyrocachetol = 1,2 dihydroxy benzene.

So a cachetolamine is a 3,4-dihydroxy-phenethylamine. Dopamine and norepinephrine are the two Big Names.


----------



## doppelgänger1

How comes the 2c-x and especially nbomes can bind to the 5-HT receptor?


----------



## sekio

> How comes the 2c-x and especially nbomes can bind to the 5-HT receptor?



Because they interact with the protien in the right way, similar to 5HT. I believe they do bind to the same site that 5ht does.
It just so happens that the non-intelligently-designed receptors in your brain are more permissive than you'd expect.


----------



## ugly

I haven't been able to get a reasonable answer to this question. I searched, but either I didn't find answers for some reason, or maybe it's common knowledge for most people. (Mods if this question is off topic, out of place, or dumb, do as you will.)

Do amphetamines cause menstrual flooding and the passing of enormous blood clots that could almost be mistaken for a liver or something?


----------



## pharmakos

ugly said:


> Do amphetamines cause menstrual flooding and the passing of enormous blood clots that could almost be mistaken for a liver or something?



that doesn't sound normal at all.  i'd probably talk to a doctor if i were you if you think there is a problem.  if you think the amphetamines are responsible then you probably should seriously consider quitting them.


----------



## ugly

I have experienced this on occasion but one of my friends (who, in my opinion, would use the stuff 24/7 if she could) has had symptoms like I described.

Well,  lately she's got a sweet sugar daddy and I am pretty sure she's using a scary amount of speed. She says most women clot on speed and she doesn't see it as an issue. 

I don't know where she "learned" that a nonstop issue of blood is a normal side effect. She's convinced all females have that response to the drug. I don't agree with her and I don't have any solid documentation to try to show her that it is NOT normal for blood clots big as man hole covers to drop out of her body.

I'm hoping to find an article or something that I could use to have a discussion with her about this. A basically unlimited amount of spendable dollars she has access to might be killing her. I really don't know, though. I saw her yesterday after about three months of not seeing her. She's looking unhealthy. Really unhealthy. One of her eyeballs has become just a red orb in her eye socket. She's lost a lot of weight, which she's never done before and she's used ever since we became friends 5 or 6 years ago. Her hair seems to be thinning also, in my estimation.

But blood clots that are so big she risks blocking up her toilet when she flushes??? Why would she think that's just part of the side effects??


----------



## DeLee

*Drug Half-life and Drugs detection time ?*

So hello folks,
Im a little unwitting about this half-life calculation on drugs detection in urine. Would like to know for real.
Lets take one example with *Phenergan(Promethzine)* a antihistamine. 
It has a half-life of 16-19 hours(wiki)
So it will go something like this
1 dose of Phenergan 25mg eaten, 
19h later you have *12,5mg*
And then it goes:
(19h) 6,25
(19h) 3,125
(19h) 1,5625
(19h) 0,78125
(19h) 0,390625

How many "cycles" does it takes for a drug to be undetectable on a drugscreening analysis methadon?

Thanks!


----------



## Transform

> But blood clots that are so big she risks blocking up her toilet when she flushes??? Why would she think that's just part of the side effects??



That sounds like it might be unrelated to the speed and whether it is or not, it's worthy of seeing a doctor ASAP


----------



## Crashing

It doesn't work like that because you have left body metabolism out of the equation completely. THC has a half life of 20 hours yet it is detectable up to 30 days after cessation. I don't think this calculation is possible.


----------



## Epsilon Alpha

Merging this with the big and dandy thread. 
Well DeLee is correct that half life is directly related to detectable limits (not going into drug testing specifics), however some drugs can be detected by metabolites or are stored in various tissues/hair. For example THC's ridiculously long half-life metabolite is what's tested for rather than THC itself. Detectable limits are the level at which the concentration of a drug in the body is below threshold X for a test.

Some drugs are even crazier with those half lifes, for example fluoxetine (Prozac) has a metabolite with a half life of ~31 days! Now that's pretty nuts. The only thing I know of with a longer half life is cadmium with a half life of ~20-30 years after the body has sequestered it.


----------



## The Plague

I was wondering if it's possible in general to cleave a molecule at an amide bond, for example:


*2-(2,6-dichloroanilino)phenol*





Into:

*1,3-dichlorobenzene *and *phenol*


----------



## sekio

Nope, not easily.

Usually atoms don't just disappear when compounds split. A more likely pattern would be metabolism to 2,6-dichloro-aniline, and 1,2-dihydroxy-benzene.


----------



## Transform

Also worth noting that that bond is an amine linkage, not an amide.

Amides can be _hydrolysed_ with water, heat and a weak acid.


----------



## teological

*Anaphylaxsis and Morphine*

Hey, I hope this is the right place to post. Now say someone is on a dose of opiates (a high recreational dose) and happens to eat something he or she is allergic to and receives a full allergic anaphylaxsis shock that only the epipen (nor-adrenaline) can fix. Will the morphine prevent the epipen from working?

Thanks, this info is very important.


----------



## blazR

Sorry, I can't answer your question.. I don't thin opioids will block (nor)adrenaline though.

BTW, isn't it adrenaline in an epipen? I imagine "epi" standing for epinephrine(andrenaline)


----------



## Epsilon Alpha

You might be best asking a pharmacist, just say you have a relative coming over after surgery with severe allergies of you get any questions.


----------



## sekio

Morphine should not stop epinephrine from working, but do realise that epinephrine is only a stopgap until you can have the anaphylaxis treated properly with e.g. corticosteroids. (Epi has a very short half life)

And yes, epinephrine is the same thing as adrenaline, and is found in Epi-Pens.


----------



## c0rt3x

Has anyone experience with extracting and isolating pure nicotine from natural tobacco?
I tried once to extract it by cooking the leafs, filtering the boiled down next to black "soup" and drying it.
But usual tobacco does not only contain nicotine but many more other alkaloids which are seemingly causing much more undesirable side effects than nicotine itself does. I know this since the isolated nicotine containing fluid for electronic cigarettes for example is much better tolerable compared to inhaling vaporized (or smoked of course) tobacco...

Actually pharmaceutical grade pure nicotine(-HCl?) is rather cheap, but all the local pharmacy stores in my area are simply to scared of it to sell it - although it was absolutely legal in my country even without any kind of prescription.

I need it pure, since I wanna make a potent and tobacco free "white" alternative for "brown" powdered tobacco leaf snuff alternative - without all those unwanted other alkaloids and especially without all that other leaf-powder that can nastily mess up your nose after a while of intense nasal tobacco consume...

Sniffing tobacco can be nearly as addicting as smoking. (if not even more, since getting cancer from it is quite unlikely compared to inhaling all those smoke toxins...) Last but not least it is much more enjoyable to me - anywhere!


----------



## Transform

Actually snuff is usually smoke treated so it still contains the carcinogenic nitrosamines. The "unwanted other alkaloids" include cabolines which have an MAOI effect which is thought to greatly contribute to the addiction potential of tobacco and some of the enjoyment too. Nicotine is regulated as a poison in most countries rather than an illegal drug.


----------



## sekio

Schema for formation of the mystery compound. The URB ring opens up to a diphenyl urea type thing and a carboxylate group, the carboxylate forms an amide I guess?








> URB754 was originally reported to be a potent, noncompetitive inhibitor of monoacylglycerol lipase.[1] However, recent studies have shown that URB754 failed to inhibit recombinant MGL, and brain FAAH activity was also resistant to URB754.[2] In a later study by Piomelli at al showed that the MGL-inhibitory activity attributed to URB754 is in fact due to a chemical impurity present in the commercial sample, identified as bis(methylthio)mercurane.



So the only reason there was any activity anyway, was organomercury contamination. I don't know why there is even methylthio mercury.

(Mercurane is the IUPAC systemic name for a compound of mercury and hydrogen. A google search misled me to think it's 1-mercurocyclohexane (pyran with oxygen replaced with mercury) but it is likely not)

This is plenty more evidence that nobody should touch "legal highs"... there really could be anything as an active ingredient unil there is independent confirmation.


----------



## Epsilon Alpha

^another case of heavy metals in a URB compound... I wonder if any cadmium was present?


----------



## pharmakos

sekio said:


> So the only reason there was any activity anyway, was organomercury contamination.



fucking lol


----------



## Dresden

How do you post pictures of chemical structures?


----------



## sekio

i draw them in chemdraw, and save them as png


----------



## Mandark

It's not about any particular drug, so I hope I'm not asking in a wrong place.

For the activation of NMDA receptor by glutamate, co-stimulation by glycine or D-serine is required. Are co-ligands also required for exogenous agonists to exert their action (they should either bind to the glutamate site or glycine site and require co-stimulation in the other site... or not?)?


----------



## endotropic

Mandark said:


> It's not about any particular drug, so I hope I'm not asking in a wrong place.
> 
> For the activation of NMDA receptor by glutamate, co-stimulation by glycine or D-serine is required. Are co-ligands also required for exogenous agonists to exert their action (they should either bind to the glutamate site or glycine site and require co-stimulation in the other site... or not?)?



I can't think of any exogenous NMDA receptor agonists off the top of my head, are you thinking of one in particular?

Most recreational drugs that act at NMDA are antagonists (ketamine, MXE, DXM, etc.) and don't require co-ligands to block receptor activation.


----------



## sekio

*NSFW*: 










Agonists at the glycine/kainate site do require a co-agonist to achieve receptor activation. There do exist synthetic exogenous NMDA agonists, e.g. NMDA itself (I think it's exogenous), tetrazolylglycine, some aminophosphonates I think... but they are not used in vivo because they are considered to be excitotoxins.

Most "NMDA antagonists" are really uncompetitive channel blockers (ketamine, MXE, DXM)


----------



## Mandark

endotropic said:


> I can't think of any exogenous NMDA receptor agonists off the top of my head, are you thinking of one in particular?


Not really, Wikipedia mentions some (like quinolinate, and obviously NMDA) but my question arose from general curiosity.


----------



## AlphaMethylPhenyl

sekio said:


> Morphine should not stop epinephrine from working



They cancel each other out to an extent though, or at least morphine decreases endogenous norepinepherine levels throughout the brain.


----------



## endotropic

Mandark said:


> Not really, Wikipedia mentions some (like quinolinate, and obviously NMDA) but my question arose from general curiosity.



The reason I asked (and I should have mentioned this in my original post) is that for a receptor like NMDA with multiple binding sites the answer to your question could depend on which site the agonist binds to, but I think sekio answered your question already so I'll leave it at that.


----------



## endotropic

Ho-Chi-Minh said:


> They cancel each other out to an extent though, or at least morphine decreases endogenous norepinepherine levels throughout the brain.



That may be true, but your logic doesn't quite fit.  There's no reason that decreasing endogenous norepinephrine would decrease the effects of exogenous epinephrine, considering epinephrine binds adrenergic receptors directly and doesn't depend on norepinephrine to produce its effects.


----------



## AlphaMethylPhenyl

epinepherine and norepinepherine the same I meant, sorry

regardless in terms of subjective and objective effects the result would be partial negation right?


----------



## pharmakos

asked over in the buphedrone megathread in OD but no response so far

any speculation as to the shelf-life of buphedrone?






pretty sure it was the hcl salt


----------



## sekio

Depending on how it's stored, probably 6 months* to 2 years, or more? Cathinones are fairly stable if kept dry, but can cleave to an amine and benzaldehyde if stored improperly (moisture, heat, acid). The primary amines like cathinone are the worst.

Keep it dry and out of bright light and it should stay good for a couple of years at least.

* Tocris Bioscience suggests a minimum 6 month shelf life for mephedrone at room temperature.


----------



## pharmakos

hm this sample i have is approaching 2 years old.  has a bit of a funny smell to it now, but i don't remember what it smelled like when i first got it.  perhaps i should just toss it.


----------



## sekio

Most of the cathinones smell wierd if they're impure or have degraded even a small amount. Fishy/sperm smells (amines) or almond/pistachio type smells (benzaldehydes) especially.


----------



## pharmakos

"fishy" was my first thought when i smelled it


----------



## sekio

That's probably methylamine from degradation/hydrolysis of the amine. But it could also be left over from synthesis. Either way, if the compound is still a white to off-white crystalline powder it's probably fine.


----------



## Incunabula

I'm not toally sure I'm allowed to ask this question, or if it's even advanced enough, but here goes....

If I have an equal mixture of 2 compounds as powder, naproxen and carisoprodol, one being "practically insoluble in water" (the naproxen) and the other "slightly soluble in water" (the soma), according to wiki.
Wouldn't it be possible for me to just dissolve it in water, apply stirring and slight heat (steam bath), and then run it through a coffee filter?

My therory: the naproxen should stay a solid and thus get stuck in the coffe filter, while the soma should dissolve in the water and run through the coffe filter. Right?


----------



## sekio

sure


----------



## pharmakos

might want to avoid the heat though

"cold water extractions" are a standard method to remove aceteminophen from opiate pills.  same method might apply with naproxen and carisoprodol.

look up the temperatures that they dissolve at perhaps


----------



## Incunabula

Thanks 

I'll give it a try

Edit. Okay, here's an update.

I measured the contents of one capsule to be 500 mg, on the bottle it's says theres supposed to be 250 mg naproxen and 200 mg carisoprodol in each. Something doesn't add up.

Anyway, I dissolved the powder in some luke warm water, in a glass, which was then placed in a small dish with some boiling water. Visually it looked as expected. Some of the powder seemed to be dissolving and some seemed fall to the bottom as solid.
I filtered it through a coffee filter, and let it evaporate off from a plate.

Yield was a measly 100 mg.

I figured this is because carisoprodol only has slight solubility in water.

My second attempt was doing the same, but just using 40% vodka (and using a smaller amount of liquid too) as carisposprodol has total solubility in alcohol, and I'm hoping that naproxen hasn´t.

Again yield came out as precisely 100 mg?! WTF, maybe my experiment was succesfull and the capsules only contain 100 mg of carisoprodol?


----------



## Transform

If I were you I would dissolve in hot water, allow the solution to cool fully and then filter it. I would definitely not use vodka.


----------



## Lombergerh

What's a melting point of 3-MeO-4iPrO-phenylethylamine?


----------



## Incunabula

Transform said:


> If I were you I would dissolve in hot water, allow the solution to cool fully and then filter it. I would definitely not use vodka.


How hot? luke warm or just below boiling?

Thanks a lot for responding, it's appreciated.


----------



## Transform

Uh. 80*C will do nicely. No need to be precise.


----------



## SONN

okay, so I keep meeting people who take absurd amounts of MDMA. I've been trying to weigh the ethics of doing MDMA and the regularity in which you should do it because I pretty much lost the magic after doing it like 8 times over the course of like 5 months I think. So I haven't taken it since october. However, I just met a person that has taken like three and a half grams of it over the course of a weekend then takes psychedelics all week and is planning to go to ULTRA this weekend and do even more. Like wtf, shouldn't she have like a massive tolerance and an insane comedown right now? and the other night I was at someones house and found out there was a person there who was on over a gram and a half of MDA. I can't believe these people, like do they even roll at all? I'm assuming that they're doing some pretty heavy damage.

so my question to you is what magnitude of damage is occuring in these people's brains and is there any possible way that they haven't lost the magic yet? they roll like every weekend.


----------



## sekio

MDMA is actually pretty benign if you don't do truly absurd doses. Sure it loses efficacy with regular usage, but going through 3-7 grams on a weekend is not going to leave you crippled. It will, however, leave you pretty drained for a couple weeks.

People who go hard on MDMA usually recover fully in about a year's time, if not a little more. It's definitely not smart, but your brain won't just suddenly turn into chalk dust with regular usage.


----------



## SONN

Idk theres just a lot of research that needs to be done. I took MDMA maybe 7 times last year. I took a lot of psyches too but it made me totally depressed and crazy. Also, I used lots of vitamins too which none of these people are doing. What types of cells are being destroyed and do we know anything about how long it takes for them to be repaired/ regrown?


----------



## Transform

Everybody is different. I use MDMA maybe three times a year, 130mg in a single dose, usually at a party or festival with some 2C-B or ketamine. In the week that follows, if I don't get a severe cold then I am quite down and generally much less able to cope with life. Clearly other people don't suffer in the same way.


----------



## sekio

> What types of cells are being destroyed and do we know anything about how long it takes for them to be repaired/ regrown?



As far as we know, MDMA doesn't cause cell death unless you overheat yourself. It does cause temprary reduction in serotonin synthesis that rebounds after about 2 weeks.

The myth that "ecstacy puts holes in your brain" or "kills serotonin cells" is unfounded. Don't abuse your body, get plenty of rest and food, and you'll be fine.


----------



## pharmakos

http://www.erowid.org/chemicals/mdma/mdma_article3.shtml

Summary

MDMA causes a sharp increase in oxidative hydroxyl radicals shortly after administration. It is now believed that this rise in oxidative stress is likely involved in MDMA's neurotoxicity, and may be involved in some of its negative side effects. Very high doses of injected antioxidants have been shown in rats to dramatically reduce or block MDMA neurotoxicity as well as reduce tolerance to MDMA's effects between neurotoxic doses. Based on these findings, it is possible that common vitamin antioxidants may be effective at reducing risks of MDMA neurotoxicity, hangover effect, tolerance, and general body stress.

The practical implications of rat-based laboratory research are difficult to reliably assess. However, well-tolerated, common antioxidant supplements such as vitamins C, E, alpha lipoic acid, and others certainly warrant further investigation as a simple means to reduce the negative impact of ecstasy use on the body. For MDMA users who already take antioxidants occasionally, there seem to be few downsides to making sure to take reasonable doses of antioxidants in the days before, during, and after their ecstasy use. The risks are low and the benefits may be immediately apparent.

A potential side-benefit to suggesting ecstasy users take vitamin supplements may be to increase awareness that MDMA is hard on the body. Taking antioxidants before, during, and after experiences could help foster more intention around ingestion, act as a reminder that ecstasy is physically stressful, and could offer an additional way experienced users and harm reduction workers can communicate to new users about risks and precautions. Harm reduction groups could engage users in the issue of toxicity by discussing proper nutrition as a way to maintain the enjoyable effects and recover more quickly.

The primary downside to suggesting antioxidants may be neuroprotective is the chance that some ecstasy users will misunderstand the information and believe that taking vitamin C will protect them from harm or that some will assume that taking antioxidants will allow them to increase their use of MDMA. Increasing MDMA dosage or frequency of use is likely to significantly increase risk of neurotoxicity. The simplest and most effective way to reduce risk of neurotoxicity is to reduce dosage, refrain from re-dosing during an experience, and reduce frequency of use.


----------



## SONN

http://www.erowid.org/chemicals/mdma/mdma_neurotoxicity1.shtml#damage

is this really dated? because this seems to cite a lot of examples of how and why MDMA causes damage.

and also there's that one extreme example of this guy
http://www.guardian.co.uk/society/2006/apr/04/drugsandalcohol.drugs1

also I heard saw person claimed that using ecstacy too often is doing worse for your brain than doing meth or crack occasionally. would anyone like to discuss this?

thanks for your educated responses you guys are always very helpful here in ADD.

one more question, there aren't any major side effects from combining ritalin and cocaine right?


----------



## pharmakos

says spring 2001 at the top


----------



## SONN

^yea I know but that being said how relevant is the information in it? how many studies have taken place since? you guys have already swayed me that MDMA isn't so bad. I'm doing research on it now and while the thought of alpha-methyl-dopamine is not a good one I have no idea what portions it is made in comparison to the dose of MDMA or how much of that actually reacts with glutathione to produce the evidently neurotoxic effects.


----------



## sekio

> no long-term serotonergic changes occurred after 2.5 mg/kg MDMA was given orally every two weeks for four months to squirrel monkeys (Ricaurte, unpublished, cited in Vollenweider, 1999). [Editor's note: a therapeutic dose of 125 mg in a 150 pound person would translate to 1.66 mg/kg]
> 
> Another commonly studied nonhuman primate species is the rhesus monkey. Determining the threshold dose for 5-HT depletions in this species is difficult since all published studies using rhesus monkeys have employed multiple dose neurotoxic regimens. In one study, 1.25 mg/kg oral MDMA did not produce any long-term serotonergic changes when given twice daily for 4 consecutive days. Similarly repeated doses of 2.5 mg/kg MDMA lowered hippocampal 5-HT (to about 80% of controls) but did not affect levels in 6 other brain regions at post one month (Ali, 1993). In another experiment, Insel (1989) found that 2.5 mg/kg MDMA given intramuscularly twice daily for 4 days to rhesus monkeys produced extensive (possibly short term) 5-HT depletions but did not alter SERT density at 16 to 18 hours after the last drug exposure. Since SERT was unaffected, the researchers concluded that axonal loss had not occurred, despite the 5-HT depletions.
> 
> In a study that raises interesting questions about possible tolerance to MDMA neurotoxicity, Frederick (1995) investigated the long-term effects of escalating doses of MDMA. Intramuscular MDMA (0.1-20 mg/kg) was given twice daily for 14 consecutive days at each dose level and followed by three dose-response regimens using single MDMA doses up to 5.6 mg/kg. One month after the final dose-response determination and 21 months after the initial escalating dose regimen, animals were sacrificed. Few significant serotonergic effects were found. MDMA exposure did not produce significant 5-HT depletions in any brain region and decreased SERT to about 60% of control levels only in the hippocampus (and not two other brain regions). Thus, data on rhesus monkeys are complex and perhaps all that can be said with certainty is that the threshold dose for long-term 5-HT depletions appears to be above 1.25 mg/kg oral MDMA in this species.



from the erowid page



> The boldest of the brain blood flow experiments was done by researchers from UCLA's Neurology, Radiology, and Psychiatry departments. They studied the amount of blood flow in current and former 'ecstasy' user's brains and found that recent users (within the past few weeks) had slightly lower blood flow to parts of the brain, but people who hadn't used for four weeks had perfectly normal levels of total and regional blood flow within their brains.[8] That wasn't the bold part, however: Not content simply to test volunteers who had used 'ecstasy' on their own, they gave recreational doses of MDMA to a number of the volunteers after their initial scan, then re-scanned their brains afterwards. As expected, there was a decrease in blood flow immediately after MDMA use, but it returned to normal within 3-4 weeks. In their final report, the researchers concluded that "Low-dose recreational MDMA use does not cause detectable persistent rCBF (regional cerebral blood flow) changes in humans."
> 
> Further research has only confirmed their findings, so the answer is...yes and no. Yes, there is a modest change to your brain after using MDMA that seems to last for about three to four weeks, give or take. It's not permanent, and there's no reason to believe it involves damage; rather, it appears to be a sort of 'hangover' effect caused by your brain's reaction to being exposed to a drug.



thedea.org - neurotoxicity page


----------



## doppelgänger1

http://www.mdpi.com/1424-8247/4/7/992
Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation
Puerta E, Aguirre N



> Abstract: The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA) along with a lower binding of specific ligands to the 5-HT transporters (SERT). Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure. In addition, MDMA produces a long-lasting down-regulation of SERT gene expression; which, on the whole, has been used to invoke neuromodulatory mechanisms as an explanation to MDMA-induced 5-HT deficits. While decreased protein levels do not necessarily reflect neurodegeneration, the opposite is also true, that is, neuroregulatory mechanisms do not preclude the existence of 5-HT terminal degeneration.


----------



## SONN

is combining ritalin and cocaine uber dangerous or no?


----------



## Epsilon Alpha

Additive stimulant effects, but there aren't massive contradictions as far as I know. Don't go overboard on them and you should be as ok as someone doing cocaine and methylphenidate can be.


----------



## Morkin

*Help Me ID Chemical Structure*

Hi - I bought two things which arrived unlabelled except for images of the chemical structure. I've forgotten what I ordered and the vendor keeps no purchasing history, nor do they detail your purchase in the email. Google image search is getting me nothing but IKEA instructions LOL

How do I upload images here or direct them to an outside link? I need help id-ing these chemical structures.

Cheers!


----------



## Epsilon Alpha

Post it to imgur or something. This isn't advanced though, so I'll move it to the big and banging thread


----------



## Lombergerh

After long-term(~1 year) of inappropriate MXE storage, could it produce/transfrom something more toxic then plain mxe?


----------



## sekio

depends on storage conditions. it's not very likely though as arylcyclohexylamines are very stable


----------



## pharmakos

Morkin said:


> Hi - I bought two things which arrived unlabelled except for images of the chemical structure. I've forgotten what I ordered and the vendor keeps no purchasing history, nor do they detail your purchase in the email. Google image search is getting me nothing but IKEA instructions LOL
> 
> How do I upload images here or direct them to an outside link? I need help id-ing these chemical structures.
> 
> Cheers!



tinypic.com is a great place to upload images imo


----------



## Morkin

^ thanks

Ok, I ID'd one of them, but what is this?


----------



## pharmakos

^^ i believe that is 4-methylethcathinone (4-MEC)


----------



## Morkin

Thanks, Google confirms same.


----------



## Incunabula

Hey, very basic question here, I hope it's okay.

2 ways of describing the same molecule:
2,5-DIMETHOXY-3,4-(TRIMETHYLENE)PHENETHYLAMINE
and
5-(2-AMINOETHYL)-4,7-DIMETHOXYINDANE)

first one is IUPAC, right? What is the second naming system called and were can I read about it?


----------



## sekio

2nd one is IUPAC. Some people "corrupt" IUPAC naming by giving "technically correct: structure names.


----------



## AlphaMethylPhenyl

I've read conflicting reports. In low doses (~15-20mg) does amphetamine cause the release and re-uptake of serotonin. How about increasing extracellular concentrations through monoamine oxidase inhibition? Sek told me in only high doses, but at least initial anecdotal reports of low-dose amphetamine seem to suggest otherwise.


----------



## Incunabula

sekio said:


> 2nd one is IUPAC. Some people "corrupt" IUPAC naming by giving "technically correct: structure names.



I get it now. The first one is kind of an abbreviation, in a way. An the second one is the right IUPAC.

Thanks, sekio. you're a sport.

Cheerio


----------



## doppelgänger1

After using a DRI, will the dopamine remain in the synaptic cleft until the DAT isn't blocked anymore or will it be broken down before that?


----------



## ebola?

> Sek told me in only high doses, but at least initial anecdotal reports of low-dose amphetamine seem to suggest otherwise.



No, anecdotal reports cannot speak to such matters even in principle.



> After using a DRI, will the dopamine remain in the synaptic cleft until the DAT isn't blocked anymore or will it be broken down before that?



MAO catabolizes intersynaptic dopamine.

ebola


----------



## doppelgänger1

I thought MAO is located in the presynaptic nerve terminal?


----------



## AlphaMethylPhenyl

What are the functions of trace amines? Similar to other sympathomimetic amines?


----------



## optimuswind

*Quick L-Tyrosine question*

I have 750mg Capsules of L-Tyrosine, I've read that in order for it to actually be absorbed I need Vitamin B-6 also. It's hard to find just Vitamin B6, but I did find this product which contains 25mg B-6 aswell as a ton of other things. Is 25mg enough to get the Tyrosine to do its job in the brain and produce more norepinephrine etc? 

I've read you build a quick tolerance to any L-Tyrosine effects though (any idea how long???)

Also, how much of each should I take, at the same time, one before the other, empty stomach, with food, morning/night, etc

Any help would be appreciated. Basically I'm depressed and also trying to come off Benzos at the same time so I'm trying everything I can to improve my mood. I'm already on Effexor 225mg. I have in the past taken 5-HTP to try and improve my mood also, but I don't think it's such a good idea with the SNRI aswell, due to the risk of serotonin syndrome(right?)

Thanks in advance if anyone can help clear some of my questions up and/or explain why this might theoretically work (I've read some people think it's just placebo)


----------



## Epsilon Alpha

Take on an empty stomach with a multivitamin and a small amount of fruit (any low protein food works). Effectively you're just getting slightly more of an amino acid you should have anyways. Personally I found it worked ok for me for two weeks, granted this was coming from a allergic reaction to an antibiotic that left me unable to eat meat for a couple weeks. Don't get sucked into fancy combination products. 

Best advice I can give you is go for a high protein diet and some long distance walks. 
This isn't really advanced so I'll move it to the questions thread.


----------



## optimuswind

Epsilon Alpha said:


> Take on an empty stomach with a multivitamin and a small amount of fruit (any low protein food works). Effectively you're just getting slightly more of an amino acid you should have anyways. Personally I found it worked ok for me for two weeks, granted this was coming from a allergic reaction to an antibiotic that left me unable to eat meat for a couple weeks. Don't get sucked into fancy combination products.
> 
> Best advice I can give you is go for a high protein diet and some long distance walks.
> This isn't really advanced so I'll move it to the questions thread.



Well the advanced bit is that i'm looking for information on how exactly this stuff works and effects the brain chemistry


----------



## Epsilon Alpha

Ah, well if you want a longer answer I'd be happy to oblige. Effectively tyrosine is the substrate right before the rate limiting step of dopamine and noradrenalin synthesis. Tyrosine hydroxylase is a tightly regulated enzyme, requiring among other things B6, tyrosine, and THB. It's activity can be increased by caffeine and nicotine, however chronically it's not significant. 

Tyrosine hydroxylase produces L-dopa, which is decarboxylated by dopa decarboxylase (thing has like 10 frigging names), producing dopamine. Dopamine is hydroxylated by dopamine beta hydroxylase to produce noradrenalin.


----------



## optimuswind

Thanks for the reply. So if i'm reading this right, some L-tyrosine with B-6 to [...] will get me more L-dopa, in small amounts? 

Wikipedia:


> L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline)



And if my depression/anxiety is due to low neurotransmitters it could theoretically help, along with my SNRI (Effexor)? According to wikipedia the best (only?) way for general public to get more dopamine in their system is this little tyrosine stack?

Wikipedia on Effexor:


> At moderate doses (>150 mg/day), it acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day), it also affects dopaminergic neurotransmission.



So I'm on 225 so it's only affecting Serotonen and noradrenergic systems, (I can't get my doc to give me 300+ a day), the tyrosine stack could be a sort of replacement for that instead without having to up the Effexor dose? (It's not licensed here in the UK above 150mg for depression/anxiety, I was lucky to get 225mg after I told him about a suicide attempt)


----------



## sekio

> some L-tyrosine with B-6 to [...] will get me more L-dopa, in small amounts?



Not neccesarily, vit. B6 is not the rate limiting factor in DOPA synthesis.

Also, the idea that depression/anxiety is due to "low levels fo neurotransmitters", and especially the idea that "more dopamine = more happiness" are both unfounded. There's no real evidence to suggest either of those things are true. Granted, some antidepressants act by temporarily increasing monoamine levels, but they also do other things, and there are some tools for treating depression that hardly effect monoamine synthesis or levels in a direct way at all...

For the average Joe, "getting more dopamine" is likely to bring on uncomfortable hyperdopaminergic side effects, not some sort of generalised euphoria.


----------



## optimuswind

sekio said:


> Not neccesarily, vit. B6 is not the rate limiting factor in DOPA synthesis.



What else is needed? 

Wikipedia again:


> The important amino acid called Tyrosine is a precursor to Levodopa and is also available over the counter. This supplement converts into Dopamine, Norepinephrine and Epinephrine as well.



from what I've read elsewhere you just need Vitamin B6 to get the L-Tyrosine to do it's thing and such, what am I missing?


----------



## sekio

There are internal genetic regulatory factors that prevent tyrosine from being turned into L-dopa in hazardous levels. When levels of DOPA go up, the enzyme making DOPA from tyrosine slows down. You can't make it go any faster by taking supplements...

If you had workers building a house, you can give them all the lumber and nails in the world, but they won't build any faster if they already have enough. Same for most enzymes in your body.

Even if you could get the enzyme making DOPA to go faster - DOPA is broken down very rapidly in the body, so very little of the produced dopamine would ever make it into your brain. When people are treated with L-DOPA they are usually treated with a drug like carbidopa that also stops L-DOPA from being broken down anywhere but the brain.


----------



## optimuswind

sekio said:


> There are internal genetic regulatory factors that prevent tyrosine from being turned into L-dopa in hazardous levels. When levels of DOPA go up, the enzyme making DOPA from tyrosine slows down. You can't make it go any faster by taking supplements...



So you actually *can* but as I said in my first post you develop a tolerance to it, which is why I asked if anyone knew how long that tolerance buildup takes before "the enzyme making DOPA from tyrosine slows down".


----------



## sekio

No, trust me on this, you can't make your body make more neurotransmitters just by taking more vitamins. Your body is not 'tolerant' to the vitamins; it is simply that the enzyme only makes the chemical reaction proceed at a certain rate and that are is unaffected by the concentration of cofactors.

There is a reason people treat Parkinsons with L-DOPA and carbidopa instead of telling them to eat a diet high in tyrosine and eat plenty of vit B6.


----------



## optimuswind

sekio said:


> Also, the idea that depression/anxiety is due to "low levels fo neurotransmitters", and especially the idea that "more dopamine = more happiness" are both unfounded.



how in the hell is it unfounded? are you just completely dismissing the entire field of psychopharmacology? there are thousands of peer reviewed tests and shit that show antidepressants working much better than placebo. To deny they do anything is just silly. If you have any evidence to the contrary i'd like to read it.

How do you explain MDMA if you think all of this is unfounded? placebo effect? people just feel intense euphoria and happiness from placebo, that just happens to react on the exact neurotransmitters we're talking about? please. I really don't get your angle. why do you have nearly 9,000 posts on a forum dedicated to discussing drugs that alter brain chemistry only to deny scientific facts, do you think they work by magic?


----------



## Epsilon Alpha

optimuswind said:


> how in the hell is it unfounded? are you just completely dismissing the entire field of psychopharmacology? there are thousands of peer reviewed tests and shit that show antidepressants working much better than placebo. To deny they do anything is just silly. If you have any evidence to the contrary i'd like to read it.
> 
> How do you explain MDMA if you think all of this is unfounded? placebo effect? people just feel intense euphoria and happiness from placebo, that just happens to react on the exact neurotransmitters we're talking about? please. I really don't get your angle. why do you have nearly 9,000 posts on a forum dedicated to discussing drugs that alter brain chemistry only to deny scientific facts, do you think they work by magic?



Calm your dick bro. The monoamine theory of depression is mostly discredited. For example though MASSIVE spikes in most monoamine levels can cause feelings of euphoria (think MDMA and high dose amphetamine), moderate though still highly significant increases have no effect. Your SNRI probably increases your 5HT and NE levels 200% but do you feel a sudden change? Not really. It's massive flux that can change mood and you're not going to get that with diet unless you want to go the JoePedo route where you're taking like 40 highly potent herbal extracts too.

http://www.bluelight.ru/vb/archive/index.php/t-494408.html

Here's some pretty damning evidence for the "DA=happy" theory. DA is more involved in wanting, lactation, and motor control than happiness. Also, amphetamines are FAR dirtier drugs than you would believe. Other receptors and downstream pathways are likely involved in the mood boost, hell there are a ton of studies suggesting endorphin activity as a major mediator of the effects.


----------



## pharmakos

i think he said "unfounded" when he meant "not entirely proven"

there definitely is a correlation though, and to not at least acknowledge that higher neurotrasmitter levels may improve depression would be ridiculous


----------



## sekio

> at least acknowledge that higher neurotrasmitter levels may improve depression



There's no real evidence that it does? Okay, sure, some depressed people have lower levels of monoamines, but when they don't respond to treatments that should work "on paper" (SNRIs)... what do you do then? You can stand around and argue about correlation all day, it doesn't change the mere nature of depression: that it is _not tied to just monoamines_! Turns out the rat model of depression that most antidepressants have been marketed for ... is a poor model for human depression!


----------



## ebola?

sekio said:
			
		

> Also, the idea that depression/anxiety is due to "low levels fo neurotransmitters", and especially the idea that "more dopamine = more happiness" are both unfounded.



Indeed.  It seems to me that localized pathology in neuroplasticity plays the primary physiological role in the presentation and maintenance of depression (in particular because this localized lack of neuroplacticity will reduce one's ability to learn from situations with novel outcomes, which can increase discouragement).  All known anti-depressants affect this mechanism indirectly.

ebola


----------



## psood0nym

I agree that the "higher neurotransmitters = happiness" idea is nonsense. Consider that the concept of functional selectivity complicates things massively at the basic level of the neuron, and that the idea is only a few years old. The human brain is the most complicated thing in known existence, and we can't even solve the three-body problem. Even lower back pain is so complicated the standard policy is to tell doctors "stop trying to interpret fMRI and give them bed rest." The most functional prosthetic limb today is hardly different than what it was in the 19th century. What we do is try to fit what we can understand to profoundly more complex phenomena and when there's some weak confirmation from evidence _that we're looking for_ we take it as validation of our gross oversimplifications. Granted, often times that's useful enough under the circumstances. I'm not saying it's not worth theorizing, but especially with the brain we need to maintain perspective.


----------



## pharmakos

sekio said:


> it is _not tied to just monoamines_!



no one ever it was absolutely tied to _just _monoamines.  it's awesome that you are spreading the knowledge that there is more to the story than that, but monoamine levels are most definitely _part_ of the story.


----------



## psood0nym

thenightwatch said:


> no one ever it was absolutely tied to _just _monoamines.  it's awesome that you are spreading the knowledge that there is more to the story than that, but monoamine levels are most definitely _part_ of the story.


^They're part of the current story, but very far from "definite," and I think that's the essential point he's making given the cogent presence of counter evidence. All this is to say that the results of grossly elevating monoamines may very well be accidents that are not remotely reflective of the truth yet help confirm oversimplified current theories we cling to because of their accessibility. Imagine that it's far in the future -- how far is totally uncertain -- and we know exactly the physical state of the brain that constitutes the optimal physiological state for happiness of some individual.  Does that individual, on average, have profoundly raised levels of monoamines relative to normal or not?


----------



## optimuswind

Epsilon Alpha said:


> DA is more involved in wanting



exactly. wanting. rewards. this is basic stuff.

Also, if http://en.wikipedia.org/wiki/Chemical_imbalance#Monoamine_hypothesis is largely discredited, then why do antidepressants work? (actual question, i'm not being sarcastic) I've tried multiple and Effexor is the only one that I actually felt a real change from, and I can tell the difference between something just in my head and something real happening. So why do they work? (again, actual question)


----------



## pharmakos

psood0nym said:


> Imagine that it's far in the future -- how far is totally uncertain -- and we know exactly the physical state of the brain that constitutes the optimal physiological state for happiness of some individual.  Does that individual, on average, have profoundly raised levels of monoamines relative to normal or not?



good thought experiment, but of course no one knows the answer to this


----------



## Epsilon Alpha

optimuswind said:


> exactly. wanting. rewards. this is basic stuff.
> 
> Also, if http://en.wikipedia.org/wiki/Chemical_imbalance#Monoamine_hypothesis is largely discredited, then why do antidepressants work? (actual question, i'm not being sarcastic) I've tried multiple and Effexor is the only one that I actually felt a real change from, and I can tell the difference between something just in my head and something real happening. So why do they work? (again, actual question)



Well there are a few theories based on neuroplasticity and transcriptional changes, but they're the kind of vague unsatisfying answer no one (my self included likes). I know that there are several receptors that are upregulated and downregulated in depression, and that all antidepressant treatments seem to result in changes to their expression, but the real answer is we don't know which are just consequences of a greater change and which effect depression directly. Monoamines are definitely involved, but in a very indirect way as best we can tell.

The monoamine theory of depression is kind of like looking at a car and saying it makes people less hungry. In reality it only looks that way because a car can help people get to the store and buy food. Hope that made sense, I'm kind of wiped out lol.


----------



## optimuswind

What are some of the most prevalent theories? I think I understand what you're saying. Basically the up/down regulated neurotransmitters may just be a symptom or a result of the actual mechanism of action? That's what I'm getting from it anyway. Which is actually kind of worrying. It sounds like we're just throwing things at the brain and hoping something sticks, and as long as it appears to work whether we know how or not, and it doesn't cause any serious side effects, it's packaged and sold?


----------



## AlphaMethylPhenyl

I think the rat/mouse model is the best we have, and clinical trials suggest that its at least similar enough.

There are several other classes of ADs other than SNRIs.

The monoamine theory (and particularly that involving serotonin) is the most founded, unless you have a multitude of sources saying otherwise, because I can search for two minutes and come up with five sources pointing to monoamine deficiency.


----------



## Transform

Oh sure, it's the best model we've got but I think the hit-and-miss nature of depression treatments is a shining example of how little we know about the topic. I don't think anyone was trying to claim they knew the underlying causes, just that raising monoamine levels is rarely an effective treatment on its own.


----------



## sekio

> It sounds like we're just throwing things at the brain and hoping something sticks, and as long as it appears to work whether we know how or not, and it doesn't cause any serious side effects, it's packaged and sold?



Unfortunately, this is the best medicine can manage at times. When we don't have a clear understanding of the underlying causal nature of a disease like depression sometimes the best we can really do is the "brute force" method of trying various compounds until you get ones that produce acceptable effects without too much in the way of side effects. 

There are still drugs prescribed like Lamictical and stuff that we know works (as an anti-seizure med for instance) but we are left in the dark grasping at straws as to exactly why. Same for some drugs that prevent cancer development. At one time people didn't even know how barbiturates worked. Honestly though, the FDA does not see this as a problem, because the alternative is leaving the condition totally untreated in a lot of cases. If the side effect profile is well-established before the drug is released, even if the mechanims is unknown, then doctors can prescribe with a modicum of safety.

The current paradigm of antidepressant development has brought us this far, but with current research, we are learning that maybe we weren't right all along. It's just going to take a while before researchers can put all the puzzle pieces together and come up with mechanistic explanations that would be more satisfying than the current ones. Like EA said, we are kind of running on fumes in the whole antidepressant department right now, and the best we can manage is something like "most antidepressants exert nonspecific changes in neural growth and plasticity". Wheether or not this effect is from activation of select serotonin receptors, activity at a secondary target, or from some combination of factors, remains to be established.



> I think the rat/mouse model is the best we have



I think honestly, murine models are pretty shitty and you might as well be using C. elegans or something. It is the best we really have, though, unless you considere "live fire testing" on real depressed people a good ethical choice. The rat depression tests, to me, do not seem to correlate to humans very well; I don't know many people who are forced to swim around to find platforms in submerged tanks, for instance. There is also evidence that other systems models beased on rats/mice, like the model of obesity, do not exactly translate very well to humans (remove gene XYZ in rats, they never become obese, remove XYZ gene in humans and they don't live past 3 months)


----------



## optimuswind

so the current understanding really isn't as clear as my GP would make it out to be? I would say even wikipedia has bias towards it on various drugs article pages, along with the bad sure, but a bit more left than right. should I even mention to him that the way he thinks they work is an outdated theory or do you think he knows that?


----------



## psood0nym

optimuswind said:


> It sounds like we're just throwing things at the brain and hoping something sticks, and as long as it appears to work whether we know how or not, and it doesn't cause any serious side effects, it's packaged and sold?


Yep, that's the essential logic behind clinical human trials.  I'm no expert but I've looked around enough to see that working with humans is really messy. That's why everyone working outside physics has "physics envy." Physics is as simple and easily controllable as it gets, yet at it's highest levels of sophistication it still takes a lifetime of devotion by the highly intelligent to be halfway competent at making reliable novel predictions in the field. Much (most) of progress is tinkering around and seeing what works well enough to convince others to fund more work or to make a profit on one's own, then rationalizing it's far more than this post hoc (just look at the enormous role of serendipity in discovery). This strategy has been surprisingly successful, and occasionally disastrous,  so it's "OK" in my book, though hopefully we find a less risky strategy.


----------



## sekio

> so the current understanding really isn't as clear as my GP would make it out to be?



Pretty much. I think some GP's spend more of their time treating patients according to their med school education, rather than reading the medical journals.


----------



## AlphaMethylPhenyl

My psychiatrist probably doesn't, or he'd still be prescribing opiates and amphetamine for depression left and right!


----------



## Lombergerh

How stable are nootropics like aniracetam, meclofenoxate and hydergine?
They all been stored in very unsuitable conditions for around 5 month.


----------



## Transform

Depends how unsuitable the conditions are. It's not a binary situation, but if you leave them moist and exposed to air for that time they may have degraded somewhat. How much? Impossible to say.


----------



## psood0nym

I know alpha-blockers have been used to treat severe cases of psychedelic vasoconstriction, but are skeletal muscle vasodilators better for alleviating the aches and tension from normal recreational doses of vasoconstricting psychedelics like LSD? Whether alpha-blockers or muscle relaxants are best, what fairly common drug among them is likely to be able to alleviate psychedelic vasoconstriction with minimal influence on mental lucidity?


----------



## pharmakos

idk if its a general rule among muscle relaxers, but the common muscle relaxer cyclobenzaprine (Flexeril) is a 5HT-2A ANTagonist.... just a heads up

i tried using it to lighten the load on my 2C-P trips a few times, the trips were a bit more dull than usual, didn't put two and two together til later


----------



## psood0nym

^I've been looking around and I'm somewhat hopeful that transdermal L-Arginine creme may be the answer. Oral L-Arginine gives me a headache, but perhaps if I just rubbed it onto my back, shoulders, and neck it would be enough to alleviate the most annoying sources of tension.

Has anybody out there successfully used such products for common psychedelic vasoconstrictive annoyances?


----------



## pharmakos

hm i wonder why oral l-arginine gives you a headache.  what dosage do you usually use, and what fluids do you usually take it with?

i have no experience with topical l-arginine, oral works fine for me so long as i drink a bunch of water with it.


----------



## psood0nym

thenightwatch said:


> hm i wonder why oral l-arginine gives you a headache.  what dosage do you usually use, and what fluids do you usually take it with?
> 
> i have no experience with topical l-arginine, oral works fine for me so long as i drink a bunch of water with it.


Well, maybe it was coincidental, but l-arginine has given me a headache twice in the past. I've used 750mg combined with citrulline orally. I can't recall the fluids. Should I take it with some minimal volume of water?


----------



## pharmakos

nah more water is better IME but i don't even have a pseudo-advanced theory for why

also i usually take 3000mg-5000mg


----------



## AlphaMethylPhenyl

Why do both 5-HT2a agonists and antagonists lead to down-regulation of 5-HT2a?


----------



## Black

i suspect that when both bind to the receptor, "faulty" receptor activation/structure is detected and the receptors in question are internalised and degraded.

what i find really intriguing, is that low doses of 5-ht2 receptor agonists / 5-ht releasers can lead to upregulation. i have no idea how that might work.


----------



## endotropic

Black said:


> i suspect that when both bind to the receptor, "faulty" receptor activation/structure is detected and the receptors in question are internalised and degraded.
> 
> what i find really intriguing, is that low doses of 5-ht2 receptor agonists / 5-ht releasers can lead to upregulation. i have no idea how that might work.



The 5-HT system is so fascinating.  I hope we come close to fully understanding it in my lifetime.


----------



## SONN

Black said:


> what i find really intriguing, is that low doses of 5-ht2 receptor agonists / 5-ht releasers can lead to upregulation. i have no idea how that might work.



splendid news  that means some of the longer lasting afterglows i've gotten from low dose Methylone may have actually been serotonin upregulation


----------



## psood0nym

> The 5-HT system is so fascinating. I hope we come close to fully understanding it in my lifetime.


As much as I share in your enthusiasm, I'm skeptical that the human brain has the capacity to fully understand itself even given infinite time (and I'm using "fully" in the weak, general, not technical or nitpicking sense). Gödel's incompleteness theorems, insofar as my cursory look at them is concerned, spring to mind as instructive analogies in considering such a task. Abandon all hope ye who entertain such shiz [smiley face].


----------



## pharmakos

there's a theory that says that if anyone ever understood exactly what the universe was and why it was here, then the universe would spontaneously cease to exist and be replaced by something even more bizarre

there's another theory that says that this has already happened


----------



## AlphaMethylPhenyl

psood0nym said:


> As much as I share in your enthusiasm, I'm skeptical that the human brain has the capacity to fully understand itself even given infinite time (and I'm using "fully" in the weak, general, not technical or nitpicking sense). Gödel's incompleteness theorems, insofar as my cursory look at them is concerned, spring to mind as instructive analogies in considering such a task. Abandon all hope ye who entertain such shiz [smiley face].



Interesting that you bring this up because it brings to mind an article which I read in class a few years ago about how computers will be constructed which have knowledge beyond human comprehension (their mathematics and such still work out when tested). So we may have a gateway, if you will.


----------



## Gaius

I have a question.

Would a 5mg/kg oral dose of agmatine be likely inhibit the beneficial effects of guanfacine? 

This paper discusses the seemingly paradoxical behavior of agmatine at the α2A adrenergic receptors, and how it displaces clonidine significantly at concentrations above 10μM or so.

Also how likely is it that agmatine would augment the effects of bupropion at those concentrations, given that this study only used 10mg/kg IV doses to assess this quality?

I take both of the aforementioned pharmaceuticals and was considering supplementing agmatine, but I'm having trouble with the cost:benefit analysis.


----------



## psood0nym

*Getting 4-ho-DPT fumerate into solution for IMing*

I believe this is the thread I said I would post back to months ago after I agreed to act on Sekio’s sage advice to just try “boiling the hell out of it” to get 4-ho-DPT fumerate in solution for IMing. It mostly worked. I could have easily got the 35mg in 2 mL but I wanted to see how far intense boiling in 90 units (0.9 ML) of sterile water and 10 units of 5% acetic acid could take it.

I put it in a tall test tube so it could boil violently without leaping out, and set the tube’s screw cap on top so that pressure could escape while confining a significant portion of the vapor to the tube. I started using my microwave’s lowest defrost setting (the tube is plastic). The longest I let it go for was 30 seconds straight. This got most of it into solution but I set it to full power to see what would happen. I boiled a little too long and, after spinning around in my living room like a lunatic with the tube at arm’s length to get the droplets condensed on the side to pool at the bottom, dumping it into a vial, and drawing the solution into a syringe, I found I had boiled off 40 units leaving 60 units 4-ho-DPT solution. I didn’t go through the work of properly quantifying what was left because I was burning daylight and had a nature-gasmic adventure in recreational drug abuse to get under way but after drying it out with a hair dryer it looked like maybe 5 mg was left. I dumped some vodka on it and swallowed it for what it was worth. 

Judging by the subjective effects of the estimated 30 mg IM dose, IMing is an improvement in potency above insufflation of maybe 70 percent. Also, like DPT, the qualitative effects significantly benefit from the “hit me fast and all in one go” onset of IM administration over insufflation. I find 4-ho-DPT to have proportionally less ego dissolving and more sensuous, aesthetic-enhancing, and synaesthetic effects than DPT while maintaining some essential qualities (it’s closer to DPT than anything else, and I’ve tried over 15 5-HT psychedelics, including 4-ho-MPT, which is probably the next closest in my experience). I’ll probably use two or maybe even three 1 mL syringes next time to do a proper strong dose of 50 to 60 mg. I’m fairly confident from my 55 mg insufflated experience in the past that this dose IM’d will be enough to maximize 4-ho-DPT’s novel beneficial effects without venturing into ego death territory, which can get confusing and more difficult to integrate in a psychologically practical way (at this point of my psychedelic career I’m finding it more productive and prone to to novel discovery to push experience within dissolved but not totally “de-patterned” ego boundaries).


----------



## psood0nym

psood0nym said:


> I believe this is the thread I said I would post back to months ago after I agreed to act on Sekio’s sage advice to just try “boiling the hell out of it” to get 4-ho-DPT fumerate in solution for IMing. It mostly worked. I could have easily got the 35mg in 2 mL but I wanted to see how far intense boiling in 90 units (0.9 ML) of sterile water and 10 units of 5% acetic acid could take it.
> 
> I put it in a tall test tube so it could boil violently without leaping out, and set the tube’s screw cap on top so that pressure could escape while confining a significant portion of the vapor to the tube. I started using my microwave’s lowest defrost setting (the tube is plastic). The longest I let it go for was 30 seconds straight. This got most of it into solution but I set it to full power to see what would happen. I boiled a little too long and, after spinning around in my living room like a lunatic with the tube at arm’s length to get the droplets condensed on the side to pool at the bottom, dumping it into a vial, and drawing the solution into a syringe, I found I had boiled off 40 units leaving 60 units 4-ho-DPT solution. I didn’t go through the work of properly quantifying what was left because I was burning daylight and had a nature-gasmic adventure in recreational drug abuse to get under way but after drying it out with a hair dryer it looked like maybe 5 mg was left. I dumped some vodka on it and swallowed it for what it was worth.
> 
> Judging by the subjective effects of the estimated 30 mg IM dose, IMing is an improvement in potency above insufflation of maybe 70 percent. Also, like DPT, the qualitative effects significantly benefit from the “hit me fast and all in one go” onset of IM administration over insufflation. I find 4-ho-DPT to have proportionally less ego dissolving and more sensuous, aesthetic-enhancing, and synaesthetic effects than DPT while maintaining some essential qualities (it’s closer to DPT than anything else, and I’ve tried over 15 5-HT psychedelics, including 4-ho-MPT, which is probably the next closest in my experience). I’ll probably use two or maybe even three 1 mL syringes next time to do a proper strong dose of 50 to 60 mg. I’m fairly confident from my 55 mg insufflated experience in the past that this dose IM’d will be enough to maximize 4-ho-DPT’s novel beneficial effects without venturing into ego death territory, which can get confusing and more difficult to integrate in a psychologically practical way (at this point of my psychedelic career I’m finding it more productive and prone to to novel discovery to push experience within dissolved but not totally “de-patterned” ego boundaries).


^I have to partially rescind/qualify this: I've since tried to get 50 mg in what was originally 2 mL by hard boiling in 9:1 water:5% acetic acid. I boiled it down to 0.7 mL and the solution was clear, but clearly too concentrated because after I drew it up into the syringe it returned to room temperature and crystals started precipitating out of the solution, which clogged the syringe. Due to time constraints and predicted weather this lead to me simply plugging the whole mess, which isn't as potent an ROA as insufflation for this compound, FYI. I can't raise the acidity too much because I want to IM it, and I prefer to IM as little volume as possible. Next time I may try citric acid monohydrate in the hope it will be better at keeping 4-ho-DPT fumerate in solution than acetic acid. I'll probably also start off with 3.5-ish mL of acid/water solution in expectation of boiling it down to ~2mL.  I also recommend using a proper boiling test tube and flame rather than a damned microwave -- the rate of heating is just not controllable enough (might need to get that before this is over).


----------



## AlphaMethylPhenyl

Does amphetamine increase proliferation of bdnf's in the hippocampus/svz? What other well-known drugs might?


----------



## Gaius

SSRIs, most likely, although I'm not sure how true this is in non-impaired models. Amitriptyline is also a TrkB receptor agonist, so it probably has similar properties to BDNF in that regard.

re: amphetamine, I'd assume so.


----------



## AlphaMethylPhenyl

http://94.236.98.247/systems_neuroscience/10.3389/fnsys.2011.00060/full this is encouraging


----------



## endotropic

Ho-Chi-Minh said:


> Does amphetamine increase proliferation of bdnf's in the hippocampus/svz? What other well-known drugs might?



Ketamine and other NMDA antagonists, probably:

Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test.


----------



## AlphaMethylPhenyl

Yet at the cost of cognition. I seem to remember that in some respects 'helpful' doses of nmda antagonists are also harmful to the brain.


----------



## Gaius

What about things like tianeptine? AFAIK that doesn't impair cognition despite NMDA antagonism.


----------



## TheAppleCore

psood0nym said:


> alleviating the aches and tension from normal recreational doses of vasoconstricting psychedelics like LSD



Magnesium supplements have been known to relieve muscle tension on psychedelics / empathogens / stimulants. (Needs to be an effective source - magnesium oxide is absorbed very poorly, in particular.)


----------



## AlphaMethylPhenyl

Does amphetamine increase concentrations of CART?


----------



## sekio

in goldfish it does, but i can't find anything in humans
http://link.springer.com/article/10.1007/s10695-012-9756-4


----------



## AlphaMethylPhenyl

Thanks! Appears to in rabbits too.
http://www.usbio.net/item/C1386-50


----------



## AlphaOdure

*Anyone aware of a barbiturate binding site?*

I am aware of the BZP binding site at GABAA. Is there any binding sites known for barbiturates, aside from them merely having the general effect of positively allosteric modulating GABAA receptors?? ...like some anticonvulsants & most GABAergics (excluding GABAB) agonists?


I am just wondering since i take high doses of butalbital (an intermediate-acting-barbiturate),,,,,,


If anyone has any sources w/ any responses along w/ their posts.. please post them as well!! B/c I couldn't find them via google


----------



## ebola?

Yes, there is a distinct barbiturate binding site on the GABAA receptor complex (I believe localized to the beta subunits).  This is part of the reason why barbiturates cause qualitatively different allosteric modulation from benzodiazepines.

ebola


----------



## AlphaOdure

Wow really??? They act primarily on GABA-a beta subunits, in more efficacy than the alpha subunits???? that's very odd, IMO??


----------



## Thorns Have Roses

This is totally not helpful, but I had it sitting around, so whatever. Will look for a more useful picture/data later.


----------



## AlphaMethylPhenyl

http://fampra.oxfordjournals.org/content/early/2013/03/12/fampra.cmt010.short

http://journals.lww.com/psychopharm...d,_Naturalistic,_Parallel_Group_Study.20.aspx

http://apt.rcpsych.org/content/18/4/259.short

http://www.hindawi.com/journals/aps/2012/416864/abs/

This aught to put to bed one really annoying theory.


----------



## Toucan

Sooo I'm really really fond of aniracetam, which unlike the many other nootropics I've tried seems to have incredible effects on my concentration & memory and a very uplifting effect on my mood.
Anyway, I've recently gotten myself some theanine which I take occasionally for it's calming effect.

I know you ADD's _love_ vague speculative questions so:
Aniracetam is purported to act on the AMPAr as a positive allosteric modulator, which could go some way to explain its nootropic effect.
Theanine also acts on AMPA but seems to act as an antagonist, from what I've read?

Could theanine be working against the nice effects I get from aniracetam?


----------



## Gaius

Ho-Chi-Minh said:


> http://fampra.oxfordjournals.org/content/early/2013/03/12/fampra.cmt010.short
> 
> http://journals.lww.com/psychopharm...d,_Naturalistic,_Parallel_Group_Study.20.aspx
> 
> http://apt.rcpsych.org/content/18/4/259.short
> 
> http://www.hindawi.com/journals/aps/2012/416864/abs/
> 
> This aught to put to bed one really annoying theory.



Well yeah, but god forbid someone actually _enjoy_ a medication that they're taking. We obviously can't have that.

Anxiety? Have some SSRIs!

I'm not bitter I swear.


----------



## 23536

How is percent THC determined for a given strain of cannabis?  More specifically, what does that refer to?  If I smoke a gram of 30% THC weed, am I ingesting 300 mg of THC?


----------



## sekio

The way I'd do it. (I'm sure this is how labs do it too)

0. Decarboxylate the weed in an oven.
1. Take some dry weed, weigh it.
2. Pulverise it and extract with warm hexanes.
3. Dry the hexanes w/MgSO4 and evaporate them. Weigh how much hash oil you get (% Oil)
4. Take a measured amount of the oil, redissolve in a known amount of solvent. and shoot it into a GC. Compare it against a chromatogram of 1mg/ml THC (or really 1mg/ml of any suitable organic compound if you have a MS and can easily ID the THC peak). This gives you a figure of %THC in oil.
4a. [% oil in flowers] x [% THC in oil] = % THC in buds.



> If I smoke a gram of 30% THC weed, am I ingesting 300 mg of THC?



Not quite. Clarke's sez the BA of smoked THC is 20-50%. Ingested is 6-20%. I have a feeling the BA of vaporised THC is much higher, 60-90%.  So if you smoke a gram of 30% THC weed, there's at best 300mg of THC in there and you deliver about 75-150mg. However a gram of 30% weed is probably massive overkill... anything above about 15% is a one hitter quitter.

Some labs use a different procedure that keeps the carboxylates seperate, in this case you get 2 sets of numbers, % free THC and % THC-COOH. (THC-COOH needs to be cooked or othwerwise decarb'd before it's active)

ed.note. I Fucking Love Clarke's Handbook.


----------



## 23536

sekio said:


> 4a. [% oil in flowers] x [% THC in oil] = % THC in buds.



I suspect they're using a different formula than that.  Like I said in another thread, I took a 10 mg marinol once and the effect was perfectly adequate.

If it's just the media and the industry making these claims, they might largely be bullshit.


----------



## sekio

THC is a partial agonist - quite a potent one though. So 100mg of THC may not neccesarily produce effects much different from 10mg, esp if you have a certain level of tolerance.



> I suspect they're using a different formula than that.


How would you measure it then?


----------



## AlphaMethylPhenyl

http://www.biomedsearch.com/nih/Che...ology-cannabis-clinical/23408483.html#CIT0019

I know this is talking about cannabis (by the way its a great source for those interested) but it does seem to imply that the specific mechanisms behind which the many systems which THC and the cb receptors interact with aren't really known. I'd bet big pharma has a lot of info they don't tell us though.


----------



## 23536

sekio said:


> THC is a partial agonist - quite a potent one though. So 100mg of THC may not neccesarily produce effects much different from 10mg, esp if you have a certain level of tolerance.



That's a really good point. 



> How would you measure it then?



You could measure it as a fraction of the weight of the oil or the resin.  According to this source, resin is 2-10% THC by weight, and oil is 10-30% THC.

Obviously, it is impossible for THC to be 10% of the weight of the resin _and_ 30% of the weight of the bud.


----------



## babylonboy

I think that source uses "resin" as a synonym for "hashish" (which is how that term is commonly understood in the UK), and is referring to traditional hashish produced in the Old World, which is made from cannabis that isn't particularly potent and contains water and leaf material and so on and so forth. I am sure that hash made using modern Western techniques from high-quality sensimilla is much more concentrated in THC than that.


----------



## AlphaMethylPhenyl

Why does it seem as if only gabaergic agents which operate on the mesolimbic pathway are useful in acute psychotic features of mental disorders whereas lithium, valproic, carbamazepine, hell, even l-theanine and valerianic acid aren't?

 Thats the justification for your d2 anti-psychotic over a typical mood stabilizer.


----------



## asecin

*agonist, releaser, reuptake inhibiting agent*

this is confusing to me and i have tried google as many people would first of all suggest and i got thousand of conflicting confusing results so i have to ask, what is such huge difference between an agent that is either releaser, agonist and/or inhibitor ? i know what antagonist is, and im sure any kid will figure it out. its blocking the uptake of neuro signals. so agonist should promote releasing of neurochemicals right ? but if agonist does that, i have never felt anything from agonist drugs. compare it to actual releaser or inhibiting reuptake. which to me seem to be actually potent when it comes to drugs. so what does agonist actually do ? its not a releaser or reuptake. and what is the difference between releaser and reuptake inhibitor since both of those increase the content of a specific neurochemical within the membrane. how do you differentiate between all three ??


----------



## Epsilon Alpha

An agonist directly activates a receptor eliciting a receptor subtype specific response. A reuptake inhibitor prevents the reuptake of a transmitter resulting in more of it being able to activate receptors, thus indirectly resulting in non-specific receptor activation. A releasing agent has the activity of a reuptake inhibitor in addition to causing the release of the transmitter often by causing reversal of the transporters. 

Potency for indirect agonists is better measured by "effective concentration 50" or EC50, rather than binding affinities as the response is more due to the amount of transmitter in the synaptic cleft than the amount of drug present.

As for subjective effects direct agonists likely lack the combination of receptor activation or other mechanisms that are typically associated with subjective liking. 

Hope that made sense. Feel free to ask any further questions


----------



## asecin

i dont understand why agonists do not create similar euphoria as reuptake or releasing agent. can you explain this better plz like if you take high doses of agonists dont they bombard the receptors to such extent that reuptake and releasing agents do and thus cause whatever effect they might be causing in excess such as euphoria one example ?


----------



## sekio

agonists of which receptors? some dopamine D1/D5 agonists (e.g. skf-81297) cause self administration (in rats and chimps) but they are not medically used in humans

some people would argue 5ht2a agonism is euphoric


----------



## SONN

I would certainly argue that 5ht2a agonism is euphoric especially in the case of a drug naive person.

However one time I saw data on how DMT, 5-Meo-dmt, and a few other drugs do indeed release some serotonin as well as being an agonist, and that 5-Meo released more which could be why it's slightly less safe, and it could also be why a lot of high dose psychedelic trips have periods of effects tht resemble serotonin syndrome, at least that's my guess. Any thoughts? Also if anyone happens to have the link to said data it would be much appreciated.


----------



## Epsilon Alpha

asecin said:


> i dont understand why agonists do not create similar euphoria as reuptake or releasing agent. can you explain this better plz like if you take high doses of agonists dont they bombard the receptors to such extent that reuptake and releasing agents do and thus cause whatever effect they might be causing in excess such as euphoria one example ?



Agonists are FAR more selective in effects, for all the hate it gets noradrenalin is pretty integral to any kind of enjoyment as are all the various receptor subtypes. Also you're probably going to have less... Writhy, side effects. Then there's pharmacokinetics which generally link rapid onset with liking. Most agonists are designed to be long lasting


----------



## Gaius

sekio said:


> some people would argue 5ht2a agonism is euphoric



I've always thought to ascribe this to a sense of novelty, amusement, or amazement more than direct euphoria.


----------



## TheAppleCore

sekio said:


> some people would argue 5ht2a agonism is euphoric



I used to think that LSD intoxication was intrinsically euphoric. But, with more experience, I realized that this was a fallacious assumption - LSD seemed euphoric only because it taught me things about myself, and there is pleasure associated with learning. To me, saying that psychedelics are pleasurable is akin to saying that books are pleasurable. Just opening a book and staring at the text is not good enough; you have to actually make an effort to read and absorb the information therein.


What do we know so far about MXE pharmacology? I remember there seemed to be some dispute as to whether or not it was a DARI, or something along those lines?


----------



## Gaius

Binding data for popular arylcyclohexamines.










So no, it's not a DRI.


----------



## sekio

also throws a big old wrench in the old claim that "methoxetamine/3-meo-pcp has a 3-methoxy group for opioid effects" because none of those arylcyclohexylamines actually have affinity for opioid receptors at all. and i guess the claim that ketamine has affinity for 5ht2a and dopamine receptors

i trust the ecmd guys more than the studies from the 70s/80s


----------



## AlphaMethylPhenyl

Bunches of questions and statements. Please affirm/laugh at.

LSD is a receptor whore, psilocybin is much more selective, though I doubt totally. LSD is said to have pro-cognitive capacities at low doses similar to hydergine? Makes sense, no?

Are selective 5-ht2a agonists psychedelic?

And why is there no information on the pharmacology of mescaline beyond 5-ht2a agonism? Beyond that does it reverse transport as other phenethylamines? Let's see, its 3,4,5 tri-methoxyphenethylamine? Popularly thought to be the least likely psychedelic to induce a bad trip?

Is the stimulant model of endogenous psychoses still standard?


----------



## sekio

> LSD is a receptor whore


this keeps getting said all the time... but psilocin is not exactly selective for 5ht2a... LSD actually binds fewer types of receptors than psilocin does at "normal" dose levels.
although lsd does have affinity for lots of receptors it's pretty tightly selective for only a few receptors at typical dose levels. smaller molecules like psilocin, dmt etc are  less complex (closer to serotonin) and therefore "dirtier".

refs:
psilocin affinity table (11 receptors w/significant binding) (scale reversed - pKi = -log Ki)
lsd affinity table (6 or maybe 7 receptors w/ significant binding)



> Are selective 5-ht2a agonists psychedelic?



functional selectivity is important (c.f. lisuride) but yes, in general... see for instance people using NBOMe compounds as psychedelics!



> And why is there no information on the pharmacology of mescaline beyond 5-ht2a agonism?



how hard are you looking? i thought that mescaline was mentioned in the big plos one psychedelics paper and i know there was a wealth of information on its effects in the 50s-60s. 
i seem to recall mescaline & friends are broad spectrum serotonin agonists w/ affinity for a2a/a2c adrenergic receptors, 5ht1a and (to a lesser extent) 5ht2a/c.
psychedelics research is not exactly easy to do anymore.



> Is the stimulant model of endogenous psychoses still standard?



i dont think there is one canonical model of psychosis considered to be "the standard".


----------



## Gaius

Ok, so I've got a question. 

I frequently take etizolam in doses of 1-5mg on any given day, usually not sequentially.

The most prominent behavioral change I notice, though, besides anxiolysis and perhaps motor impairment is that it causes me to compulsively clean, reorganize, and optimize things.

Doing a cursory search of The Google it seems that I am not alone in experiencing this phenomenon. 

I am baffled, though, as to why taking a benzo-like would make me rearrange my friend's entire living room to the optimal configuration in terms of television visibility and coffee table accessibility. Similarly, I find myself organizing my various manila folders containing medical records, financial documents, academic transcripts etc. 

I sometimes even feel compelled to optimize my social life by critically evaluating facebook friends and deleting or blocking them as appropriate based on anticipated future interactions, which I usually wouldn't otherwise bother with. I do trivial chores I've been putting off for weeks. I do other people's dishes and sweep the kitchen.

The list goes on.

But why? It's etizolam not dextroamphetamine.


----------



## AlphaMethylPhenyl

Good morning Sekio,

I will try not to repeat information.

Informed, lengthy response with sources much appreciated .

I once read that LSDs ability to target more receptors makes it more of a gentle hallucinogen than psilocybin, that it has less of an ability to induce a negative experience due to this, but I can see how this might lead to the opposite case too. Perhaps in regards to more selective agonism of receptor sub-types which are associated with hallucinogenic effects the mind is more likely to begin to feel scared due to such a rapid diversion from our "collective conscience", if you will, and may be able to distract its attention to the feeling of other neurotransmitters if such action is present. Just speculation.

Yes but it seems as if psilocybin and mdma are gaining more ethos every year; the former is liable to produce a bad trip while the latter the produce organ damage. Mescaline is an extremely valuable drug insofar as a combination of negative experiences being rare, effects being similar to mdma (I know, people say that about a lot of drugs, but please take all points in sum), and physical safety evidenced by thousands of years of use with no data of permanent toxicity after a therapeutic dose to my knowledge (it causes vomiting too, so though it has a lower LD50 than other psychedelics it has a safety-catch). It is not being scientifically investigated to my knowledge.

And why would it be the psychedelic most sanctioned for religious use by The United States? Chance? Less potential to cause widespread egalitarianism? A bone for Native Americans in lieu of broken treaties and stolen lands? Greater mental safety relative to the other 5-ht2a agonists?

I recommend the book entitled "On Speed". It holds that the medical profession once considered the closest approximation of endogenous psychosis to drug intoxication being that of amphetamine overdose. I guess there's no way to really know. If the last twenty years are any indication, with the introduction of serotonergic antagonists as anti-psychotics, it would seem as if the viewpoint has changed to that of psychedelic overdose. Of course excessive and/or chronic NMDA antagonism and CB1 agonism can cause it too. I wonder if its possible to manufacture a drug which functions as a d2/5-ht2a/cb1 antagonist and 5-ht2c/5-ht1a/cb2 agonist and serotonin-norepinepherine re-uptake inhibitor. 

Hey, Gauis,

I think your general question is better answered more through an artistic, psychiatric viewpoint than from that of a psychopharmacologist.

consider genetic polymorphism perhaps, broface

FYI paradoxical and different responses to psychoactives are well-documented, mostly regarding compounds with hallucinogenic activity, but regarding gabaergic compounds I recall that the potent hypnotic benzodiazepine triazolam was removed from the market in several countries due to it causing agitated/psychotic reactions in some people in doses of .5mg+; in fact high doses of drugs which act on benzo sub-units which are mostly a1 selective are somewhat notorious for causing a strange, delirious state in some users. 

I also recently read a case study in which a young man was admitted to a hospital in a severely agitated, psychotic and violent state. He was given benzodiazepines and neuroleptics, both of which didn't abate his symptoms. Don't ask me why, as this could have been catastrophic, but he was also given methylphenidate, which immediately stabilized him.

I know this is ADD but we must take individual experience into account to verify the physical variation in our brains. Allow me elaborate on the symptomatic effect of two apparently competing substances on me.

Case Study: Me on dextroamphetamine: I feel a sense of calm and control that only meditation can give to such an extent (save if I'm severely intoxicated on a gabaergic, and even so the quality is "crude" in comparison); I have much compassion for those around me (after six months use even); I have much, much, much less trouble breathing and talking to people due to overwhelming physio-emotional anxiety that I would otherwise regularly experience (this is key); I am peaceful; I can sit in one seat for ten hours; I am, though, ready for anything, willing and 100% capable though not eager to assert my presence; I am, metaphorically speaking, a consolidated individual with purposeful conviction, counter to my usual self of terrified godless fanaticism. On dextroamphetamine, I am! As for negative symptoms, I really can't think of any, as for a "crash" I just get tired.

Case Study: Me on clonazepam: the world takes on a certain fluidity; time and circumstance doesn't pass in rigid performances so much as in a casual flow; stressful barriers to physical movement are removed (beforehand I would feel the need to establish an almost forceful presence or I would otherwise feel enslaved whenever entering a novel space, especially in which there are other people, its hard to explain but maybe someone can relate); there is a definite component of freedom about it; it is a liberal substance in that it vanquishes my constant propensity to evaluate myself based on other peoples standards, an irrational, debilitating symptom; it simply removes the edge from any stressful situation through direct "chillness"; paradoxically, I can sometimes feel too numbed on this agent, usually if I'm stupid enough to sit around and make myself depressed.

If I had more time to brainstorm I would, but as you can read, the aforementioned potent stimulant and latter potent depressant have complementing, augmentative effects on each other for my weird illness, which I can't even described (I sat here for two minutes and realized I didn't have the timee to do it justice). When it comes to relieving symptoms of anxiety/paranoia, at least for me, they overlap.

Both activate the reward pathway, as does etizolam. Perhaps it just reduces depression, prompting more activity.

It sounds like etizolam clears the mind for you. Not uncommon. Once the mind is clear/organized, it's less weighed down, and can act. Less bureaucracy (f.o. over-analysis and stress) leads to a more efficient course. One sign of a good medicine is a more productive life after taking it. Mental illness generally erects barriers to life that healthy people don't have to deal with, and medications help remove those barriers.

Mind if I ask if why the great variation in dose and if you're prescribed it? If you're not, and you have a disorder which it would significantly help with, it would be more safe to take under a doctor's supervision. Please consider. Thanks.

Hope that wasn't too off-topic.


----------



## Gaius

To my knowledge, there isn't _anyone_ prescribed etizolam in English speaking countries.

The variation in dose is because sometimes I'm just on edge and other times I use it for enjoyment. I've never blacked out, though higher doses do cloud my memory to some degree.

My psychiatrist refused to give me a benzodiazepine for anxiety because, between me being suspiciously knowledgeable about drugs and the fact that I threw him a bone and told him a few of the benign psychedelics I've done, he assumes I would get addicted to any benzo he gave me.

This is also a doctor who, when I asked what he would first prescribe for insomnia to any given new patient, told me trazodone. _Trazodone_.

Besides, etizolam is about as cheap as an actual prescription benzo would be.



> Both activate the reward pathway, as does etizolam. Perhaps it just reduces depression, prompting more activity.
> 
> It sounds like etizolam clears the mind for you. Not uncommon. Once the mind is clear/organized, it's less weighed down, and can act. Less bureaucracy (f.o. over-analysis and stress) leads to a more efficient course. One sign of a good medicine is a more productive life after taking it. Mental illness generally erects barriers to life that healthy people don't have to deal with, and medications help remove those barriers.



This is the line of reasoning that first came to me as well, but I find abstract explanations really unsatisfying.


----------



## AlphaMethylPhenyl

(people speak english just about everywhere)

Sorry mate, I'm inclined to agree with your doctor if you use it for enjoyment, but not based on what you state you told him. Of course people get addicted to benzodiazepines when they're prescribed them; call it "physical dependence", whatever.

Can't think of any reason to hate on trazodone. Its a really sophisticated, effective drug which isn't relatively hard to stop using.


----------



## Gaius

How does recreational use necessarily mean addiction? I wouldn't even take them daily.

And re: trazodone, I just feel like there are a dozen drugs that would make a lot more sense for insomnia without the side effects of its dirtyness/non-selectiveness.


----------



## AlphaMethylPhenyl

Gaius said:


> I frequently take etizolam in doses of 1-5mg on any given day, usually not sequentially.



Being a relatively recreational gabaergic, I would be highly surprised if you weren't addicted even taking it once a week. And not at a small dose either. 5mg man? Christ.

Insomnia is almost always a symptom rather than a disorder in its own right. Makes sense to treat it that way.

You must be kidding. A dozen? Small side effect profile. Multiple neurogenic/antidepressant/anxiolytic/anti-psychotic mechanisms. Not to mention its metabolite.


----------



## Gaius

I took it three times in the last week, and before that I hadn't taken it for a month, and I took it maybe three times in the two weeks before that month. When I say "frequently" I mean "more than once a month." Even besides that, we don't seem to have the same definition of addiction, 'cause I would not consider taking a mild gaba agonist once a week an addiction.


----------



## ebola?

Mirtazapine is surprisingly effective for insomnia, with surprisingly few side-effects (at least for me, at 7.5 mg doses).  It is incidentally the strongest h1 agonist on the market in the US.  But mirtazapine is such a receptor-slut, I really expected a something more than mild early-morning drowsiness.

ebola


----------



## bloodshed344

sekio said:


> Schema for formation of the mystery compound. The URB ring opens up to a diphenyl urea type thing and a carboxylate group, the carboxylate forms an amide I guess?
> 
> 
> 
> 
> 
> 
> 
> 
> So the only reason there was any activity anyway, was organomercury contamination. I don't know why there is even methylthio mercury.
> 
> (Mercurane is the IUPAC systemic name for a compound of mercury and hydrogen. A google search misled me to think it's 1-mercurocyclohexane (pyran with oxygen replaced with mercury) but it is likely not)
> 
> This is plenty more evidence that nobody should touch "legal highs"... there really could be anything as an active ingredient unil there is independent confirmation.


Does anyone know of the potential psychoactivity of "(N,5-dimethyl-N-(1-oxo-1-(p-tolyl)butan-2-yl)-2-(N′-(p-tolyl)ureido)benzamide)"?


----------



## ebola?

gaius said:
			
		

> The most prominent behavioral change I notice, though, besides anxiolysis and perhaps motor impairment is that it causes me to compulsively clean, reorganize, and optimize things.



It could be a personality thing.  Benzodiazapines are actually the only class of compound that has ever motivated me to clean.  For me, at least, anxiety is a large part of what hinders my ability to organize my external environment (I'm really quite a messy person).  It's like the task is too daunting, as there are too many available, equally valid organizational schemes (feeling like it doesn't matter doesn't help either ).  On a benzo, I can just "go" and "do" instead.  On stimulants, however, I always feel like I have 'more important' shit to do, namely producing and consuming things made of ideas and talking people's ears off. 

Do you believe in the Meyers-Briggs personality inventory (MBTI)?  Are you an INTP?

ebola


----------



## babylonboy

Isn't the majority of the BL populace INTP?


----------



## ebola?

Not necessarily: a survey found INTP to be the most common type among Philosophy and Spirituality readers, though it was far from a majority.  Out of all the types, INTPs are most attracted to philosophy, though they tie with INTJs for most irreligious.

ebola


----------



## Epsilon Alpha

babylonboy said:


> Isn't the majority of the BL populace INTP?



ENTJ, hail to the chief baby! =P
Well actually it's really close between ENTP, but it's like a 60/40 split haha


----------



## ebola?

> ENTJ, hail to the chief baby! =P



We shouldn't enter a working relationship together.  ENTJs tend to be 'generals', organizing systems of individuals.  As footsoldiers, INTPs are about as compliant and organizable as cats. 

ebola


----------



## psood0nym

Epsilon Alpha said:


> ENTJ, hail to the chief baby! =P
> Well actually it's really close between ENTP, but it's like a 60/40 split haha





> We shouldn't enter a working relationship together. ENTJs tend to be 'generals', organizing systems of individuals. As footsoldiers, INTPs are about as compliant and organizable as cats.
> 
> ebola


I'm sort of like you both, then. I'm consistently around 50:50, E:I; 50:50, P:J -- so, E/INTP/J. Perhaps I could be a liaison between General Alpha and the cat army?






... I was a philosophy minor.


----------



## ebola?

(if this keeps up, I'll fold these few posts into the social thread)

Hahahah...so at which point in the glorious felitarian revolution does General Meow become Chairman Meow?



> I'm consistently around 50:50, E:I; 50:50, P:J -- so, E/INTP/J. Perhaps I could be a liaison between General Alpha and the cat army?



More seriously, borderline dimensional results don't really make sense in the MBTI, as each of the 16 possible types points to a unique top 4 rank-ordered preferred modes of cognition (out of 8 described by the theory).  An odd exception is the E/I split.  For any two types Exyz and Ixyz, they will have all 4 cognitive modes in common, but with a different rank-order.  Thus, insofar as secondary through quaternary functions are well developed, the two types will blur.  However, for any two types xyzP and xyzJ, there will be no preferred cognitive modes in common.

In this way, E vs. I is highly salient but simultaneously superficial.

ebola


----------



## psood0nym

^Heh, interesting and good to know. I'm just reporting what I remember of the interpretation of my test results as described to me by others a couple times. I simply read those two posts and started giving some serious thought to cat armies, whose natural leader I determined would have to be "Chairman Meow." A Google Images search to see what people had done with that brought up General Meow there, and I had just read you describe Epsilon as a "General," and, well ... I thought the good citizens of Advanced Drug Discussion might find inspiration in the image of one of their moderators as a cat wearing a funny little hat.


----------



## SwampFox56

*L-Tyrosine*

I was having an argument with a friend of mine a couple minuets ago as to what the L in "L-Tyrosine" means. 

I told him that because tyrosine is chiral the L is an abbreviation for "Levo" as in the levrotory entiomer on tyrosine (Levotyrosine). 

He claims that the full name of L-tyrosine is some very long name and the abbreviated "L-" is just used to make the word shorter. 

Which one of us is right?


----------



## ebola?

You're right.  Ummm...I'm going to close this, as it's just that simple. 

ebola


----------



## sekio

L is used to indicate tyrosine is levorotary in this case.

Confusingly, smallcaps D and L (absolute configuration relative to glyceraldehyde) are unrelated to "normal caps" D and L (and +/-) (which indicate which direction the compound rotates plane-polarised light). Fortunately, when modern chemists talk about D and L forms they are almost always referring to measured rotation of polarised light and not absolute configuration. (The only way to determine absolute configurations is X-ray diffraction)

I think I'll fold this into the Big and Dandy thread if it's OK?


----------



## isetpeopleonfire

*What are the chemicals depicted in this picture?*







I was able recognize some sort of benzodiazepine (but, which one?), some sort of strange indole-based lysergide thingy (which one?), cocaine, meth disguised with a "Ph" for the phenyl ring, MDMA, some tricyclic antidepressant (which one?), aaand heroin; the scorpion molecule  I want to knooooooow


----------



## pasha

Merged.


----------



## The.Ghost

You can do a structure / substructure search in the NIST WebBook. Draw it out, hit "Done", and make sure to do a *sub*structure search. The interface is rather clunky, but it works. I drew out the top left one and got heroin. Too lazy to do the others.


----------



## sekio

top, l to r
heroin, mescaline, amphetamine, cocaine

middle
mda, heroin (big one in centre), lofepramine (tricyclic antidrepressant looking thing)

bottom
lamotrigine, lorazepam, LSD, cocaine


----------



## isetpeopleonfire

sekio, sir, I don't believe that bottom chemical is LSD. 
Thaaaanks ghost :D


----------



## pharmakos

nah that is LSD, just a really poorly drawn version of it


----------



## isetpeopleonfire

Yeah, they have the diethyl at "Et2" so it's confusing; but. I feel like there's a missing hydrogen somewhere.


----------



## sekio

it's lsd, there are no missing hydrogens, Et2NCO is a valid abbreviation for a diethylamide group.


----------



## SwampFox56

I hate this thread. It makes me feel dumb -_-


----------



## ebola?

We all start somewhere!  It's okay to be initially ignorant (everyone who learns anything is by definition so).  It's also fine to be open about personal uncertainty as you learn.   I am, at least. . .

ebola


----------



## Incunabula

What's the difference between a structural and positional isomer? any one 

To me it seems to be the same thing....


----------



## babylonboy

Positional isomers are a subset of structural isomers. A structural isomer is just a chemical that has the same empirical formula (C6H10N or whatever), so it can really refer to two very different chemicals (there's an endogenous hormone that's a structural isomer of THC, for example). Structural isomers have the same number of each type of atom, but can have those atoms arranged in any structure, and might look nothing like each other. A positional isomer is a special case where the hydrocarbon skeleton is the same, but functional groups are at different positions (like 5-OH-DMT and 4-OH-DMT, for example). So, all positional isomers are also structural isomers, but the former is a much narrower group. We might reasonably expect positional isomers of drugs to also be functional analogues, whereas knowing that two chemicals are structural isomer is pretty useless to us, given that they aren't necessarily structural analogues.


----------



## Incunabula

I get it. Thanks a lot


----------



## babylonboy

Du rien.


----------



## babylonboy

So, say one were to be working with a pure fentanyl salt, would dosing buprenorphine beforehand be a sensible and effective precaution? Would this sufficiently preclude any fentanyl that were accidentally ingested from binding?


----------



## sekio

No, fentanyl has a higher affinity than buprenorphine. hence why docs can use it in surgery for people on suboxone.

The best option is to not fuck around with drugs that can put you 6 feet under.


----------



## endotropic

Or you could source some Diprenorphine from your local large animal veterinarian.


Just kidding don't do that.


----------



## Dresden

It is my understanding that MDMA releases 5-HT, DA, oxytocin, and prolactin.  I know MDA releases 5-HT and DA too at the right dose, but does MDA also release oxytocin and prolactin?


----------



## ebola?

Increased oxytocinergic activity is a downstream effect, likely stemming from 5ht1a activation via serotonergic release.  However, the entire pathway hasn't been traced out in detail.  The effect on prolactin is even more poorly understood.  This study suggests that vesicular 5ht is involved but SERT reversal is not (Nash et al. 1988) (wow, cutting edge, this ain't ).

ebola


----------



## sekio

The pharmacology of MDA and MDMA should share a lot of ground. I think they are pretty similar, with MDA having more activity at postsynaptic serotonin receptors (c.f. more hallucinogenic).

There's no reason to expect MDA wouldn't release oxytocin.


----------



## 23536

This is a silly question, but when I cut a piece of paper or a plastic jug with scissors, am I splitting covalent bonds?  If so, what happens to the severed polymer tips?


----------



## babylonboy

It doesn't seem impossible, after all, when you smash a quartz crystal you're breaking covalent bonds. It is interesting, I look forward to hearing an informed response.


----------



## buildersoftime

*al-lad binding profile*

I had a look but couldnt see this previously mentioned on ADD.

Can anyone point me towards any information regarding the selectivity of al-lad vs LSD?


----------



## endotropic

buildersoftime said:


> I had a look but couldnt see this previously mentioned on ADD.
> 
> Can anyone point me towards any information regarding the selectivity of al-lad vs LSD?




Good luck with this one.  This report discusses AL-LAD chemical characteristics compared to LSD:
Synthesis and LSD-like discriminative stimulus properties in a series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives.

In that paper they mention that "pharmacological assays" of other N-alkyl substituted N,N-diethylamide derivatives (not necessarily AL-LAD) was done by:
Hashimoto, H., et al., Eur. J. Pharmacol. 1977, 45, 341.
and
Hashimoto, H., et al., Arch. Int. Pharmacodyn. Ther. 1977, 228, 314.


----------



## shishigami

I had a quick question that might deserve it's own thread but I'm just looking for some scholarly articles:

What exactly about the nBOMe series causes their increased toxicity (greater ratio of 5-HT2A?)?



23536 said:


> This is a silly question, but when I cut a piece of paper or a plastic jug with scissors, am I splitting covalent bonds?  If so, what happens to the severed polymer tips?



Also yea for sure, they probably react with themselves, other polymer tips, the air. Aluminum foil is a good example of this, cut a big piece of it and it'll be initially shiny where unprotected aluminum is, and then dull as it is oxidized.


----------



## Roger&Me

shishigami said:


> What exactly about the nBOMe series causes their increased toxicity



they are full agonists at 5-HT receptors, whereas most (safer) psychedelics are partial agonists.


----------



## shishigami

Roger&Me said:


> they are full agonists at 5-HT receptors, whereas most (safer) psychedelics are partial agonists.



I guess my question is looking for a more in depth reason of why these full agonists may be causing seizures. Especially useful would be any scholarly articles on the topic as my searches came up with little.


----------



## babylonboy

The nature of a novel grey market research chemical is that there is little solid data about it.


----------



## ebola?

> What exactly about the nBOMe series causes their increased toxicity (greater ratio of 5-HT2A?)?



Honestly, we don't yet know.  It could be that they're not as selective as once thought, and broad-spectrum 5ht2 full agonism poses cardiovascular and seizure risks.  Or it might be something about extremely tight binding at 5ht2a.

ebola


----------



## pharmakos

do they bind to the same spot on 5HT-2A as other psychedelics?


----------



## Roger&Me

there's probably a secondary signaling angle to the issue, too (there usually is, and its almost always poorly understood or outright ignored). 

IIRC, partial agonist psychedelics actually elicit a different signaling cascade than full agonists.


----------



## endotropic

ebola? said:


> Honestly, we don't yet know.  It could be that they're not as selective as once thought, and broad-spectrum 5ht2 full agonism poses cardiovascular and seizure risks.  Or it might be something about extremely tight binding at 5ht2a.
> 
> ebola



I thought I remembered seeing fairly complete binding data for 5-HT receptors somewhere?  These compounds were developed to be 5-HT2A selective radioligands IIRC, so we must know something about their binding.


----------



## ebola?

There are current conflicting data from multiple studies, one showing the compounds in the series to be highly selective for binding at 5ht2a over 5ht2c, the other showing them to be broad-spectrum 5ht2 agonists.  I don't think that these discrepancies have yet been adjudicated.

ebola


----------



## SONN

One Question:

http://en.wikipedia.org/wiki/Sceletium_tortuosum

How do half of the active compounds in this not even have wikipedia pages?

each time I've tried this it's antidepressant effect has been noticeable enough to say it works, how has no scientist tried to research the earths only natural SSRI?

With the amount of people suffering from depression in the world this could truly change it for the better.

at least we know that Kanna is a PDE4 inhibitor and an SSRI, but then how did nobody care once that was discovered??


----------



## sekio

> How do half of the active compounds in this not even have wikipedia pages?



because al of the research is in the peer reviewed literature and not in easily digested formats on wikipedia



> how has no scientist tried to research the earths only natural SSRI?



you must have missed the multiple studies suggesting sceletium and its extracts are useful for depression and anxiety.


----------



## babylonboy

Is there a reason that methamphetamine synthesis didn't boom into a cottage industry in the states until the RI/P and Birch methods became widely used, when there are plenty of other reducing agents that spring to mind that are just as easy, if not easier, to acquire? Is it just a coincidence of history, those are the methods that were disseminated within a community of people who didn't have a lot of chemistry knowledge? I know I'd rather prepare an amalgam than steal anhydrous ammonia and dissolve lithium in it in a motel room, but that's not what a nation of meth cooks chose to do. If this is too much synthy talk then so be it, I was just wondering.


----------



## pharmakos

*BREAKING BABYLONBOY d*


----------



## buildersoftime

*Binding affinities for tryptamines*

Can anyone point me toward binding affinity data for 4-sub, 5-meo and unsubstituted tryptamines please? Google isn't delivering. I'm particularly interested in 5-HT1B and 5-HT1D agonism.

Edit: Glennon RA has written a bunch of papers on this but I cant find anything that isn't behind a paywall.


----------



## sekio

This PLoS one study is probably what you want


----------



## ebola?

Heh, to what extent do we believe the PLoS One study, and why?
...
What is up with VMAT2?  To what extent should we attribute releasers' effects as dependent on VMAT2?  Are there available cross-substance comparisons that shed light on this question?  And might VMAT2 substrate + 5ht2b agonist be sufficient alone for proper entactogenesis?

ebola


----------



## tweex

ebola? said:


> What is up with VMAT2?  To what extent should we attribute releasers' effects as dependent on VMAT2?  Are there available cross-substance comparisons that shed light on this question?  And might VMAT2 substrate + 5ht2b agonist be sufficient alone for proper entactogenesis?



Most of the research related to VMAT2 seems to be on dopamine.

Interesting new paper out on VMAT2 and dopamine, seeming to point to VMAT2 downregulation being responsible for a lot amphetamines' negative long term effects: http://www.sciencedirect.com/science/article/pii/S0028390813003481

Apparently this is an issue with cocaine also, which is a bit surprising: http://www.ncbi.nlm.nih.gov/pubmed/22193525

Although earlier research claims reversing the dopamine transporter is still the main mechanism of action for amphetamines as dopamine releasers: http://www.ncbi.nlm.nih.gov/pubmed/9482784

I'd seen a paper before speculating that bupropion may be a VMAT2 enhancer, but I can't find anything on its interaction with amphetamines long term. I think looking at that interaction long term might really shed some light on it.

I'm still a bit in the dark on possible efficacy as an entactogen, but everything I've read on VMAT2 inhibitors _and_ 5-HT2B agonists would sort of point me away from intentionally using them (at least for a drug taken remotely often). Wouldn't combining 5-HT1A agonists and OXTR agonists be a much safer route?


----------



## Incunabula

Bloody hell. I'm shocked to just see the phenetylamine skeleton in Phenylpiracetam. 

Anybody want's to speculate on what that means for it's SAR?

piracetam:





Phenylpiracetam:


----------



## pharmakos

imo it also bares a striking resemblance to Placebomine


----------



## ebola?

That's really a great lot of bulk on the nitrogen for one to expect activities related to phenethylamine SAR.

ebola


----------



## Incunabula

ebola? said:


> That's really a great lot of bulk on the nitrogen for one to expect activities related to phenethylamine SAR.
> 
> ebola


Yes, of cause, I see what you mean. But how is it metabolized? What parts come off in the body? If you remove the amide part it starts looking a bit like aminorex. 

Anyway, just thought it was a funny coincedence, did't think it would have any real bearing on it's effects. Or it would propably have been known already.



thenightwatch said:


> imo it also bares a striking resemblance to Placebomine



Phenylpiracetam is actually supposed to be one of the racetams that _really_ work. Stimulation from just one dose is supposed to be on par with a cup of coffe, just different obvisously. 

I'm about to find out.


----------



## tweex

Fagott said:


> Yes, of cause, I see what you mean. But how is it metabolized? What parts come off in the body? If you remove the amide part it starts looking a bit like aminorex.



Yeah, I think it is metabolized the same way as piracetam, which ends up 2-(2-oxopyrrolidin-1-yl) acetic acid.

You end up with this funky-ass molecule:
*(2-oxo-4-phenylpyrrolidin-1-yl)acetic acid*





...and what does Pubchem have to say about it?

High throughput screening has shown it _doesn't_ kill a few scary types of bacteria.

_Thanks, Obama!_ 

Yet it seems like every supplier under the sun offers it, and has no idea what it does. I'm guessing none of them actually have it on hand, and no one ever orders it.



Fagott said:


> Anyway, just thought it was a funny coincedence, did't think it would have any real bearing on it's effects. Or it would propably have been known already.



Definitely don't jump to conclusions like that with the racetams! In my opinion they as interesting a class as phenethylamines and tryptamines (albeit mostly in different ways), but horribly under-researched. You look through pubchem and see the occasional assay here and there, and almost nothing on SARs or finding new derivatives. It's almost like some kind of conspiracy to keep smart drugs under wraps  I'm only half kidding

There are even only a few papers on phenylpiracetam, and afaik none exploring potential derivatives despite showing pretty amazing effects in clinical trials. *I'd love to see what happens when you start substituting on the phenyl ring.*

Really the only two racetams that have been heavily researched are Piracetam and Keppra, and we still barely have any idea how the fuck they work. Heck, Keppra is still the only known drug to target SV2A. And there are some really interesting ones out there, like Coluracetam... another first in class drug as a high-affinity choline uptake enhancer now in clinical trials that I'm also a big fan of.



Fagott said:


> Phenylpiracetam is actually supposed to be one of the racetams that _really_ work. Stimulation from just one dose is supposed to be on par with a cup of coffe, just different obvisously.
> 
> I'm about to find out.



Yeah, it's pretty stimulating. I'd compare it more to dexedrine than coffee, it won't get you jittery. Most people claiming racetams don't work are expecting to notice some change in perception, and phenylpiracetam+oxiracetam+coluracetam are really the only ones that do that to any real degree, the former two as stimulants and the latter as a very, very weak psychedelic (just color enhancement, I wonder if that's why the named it). The stimulation on phenylpiracetam is pretty unlike anything else I've tried in the stimulant world, its very smooth and slightly euphoric, gives a big increase in heat/cold+exercise tolerance (why its banned in competition) despite being weakly adrenergic at most, increases cognitive tempo and reasoning abilities *a lot*, and has modest improvements in both short and long term memory retention. I'd compare it to dexedrine but it's less euphoric, less focusing and far more pro-cognitive. I'd compare it to 2-FMA, but it's more euphoric and pro-cognitive, but less adrenergic and far less focusing. I'd compare it to Armodafinil, but it's far more effective at enhancing physical performance and less wake-promoting+focusing.

Yeah, it's basically just... phenylpiracetam.

The only downside is tolerance builds pretty fast, I have to cycle 3 days on and 5 off to return to baseline. The wikipedia article on it is a good summery of all the known info on it.

Racetams, Y U NO RESEARCHED BETTER!? 

Edit:
*In Soviet Russia, Carphedon research you!*


----------



## Incunabula

Thanks Tweex 

very interesting


----------



## tweex

Alright so my rant on lack of racetam research got me thinking... how does one get into computational modeling of drug-receptor binding?

Anyone care to point me in the right direction?

I've got access to some fairly high end GPU hardware and a decent background in computer science, by the way.


----------



## nAON

tweex said:


> Alright so my rant on lack of racetam research got me thinking... how does one get into computational modeling of drug-receptor binding?
> 
> Anyone care to point me in the right direction?
> 
> I've got access to some fairly high end GPU hardware and a decent background in computer science, by the way.



Check out ISIS Draw for drawing molecules, Accelerys DS Visualiser to slam them into proteins, and RCSB.org to get receptor model files.


----------



## toastmann

https://en.wikipedia.org/wiki/Dinoxyline

What about this one? This compound is a full agonist at all dopamine subreceptors. It looks somewhat similar to LSD, could this be why LSD (or some of its metabolites) have some dopamine action?


----------



## Soulspark

*Substrates and concentration/metabolism*

Hi, I posted this in BDD, but I wasn't sure where it belonged, so I suppose I will post it here as well. 

I have a question about substrates. If two substrates which are acted upon by the same enzyme are coadministered, (regardless of whether either inhibits or induces that enzyme), what is the effect on the rate of metabolism of those two substrates (substances)? I would assume they would "compete" for the enzyme's attention -- thus possibly causing a raised available concentration of each substance for a shorter amount of time. I am not sure if I got the mechanism reversed, though. Would it be the opposite? Would it make no difference? Could someone help out? I was prescribed new meds and just want to be extra cautious.


----------



## ebola?

toastman said:
			
		

>



This compound looks pretty similar to apomorphine, morso than it does to bromocriptine, lsd, or any other known ergoloid, so standard SAR for well known DA agonists applies here.

ebola


----------



## ebola?

SoulSpark said:
			
		

> I would assume they would "compete" for the enzyme's attention



This is true under conditions where the enzyme is saturated or near-saturated by available substrates.  Under conditions where the enzyme is opulent, the presence of one substrate won't have much of an effect on metabolism of the other.

ebola


----------



## ebola?

I'm going to merge this into the "Big 'n' Bangin'" thread.

ebola


----------



## polymath

@Soulspark: If you administer two compounds that compete for the same enzyme, the rate of metabolism of both compounds is slowed down. This effect is stronger if the amount of enzyme is the rate-limiting variable in the metabolism. This is called competitive inhibition.

For example, alcohols are metabolized to the corresponding aldehydes by the enzyme alcohol dehydrogenase. Ethyl alcohol is typically ingested recreationally in amounts that are sufficient to saturate the enzyme and it is eliminated with constant rate instead of having a half-life. Here the amount of enzyme is the rate-limiting variable.

Methanol is also oxidized by alcohol dehydrogenase, but the product of this reaction is formaldehyde, which is toxic and causes damage to the optical nerve, resulting in blindness.

If methanol and ethanol are administered at the same time, ethanol is better at competing for the ADH enzyme. Therefore, if someone goes to the ER with methanol poisoning, they are treated by giving ethanol regularly around the clock, maintaining a BAC of about 0.15 for a couple of days. Because the competitive inhibition, methanol is then not oxidized to toxic formaldehyde, but is instead slowly excreted in the urine and exhaled air. This is an example of a practical application of competitive inhibition.


----------



## babylonboy

^I have a friend who accidentally ingested antifreeze whilst very drunk, and was hospitalised. The doctors said that, without so much ethanol in his body, he would most likely have been killed.


----------



## pharmakos

apomorphine always interested me.... i had such visual clarity with blue lotus.   that is an underexplored compound imo


----------



## pharmakos

sorry for the double post, but i feel i must lament the withering of entheogen.org

that was such an excellent site


----------



## Thanatos

Are there any books specifically dedicated to pharmakonetics and pharmacology that were written/compiled for the education of a novice in the field. I of course can always go look through my organic chem text books from college but I'd like to have some literature that focuses directly on the subject in question instead.
If you guys could compile a list of books I could buy instead of looking into online databases I would greatly appreciate it.


----------



## endotropic

entheo said:


> Are there any books specifically dedicated to pharmakonetics and pharmacology that were written/compiled for the education of a novice in the field. I of course can always go look through my organic chem text books from college but I'd like to have some literature that focuses directly on the subject in question instead.
> If you guys could compile a list of books I could buy instead of looking into online databases I would greatly appreciate it.



Every pharmacology text book I've ever come across expects a basic knowledge of molecular biology and human physiology at least, and usually some chemistry as well.  There might be some great resource out there exactly at your level, but I would suggest picking up some books on molecular biology and human physiology first.  Everything you learn will be much more meaningful if you have the right foundation to build on.

edit:  You are aware of the Erowid/BlueLight Neuropharmacology Text no?  That might be around the level you're looking for.


----------



## BallsStapledToLeg

entheo said:


> Are there any books specifically dedicated to pharmakonetics and pharmacology that were written/compiled for the education of a novice in the field. I of course can always go look through my organic chem text books from college but I'd like to have some literature that focuses directly on the subject in question instead.
> If you guys could compile a list of books I could buy instead of looking into online databases I would greatly appreciate it.



Best intro pharmacology book IMHO is Rang and Dales "Pharmacology", and older copies are easy to find online/college book stores. Be warned, you need a basic understanding of cellular biology and chemistry to make sense of a lot of it. However, it does a decent job explaining most of the broader points in those topics.


----------



## Thanatos

I have 3 years of organic chem, 2 years of biochem, and 4 years of university level Biology under my belt. I think I should be fine, if the concepts are explains thoroughly; without divergence from the topic at hand.


----------



## endotropic

entheo said:


> I have 3 years of organic chem, 2 years of biochem, and 4 years of university level Biology under my belt. I think I should be fine, if the concepts are explains thoroughly; without divergence from the topic at hand.



With that kind of experience you can pick up a textbook at any level.  Considering pharmacology is basically just a practical application of all of those disciplines I definitely wouldn't describe you as "a novice in the field".

If you want something very thorough you can't go wrong with any recent edition of Goodman and Gilman's The Pharmacological Basis of Therapeutics, especially if you're interested in therapeutic aspects.


----------



## Thanatos

Thank you sir, I appreciate it. I have the knowledge of most aspects of the subject, but the nuances of putting them together and understanding the dynamics of their mechanisms are a bit harder to teach yourself.
Ive never take a pharmacology course, so I wasnt sure what I would be gettin myself into.


----------



## jodasa

*heart rate and adhd medications*

The averige increase landed on 5 bpm after a national investigation how ever in sweden methylfenedrate is the most common drug (witch is strange couse we started to treet hyperactivety and som autistic condition with dexadrin 1936 and did so until ritalin (used as weightloss treatment since the 1955) and some other brands grabed the market after a 5 year ban on amfetaminbased treatment in the eyrly ninties. Any way it is fairly known that amfetaminsulfates/salt har less impact on cardio system then methylfenydrates. There are several options on drugs so wy not try out them untill you found the one that effect your hart the least? Its how it s usely done here anyway. If that drug is insufficient in other way then you can have another to use temperarely when you need it. Mostly the increase is not as high as it feels. And there is usely a way to get aourond this if you and your doctor are willing to experiement, som times a crossuse of different amfetaminesulfades and methylfenidades is the solution or it will simply go avay after a regural use, somtimes irregular use is worse in regard to the stressfactor. This issue is however very induvidual and will need a induvidual solution. There is hoewer no indications that adhd treatsment elivates the risk of serios hartfailuer. Hart condisions ar much more complex and is not determent by pulse and pressure alone. The reports of serius reaktions with the adhd drugs is with interraktions with ssri. But ofcurse its all up to you if you feel you want to have the treatments. 








Dysphoric said:


> How much exactly does your heart rate increase on Meth/Amps?
> 
> 1.) Lets say a fairly healthy individual took 40mgs of Adderall, how much would their heart rate go up?
> 2.) And now I want to know what the difference would be if instead they would take Desoxyn at around 20-30mgs, how much of increase?
> 
> I would assume Adderall (d-l Amphetamine) is slightly more Cardio-toxic, correct?
> 
> I'm curious because that is one thing that gives me anxiety when it comes to drugs, is fast BPM (tachycardia) I have a prescription for Desoxyn, but I've hardly touched it and now that I've started college I want to start taking here and there, around 20-30 mgs. I can handle an increase in BPM, I just don't like too fast, obviously.
> 
> Also, I've talked to most of my friends that I've let try Desoxyn before and they said it hardly raised their BPM (vs Adderall), so would Desoxyn hardly touch my BPM at around 20-30mgs?
> 
> Also, I'm referring to Oral dosing.


----------



## babylonboy

I assume it's complex, but determines wheher or not a compound in the solid pase is soluble in its liduid phase? Ice doesn't disolve in water, are there substances that for autosolutes? If so, why?


----------



## pharmakos

technically ice *does* dissolve in water, it just takes a bit =p

depending on the temperature of the external environment, of course.  if the external environment is cold enough then the water will also turn into ice.


----------



## babylonboy

Really? I thought the solid phase was virtually insoluble.


----------



## pharmakos

depends how you look at it -- drop some ice cubes into room temperature water and eventually... does the ice melt, or does it dissolve?  to me the difference seems to mostly be a matter of semantics.


----------



## sekio

Ice in water can be an equilibrium state where ice forms/"precipitates" and redissolves/"melts"... see also: a Slurpee machine.


----------



## ebola?

Is it logically coherent to claim that a compound is its own solvent?

ebola


----------



## pharmakos

^ it is definitely a little ambiguous under current definitions

In chemistry, a solution is a homogeneous mixture composed of only one phase. In such a mixture, a solute is a substance dissolved in another substance, known as a solvent. The solvent does the dissolving. The solution more or less takes on the characteristics of the solvent including its phase, and the solvent is commonly the major fraction of the mixture. The concentration of a solute in a solution is a measure of how much of that solute is dissolved in the solvent.

Characteristics

- A solution is a homogeneous mixture
- The particles of solute in solution cannot be seen by naked eye.
- The solution does not allow beam of light to scatter.
- A solution is stable.
- The solute from the solution cannot be separated by filtration (or mechanically).

....

solution -- 

a :  an act or the process by which a solid, liquid, or gaseous substance is homogeneously mixed with a liquid or sometimes a gas or solid
b :  a homogeneous mixture formed by this process; especially :  a single-phase liquid system
c :  the condition of being dissolved

....

would it make a difference if the ice was entirely made of heavy water (D2O) and the liquid entirely of "regular" water?

....

“There are no differences but differences of degree between different degrees of difference and no difference.” -- William James

perhaps the place where i took this discussion would be better suited for the Philosophy forum =p


----------



## psood0nym

> Ice in water can be an equilibrium state where ice forms/"precipitates" and redissolves/"melts"... see also: a Slurpee machine.


I find this video of tertbutylalcohol's triple point fascinating to watch.





Have theories seeking to explain the subjective variability of open eye visual intensity experienced between non-tolerant equally dosed psychedelic sessions been forwarded? If not, what are the key factors thought to modulate this variability within the brain? Presumably open eye visuals manifest perceptually due to the presence of psychedelic compounds within the visual cortex and connected regions altering normal signalling patterns (typically through net decreases in activity if my memory serves), but what pharmacodynamic factors dictate transference of compounds within these regions and what are the most promising practical measures that might be taken to modulate them?


----------



## SONN

Thanatos said:


> Are there any books specifically dedicated to pharmakonetics and pharmacology that were written/compiled for the education of a novice in the field. I of course can always go look through my organic chem text books from college but I'd like to have some literature that focuses directly on the subject in question instead.
> If you guys could compile a list of books I could buy instead of looking into online databases I would greatly appreciate it.



this might really help if you're looking for psychedelic pharmacology

Dr. Nichols is a good teacher. I feel as though I absorbed up until some of the SAR stuff quite nicely. I only have a college course called "brain matters" under my belt so maybe you'd get more out of it than me 

edit: actually theres a lot of unpublished data he uses in various parts of the video so even some of you really well versed in psychedelic pharmacology could learn a thing or two from that video series. MAPS is truly a wonderful thing.


----------



## MrKhazar

SONN said:


> this might really help if you're looking for psychedelic pharmacology
> 
> Dr. Nichols is a good teacher. I feel as though I absorbed up until some of the SAR stuff quite nicely. I only have a college course called "brain matters" under my belt so maybe you'd get more out of it than me
> 
> edit: actually theres a lot of unpublished data he uses in various parts of the video so even some of you really well versed in psychedelic pharmacology could learn a thing or two from that video series. MAPS is truly a wonderful thing.



Thank you good sir.


----------



## SONN

So this is more of an organic chemistry question but, is there a fermenting process that could produce tert-amyl alcohol rather than ethyl alcohol? I know that tert-amyl-alcohol a byproduct of large brewing operations, but could there be a practical way to brew a beer with negligible amounts of alcohol but a substantial amount of tert-amyl-alcohol? I suppose someone with extensive knowledge of the fermentation process could at least give me a point of reference.


----------



## Black

no. the metabolism of yeast in conditions with low oxygen concentration goes from glucose to pyruvate to acetaldehyde to ethanol. you could certainly produce t-amyl alcohol with GMO yeast (probably even normal yeast, but i don't have the relevant textbook here), but you'd also have to feed it different chemicals.


----------



## Limpet_Chicken

Re: apomorphine-it is unlikely to lead to anything pleasant, save maybe in microdoses. It is a very potent emetic.


----------



## jackie jones

Can anyone tell me how well pure GABA crosses the BBB?


----------



## sekio

It doesn't, to the best of my knowledge. Too polar.


----------



## ebola?

Do we know of any selective VMAT2 inhibitors?  To the extent that we do not, what aspects of SAR (of families of compounds that interact with monoamine transporters) would cause their rarity?  Is the structure of VMAT2 similar to these transporters?

ebola


----------



## sekio

Tetrabenazine and reserpine?


----------



## ebola?

whoops: was I thinking of VMAT2 substrates instead?

ebola


----------



## ebola?

useful chart:






I'm wondering, though, if it's missing pertinent intracellular processes involving the NMDA receptor...

ebola


----------



## pharmakos

hare-brained, likely underinformed thought: 

would it be possible to create a drug test for hallucinogens as a broad class via testing for downstream biochemical reactions? (perhaps arachidonic acid levels or some such)

what would the moral and philosophical ramifications of such a test be?


----------



## pharmakos

^ perhaps better left unexplored, i suppose.


new question:






this common food coloring^, Red #40 aka Allura Red AC, has been linked to hyperactivity and attention deficit disorder in children.  any theories as to the mechanism of action that causes those effects?


----------



## endotropic

thenightwatch said:


> hare-brained, likely underinformed thought:
> 
> would it be possible to create a drug test for hallucinogens as a broad class via testing for downstream biochemical reactions? (perhaps arachidonic acid levels or some such)
> 
> what would the moral and philosophical ramifications of such a test be?



You're thinking of a blood test or something?  Probably not possible, hallucinogens have such pharmacologyically diverse mechanisms that the downstream signaling won't match up from class to class.  If there is some downstream biochemical event that occurs with every hallucinogen, it's probably localized to one brain region, and the effect would be too small to detect in the blood.  

I bet someone could devise an fMRI based test that would identify hallucinating people, but that wouldn't really be useful for anything.


----------



## Black

endotropic said:


> You're thinking of a blood test or something?  Probably not possible, hallucinogens have such pharmacologyically diverse mechanisms that the downstream signaling won't match up from class to class.  If there is some downstream biochemical event that occurs with every hallucinogen, it's probably localized to one brain region, and the effect would be too small to detect in the blood.
> 
> I bet someone could devise an fMRI based test that would identify hallucinating people, but that wouldn't really be useful for anything.



for classical psychedelics you could theoretically measure the second messenger responses in a cell culture population expressing the 5-ht2a receptor, but it would obviously take too long and be too labour-intensive, equipement-intensive and expensive for practical use. besides the person you want to test would in all likelyhood be a lifeless and most of all blood-less husk if you want to gather enough material for this test to work (given current methods).


----------



## sekio

> this common food coloring^, Red #40 aka Allura Red AC, has been linked to hyperactivity and attention deficit disorder in children. any theories as to the mechanism of action that causes those effects?



Food dyes in general are bogeymen because downstream metabolites could include shit like anilines and benzidines that are, well, not good.


----------



## pharmakos

^ yeah seems like it

i was looking at some other food colorings.... Blue #1 here looked like it could potentially have some active metabolites to me:


----------



## sekio

Those sulfonate groups decrease the likelihood of anything actually crossing the BBB much; they are charged at physiological pH and only become nonpolar in acidic media.

Realistically, there are lots of outright crazy wierd structures in artificial colors. Tartrazine and erythrosine are some of my faves.


----------



## vortech

I'm confused why there is still so much confusion about the pharmacological actions of Methoxetamine. After this binding data was made public (http://www.bluelight.org/vb/threads/649843-Binding-data-for-popular-arylcyclohexamines/) people were scratching their heads because most had thought that it increased levels of dopamine in the brain, yet this binding data shows that there isn't any action that directly releases or inhibits dopamine reuptake. Is there some other way that it could increase dopamine levels? Maybe it only has an action at higher doses and this was tested with low doses? People were saying the same with the mu opioid affinity, that according to this it doesn't have an affinity, but maybe it does at higher doses (at least may be the case for ketamine). 
Any clarification would be appreciated! Up until today I had thought MXE has DRI properties.


----------



## sekio

> I'm confused why there is still so much confusion about the pharmacological actions of Methoxetamine.



Conformation bias.

I for one trust the ECMD numbers pretty well.


----------



## endotropic

vortech said:


> I'm confused why there is still so much confusion about the pharmacological actions of Methoxetamine. After this binding data was made public (http://www.bluelight.org/vb/threads/649843-Binding-data-for-popular-arylcyclohexamines/) people were scratching their heads because most had thought that it increased levels of dopamine in the brain, yet this binding data shows that there isn't any action that directly releases or inhibits dopamine reuptake. Is there some other way that it could increase dopamine levels? Maybe it only has an action at higher doses and this was tested with low doses? People were saying the same with the mu opioid affinity, that according to this it doesn't have an affinity, but maybe it does at higher doses (at least may be the case for ketamine).
> Any clarification would be appreciated! Up until today I had thought MXE has DRI properties.



Based on that evidence, we don't know whether MXE increases dopamine levels in the brain or not.  All that we can say is that MXE doesn't increase dopamine levels by inhibiting the dopamine reuptake transporter.  Or in other words we could say that MXE doesn't DIRECTLY increase dopamine levels.

There are plenty of INDIRECT ways that MXE could increase dopamine levels, none of which are ruled out by binding data.  For example antagonism of NMDA receptors on GABAergic interneurons connected to the dopamine system could disinhibit dopamine release.  In all likelihood the interaction is much more complicated than that.  Here's a couple of reviews on the interaction between Glutamate and Dopamine signaling:

http://www.ncbi.nlm.nih.gov/pubmed/24735820
http://www.ncbi.nlm.nih.gov/pubmed/22763587
http://www.ncbi.nlm.nih.gov/pubmed/24409148

Also keep in mind, with the possible exception of 5-HT2A psychedelics, every single recreational drug increases striatal dopamine levels, and only a small proportion of those do so through a direct mechanism (see the 3rd review posted above).  With that in mind it would be incredibly strange if MXE didn't increase dopamine levels in the brain, considering how readily people  take it.


----------



## vortech

Thank you endotropic, that's exactly the information I was looking for.  
I was also just reading this article on PCP http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859735/ and read that PCP increases dopamine and norepinephrine production by stimulating tyrosine hydroxylase, so I am seeing the other ways in which drugs can increase neurotransmitter levels.


----------



## endotropic

^ That's really interesting about PCP, tyrosine hydroxylase is one step I never would have even considered for an interaction!

edit: I decided to go back and read more about PCP and tyrosine hydroxylase so I did some reading and found this:

Phencyclidine: behavioral and biochemical evidence supporting a role for dopamine.

They claim that PCP's stimulatory effect on tyrosine hydroxylase is indirect, a consequence of its dopamine reuptake inhibition.  Other dopamine reuptake inhibitors share this effect, while drugs like MXE without dopamine reuptake inhibition don't affect TH like this.


----------



## BallsStapledToLeg

Is anyone aware of studies covering different pharmacokinetics or dynamics of drugs (more specifically MDMA) in Native American populations? I swear every time I hear of a case of massive acute MDMA toxicity in my region it seems to consistently be an aboriginal female. Any info or educated conjecture would be appreciated

Thanks,
Balls


----------



## endotropic

BallsStapledToLeg said:


> Is anyone aware of studies covering different pharmacokinetics or dynamics of drugs (more specifically MDMA) in Native American populations? I swear every time I hear of a case of massive acute MDMA toxicity in my region it seems to consistently be an aboriginal female. Any info or educated conjecture would be appreciated
> 
> Thanks,
> Balls



Off the top of my head I could probably point you towards a dozen studies showing increased incidence of drug use amongst Native Americans in the US, but I haven't seen anything like you're asking about specifically for MDMA.  Take a look at these though (especially the last):

Prevalence of CYP2C19 variant alleles and pharmacodynamic variability of aspirin and clopidogrel in Native Americans.

Pharmacogenetics in American Indian populations: analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the Confederated Salish and Kootenai Tribes.

Evidence for a genetic component for substance dependence in Native Americans.


Moving you in the right direction I hope


----------



## geron13

hello chemistry people hopefully.  could someone explain the difference and differing affects of [FONT=&#40657]C18H21NO4 [/FONT]Boc-3-(2-naphthyl)-D-alanine,  CAS：[FONT=&#40657]76985-10-9[/FONT][FONT=arial, 宋体, sans-serif]    and the oxycodone pills people receive for pain?  if any.   thanks.  [/FONT]


----------



## ebola?

What?  Can you explain how they're similar?

ebola


----------



## endotropic

geron13 said:


> hello chemistry people hopefully.  could someone explain the difference and differing affects of [FONT=黑]C18H21NO4 [/FONT]Boc-3-(2-naphthyl)-D-alanine,  CAS：[FONT=黑]76985-10-9[/FONT][FONT=arial, 宋体, sans-serif]    and the oxycodone pills people receive for pain?  if any.   thanks.  [/FONT]




The real question is, what makes you think they should have any similarity?  The chemical you mentioned is totally unknown (best I can tell) and the chemical structure is nothing like oxycodone.


----------



## sekio

They both have 18 carbons, 21 hydrogens, 1 nitrogen, and 4 oxygens. That's the end of the similarities 

Compare the structures:
Boc-3-(2-Naphthyl)-D-alanine





Oxycodone


----------



## pr0d1gy

Nichols published a paper demonstrating the activity of benzofuran analogs of some tryptamine. I was wondering if this trend might extend to thianaphthene as well. Thianaphthene is quite different in terms of electronics and reactivity relative to indole and benzofuran. I'd imagine it would also be very different in terms of biochemistry as the sulfur is fairly easily oxidized, maybe it would be excreted much fast? 

I am quite curious about this, but I don't have any real biochemistry/pharma experience. I've been searching around a bit but haven't found much. If anything I've found my organic experience makes it much more difficult for me to wrap my head around bio and pharma publications. It messes with my mind that what might be considered analogous in organic doesn't apply in the realm of biochemistry so much.


----------



## toastmann

Just a quick question, why don't scopolamine and cocaine share (at least a few) pharmacological mechanisms, since the structures look so similar?

You'd expect they would if you compared the structure.


----------



## AlphaMethylPhenyl

Therapeutic doses of amp don't deplete DA stores

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753078/


----------



## sekio

> Just a quick question, why don't scopolamine and cocaine share (at least a few) pharmacological mechanisms, since the structures look so similar?



The arrangement of atoms in space matter more than the skeleton of the compound mapped to 2d. In atropine the tropine group has the hydroxyl pointing down (axial), while in cocaine the hydroxyl points "up" (equatorial).

Also, for stimulant efficacy you need to have that carbomethoxy group that cocaine and methylphenidate share. This is why stuff like lidocaine is just an anesthetic and stuff like tropacocaine (cocaine minus the carbomethoxy group) is basically not worth writing home about either.


----------



## AlphaMethylPhenyl

Anyone know to what extent amp inhibits maoi, and if its a b or a inhibitor? comparisons with dose of phenelzine/tranylcypromine?


----------



## sekio

14 to 20 micromolar Kd at human placental MAO-A for D-amph (14,000-20,000 nM). (Moclobemide is 200-400 nM) And it's reversible. Essentially no activity at MAOB. Not worth worrying about I think.

http://link.springer.com/article/10.1163/156856003765764290#page-1



> The  discovery  that  MAO  exists  in  two functionally  distinct  activities  {MAO-A and  MAO-B)  was  followed  by  studies showing  AMPH  to  be  a  preferential MAO-A  inhibitor.  In  vitro,  (+)-AMPH is  many  times  more  active  against MAO-A  than against  MAO-B.  Also  the (+)-isomer  is  at  least  3  to  4  times  more active against  MAO-A  than  the (-)-forms”.  However,  AMPH  is a  reversible  MAO  inhibitor  and  as  such  it  is difficult  to  show  a  direct  inhibitory  effect  in  vivo. [...]


http://www.sciencedirect.com/science/article/pii/0165614780900322


----------



## AlphaMethylPhenyl

genius, thanks


----------



## JBrandon

Ho-chi, 
I honestly thought for the last decade that you wouldn't deplete DA as long as you kept the dose low, had acceptable nutrition, and slept regularly.

 I truly didn't know there was a concern about DA depletion at reasonable doses!


----------



## surly1

Anyone have a guess as to how turn AL-LAD ( http://en.wikipedia.org/wiki/AL-LAD ) freebase into a salt?


----------



## pharmakos

^ i've heard that is a difficult one to salt for some reason.  dunno details as to why.


----------



## surly1

thenightwatch said:


> ^ i've heard that is a difficult one to salt for some reason.  dunno details as to why.



It's not as simple as mixing a solution of the freebase with a solution of an acid? That would raise the question of what is the freebase soluble in?


----------



## Jabberwocky

JBrandon said:


> Ho-chi,
> I honestly thought for the last decade that you wouldn't deplete DA as long as you kept the dose low, had acceptable nutrition, and slept regularly.
> 
> I truly didn't know there was a concern about DA depletion at reasonable doses!



He said there's _not_ depletion at therapeutic doses.


----------



## twoci

surly1 said:


> Anyone have a guess as to how turn AL-LAD ( http://en.wikipedia.org/wiki/AL-LAD ) freebase into a salt?


 Dissolve the freebase in chloroform, add tartaric acid dropwise with stirring until precipitation ceases, collect the precipitate.


----------



## sekio

Tartaric acid is a solid? Do you mean make a solution first?

from TiHKAL LSD:



> This base was dissolved in warm, dry MeOH, using 4 mL per g of product. There was then added dry d-tartaric acid (0.232 g per g of LSD base), and the clear warm solution treated with Et2O dropwise until the cloudiness did not dispel on continued stirring. This opaqueness set to a fine crystalline suspension (this is achieved more quickly with seeding) and the solution allowed to crystallize overnight in the refrigerator. Ambient light should be severely restricted during these procedures. The product was removed by filtration, washed sparingly with cold methanol, with a cold 1:1 MeOH/Et2O mixture, and then dried to constant weight. The white crystalline product was lysergic acid diethylamide tartrate with two molecules of methanol of crystallization, with a mp of about 200 °C with decomposition, and weighed 3.11 g (66% ). Repeated recrystallizations from methanol produced a product that became progressively less soluble, and eventually virtually insoluble, as the purity increased. A totally pure salt, when dry and when shaken in the dark, will emit small flashes of white light.


----------



## Jabberwocky

> A totally pure salt, when dry and when shaken in the dark, will emit small flashes of white light.


lsd can emit flashes in the dark?  how fitting :D
[edit: holy shit i just heard he died... RIP mr. shulgin  ]


----------



## crOOk

thenightwatch said:


> ^ yeah seems like it
> 
> i was looking at some other food colorings.... Blue #1 here looked like it could potentially have some active metabolites to me:


The article you are referring to must be this one: http://www.feingold.org/Research/PDFstudies/Stevenson2007.pdf

They were using a mix of various coloring agents and sodium benzoate. Yes, allura red ac was contained in one of those mixes, but there really is no strong evidence showing that allura red ac would exacerbate adhd symptoms or induce hyperactivity in healthy children. There is a shit ton of articles on this, most of them financed by the food industry. Good luck finding any conclusive information lol. One issue is that almost no one will let anyone perform tests on their children with excessive doses of food additives that are proven to be toxic, even if only at very high doses. I honestly don't know how they even pulled off that 2007 study, but I'm not too familiar with this field anyway.



surly1 said:


> Anyone have a guess as to how turn AL-LAD ( http://en.wikipedia.org/wiki/AL-LAD ) freebase into a salt?


You must have a shitload of AL-LAD... I wouldn't try this on just a few mg personally.

@sekio: Wouldn't the process suggested there fail to yield a racemate (for lack of a better word when 4 isomers are present) if d-tartaric acid was used? "d-lsd" is the right isomer for lsd (its d at both the 5th and 8th c), but is it the same for al-lad? (edit: i guess it should be since it has the same stereocenters. i guess its safe to assume that d-al-lad is also the active isomer of al-lad, so forget what i said, im not familiar with lsd chemistry. :D )


----------



## AlphaMethylPhenyl

sekio said:


> 14 to 20 micromolar Kd at human placental MAO-A for D-amph (14,000-20,000 nM). (Moclobemide is 200-400 nM) And it's reversible. Essentially no activity at MAOB. Not worth worrying about I think.
> 
> http://link.springer.com/article/10.1163/156856003765764290#page-1
> 
> 
> http://www.sciencedirect.com/science/article/pii/0165614780900322



Any idea at what dose amp would significantly (in a statistical sense, meaning that it has antidepressant effects basically) inhibit maoi? My guess is it's higher than all but a few users would ingest. I wonder because I took a therapeutic dose of it and wanted to know whether the AD effect I experienced was sustainable or not. Thanks.


----------



## endotropic

Ho-Chi-Minh said:


> Any idea at what dose amp would significantly (in a statistical sense, meaning that it has antidepressant effects basically) inhibit maoi? My guess is it's higher than all but a few users would ingest. I wonder because I took a therapeutic dose of it and wanted to know whether the AD effect I experienced was sustainable or not. Thanks.



Take a look at this article:

http://www.ncbi.nlm.nih.gov/pubmed/16343411



> Group 4 ranged from 0.54 mg/l to 1.00 mg/l, corresponding to the Cmax after the intake of approximately 140–300 mg amphetamine.



Let's just assume the 1.00mg/l corresponds to the 300mg dose.  That works out to 7.39uM concentration in the blood.  So even with a 300mg dose you're not even approaching the Kd.  That's at a maximal blood level as well, levels will be much lower for the majority of the experience.  d-Amph as an MAOI is all but an in vitro experimental artifact - it doesn't happen in practice.


----------



## AlphaMethylPhenyl

I'd imagine that has to do with a lack of patience combined with...never mind, the study wasn't done in the US. I was going to say combined with over-prescribing. n>1000, nice. The study does mention that since these were people who had been illicitly found to be taking it from drug testing, the dose was more like 50mg-300mg, 60mg being the maximum recommended amount in many countries. Some need a higher dose but I'd doubt you would find a lot of people taking 100mg or more, but I guess in some places (like America) people are fat as all hell. Some pertinent information on the matter: http://pro.psychcentral.com/prescribing-and-dosing-stimulants-practical-issues/004421.html#. (obviously if its abused you're kind of screwed)

Anyways I think evaluating amphetamine-induced cognitive deficits/benefits based on driving is a little bit forward seeing as driving involves things you wouldn't have to deal with when taking an IQ test, doing paperwork, or otherwise completing a more individualized cognitive task. Of course stimulants raise blood pressure, high blood pressure being a main contributor to road rage. We all know that getting too angry or excited leads to that animalistic feeling that impairs you overall. Thanks for the source though.


----------



## endotropic

I'll admit I didn't read the article in any detail, I just used it to find a blood concentration associated with a dose range to answer your MAOI question.


----------



## vortech

Dr. Mind said:


> New studies on neurological compounds have found that these new compounded chemicals can tap into an area of receptors damaged by drug or alcohol use, and slowly repair them to their normal state.



What compounds are you referring to? 
I've heard this same thing said of ketamine when used therapeutically and suspect MXE is capable of the same in the right amount.
Regarding MXE, on the last page of this thread I brought up MXE pharmacology and was interested in how it could increase dopamine levels even though it may not actually be a DRI or agonist directly.  I was looking for evidence that the changes in glutamate function could cause changes in dopamine levels and, indeed, found this: http://apt.rcpsych.org/content/8/3/189.full " Thus, a reduced glutamate function, for example as induced by ketamine, may cause some elevation of dopamine release" 
So there's that.


----------



## ebola?

^^^^
The guy you were replying to was a bizarre spammer who was banned.
...
But what indications do we have that these changes would be positive?  I also suspect that the benefit doesn't extend to chronic usage, which at the very least lays outside the study's scope.

ebola


----------



## Jktm

would 2mg of Prazosin (an α-antagonist) completely block the effects of amphetamines (300mg IV methamphetamine to be exact)? I take it for nightmares for PTSD, but thinking of dropping the med anyway and trying to get through them without it, but if the opportunity arises, "I dun wanna waste ma skrilla. Yanno wudda meen, monika?"


----------



## AlphaMethylPhenyl

Hate to be that guy, but if you have nightmares from PTSD so terrible that you need medication then 300mg intravenous methamphetamine definitely isn't for you. It could make things much permanently worse.


----------



## ebola?

^^^^^
He's essentially right.
...
Unopposed beta agonism doesn't pose the same danger as unopposed alpha agonism (as the beta receptor exerts cardio effects similar to amp), so I think that you're okay, but your dose of meth is really high, and I'm not 100 percent confident in my info.

ebola


----------



## DL-ark

So, whats the deal with apigenin? It has a 0.2% BA from parsley but is supposed to be the active constituent in chamomile tea. It has a rich non selective pharmacology. GABA PAM and second order pam. It also has effects on adenosine and Serotonin reuptake.

What is also interesting about chamomile tea is that it has been shown to increase glycine levels in humans. Perhaps something in it is a glycine releaser?


----------



## black53

Is there any rule about how benzodiazepines changed to their thienodiazepine analogues (and the other way around) perform?

For example would the benzo version of etizolam retain activity:





Or the thieno version of alprazolam:


----------



## pharmakos

does Tums actually increase absorption of opiates, or is that just a myth?


----------



## DL-ark

thenightwatch said:


> does Tums actually increase absorption of opiates, or is that just a myth?


I don't know whether it would absorb more opiates than normal, but it would probably absorb slower.


----------



## AlphaMethylPhenyl

Which NMDA antagonist would you hypothesize best creates the model of schizophrenia? Why?


----------



## sekio

MK801 probably does a great job. I think that's what they use in primate models.


----------



## ebola?

I'm just skeptical of the whole idea of a psychotomimetic.  That a drug causes hallucinations and delusions does not suggest that it is qualitatively similar to organic psychosis, let alone any particular specific type thereof.  Even the analogy between stimulant psychosis and paranoid schizophrenia is incomplete.  And even if two states are qualitatively similar, this does not entail that they have similar biochemical bases.

In short, knowledge about one type of crazy rarely sheds light on another.

ebola


----------



## endotropic

^ Great place to start though no?  I mean you're right to be skeptical, drug induced psychosis never fully mimics schizophrenia.  But studying psychotomimetic states allows us to tie a specific biochemical change to a psychotic state, then make predictions based on that association about causes/treatments for endogenous psychosis.  When those predictions don't hold up it still informs what we know about those conditions, even though the model isn't perfecr.


----------



## crOOk

endotropic said:


> ^ Great place to start though no?  I mean you're right to be skeptical, drug induced psychosis never fully mimics schizophrenia.  But studying psychotomimetic states allows us to tie a specific biochemical change to a psychotic state, then make predictions based on that association about causes/treatments for endogenous psychosis.  When those predictions don't hold up it still informs what we know about those conditions, even though the model isn't perfecr.


This.^ QFT


----------



## DL-ark

Yeah, but they used to use psychedelics to mimic schizophrenia and psychosis. We now know that psychedelia is very, very different from schizophrenia. Testing for psychotic symptoms on animals with any sort of hallucinogenic or proposed psychotomimetic is going to turn up looking pretty similar to schizophrenia, simply because a lot of their surface symptoms are similar. If one wants to understand schizophrenia using drugs, one must find a drug that acts uniquely both chemically, and on the subjective effects in humans. To test this again, a pharmacologically similar chemical should be tested. If they both have effects which in humans, in vivo, cause symptoms highly reminiscent of both the negative and positive effects of schizophrenia, then perhaps you have found how the disease works. Unless NMDA antagonist dissociatives all have highly schizophrenic-like symptoms, then perhaps you have found something. Unless MK801 or something very structurally similar exists in the human brain in schizophrenic patients, it is not very helpful.


----------



## crOOk

DL-ark said:


> Yeah, but they used to use psychedelics to mimic schizophrenia and psychosis. We now know that psychedelia is very, very different from schizophrenia. Testing for psychotic symptoms on animals with any sort of hallucinogenic or proposed psychotomimetic is going to turn up looking pretty similar to schizophrenia, simply because a lot of their surface symptoms are similar. If one wants to understand schizophrenia using drugs, one must find a drug that acts uniquely both chemically, and on the subjective effects in humans. To test this again, a pharmacologically similar chemical should be tested. If they both have effects which in humans, in vivo, cause symptoms highly reminiscent of both the negative and positive effects of schizophrenia, then perhaps you have found how the disease works. Unless NMDA antagonist dissociatives all have highly schizophrenic-like symptoms, then perhaps you have found something. Unless MK801 or something very structurally similar exists in the human brain in schizophrenic patients, it is not very helpful.


I agree that intoxications with classical/serotonergic psychedelic is usually very unlike schizophrenia, but I have seen and experienced my fair share of psychedelics induced psychotic episodes (sometimes only for the duration of the intoxication) which strongly resemble paranoid schizophrenia to the last detail, both in people who turned out to be schizophrenic later in life and people who were never diagnosed with any psychotic illness. That being said, some dissociatives resemble schizophrenia a lot more I think, e.g. diphenidine and pcp come to mind.

Also it's probably noteworthy that when I had my first full-blown manic episode, I saw visuals that were subjectively identical to those I see on low dose tryptamines. However different all these states might be, they also bear some resemblance in many aspects.


----------



## DL-ark

crOOk said:


> I agree that intoxications with classical/serotonergic psychedelic is usually very unlike schizophrenia, but I have seen and experienced my fair share of psychedelics induced psychotic episodes (sometimes only for the duration of the intoxication) which strongly resemble paranoid schizophrenia to the last detail, both in people who turned out to be schizophrenic later in life and people who were never diagnosed with any psychotic illness. That being said, some dissociatives resemble schizophrenia a lot more I think, e.g. diphenidine and pcp come to mind.
> 
> Also it's probably noteworthy that when I had my first full-blown manic episode, I saw visuals that were subjectively identical to those I see on low dose tryptamines. However different all these states might be, they also bear some resemblance in many aspects.


All I am saying is that the purpose of using drugs to mimic schizophrenia is that if you make a drug, you will be able to know its pharmacology, and if it induces schizophrenesque psychosis without failure, then you can study its pharmacology and therefore learn the pharmacology of schizophrenia. Certain drugs causing psychotic episodes or full blown psychosis is not the same as this.


----------



## ebola?

endo said:
			
		

> Great place to start though no? I mean you're right to be skeptical, drug induced psychosis never fully mimics schizophrenia. But studying psychotomimetic states allows us to tie a specific biochemical change to a psychotic state, then make predictions based on that association about causes/treatments for endogenous psychosis.



Right, this is useful, but at no point does it actually confirm the set of physiological processes underlying organic psychoses.  Even with a properly psychotomimetic drug, we wouldn't gain a firm understanding of such, nor does the pharmacology of prevailing treatments provide a great deal of useful evidence.  I hypothesize that the causal processes underlying organic psychosis occur at the ontological and epistemological level of neural circuits, so looking for a receptor or neurotransmitter that "mediates schizophrenia" is wrong-headed in the first place.  However, this wouldn't preclude effective treatments rooted in drug-receptor interactions.

ebola


----------



## crOOk

ebola? said:


> Right, this is useful, but at no point does it actually confirm the set of physiological processes underlying organic psychoses.  Even with a properly psychotomimetic drug, we wouldn't gain a firm understanding of such, nor does the pharmacology of prevailing treatments provide a great deal of useful evidence.  I hypothesize that the causal processes underlying organic psychosis occur at the ontological and epistemological level of neural circuits, so looking for a receptor or neurotransmitter that "mediates schizophrenia" is wrong-headed in the first place.  However, this wouldn't preclude effective treatments rooted in drug-receptor interactions.
> 
> ebola


You are making valid points there and if you asked me the entire psychopharmacological field would be on the wrong track if it simply kept looking "for a receptor or neurotransmitter that" mediates any psychiatric illness. Your hypothesis is probably correct, at least I would agree, but I don't think that makes a case against the idea of using drug induced parapsychotic states to gain a better understanding of the processes involved in what we actually refer to as psychotic states. 

We have a good concept of what "the ontological and epistemological level" consists of from a philosophical point of view, but there is very little (->no) understanding of the neurophysiological implications. Integrating these concepts into the picture should indeed be a long term goal and needless to say most neuroscientists will agree that a single proteine will not supply any answers. However at the current time our psychopharmaceuticals are simply at a very early, I dare say primitive stage and all we can really do is target select proteins and more often than not select actually means random ("look at what pushing this does, we didn't see that coming, did we?"). So for the time being, it might not be so bad to focus on this strategy for within-our-grasp treatment options which have already saved countless lives while still keeping in mind that we are actually not really on track in our quest to understand psychiatric illness.


----------



## InterestingFACT

DL-ark said:


> All I am saying is that the purpose of using drugs to mimic schizophrenia is that if you make a drug, you will be able to know its pharmacology, and if it induces schizophrenesque psychosis without failure, then you can study its pharmacology and therefore learn the pharmacology of schizophrenia. Certain drugs causing psychotic episodes or full blown psychosis is not the same as this.


Hold on here, this is not necessarily--and in fact probably is not--true. 

Just because a drug mimics schizophrenia does not mean that something endogenous is mimicking that drug in the schizophrenic brain. Rather, to use an example, if stimulant psychosis can imitate schizophrenia it would be because the excess dopaminergic activity relative to other neuronal activity would be simulating the outcome of a brain that has differing numbers either of dopaminergic neurons, neurons that synapse onto dopaminergic neurons, or neurons that dopaminergic neurons synapse onto. 

In other words, it doesn't tell you much of anything about dopamine and schizophrenia, but rather--once you examine the dopamine neuron subtypes most related the the schizoid activity--can tell you what physical portions of the brain are behaving differently in the schizophrenic model.


----------



## AlphaMethylPhenyl

ebola? said:


> Right, this is useful, but at no point does it actually confirm the set of physiological processes underlying organic psychoses.  Even with a properly psychotomimetic drug, we wouldn't gain a firm understanding of such, nor does the pharmacology of prevailing treatments provide a great deal of useful evidence.  I hypothesize that the causal processes underlying organic psychosis occur at the ontological and epistemological level of neural circuits, so looking for a receptor or neurotransmitter that "mediates schizophrenia" is wrong-headed in the first place.  However, this wouldn't preclude effective treatments rooted in drug-receptor interactions.
> 
> ebola



You're essentially stating that there isn't a biological route explaining schizophrenia? That the environment and sense of self determines it, so that we can't find its source? Dualism? Don't understand...

Perhaps you're bridging into the territory of stating that it's merely an illness relative to environment, which is okay, but it seems like a bit of a fallacy given the original statement.


----------



## endotropic

Ho-Chi-Minh said:


> You're essentially stating that there isn't a biological route explaining schizophrenia? That the environment and sense of self determines it, so that we can't find its source? Dualism? Don't understand...
> 
> Perhaps you're bridging into the territory of stating that it's merely an illness relative to environment, which is okay, but it seems like a bit of a fallacy given the original statement.



Well, if I may speculate on ebola?'s thoughts for a moment (dangerous proposition, I know), I think he means that schizophrenia is far more complicated than "too much of neurotransmitter A, too little of receptor B" which are the kinds of questions we can answer with neuropharmacological studies.  Instead subtle developmental changes in neural organization might explain the true genesis of the disease more accurately - changes brought about by a combination of genetic abnormalities and various life experiences.  How'd I do ebola?? 

I still think psychotomimetic neuropharmacological models are the best way to understand those differences in a preclinical setting though.  You can't ask an animal if they're paranoid, or what the voices in their heads are saying, so we need some method to reliably induce "a psychosis-like state".  I can't really imagine how you would study psychosis in an animal without some manipulation that causes psychosis in humans, but I'm not very imaginative either.  Maybe if we can find a genetic profile that 100% reliably causes psychosis in humans (gosh I hope not) we can use that profile in animals, but we don't have that yet.


----------



## crOOk

endotropic said:


> I still think psychotomimetic neuropharmacological models are the best way to understand those differences in a preclinical setting though. You can't ask an animal if they're paranoid, or what the voices in their heads are saying, so we need some method to reliably induce "a psychosis-like state".


Exactly. We run into similar issues when it comes to researching affective illness. What we have been doing successfully for quite some time now is mimicking depression in lab animals. Either through genetic knockouts, pharmacological treatment or training. None of these states is ever the same as the specific depressive state of a particular individual, since the pathogenesis and symptoms of depression show a huge variance (the same goes for psychotic states), but they still comes close enough for us to find remedies and to find whatever clues we pick up on the way bit by bit. It's simply all we got and we have to work with it for the time being.


----------



## AlphaMethylPhenyl

So if harmaline isn't responsible for the majorly addictive principles of tobacco relative to nicotine itself, what chemicals might be?


----------



## endotropic

Ho-Chi-Minh said:


> So if harmaline isn't responsible for the majorly addictive principles of tobacco relative to nicotine itself, what chemicals might be?



It's not?


----------



## InterestingFACT

endotropic said:


> It's not?


Since when was it ever questioned that nicotine itself was the addictive component?

Or are you referencing the theory that harmaline makes cigarettes more addictive than e-cigarettes?


----------



## AlphaMethylPhenyl

Not according to sekio's research

edit: I think


----------



## endotropic

InterestingFACT said:


> Since when was it ever questioned that nicotine itself was the addictive component?
> 
> Or are you referencing the theory that harmaline makes cigarettes more addictive than e-cigarettes?



My last post was a bit ambiguous, I've always heard that the MAOIs (e.g. harmaline) in tobacco were responsible for turning nicotine into an addictive compound, as nicotine clearly lacks addictive properties on its own.  I was questioning why ho-chi thought otherwise.




Ho-Chi-Minh said:


> Not according to sekio's research
> 
> edit: I think



Are you referring to something in particular?  I don't remember what research sekio did on this topic.


----------



## sekio

From what I understand, pure nicotine doesn't cause self administration in animals the same way cocaine or whatever does. The complex mixture of chemicals emitted from a burning cigarette including the harmala alkaloids and other stuff (menthol, etc) that potentiate and alter nicotine's pharmacological profile, as well as the incredibly fast delivery of the same compounds to the brain - due to smoking being the most rapid drug administration route, are responsible for the wholly different experiences between smoked tobacco, snuff/snus, inhaled nicotine vapors (e-cigs), and pure nicotine either in gum, transdermal patches, etc.

At least this is what I've gathered. I'm not saying that regular nicotine use won't cause dependence, that's obvious. I'm just saying that it could be a reason why cigarette smokers generally prefer cigarettes (with e-cigs coming in a close second) and generally substituting pure nicotine gum or patches for a moderate to heavy tobacco smoking habit is not as effective as it could be. (I've heard that Champix (varenicline) works pretty well.)

Really this is just more proof that route of administration matters a lot, just as much as the actual preparation (pure nicotine vs tobacco). Smoking crack rocks is a pretty different experience from doing cocaine nasally, for instance. (not that I've ever smoked crack.)


----------



## pharmakos

so lab animals get hooked on smoked tobacco but not vaporized nicotine.  what happens if you take an animal hooked on smoked tobacco and try switching his smoke out with vaporized nicotine?  would he stick with it or would he quit?


----------



## endotropic

thenightwatch said:


> so lab animals get hooked on smoked tobacco but not vaporized nicotine.  what happens if you take an animal hooked on smoked tobacco and try switching his smoke out with vaporized nicotine?  would he stick with it or would he quit?



Forget the rats, let's look at some people.  If you gave nicotine to non-smokers to try to make them dependent ethics committee would be none too pleased, but if you give them the nicotine to try to help them in some way maybe you could look at dependence on the side?

Nicotine treatment of mild cognitive impairment - A 6-month double-blind pilot clinical trial

So give non-smokers 15mg of nicotine/day every day for 6 months and what happens?



> There was no withdrawal syndrome and no subjects continued to use nicotine products.



That doesn't sound like an addictive drug to me, but would inhaling nicotine vapor lead to a different result?  Hopefully someone tricks an ethics committee into approving that one soon!


----------



## sekio

I think with the prevalence of e-cigs nowadays that couldn't be too hard to do.


----------



## pharmakos

endotropic said:


> Forget the rats, let's look at some people.  If you gave nicotine to non-smokers to try to make them dependent...



not what i'm wondering.  i'm wondering what happens in animal models if you give vaporized nicotine to animals already hooked on smoked tobacco.  we know that the switch to e-cigs works pretty well for many tobacco-dependent humans.  i'm wondering how tobacco-dependent animals cope with a switch like that, though.  would it fully substitute?  i'm guessing not but it would be interesting to see.


----------



## endotropic

thenightwatch said:


> not what i'm wondering.  i'm wondering what happens in animal models if you give vaporized nicotine to animals already hooked on smoked tobacco.  we know that the switch to e-cigs works pretty well for many tobacco-dependent humans.  i'm wondering how tobacco-dependent animals cope with a switch like that, though.  would it fully substitute?  i'm guessing not but it would be interesting to see.



It sounds like the study you want to see would look at how nicotine affects tobacco withdrawal syndrome in a rodent model?  I haven't seen much at all in that realm using tobacco smoke or even a tobacco extract.  It's really difficult to standardize dosage with an animal inhalation model, which is why you usually see these kinds of studies with IV nicotine instead.


----------



## toastmann

Does anybody know an explaination of why I only seem to get tachycardia and some minor arrhytmia  near the tail end of an mixed levo/dextro amphetamine experience? Whilst the experience lastst minor tachycardia (80->90 bpm) but near the and a few double/ empty beats and more tachycardia (ranging from 95 to 130bpm) I cant seem to find an explaination.


I mean with methamphetamine you could blame it on the conversion from methamphetamine to amphetamine but thats bit the case here.

I wonder why I have these things at the end of the experience.


----------



## crOOk

toastmann said:


> Does anybody know an explaination of why I only seem to get tachycardia and some minor arrhytmia  near the tail end of an mixed levo/dextro amphetamine experience? Whilst the experience lastst minor tachycardia (80->90 bpm) but near the and a few double/ empty beats and more tachycardia (ranging from 95 to 130bpm) I cant seem to find an explaination.
> 
> 
> I mean with methamphetamine you could blame it on the conversion from methamphetamine to amphetamine but thats bit the case here.
> 
> I wonder why I have these things at the end of the experience.


Same for me and this goes for some of the psychological effects as well. For 6h or so I'd be alert, but with minor tachycardia and relatively calm to the outside. Afterwards I'll get really hypomanic and my heart would be beating a lot faster. I've personally always attributed this to having bipolar I disorder since I've seen it in other bipolars as well, while most other people just crash and come down.


----------



## crOOk

thenightwatch said:


> not what i'm wondering.  i'm wondering what happens in animal models if you give vaporized nicotine to animals already hooked on smoked tobacco.  we know that the switch to e-cigs works pretty well for many tobacco-dependent humans.  i'm wondering how tobacco-dependent animals cope with a switch like that, though.  would it fully substitute?  i'm guessing not but it would be interesting to see.


I did at least find the following studies and have also seen a lot of studies expose test animals to tobacco smoke, eventhough I can't recall if these were studies looking at addictive properties of tobacco.



			
				Exp Clin Psychopharmacol. 2014 Feb;22(1):9-22. doi: 10.1037/a0035749. said:
			
		

> *Nicotine-like behavioral effects of the minor tobacco alkaloids nornicotine, anabasine, and anatabine in male rodents.*
> 
> Accordingly, we systematically evaluated the minor tobacco alkaloids nornicotine, anabasine, and anatabine using assays of behavioral tolerability, nicotine withdrawal, nicotine discrimination, and nicotine self-administration in male rodents. At doses that were well tolerated, all 3 minor alkaloids dose-dependently engendered robust substitution for a nicotine discriminative stimulus in mice (0.32 mg/kg, IP), and anabasine attenuated nicotine withdrawal. When the ED50 dose of each alkaloid was administered in combination with nicotine, the discriminative stimulus effects of nicotine were not enhanced by any of the alkaloids, and anatabine blunted nicotine's effects. In drug self-administration studies, only nornicotine was self-administered by rats that self-administered nicotine intravenously; anabasine and anatabine had no reinforcing effects. Moreover, prior administration of each of the minor tobacco alkaloids dose-dependently decreased nicotine self-administration. Collectively these results suggest that the minor tobacco alkaloids may substitute for the subjective effects of nicotine and attenuate withdrawal and craving without the abuse liability of nicotine.



And even better:



			
				Behav Pharmacol. 2007 Nov;18(7):601-8. said:
			
		

> *The monoamine oxidase inhibitor phenelzine enhances the discriminative stimulus effect of nicotine in rats.*
> 
> In addition to delivering nicotine, tobacco smoke also inhibits monoamine oxidase (MAO). Although MAO inhibitors (MAOIs) can increase nicotine self-administration in rodents, the effects of MAOIs on the discriminative stimulus effect of nicotine are not known. This study examined the effects of three MAOIs (phenelzine, clorgyline and pargyline) with varying selectivity for MAOA and MAOB in the nicotine drug discrimination procedure in rats. Adult male Sprague-Dawley rats were trained to discriminate nicotine (0.3 mg/kg, subcutaneously) from saline in a standard, two-lever food-reinforced operant task. Once the discrimination was acquired, the ability of each MAOI to substitute for or alter the discriminative stimulus effect of nicotine was determined. In substitution tests, nicotine (0.03-0.3 mg/kg) produced full, dose-dependent substitution. Although the selective MAOA inhibitor clorgyline (3-56 mg/kg) and the selective MAOB inhibitor pargyline (3-56 mg/kg) did not elicit any nicotine-appropriate responding, partial substitution was obtained with the nonselective MAO inhibitor phenelzine (1-17 mg/kg). Phenelzine (10 mg/kg) also enhanced the discriminative stimulus effect of a low dose of nicotine (0.056 mg/kg) and prolonged the time course effect of the nicotine-training dose. These findings indicate that concomitant inhibition of MAOA and MAOB can enhance the discriminative stimulus effect of nicotine in rats.


----------



## Jabberwocky

Ho-Chi-Minh said:


> So if harmaline isn't responsible for the majorly addictive principles of tobacco relative to nicotine itself, what chemicals might be?





endotropic said:


> My last post was a bit ambiguous, I've always heard that the MAOIs (e.g. harmaline) in tobacco were responsible for turning nicotine into an addictive compound, as nicotine clearly lacks addictive properties on its own.


harmaline is one of (if not _the_) alkaloids that are responsible for the massive dependence that tobacco has over raw nicotine. Nicotine is reinforcing, but not much more than caffeine; nicotine + a low-level MAOi(MAO-a, if i recall correctly; pretty sure nicotine + deprenyl[an MAOb-i] doesn't do this), which is a pretty central theme in nicotine addiction/recovery. 
Anecdote: much over a yr ago, i swapped from cigs to a vaporizer (ie., from tobacco, to pure nicotine), and it wasn't working for me.  I even tried the 21mg patches w/ a vaporizer, and it didn't cut it.  Fast-forward a while, and I was at the point of using zero cigarettes, and only using my vaporizer (at a 1.2% potency, cuz i tended to vape w/o noticing... g'damn delicious flavours!), BUT i had gotten into another tobacco-habit: smoking tobacco several times a day, errr... probably 2 or 3x during the day and another 2 at night... out of a tobacco pipe.  I'm still there now, although i've 'kicked'* the vaporizer, and haven't used a patch in forever, but i still smoke 2-5 hits of tobacco a day through my(boss-ass)tobacco pipe.  I get lightheaded and a rush everytime i do it; i do not think i intend to stop at this point, i'm very happy that my overall nico intake** is down but, the only thing of importance: burnt tobacco consumption, is at incredibly low levels, even compared to 1 or 2 cigarettes daily.
*vaporizer was kicked cuz, after a while using it while doing a handful of tobacco hits out of my old-man-style, wooden tobacco pipe daily, the vaporizer ended up unappealing to me; i intended to use it for a while, but right now i have cartridges and liquid that've sat for months and i doubt i'll ever touch them.  
**my nico intake right now is only a good handful of hits daily from a pipe, w/ regular/generic rolling tobaccos.  I switch them up routinely, but notice no difference.  I take a good puff of tobacco, i get a headrush for half a minute, and i do this a handful of times a day.  I'm early 30's and smoked since i was mid-teens.  I stopped using cigarettes about a year ago, when i got into vaporizers, and i got off vaporizers&patches when i got into my 'pipe-smoking phase'.  I don't intend to stop this phase, cuz i smoke so little that it's not worrying me.  When i get a chance to smoke bud, i choke on it like a virgin.  I love my hits of tobacco, they're much more rewarding than any cigarette ever was, and i NEVER crave them, i just tend to do them at nighttime, they're a night-cap thing for me.  

It blows my mind to think that i spent over a decade trying, w/o any success whatsoever, to get off tobacco, and after finding the right products i was able to kick it to the point that _cigarettes have abso-fucking-lutely zero appeal to me now, and haven't for a long time._  Sometimes i'm in a social setting (not terribly often for me right now), and am drinking and just really.want.to.hit.my.tobaccy.pipe, but cannot; my mind immediately goes to 'a puff from someone's cigarette?', and then  my subconscious counters it, and i realize once again that cigarettes suck for me now- which is the ultimate triumph for someone who was cigarette/tobacco dependent.  

I do love my nico+maoBi hits, and the handful i take daily are so much more rewarding than when i smoked cigarettes; i got here by doing a long-ish, nicotine-only regimen (vaporizers) but in the end i can 100% say that the tobacco blend is what's addictive, not the nicotine.   I could also link a million pubmeds to prove that nicotine is hardly reinforcing while tobacco is heavily reinforcing, but ya'll can google so figure my lil op-ed is all that's relevant to type out


----------



## Puzzled

*Recommendations*

Hi, can anyone recommend a sort of "for dummies" text on neuropharmacology? I'd like to have a better understanding of the basics ie neurotransmitters etc


----------



## endotropic

Puzzled said:


> Hi, can anyone recommend a sort of "for dummies" text on neuropharmacology? I'd like to have a better understanding of the basics ie neurotransmitters etc



Have you found the Erowid/BlueLight Neuropharmacology Text?  Depending on the balance of thorough/simple you're looking for that could help you get your foot in the door.  Most texts published on neuropharmacology these days assume you have a basic understanding of neuroscience, molecular biology and physiology before you open them.


----------



## Jabberwocky

^damn i hadn't seen that, thnx
[edit: LOL that's too funny: 





> If you "don't know what enzymes has to do with the neuropharmacology", then it's probably best if you don't write the section specifically dealing with that question.


poor bliz0r setting that up lol]

puzzled- instead of a specific, i'll just say that if you search on bluelight in this subforum (and its archives.  they may be called ADD still), and on reddit (subreddits r/drugs and r/drugnerds), you'll find many threads of the same question as yours, w/ many many answers


----------



## DL-ark

Any chance some of Leonurine's activity is through dopamine reuptake a la dimethocaine? Their structures are fairly similar but Leonurine has an extra carbon in between the ester and the nitrogen. I have really found some good effects with an unknown species of leonotus. I find boiling the flowers/large quantity of leaves in a small amount of water, and taking small 5ml doses of this water leaves me with a moderate euphoria which lasts anywhere from 3-5 hours. Interestingly higher doses result in a longer duration with only slightly stronger subjective effects.

Leonotus does not feel that stimulating, but I really would like to discover the pharmacology of this plant. Of course, I think I first need to determine what species I have in my possession, as it looks vastly different from the ornamental dagga plants that people grow.

http://www.bluelight.org/vb/threads...(Dagga-alkaloid)-adenosine-reuptake-inhibitor

This analysis of leonurine seems sound, but I would like to point out that the chemical structure on the wikipedia page is different from the actual chemical. The double bond is from the central carbon to one of the terminal nitrogens, rather than the one after the carbon chain. If I'm not making sense compare this: http://www.chemspider.com/Chemical-Structure.23089765.html with the structure on basement_shaman's post. Although I don't believe this would vastly change how leonurine binds to receptors, it does make the actual chemical much less water soluble than the one seen on wikipedia.

If anyone has any information on the alkaloids/terpenes of leonotus sp. or any information on the pharmacology of any of the chemicals found in this plant, I'd be very, very happy to see it.

I really don't know why so many people have felt that dagga is so lackluster, while I have found it quite a boon.


----------



## pharmakos

i believe that dagga needs to be pretty fresh in order to achieve effects from it.  i had one supplier a few years ago that could get dagga petals to my mailbox within a week of harvest and that stuff produced a really nice effect.  other times the same vendor would admit his stock had been sitting for a few months, and that older stuff was never as good.


----------



## DL-ark

thenightwatch said:


> i believe that dagga needs to be pretty fresh in order to achieve effects from it.  i had one supplier a few years ago that could get dagga petals to my mailbox within a week of harvest and that stuff produced a really nice effect.  other times the same vendor would admit his stock had been sitting for a few months, and that older stuff was never as good.


 
Yup, mine comes straight out of my backyard (more or less)! Fresh as can be!


----------



## ParappaTheRapper

*Altering Serotonin Levels Changes Monkey Behavior and Status*






I am curious to peoples' reactions to the lecture.


----------



## ...

What could we do to caffeine's structure to shorten its duration of action?  I am interested in developing a xanthine derivative geared towards late-night studying: something you could take for a boost at 10 pm yet be in bed by 1 am.  Any ideas?


----------



## AlphaMethylPhenyl

uhhh, melatonin?

Sorry I don't know. I think you should just titrate your caffeine earlier.

I have a few questions:

Is MXE neurotoxic? (I read the study concluding acute toxicity, but only with three subjects and in the acute phase). Any other toxicities?

What dose/ratio of dexamphetamine is neurotoxic in chronic usage? cardiotoxic? I'm thinking anything that exceeds .5-2mg/kg? But I'm looking for a smaller margin of error. And methylphenidate is neuroprotective at reasonable doses, got that. I'm just wondering because I'm looking out for a friend. I take the safer route.

Why does US prescribe stimulants so much?

Do benzos really cause brain damage after chronic use?


----------



## Solipsis

I thought MXE shows only acute celebellar toxicity which is just a way of saying severe intoxication affecting some motoric / semi autonomic functions. But nothing that says it isn't reversible or related to dangerous CNS depression.


----------



## endotropic

Ho-Chi-Minh said:


> Why does US prescribe stimulants so much?



Because it's cheaper and easier than any other method of controlling rambunctious children, combined with an extremely powerful pharmaceutical lobby with direct marketing to parents, teachers and doctors.  My guess anyways.


----------



## Dresden

toastmann said:


> Does anybody know an explaination of why I only seem to get tachycardia and some minor arrhytmia  near the tail end of an mixed levo/dextro amphetamine experience? Whilst the experience lastst minor tachycardia (80->90 bpm) but near the and a few double/ empty beats and more tachycardia (ranging from 95 to 130bpm) I cant seem to find an explaination.
> 
> 
> I mean with methamphetamine you could blame it on the conversion from methamphetamine to amphetamine but thats bit the case here.
> 
> I wonder why I have these things at the end of the experience.



I would venture that it's because the amphetamine is, albeit in small quantities, being metabolized into 4-OH-amphetamine, which is structurally very similar to PMA, and as PMA is known to be responsible for increased blood pressure, so probably is 4-OH-AMP.

As for the tobacco smoke component of this thread, tobacco smoke is known to contain over 7000 chemicals.  Who knows what they all do?


----------



## ~QuirKyNai~

MattPsy said:


> If something is a suicide substrate (like a covalently binding agonist) then eventually receptor internalization will occur (and the receptor is replaced eventually). However until internalization occurs signal transduction can usually still take place so the effect of an irreversible agonist is not that of an antagonist, effectively, because the receptor population is not immediately destroyed.





red beard said:


> I found this paper that demonstrated inhibition of CYP2D6 and CYP3A4 enzymes by kratom.
> 
> Does anyone know how to compare the concentrations of extract used in the paper to plain leaf dosages?  I'm wondering at what dose this sort of inhibition becomes relevant.




I wonder if.that.can be used to.potentiate suboxone.in my.experiences i.dont really feel like taking.subixone after kratom precipitates withdrawl.
I.know there's a book.that shows the binding affinity at mu,delta,and.kappa  receptors.
Anyway.i..have been on .25-.50mg suboxone daily,and.have taken kratom.about.3-4 hrs later with me def. feeling the antidepressant.qualities for sure and maybe.some pain relief....one the last time i had taken kratom i.took .25mcg about 3-4hrs later...what i felt i think was some knocking off the kratoms antidepressant effect,and def felt pain relief again..so im not sure how strongly kratom.binds at.mu..or how much the delta attaches.but i think that delta plays more.of a role in the analgesislc amd.amtidepressant effects of kratim....but dont hold me to that

I think kratom shud be looked at more,especially in.conjunction with sunoxone/subutex.


----------



## ~QuirKyNai~

Also...can kratoms mitrigynine and 7-hydroxy-mitrigynine.be.turned into.base.form in the.stomach.with tums?.
Or.can it be turned into.base.form in any way.for ingestion..NOT for smoking...
I was wondering of basifying.the alkaloids cud possibly have a.better effect.
If anyone wants.to chime in on this one,id appreciate it


----------



## nickfurry

*Readily available inert gasses for storage*

Since I'm not a chemist I don't have access to lab grade argon gas. If I   jump through the hoops to be allowed to buy it, it is still   ridiculously expensive to get a large tube and it would probably get me   on some watch list. Same thing with helium in my country.

So I'm  trying to figure out the best alternative that can be easily  bought OTC  and used to create an inert environment for very long term  storage of  chemical substances to prevent them from degrading into  poisonous  compounds.

Would any of these work?

CO2 bulbs for soda machines
N2O whippets
Pure argon used for welding ('technical grade')
85% Argon + 15% CO2 for welding
Anything else?


----------



## sekio

Why not nitrogen? Argon would work fine but it's like 100x more expensive than N2. CO2 would work too as long as you're not planning to store anything acid sensitive(!).

Realistically most drugs are fine to be stored under air, they don't oxidise at an appreciable rate.


----------



## sekio

Welding argon is probably fine.

Nitrous oxide is not a good packaging gas as it's an oxidiser under some conditions. CO2 is not a good packaging gas either as it can react with moisture to form carbonic acid & can under some circumstances react with certain functional groups.



> How do I find out if a novel drug, such as a cathinone or novel tryptamine, is acid sensitive?



You make it and do long term storage and stability studies. Or read the chemical literature.

Generally speaking, storing compounds as cold as you can get them, in well sealed containers, is more important than storing them under inert gas. The amount of oxygen in a typical vial headspace is not very much, so the extent of oxidation will be limited.


----------



## Incunabula

nickfurry said:


> I don't know where to get N2 apart from in a large  liquid nitrogen tube that would cost $$$$ and I would also have to come  up with an explanation for why I needed it. Is it sold for any  non-medical purpose such as model trains or something?
> 
> Is N2O inert?
> 
> How do I find out if a novel drug, such as a cathinone or novel tryptamine, is acid sensitive?
> 
> Argon, in the form of welding gas, is actually very easy to find even in small quantities. Is this technical grade good enough, or will it contain harmful impurities that might cause oxidation?
> 
> I understand an inert gas is usually not necessary, but I'm interested in the theoretical optimum.



Nick, the best thing for you would be to get argon. You can buy it online in containers with easy dispension, made for wine preservation (just google winesave) I'm sure it's pure, since it's intended to be in contact with "food". I don't use it myself, but I'm considering it for my jar of acid blotters.

But as Seiko says, it's not really neccesary for most compounds. If you have vials with proper lids and pack them thightly to the brim, and store them in the freezer, you should be good. The argon is just going to be an unnessecary hassle.

The vials you want to get, would be amber pyrex glass vials, size 5/8 dram. Fits approximately one gram of most compounds, give or take, depending on the density obviously. The lid should be be lined with some kind of foam (it's often PE) Don't get the lids with foil linning, I don't think they seal as tightly. Again, google is your friend 

If you need to find out about the stability of a certain compound, ask in the respective threads. Some one there might have first hand experience with its stability. Otherwise, ask around if any one can see any easily reactive groups on the structure. But generally, discussions on the stability of specific chems belongs in their respective threads.

We do have two threads on the topic, though.
The-Big-and-Dandy-Storage-Thread
The-Big-and-Dandy-Solubility-and-Stability-Thread


----------



## Incunabula

... said:


> What could we do to caffeine's structure to shorten its duration of action?  I am interested in developing a xanthine derivative geared towards late-night studying: something you could take for a boost at 10 pm yet be in bed by 1 am.  Any ideas?



Wait, this isn't such a bad idea. Coffee has a pretty long half-life, 3-7 hours. If you drink coffee in the afternoon, you still have half of the caffeine in your body when you go to sleep, which can have an impact on the quality of your sleep.

I just remember I once looked at a bunch of methylxanthine analogs that had been made. Might be worth checking out again what is known about caffeines SAR (probably a lot)


----------



## Hermetic0ne

i love calculations and possibilities on my favorite brain boosters. Ive spent a long time reading abstracts, extracts and patents. I learned a lot, kept learning so then i got curious because all these methods cross over in little ways of course. i started wondering things like.. instead of doing azide swaps in a PTC, why not use weight lifting supplements like NO2 in (NaNO) NO Explode? 

Or things like Microwave or Electro synthesis and substitutions of starting/ending materials. Ive started to feel like sometimes the possibilities of different routes are endless. Vitamin b and supplements.. and even thought of hypothetical scenarios like oxidation of methocarbamol. Yes, I have slightly talked about several different routes and not to completion.. I know  But this is what excites me..talking what ifs and using the citations back to the early 1900s. Anyone here considered any of these?


----------



## nickfurry

Do you guys think Phen*e*trazine is made from left over N-ethyl-buphedrone by the Chinese? What kind of cyclization and more importantly, what likely impurities?


----------



## sekio

> Do you guys think Phenetrazine is made from left over N-ethyl-buphedrone by the Chinese?



Nope.


----------



## Sprout

Fagott said:


> Wait, this isn't such a bad idea. Coffee has a pretty long half-life, 3-7 hours. If you drink coffee in the afternoon, you still have half of the caffeine in your body when you go to sleep, which can have an impact on the quality of your sleep.
> 
> I just remember I once looked at a bunch of methylxanthine analogs that had been made. Might be worth checking out again what is known about caffeines SAR (probably a lot)



IIRC, DMX had a greater potency and shorter duration than Caffeine (TMX) as well as being much more selective for receptor subtypes.

I have done a fair bit of reading, myself so look forward to any discussion.


----------



## sekio

There are three dimethylxanthines (paraxanthine, theobromine, theophylline), so you'll have to be more specific.


----------



## Dresden

Plus there's always Middle Eastern captagon, which contain fenethylline, the methamphetamine plus caffeine in a single molecule adduct.


----------



## crOOk

Dresden said:


> Plus there's always Middle Eastern captagon, which contain fenethylline, the methamphetamine plus caffeine in a single molecule adduct.


I never knew what's in those, my friend's mum who I hated with a passion was taking it when I was in 5th grade.

By the way fenethylline contains regular amphetamine, there is only one methyl group on amphetamine's side. It was also introduced in the USA if I am not mistaken. I wonder why that never became popular.



EDIT: omg lol
http://en.wikipedia.org/wiki/Amfecloral
http://en.wikipedia.org/wiki/Dexamyl

How the fuck did I not know these?!


----------



## ...

But so generally speaking, how would one alter a molecule to _diminish_ its duration of action?  Is there a functional group that tends to increase affinity for cytochromes or xanthine oxidases or something?


----------



## SONN

okay so I'm going to sound like i'm in the wrong forum but usually you guys are pretty nice to me despite my lack of pharmacology knowledge lol

I recently went to a weird underground supermarket in chinatown where they had all these things that pretty much were completely novel to the western world, I decided to look up a few of the herbs in the tonic section because I wanted to make a new tea that would somehow make me feel better and I found Glehnia Root.

So according to eastern medicine if you boil glehnia root for a couple minutes in water then drink it, it's supposed to have an analgesic effect and help moisturize your lungs or something to help with coughs, Presumably because it contains the active ingredient "naphthisoxazole A" which has no wikipedia page. I decided to use my Uni powers and look up if anyone had done anything with naphthisoxazole A and I found the jstage article below saying that they made a bunch of derivatives of it in the seventies but I can't figure out much more than that.

either way this is Naphthisoxazole A






I'm assuming some other people on here will have access to Jstage so they can hopefully see the derivatives. I thought It was a pretty interesting chemical structure and it totally made my lungs feel better, so I was wondering what the geniuses of NAPD would think of it.

https://www.jstage.jst.go.jp/article/yakushi1947/95/7/95_7_815/_pdf

to a layman like me it looks like a mirrored MDMA just a tad, That pentagonal chain looks like a mirrored methylene-dioxy but with extra substitutions. I wonder what MDMA with that attachment mirrored instead of the methylene-dioxy would be like.


----------



## endotropic

Well it's got an amphetamine buried in there if you squint hard enough, with the alpha methyl constrained in the ring system.  I'm not sure if that's relevant to its activity but interesting at least.


----------



## sekio

It looks like a DNA intercalator to me.


----------



## crOOk

sekio said:


> It looks like a DNA intercalator to me.


Indeed, reminds me a lot of Thalidomide (which is a DNA intercalator afaik, correct mer if I'm wrong).


----------



## nickfurry

Are there any other reagents than Marquis, Mendelin et al, that could be used for testing chemicals, that are not based on concentrated sulfuric acid? The latter is hard to get, actually it is outright illegal to possess in some countries. The European Union will most likely slowly but eventually make most pure chemicals illegal or at least unavailable on the open market.


----------



## Dresden

Sulfuric acid is commonly used as car battery acid.  
I don't know if that form is suitable for your purposes or not.


----------



## nAON

Random question that doesn't quite warrant a thread - would SSRIs have an acute effect on the brain from preventing 5HT reuptake? Am aware that the clinical is from weeks of desensitization, but surely the increased concentration does something involving a direct interaction with the receptors? Why don't they get you high, for example?


----------



## endotropic

They don't get you high like say MDMA because the increased serotonin concentrations cause increased activation of 5-HT autoreceptors.  That process leads to reduced 5-HT neuron activation and reduced 5-HT release.  The net effect of reduced 5-HT release combined with 5-HT reuptake blockade is that extracellular 5-HT levels hardly increase at all until the 5-HT autoreceptors desensitize.  You can see evidence for those processes in microdialysis and e.phys studies in rodents, and clinical brain imaging studies.

So I guess the acute effect of SSRI's is the reduction in 5-HT neuronal excitability, plus any off target effects.  I think its interesting that people with naturally high 5-HT autoreceptor levels tend to have worse response to SSRI's, which makes sense when you think about the effect that would have on their 5-HT levels during the first few weeks.


----------



## pharmakos

from Time:



> One dose of antidepressant is all it takes to change the brain, finds a small new study published in the journal Current Biology.
> 
> The study authors took brain scans of 22 healthy people who weren’t depressed and who had never before taken antidepressants. Some were randomized to take a dose of the most common kind of antidepressant, an SSRI (selective serotonin reuptake inhibitors).
> 
> After another brain scan three hours later, researchers saw a dramatic change: a widespread drop in connectivity throughout the brain, except where it was enhanced in two brain regions, the cerebellum and thalamus.
> 
> The results suggest that antidepressants may alter brain connections much faster than previously thought. “We were surprised,” says study author Julia Sacher, of the Max Planck Institute for Human Cognitive and Brain Sciences, in an email to TIME. “We were not expecting the SSRI to have such a prominent effect on such a short time-scale and the resulting signal to encompass the entire brain.”
> 
> Antidepressants are generally thought to take several weeks to kick in. “It is possible that these connectivity changes are the first step in remodeling the brain, as there is evidence from other experiments that such functional connectivity changes can reflect neuroplastic change,” Sacher says.
> 
> “However, much work remains before we understand how different antidepressants affect the brains of people with and without depression, not only after the first dose, but also over the longer term. The hope that we have for future studies is to uncover distinct differences in brain connectivity between depression patients who ultimately respond to an antidepressant and those who do not.”



http://time.com/3399344/antidepressant-changes-the-brain-study-finds/


----------



## nAON

endotropic said:


> They don't get you high like say MDMA because the increased serotonin concentrations cause increased activation of 5-HT autoreceptors.  That process leads to reduced 5-HT neuron activation and reduced 5-HT release.  The net effect of reduced 5-HT release combined with 5-HT reuptake blockade is that extracellular 5-HT levels hardly increase at all until the 5-HT autoreceptors desensitize.  You can see evidence for those processes in microdialysis and e.phys studies in rodents, and clinical brain imaging studies.
> 
> So I guess the acute effect of SSRI's is the reduction in 5-HT neuronal excitability, plus any off target effects.  I think its interesting that people with naturally high 5-HT autoreceptor levels tend to have worse response to SSRI's, which makes sense when you think about the effect that would have on their 5-HT levels during the first few weeks.



Aha, so the 5HT release from MDMA would also cause 1A activation, but that itself wouldn't affect MDMA-induced 5HT release because it's via SERT-reversal which isn't being regulated by autoreceptors/neuronal excitation? Think I get it now 

And gonna give that paper a read now nightwatch, cheers.


----------



## endotropic

^ yea you've got it nAON, releasers act independent of neuronal excitation.


----------



## InterestingFACT

endotropic said:


> They don't get you high like say MDMA because the increased serotonin concentrations cause increased activation of 5-HT autoreceptors.  That process leads to reduced 5-HT neuron activation and reduced 5-HT release.  The net effect of reduced 5-HT release combined with 5-HT reuptake blockade is that extracellular 5-HT levels hardly increase at all until the 5-HT autoreceptors desensitize.  You can see evidence for those processes in microdialysis and e.phys studies in rodents, and clinical brain imaging studies.
> 
> So I guess the acute effect of SSRI's is the reduction in 5-HT neuronal excitability, plus any off target effects.  I think its interesting that people with naturally high 5-HT autoreceptor levels tend to have worse response to SSRI's, which makes sense when you think about the effect that would have on their 5-HT levels during the first few weeks.


 also note that while most people wouldn't characterize it as "getting high," some people do note initiation symptoms like color enhancement, mild euphoria on their first couple days on an ssri.


----------



## JBrandon

^ yes! For both my wife and I, there was a clear euphoria, stimulation, alteration in taste and smell, and other effects beginning on the first day. Lasted about a week or two.


----------



## Nagelfar

What are forum members thoughts on this 2014 publishing (pdf file) claiming cocaine & methylphenidate differ from other MAT inhibitors by being "inverse agonists" at the transporter and facilitating release of monoamines thereby?

Essentially, there is an inward and outward facing conformation of DAT, cocaine/MPH binds to the outward facing conformation stabilizing it, and thus causing reverse transport via the inward/outward concentration gradient. The binding site is distinct from that of other reuptake inhibitors, being at TMs 9-11 on DAT whereas other bind to TMs 10-12 (with overlapping loci at 1 & 7).


----------



## nAON

^ seems to make sense really. I had a bit of a confusing moment the other day when I was browsing wikipedia and saw things being described as 'silent antagonists', only to realise they've just started using new terminology for regular old (but evidently inaccurate) antagonists.


----------



## endotropic

Nagelfar said:


> What are forum members thoughts on this 2014 publishing (pdf file) claiming cocaine & methylphenidate differ from other MAT inhibitors by being "inverse agonists" at the transporter and facilitating release of monoamines thereby?
> 
> Essentially, there is an inward and outward facing conformation of DAT, cocaine/MPH binds to the outward facing conformation stabilizing it, and thus causing reverse transport via the inward/outward concentration gradient. The binding site is distinct from that of other reuptake inhibitors, being at TMs 9-11 on DAT whereas other bind to TMs 10-12 (with overlapping loci at 1 & 7).



They put forward an interesting theory but never provide anything beyond circumstantial evidence to support it.  If their theory on cocaine's MOA is true that would be great for the drug they're selling by the way.

Their mechanism doesn't really make sense to me either.  They claim that cocaine stabilizes an outward conformation of the transporter leading to reverse transport of cytosolic dopamine into the synapse.  But where does that cytosolic dopamine come from?  Vmat makes sure that dopamine accumulates in vesicles and stays out of the cytosol.  

Amphetamine reverse BOTH Vmat and DAT so that DAT has lots of cytosolic dopamine to reverse transport, but the authors of this paper don't give any explanation for where the cytosolic dopamine would come from with cocaine.


----------



## Nagelfar

endotropic said:


> Amphetamine reverse BOTH Vmat and DAT so that DAT has lots of cytosolic dopamine to reverse transport, but the authors of this paper don't give any explanation for where the cytosolic dopamine would come from with cocaine.



They do touch on that actually, talking about how such an inverse agonist would have a ceiling effect because of its lack of affinity for VMAT.

I think it has to do with influx of Na+ ions from extracellular space. And even though "maximum effect of competitive DAT substrate releasing agents on dopamine efflux is greater
than that of DAT “inverse agonists”" it seems to say neuronal firing is greater (though still reduced) with inverse agonists over substrate releasers (though I can't find where I read that now).


----------



## endotropic

Nagelfar said:


> They do touch on that actually, talking about how such an inverse agonist would have a ceiling effect because of its lack of affinity for VMAT.



Right, they discuss how cocaine would have a lower maximum effect than a releasing agent, but not how cocaine could have a greater maximum effect than a standard reuptake inhibitor.  My understanding is that Vmat has such a high affinity for Dopamine that cytosolic concentrations stay very low, so even if cocaine can reverse the transporter, what dopamine does it have access to for reverse transport?




Nagelfar said:


> I think it has to do with influx of Na+ ions from extracellular space. And even though "maximum effect of competitive DAT substrate releasing agents on dopamine efflux is greater
> than that of DAT “inverse agonists”" it seems to say neuronal firing is greater (though still reduced) with inverse agonists over substrate releasers (though I can't find where I read that now).



I think Na+ concentration gradient can help to explain the mechanism of transporter reversal, my question is what possible effect can transporter reversal even have without concurrent Vmat reversal?

Besides, multiple groups have compared the effects of cocaine and other reuptake inhibitors on extracellular dopamine levels, do actual experimental results suggest cocaine can drive more dopamine out of the cell than a standard reuptake inhibitor?


----------



## Nagelfar

endotropic said:


> ...do actual experimental results suggest cocaine can drive more dopamine out of the cell than a standard reuptake inhibitor?



That seems to be what they're saying. Coke & MPH, anyway.


----------



## endotropic

Did they provide a reference where that was actually shown?  Or is that just consistent with what they want us to believe about cocaine vs. their product?


edit: I see where they addressed this (briefly): they cite a study that compares methylphenidate to GBR-12909, and show that GBR has a much lower maximum effect than methylphenidate.  I don't find that very convincing considering GBR-12909 has been shown to inhibit dopamine release in addition to blocking its reuptake.


----------



## ebola?

GBR-12909 has also been shown to have ceiling-effects in releasing dopamine unique to the compound.

ebola


----------



## neurotic

does 5HT1A agonism play a reasonable role in MDMA's empathogenic effects?

because i was reading this article comparing mephedrone and MDMA (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246659/), and mephedrone also seems like one hell of a serotonin releasing agent too, more potent than MDMA, raising serotonin levels by 940% at 3mg/kg doses, compared to 910% with MDMA at the same doses. but afaik (never tried it) it's not very empathogenic (when compared to MD)

i ask so because i read that 1A agonism supposedly raises oxytocin levels and increases social behaviour in rats as shown by one study with 8-OH-DPAT which is a selective agonist for that receptor

also there doesn't seem to be any instance of mephedrone-induced comedowns as heavy as some of the ones from MDMA, even if apparently people go way overboard with it due to its fiendiness (which btw could be due to simultaneous increased DA levels - much like cocaine -, which MDMA doesn't do as much)... if those severe acute episodes of depression were from 5HT depletion alone, mephedrone should cause it too right?

i guess what i'm asking is, what is the difference between the two here?

i'm curious


----------



## Nagelfar

^Not to jump in front of you and I hope your question gets addressed but I just had a thought/question and it might be quite basic.

It was about Ki ratios, their IC50s etc. Lower is higher binding correct? So a Ki of say 0.00007 is a high affinity, but 150,000 is basically no affinity....

Is there a higher bound in the molecular attraction of any ligand to bind on the largest number possible? Meaning, is there a number (e.g. no affinity, >150,000 or somewhere before/beyond I am assuming) to that value that is basically it has the same amount of affinity to every ligand at that point (which is "none" but a specific number for which I'm asking) and it is as likely to dock with that as any other place in any molecular build? (Somewhat like in quantum its possible for all electrons to shift at once and randomly change gravity or turn air into gold, but its infinitesimally unlikely)

...is there an upper bound where affinity "bottoms up" at a highest number?

Does my question make sense? Is it an entry chemistry school 'everyone knows' type answer perhaps?


----------



## Incunabula

Does anybody know were I can find this Paper by Hoffman online? According to Erowid it's private.

“Pharmacologic Properties and Psychotogenic Effects of some Lysergic Acid Derivatives : Comparison with Delysid (LSD25)”. 
Sandoz Internal Publication. 1958;1.

I did google.


----------



## Nexus_Tripper

I call it TCB-3, the 3 specifying the three-carbon chain. It is the amphetamine counterpart of TCB-2.


----------



## Incunabula

I think you meant to post that in the "I like to draw random molecules thread" 

Anyway, this is from the TCB-2 thread:



Solipsis said:


> Probably not, because there is not a simple and linear amine chain it is not appropriate anymore to just simply count carbon atoms and call them alpha and beta. Now it is a bicyclic molecule, the main part is the body with 2 rings and it has a mini-"chain" sticking out on the right now with only one carbon. In the main bicyclic body the total number of carbons are counted which makes 8. Then the number of carbon are counted that are between the carbons that unite the rings.
> 
> What used to be the alpha is now the 1-position.
> 
> There is no corresponding amphetamine because there is no more alpha-position to justify the name amphetamine (= alpha-methyl PEA). If you add a methyl on the 1-position, *AFAIK it would probably be constrained (forced) to stick out in a direction that is uncomfortable for binding.*
> Whether it can be called TCB-3 or not would mostly depend on whether you still find that molecule to be a modification of 2C-B rather than DOB.
> IMO what you propose would be appropriately named DOB-CB
> The name TCB-3 is not reserved for the cyclopentene analogue, which is called 2CB-Ind so it would be hard to continue the nomenclative series consistently.


I think he has some good points. And any activity, if it's there at all, will probably be less than with TCB-2.


----------



## neurotic

any ideas about the metabolism of the APDB's (dihydrofuran analogs of MD)?

i found an article about APB metabolism but couldn't for the APDB's... i tried searching for other compounds with benzodihydrofuran rings and look up what happened to them but couldnt find anything, i couldnt find any molecule like that that seemed studied anyway... may be you guys know

also would the 3-carboxymethyl-4-hydroxy-amph metabolite of one of the APB's subject to any further metabolism?


----------



## Dresden

Neuropharmacological jargon is largely nonsense, with no application in drug design much.


----------



## pharmakos

i was thinking the other day about the Ouroboros, the archetypal image of the serpent that eats its own tail, and had the thought that a benzene ring is sort of like an Ouroboros, with its constantly shifting resonant state of altering single/double bonds.  i checked out the Wikipedia page on Ouroboros, and saw this blurb:



> *Chemistry*
> 
> The German organic chemist August Kekulé described the eureka moment when he realized the structure of benzene:
> 
> 
> 
> 
> I was sitting, writing at my text-book; but the work did not progress; my thoughts were elsewhere. I turned my chair to the fire and dozed. Again the atoms were gamboling before my eyes. This time the smaller groups kept modestly in the background. My mental eye, rendered more acute by the repeated visions of the kind, could now distinguish larger structures of manifold conformation: long rows, sometimes more closely fitted together; all twining and twisting in snake-like motion. But look! What was that? One of the snakes had seized hold of its own tail, and the form whirled mockingly before my eyes. As if by a flash of lightning I awoke; and this time also I spent the rest of the night in working out the consequences of the hypothesis.
Click to expand...


pretty neat


----------



## trip407

Can someone tell me why midazolam is so short acting and has such a low potency compared to clonitrazolam and flubromazolam?  Both are much more potent and longer lasting.  And i dont see that big of a difference in midazolam and flubromazolam. 
Edit: i just recognised,  midazolam is not a triazolo compound,  so the question is obsolet, sorry.


----------



## adder

I think the question might stand as triazolam is also a short-acting benzodiazepine and it's a triazolo derivative, basically it's 2'-chloroalprazolam. How does the additional chlorine atom impact the half-life? For classic benzodiazepine derivatives ortho-substitution of the phenyl group doesn't always have a positive or negative effect on the half-life, perhaps functional groups at other positions impact the affinity towards CYP enzyme subtypes that mediate hydroxylation of the phenyl ring. It might also be related to the extent different benzodiazepines are bound by proteins. Does anyone know the answer?


----------



## AlphaMethylPhenyl

All right so you guys are probably the most likely to provide a valid answer to this question. Though it may not strictly pertain to pharmacology, "and more" makes it suitable .

I can pop on Google and read all about how selegiline has nootropic potential. It's literally all over. However, there is a painfully small amount of information regarding the other MAOIs and cognition. Okay, so MAOIs may increase feelings of novelty and therefore attention roughly because of increased indirect dopaminergic neurotransmission (even though I found at least one source which points to reuptake inhibition/monoamine release as potential explanations behind some of the mental manifestations of MAOIs). But that doesn't necessarily mean they have nootropic potential. Can someone provide a source which centers on possible cognition-increasing/nootropic action of MAOIs which are treated for depression/anxiety/phobia (as in not rasagiline and not selegiline and not moclobemide because the first and second is not an option and information on selegiline is everywhere).

When it comes down to it, I'd almost rather be unhappy and more intelligent/fast/whatever you want to call it than happy and stupid. It's not like one source would turn my opinion either way, and I know it comes down to individual experience, but I want to see what's out there before I push something past my BBB. Thanks .


----------



## Epsilon Alpha

endotropic said:


> They put forward an interesting theory but never provide anything beyond circumstantial evidence to support it.  If their theory on cocaine's MOA is true that would be great for the drug they're selling by the way.
> 
> Their mechanism doesn't really make sense to me either.  They claim that cocaine stabilizes an outward conformation of the transporter leading to reverse transport of cytosolic dopamine into the synapse.  But where does that cytosolic dopamine come from?  Vmat makes sure that dopamine accumulates in vesicles and stays out of the cytosol.
> 
> Amphetamine reverse BOTH Vmat and DAT so that DAT has lots of cytosolic dopamine to reverse transport, but the authors of this paper don't give any explanation for where the cytosolic dopamine would come from with cocaine.



My understanding was that it also has some sort of odd effect on the vesicle transport regulatory mechanisms as it leads to more normal exocytosis of dopamine as well
http://www.ncbi.nlm.nih.gov/pubmed/16554471


----------



## endotropic

Epsilon Alpha said:


> My understanding was that it also has some sort of odd effect on the vesicle transport regulatory mechanisms as it leads to more normal exocytosis of dopamine as well
> http://www.ncbi.nlm.nih.gov/pubmed/16554471



That study suggests a third mechanism for cocaine induced dopamine accumulation independent from its effects on the dopamine transporter (whether reuptake inhibition or inverse agonism).

Basically they claim that cocaine mobilizes a specific pool of vesicles that normally only release in response to continuous action potentials.  Then  they apply continuous action potentials and see increased synaptic dopamine with cocaine, but to a lesser degree when they knock out the proteins that allow those vesicles to dock.  Even if cocaine can mobilize those vesicles directly they would release into the synapse, not the cytosol, so a dopamine transporter working in reverse still wouldn't have access to that dopamine.  

If they can show that other DAT blockers don't depend on synapsin expression to increase dopamine then I might believe that cocaine has some special effect on vesicle mobilization, but lacking that negative control I think DAT blockade alone can explain all of the findings outlined in this paper.


----------



## pharmakos




----------



## neurotic

neurotic said:


> does 5HT1A agonism play a reasonable role in MDMA's empathogenic effects?
> (...)



apparently not: No evidence that MDMA-induced enhancement of emotional empathy is related to peripheral oxytocin levels or 5-HT1a receptor activation


----------



## endotropic

^ that study has some serious problems.  For one Pindolol acts as a 5-HT1A partial agonist, not an antagonist, so it doesn't make much sense to reverse a 5-HT1A mediated effect with that drug.


----------



## InterestingFACT

endotropic said:


> ^ that study has some serious problems.  For one Pindolol acts as a 5-HT1A partial agonist, not an antagonist, so it doesn't make much sense to reverse a 5-HT1A mediated effect with that drug.


A weak partial agonist would still displace MDMA off 5ht1a receptors. If it has less intrinsic activity than MDMA at the site, a difference in response should be measurable.


----------



## neurotic

^ yes that was the reasoning they presented in the study for using the Pindolol. Wiki also lists it as "a 5-HT1A receptor weak partial agonist / antagonist (Ki=33nM). Alprenolol would be ideal since it is in fact a 5-HT1A antagonist, but, well...


----------



## endotropic

InterestingFACT said:


> A weak partial agonist would still displace MDMA off 5ht1a receptors. If it has less intrinsic activity than MDMA at the site, a difference in response should be measurable.



Yes it would displace MDMA, but if the empathy response has a low efficacy requirement then a partial agonist wouldn't block the response.  Their conclusions might be correct, I just don't find that study particularly convincing.


----------



## serotonin2A

endotropic said:


> ^ that study has some serious problems.  For one Pindolol acts as a 5-HT1A partial agonist, not an antagonist, so it doesn't make much sense to reverse a 5-HT1A mediated effect with that drug.



Pindolol acts as an antagonist at _postsynaptic_ 5-HT1A receptors.   Despite the fact that pindolol may be a partial agonist at _presynaptic_ receptors, it doesn't make a lot of sense that MDMA would be working through presynaptic 5-HT1A receptors.    The only function of presynaptic 5-HT1A receptors is to inhibit the firing of serotonergic neurons, so any effect that MDMA has on presynaptic 5-HT1A would be completely washed out by the huge efflux of serotonin produced by MDMA, which is impulse-independent.


----------



## Mr.M.301

Forgive me if this has already been asked, as I haven't read the entire thread, but I have a question about our current understanding of opioid tolerance and withdrawal.

As I understand it (albeit a very limited understanding), tolerance is caused by downregulation of opioid receptors in the brain.  In order to feel 'good' or even 'normal', our brains produce a certain small amount of endogenous opioids (endorphins), and this small amount activates a small number of receptors in the brain (not enough to cause any (down or up)regulation on any discernable scale).  When exogenous opioids are taken (say one was to inject heroin), the receptors are flooded with heroin (acting as a ligand (correct me if this term is wrong)), causing a kind of cascading action that produces what we all know and love (the high), and consequently the brain adapts by downregulating (essentially eliminating? or 'deadening'?) the (mu) opioid receptors.

My best attempt at an analogy is that the brain's opioid receptors can be thought of as a bundle of fiber-optic threads.  Normally a small little light shines (endogenous production) that keeps us feeling okay.  When we take a shot of heroin, it is like pointing a huge floodlight at the strands, and this causes our brain to adapt by removing or disabling many of the strands, and by shutting off the little light (endogenous production).  After a while, when heroin use is stopped, the light is off or very dim, and the number of fiber-optic strands are so few that almost no light is getting through, thus we experience withdrawal, until the brain adapts by upregulating (adding / enabling more fibers) and increasing the little light output to previous levels so that we feel normal again.


My problem with this is that I don't see how it explains certain empirical observations, such as the fact that administering an opioid antagonist (naloxone or naltrexone) to opioid naive individuals seems to have no effect.  If the above model were correct, wouldn't the antagonist block the effect of endogenous opioids, thus causing dysphoria or even symptoms similar to mild precipitated withdrawal?

Is there any other theory of tolerance and dependence that has any sort of traction?  From my own naive perspective, it would seem to make as much sense that the body produces its own endogenous opioid antagonists, in proportion to how much activity is detected at the receptors.  In addition to explaining tolerance (the more activity at the receptors, the more antagonist production occurs, thus lowering the number of available receptors open to exogenous opioids, i.e. heroin, and necessitating an increase in dose for the same effect), as well as withdrawal (when the exogenous opioids are ceased, the receptors are blocked by the endogenous antagonist produced, thus causing withdrawal effects until the antagonist is metabolized and production is ramped back down).  I don't pretend to think this is correct, but I'm wondering if this has been explored and rejected, and if so what the explanation is, or if there is a possibility that this mechanism or something similar to it is even realistic.

Thanks.


----------



## sekio

> the fact that administering an opioid antagonist (naloxone or naltrexone) to opioid naive individuals seems to have no effect.



That's untrue. If you give a sober person a shot of naloxone they'll almost assuredly feel like crap.



> wouldn't the antagonist block the effect of endogenous opioids, thus causing dysphoria or even symptoms similar to mild precipitated withdrawal?



They do.

Something to consider is that morphine and 6-acetylmorphine are synthesized in mammals, including humans. So opioid usage may actually be disrupting a natural equilibrium in a pretty obvious way.



> it would seem to make as much sense that the body produces its own endogenous opioid antagonists, in proportion to how much activity is detected at the receptors.


If cells were secreted opioid antagonists people would be able to collect those compounds and test them on control cells.


----------



## pharmakos

sekio said:


> That's untrue. If you give a sober person a shot of naloxone they'll almost assuredly feel like crap.



i've had arguments about this with several people, both "IRL" and online.  some day i am going to take a naloxone shot while sober as a way to try to prove that opioid antagonists are indeed dysphoriants.  i suppose proving that i am not just experiencing the placebo effect with be difficult.

and re: endogenous opioid antagonists... i think if the body knew how to produce opioid antagonists, it would have by now evolved a mechanism for mass-producing them as an antidote to accidental opioid overdose.  but, considering how deadly opioid overdoses are, i doubt humans have any sort of a mechanism for producing opioid antagonists.  though the possibility that we just haven't made that evolutionary leap yet remains.


----------



## neurotic

^ that dude from Vice tried that already didn't he


----------



## endotropic

Mr.M.301 said:


> My best attempt at an analogy is that the brain's opioid receptors can be thought of as a bundle of fiber-optic threads.  Normally a small little light shines (endogenous production) that keeps us feeling okay.  When we take a shot of heroin, it is like pointing a huge floodlight at the strands, and this causes our brain to adapt by removing or disabling many of the strands, and by shutting off the little light (endogenous production).  After a while, when heroin use is stopped, the light is off or very dim, and the number of fiber-optic strands are so few that almost no light is getting through, thus we experience withdrawal, until the brain adapts by upregulating (adding / enabling more fibers) and increasing the little light output to previous levels so that we feel normal again.



It might be more useful to imagine endogenous opioids as a faint light that only blinks occasionally rather than a constant "small little light".  Most of the time there is hardly any endogenous opioids in the synapse available to act on the opioid receptors, but certain situations (sex, excessive exercise, certain types of pain, etc.) can cause a release.  

Taking an opioid antagonist might have a disruptive effect on how you feel in those types of situations without having a noticeable effect most of the time.


----------



## neurotic

Not much happens in the opioid receptor system in regular conditions then? Like it doesnt work constantly like say serotonin or dopamine?


----------



## sekio

I suspect endogenous opioid release is required for proper functioning of e.g. reward and pain regulation circuitry. It's probably more active than you'd expect.


----------



## nAON

^ innit. Otherwise pinning sober people up with naloxone wouldn't have any effect until you get yer cock out. Hell there's even a bit of flipflop there when you mentioned serotonin, and I immediately thought about the subtle effects of SSRIs that become most evident when you're trying to have an orgasm.


----------



## InfectedWithDrugs

Maybe I should have posted this - http://www.bluelight.org/vb/threads/765123-Need-to-understand-buprenorphine-better  here..? It seems like nobody knows much about buprenorphine, but I only made that thread yesterday...


----------



## Mr.M.301

I wanted to note two other phenomena in which my understanding of the opioid system doesn't seem to explain:

-I have noticed that after I had been using opioids for quite a while and had become heavily dependent as well as tolerant to them, that the effects of the 'high' and the withdrawal effects started to overlap.  This was most noticeable with short half-life full-agonists (e.g. heroin); I would start noticing the beginning of withdrawal symptoms before the intoxicating effects had completely worn off (my pupils would still be pinned, I would still feel slightly euphoric, the analgesic effect would still be there, but I would start yawning, tearing up, have that 'throat gurgling', etc, indicative of the onset of withdrawal).

-I have also noticed (I'll try to describe this as professionally as possible but it's inherently a little gross) that when on the toilet (while defecating), I would notice by body was experiencing symptoms identical to worsening withdrawal (pupils dilating, chills/sweats, goosebumps, runny nose, tearing, etc) while defecating.  This was pretty rapid and fairly drastic, and would subsequently reverse effects (presumably due to endorphin release) when I was done.  I would get up and wash my hands, notice my pupils were slightly pinned, feel the typical endorphin effects for at least a few minutes afterwards.  The latter effect seems to clearly be related to endorphin release, but what about the former effect?

Clearly the gi-tract is heavily influenced by opioids; is it possible that the brain uses them somehow as a signalling mechanism to induce defecation, by temporarily increasing gut motility and muscle contractions, or something like that?  I was reading the following but I'm having a little bit of a hard time understanding exactly what it is saying with regards to this issue specifically:



> The release of opioid peptides from enteric neurons can be accompanied by substantial changes in motility and secretion (8, 43). The inhibitory effect of opioid agonists is related to interruption of neurotransmission within the enteric nerve pathways governing gut muscle activity (8, 46, 47, 48). Opioid receptor agonists can interrupt both excitatory and inhibitory neural inputs to the musculature of the gastrointestinal tract; inhibition of excitatory pathways inhibits the release of excitatory neurotransmitters, such as acetylcholine, and blocks distension-induced peristaltic contractions (Figure 2). In contrast, blockade of inhibitory neurotransmission results in suppression of nitric oxide release from inhibitory motor neurons, disinhibition of gastrointestinal muscle activity, elevation of resting muscle tone, as well as nonpropulsive motility (7, 8). Because opioid receptor agonists can influence both excitatory and inhibitory activity, as well as activate the interstitial cell–muscle network, their effects on gastrointestinal motility and secretion can be complex. μ-Opioid receptor agonists inhibit gastric emptying, increase pyloric muscle tone, induce pyloric and duodenojejunal phasic pressure activity, disturb the migrating motor complex, delay transit through the small and large intestine, and elevate resting and sphincter pressure (8). In addition, the μ-opioid receptor agonists inhibit gastrointestinal ion and fluid transport (Figure 2). As a result of the combination of prolonged contact of the intestinal contents with the mucosa and interruption of prosecretory enteric reflexes, opioids attenuate the secretion of electrolytes and water and facilitate the net absorption of fluid (8).
> 
> The effects of μ-opioid receptor agonists on the gut are mediated by interaction with enteric μ-opioid receptors. The transduction of a signal through these receptors can result in activation of a number of pathways, including activation of potassium channels, membrane hyperpolarization, inhibition of calcium channels, and reduced production of cyclic adenosine monophosphate (8). All three classes of opioid receptors—δ, κ, and μ—have been shown to contribute to opioid-induced inhibition of muscle activity in isolated human intestinal tissues (5).


----------



## IndustrialStrength

^ I don't have much to contribute in terms of an answer to your question;
but would like to anecdotally add that I also have experienced these same effects.
Though I would like to add that the effects don't necessarily reverse themselves.
Also the effects as he stated are quite drastic, sweats, tearing, pain, etc.
Often I take medication on the way to the bathroom to counteract the after effects.
IE. Oral Methadone or Oxycodone (What I'm currently prescribed) so that upon completion
of the aforementioned movement I don't enter withdrawals.
As such I would also be interested in anyone's take on this particular question.
Thanks to anyone who has any input on said questions of the above poster.


----------



## Oxide

http://www.sciencemag.org/content/349/6249/677.full

neat discovery.


----------



## IndustrialStrength

@Oxide neat discovery indeed, thanks for sharing.

Has anyone found or know of any references to what Mr.M.301 was referring to?
If so I'd be very interested in reading them, so please post or PM me any that anyone happens to find.

On a similar note I have noticed that eating tends to bring on opiate withdrawal symptoms in my case.
I've been searching for any journal articles or references to this phenomena but to little avail.
If anyone has any links to articles or other information regarding the stated phenomena please post or PM.
Thanks to whoever may post or PM said information.
And as always thanks to those who contribute to the knowledge base available here.
It's greatly appreciated even by those who usually prefer to lurk more than post here. Thank you.


----------



## Kittycat5

MrM301, the article you quoted is talking about the enteral nervous system, not the central nervous system. The GI tract has a large neuronal network that can act independent from the brain for digestive processes. That quote is basically saying both endogenous and exogenous opioid agonist affect nearly all pathways involved in proper function thus leading to constipation. Your thoughts on endorphins and enkephalins stimulating GI motility are incorrect. They do exactly the opposite within the enteric nervous system.

I imagine the brain has some involvement, as it does on every organ system, but the natural opioids in the CNS would still most like have an inhibitory effect on motility, fluid secretion etc. It is just not as clear on how much they effect the GI tract.


----------



## Dresden

Why does time go by faster when you're on a goodly dose of (meth)amphetamine?


----------



## Dresden

What is delta-FosB exactly and what does it do, such as in response to methamphetamine administration?


----------



## sekio

Wikipedia has a pretty good writeup.


----------



## aced126

Anyone got any information on beta carboxylate amphetamine? If it has similar pharmacology to either methylphenidate or amphetamine?

Also on this Wikipedia page it says serotonergic indane amphetamines are non neurotoxic because the methyl group can't form free radicals like in open chain counterparts. I searched the net for more detail on this but couldn't find any papers. Anyone know of any? 

How are rats trained to discriminate a drug from saline?

Finally, could anyone speculate on the activity of tetralin and indane derivatives of mephedrone?


----------



## Dresden

sekio said:


> Wikipedia has a pretty good writeup.



Thanks, sekio.  I thought it was a good writeup as well.  Oh well, I guess I need some sodium butyrate:






Or a viral delta-JunD expression increasing vector; however, both of these phosphorylated delta-FosB reducers would seem to me to be capable of possibly inducing a whole plethora of malevolent unintended consequences such as anhedonia, adverse sexual side effects, or who knows what else.

Also, it would be scary even if they do work with no serious side effects because LE or rehab or family members might start forcing addicts to undergo treatment which many of us don't want.  I mean, I think I like having elevated delta-FosB for the most part and think it is a good thing to have as long as harm reduction is employed.

aced126,

You don't want beta-carboxylate-amphetamine.  You want beta-carbomethoxy-amphetamine:






It crosses the BBB much better.  Its pharmacology is unknown to my knowledge, but I would bet money that it is, in fact, a psychostimulant.  Of course, I might lose that bet, but c'est la vie!!!

Que sera, sera!  Whatever will be, will be.  The future's not ours to see.  Que sera, sera!


----------



## aced126

Is that why ritalinic acid is inactive? What if the carboxylate was administered directly into the brain? Would it be efficacious?


----------



## Dresden

aced126 said:


> Is that why ritalinic acid is inactive? What if the carboxylate was administered directly into the brain? Would it be efficacious?



Yes and possibly yes, but in the case of the possibly yes, injecting beta-carboxylate amphetamine directly into the brain would be extremely hard to do without overdosing because when a drug is directly injected into the brain it is something like 140x stronger on a weight basis than usual, and it is likely that beta-carboxylate amphetamine and beta-carbomethoxy amphetamine have somewhat different, mainly subjective effects because, after all, they have slightly different chemical structures.  Still, I would venture that both are active though likely not identical in terms of effects; the carboxylate is just a lot harder to safely and effectively administer.


----------



## aced126

What other roles would the carbomethoxy group play other than making the molecule more polar? Would, say, bcm-amph enter dopaminergic neurons at all? I heard ritalin doesn't actually cause vesicular dopamine release into the cytosol but rather just blocks the reuptake pump. Would bcm-amph do the same? I'd guess so.

What are the fundamental differences between just a normal membrane say in the GIT versus the BBB, in terms of molecules being able to diffuse through. I understand there are tight junctions in the BBB, and also that some molecules can pass through normal membranes through endocytosis etc which can't happen in the BBB. But what I'm asking is if a molecule is lipophilic enough to diffuse through the GIT into the blood because it is lipophilic enough to do so, then what's to stop it from diffusing across the BBB?

Edit: Just realised cocaine does have an effect on VMAT. So is the only difference in mechanism of amphetamine and cocaine that cocaine isn't a substrate of TAAR? Also, would a molecule that induces more exocytosis of monoamine vesicles not be neurotoxic? It seems that cytosol is no man's land for monoamines, hence the function of VMAT itself.

Furthermore, I'm finding it hard to believe that a molecule can literally make the transporter work in reverse. I can get to grips with conformational changes (although I will probably never understand the chemistry behind it), but normally since it is such a complex biological mechanism I'd expect it to have a function. Haemoglobin undergoes conformational changes for a biological reason. What is the reason for the ability of DAT or SERT to flip itself when bound to some molecules? 

Is there any literature where researchers provide a reaction mechanism for a very simple (or not so simple) protein of probably few amino acids undergoing a conformational change when bound to a substrate?


----------



## aced126

What are the challenges to crystallizing DAT with covalent ligands in place so that an exact structure for the transporter can be determined?


----------



## Dresden

Neurobiology is not my expertise, although I have formally studied it.  I have a degree in Chemistry, instead, and mainly just study drugs' structures, classes, and subjective effects to come up with "random," new molecular structures, so I can't answer all your questions other than to say if a molecule has more than 2 or 3 hydroxyls or even one or two carboxyls, then that is enough polarity to negatively impact its crossing of the blood brain barrier.  To my limited Biology knowledge, hydrophobicity is not a requirement for a molecule to enter the body through the gastrointestinal tract, if that's what you were referring to.  It is, however, for a drug to enter the brain by crossing the BBB.  I take neurobiology/chemistry/pharmacology with a grain of salt in many cases and often learn more from reading a trip report and a structure than a table of values of a drug's effects on various neurotransmitter subunit binding affinities.


----------



## InterestingFACT

aced126 said:


> What other roles would the carbomethoxy group play other than making the molecule more polar? Would, say, bcm-amph enter dopaminergic neurons at all? I heard ritalin doesn't actually cause vesicular dopamine release into the cytosol but rather just blocks the reuptake pump. Would bcm-amph do the same? I'd guess so.
> 
> What are the fundamental differences between just a normal membrane say in the GIT versus the BBB, in terms of molecules being able to diffuse through. I understand there are tight junctions in the BBB, and also that some molecules can pass through normal membranes through endocytosis etc which can't happen in the BBB. But what I'm asking is if a molecule is lipophilic enough to diffuse through the GIT into the blood because it is lipophilic enough to do so, then what's to stop it from diffusing across the BBB?
> 
> Edit: Just realised cocaine does have an effect on VMAT. So is the only difference in mechanism of amphetamine and cocaine that cocaine isn't a substrate of TAAR? Also, would a molecule that induces more exocytosis of monoamine vesicles not be neurotoxic? It seems that cytosol is no man's land for monoamines, hence the function of VMAT itself.
> 
> Furthermore, I'm finding it hard to believe that a molecule can literally make the transporter work in reverse. I can get to grips with conformational changes (although I will probably never understand the chemistry behind it), but normally since it is such a complex biological mechanism I'd expect it to have a function. Haemoglobin undergoes conformational changes for a biological reason. What is the reason for the ability of DAT or SERT to flip itself when bound to some molecules?
> 
> Is there any literature where researchers provide a reaction mechanism for a very simple (or not so simple) protein of probably few amino acids undergoing a conformational change when bound to a substrate?



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729543/

Here is a good summary of the structure and mechanism of monoamine transporters and the phosphorylation sites that modulate their function. 

In short, they use an "alternate access" process where Na+ co transport fuels conformational change between inward-facing and outward-facing positions. 
Beyond this basic functionality there's several proposed/involved mechanisms for amphetamine induced reverse transport: amph influx via DAT increases the number of inward facing DAT, amph-induced increaes in intracellular sodium would drive reverse transport, and amph also appears to cause a burst/channel-like function in DAT releasing a quanta of DA. 

Keep in mind how similar amphetamine is to endogenous phenethylamine--it behaves essentially identically except for its resistance to MAO. So any functionality of AMPH at monoamine transporters isn't really an accident of chemistry and nature, but rather a utilization of existing functional mechanisms normally driven by endogenous phenethylamine.


----------



## aced126

Do relevant substitutions to amphetamine like 3,4-methylenedioxy, 4-chloro etc actually reduce the affinity at DAT and other dopamine releasing mechanisms? You'd need around 150mg of MDMA for good recreational effects, but for the amphetamine counterpart you need significantly less. Obviously amphetamine has very little serotonergic properties.


----------



## neurotic

Do benzodiazepines not get sold as salts because they already have a pretty good bioavailability as it is? It is my understanding that drugs get sold as salts to be better absorbed (and more stable).

I mean there are plenty of nitrogens there that could be protonated so it's not the same case as say THC.

I wondered if there was something funny with the nitrogens in the diazepine/triazolo rings so they didn't readily donated electrons or something but i think midazolam is in fact available as the HCl salt. Any particular reasons why midazolam in particular is salted? When they IV diazepam why instead of using PEG as vehicle (which causes metabolic acidosis or smth, the reason midazolam HCl is prefered) don't they use diazepam HCl?


----------



## adder

In acidic solutions protonated benzodiazepines exist in an open-chain form. The triazole ring doesn't take part in protonation in any way (other than impacting basicity of the amine in some way), but I guess imidazo- and triazolobenzodiazepines in open-chain form may be more stable because there is no way they could undergo irreversible hydrolysis while classic benzodiazepines have a carbamoyl moiety which may be further hydrolysed. Perhaps classic benzodiazepines can't be stored under acidic conditions for too long, but that's just a guess.


----------



## aced126

What is the rate at which a non charged lipophilic molecule crosses the GIT bilayer?

Is it proportional to the concentration of the molecule itself, or is it something more complicated ?


----------



## pharmakos

how dorky would it be to name my daughter Ethyl Ester?


----------



## Dresden

pharmakos said:


> how dorky would it be to name my daughter Ethyl Ester?



It would be beyond awesome.


----------



## Dresden

adder,

I hate to be a naysayer with no good source to back up my counterclaim, but I really kind of doubt benzodiazepines spontaneously break open in acidic aqueous media such as the stomach.  I know that imines are unstable in aqueous media, but I think the cyclic ones are much more stable.  As for which salt the benzos usually are, I think the companies bringing them to market first starting in the 70s or late 60s or whenever it was were lazy and just never really felt the need to list which salt they were using.  It's probably usually the fumarate salt or something.

aced126,

I know that peppering one's speech or writing with a good amount of acronyms lends the air of erudition to one's speech or writings, but personally, I generally try to avoid doing so, as technical acronyms often also impede the ability for one's fully formed thought/message to reach one's users' understandings.  Case in point, what do you mean by "GIT" exactly?  If you mean gastrointestinal tract, then it is a not easily predictable property of a drug that is also drug specific.  For example, some drugs are best absorbed on an empty stomach, others (ziprasione) are much better absorbed on a full stomach, and others yet (amphetamines) are well-absorbed with or without food.  I mean, I've heard of GIT HER DONE or GIT HER DRUNK, but science acronyms such as the HOMO-LUMO (highest occupied molecular orbital lowest unoccupied molecular orbital) gap just make me laugh, especially when they're in all caps.  It's highly DISTRACTING.


----------



## sekio

> As for which salt the benzos usually are, I think the companies bringing them to market first starting in the 70s or late 60s or whenever it was were lazy and just never really felt the need to list which salt they were using. It's probably usually the fumarate salt or something.



most benzos are sold as freebase, drug labeling laws* require* the specification of a salt if you're selling a salt (i.e. nobody is allowed to sell dextromethorphan hydrobromide as just 'dextromethorphan', it must be labeled HBr if it is the hydrogen bromide salt... you can't just "get lazy")

i thought most BZDs actually were amides that lacked basic nitrogens which could get protonated with the exception of a few (midazolam)... the imide doesn't pick up a proton like a 'normal' amine does, IIRC


----------



## Dresden

Ok, maybe I'm missing something still, but then how do benzodiazepines dissolve in aqueous media if they're sold as the freebase?  Also, do they really break open like that?  I think not.


----------



## clubcard

sekio said:


> i thought most BZDs actually were amides that lacked basic nitrogens which could get protonated with the exception of a few (midazolam)... the imide doesn't pick up a proton like a 'normal' amine does, IIRC



Even midazolam has to be in a low pH solution - any of the triazolo class WILL salt. I know they are way inaccurate, but the Marvinsketch on-line software does allow LogP & PKa so you can look at the different (un)protonated forms against pH. Free to all, knocks out 90% of randoms and gives everyone a leg up on the knowledge base.


----------



## neurotic

Dresden said:


> Ok, maybe I'm missing something still, but then how do benzodiazepines dissolve in aqueous media if they're sold as the freebase?  Also, do they really break open like that?  I think not.



Actually they do... And that irreversible hydrolysis of the benzodiazepinones adder said makes a lot of sense, still don't know why specifically midazolam is chosen though. There is a paper called something like "chemical structure of midazolam compared to other benzodiazepines" if you're still not convinced. Somewhere in it there might be an explanation for the choice of midazolam over triazolo benzos for this application but it's more chemistry than I could understand...


----------



## Dresden

I'll take ya'lls word for it.  But why bother even cyclizing the benzodiazepines if they're just going to break open to begin working when inside the low pH stomach?  I'm confused.

Oh yeah, and seiko I believe you about the law requiring the salt form used be listed on the drug label, and maybe this is the exception that proves the rule, but ibuprofen labels never say anywhere as far as I can tell what salt (or is it the freebase?) of ibuprofen being used in Advil, Motrin, etc.  I am thinking it must be the carboxylate sodium salt like naproxen sodium (Aleve), a similar drug, but I really haven't been able to figure that one out, either.


----------



## sekio

> ibuprofen labels never say anywhere as far as I can tell what salt (or is it the freebase?) of ibuprofen being used in Advil, Motrin, etc.



That's because it's just plain ibuprofen as the free acid, it's not a salt.


----------



## clubcard

as an aside - Ibuprofen is totally insoluble in water so Vicoprofen should really use the lysine derivative.


----------



## sekio

I think Vicoprofen was invented before the lysine salt came about? For whatever reason ibuprofen is absorbed orally anyway even though it's not water sol. (emulsifiers in bile? alkaline environment in small intestine?) Nevertheless I agree I'd like to see wider usage of ibuprofien lysine.


----------



## aced126

Why is it that in general serotonin releasers (e.g MDMA) are fundamentally less usable long term (and over elongated periods of use eventually lose most of their efficacy) compared to dopamine releasers (e.g. methamphetamine), which can be used continuously for long periods of time, and work with as much efficacy (one doesn't "lose the magic" of meth) ?


----------



## aced126

Do SSRIs like paroxetine actually enter (serotonergic) neurons like SRAs such as MDMA? If not, does the 1,3-benzodiox-5yl part of paroxetine bind analogously to MDMA at SERT?


----------



## AlphaMethylPhenyl

I think that in fact many would say that the "magic" of methamphetamine does wane considerably. The same goes for less damaging stimulants. A lot of the time, people are prescribed a stimulant (ritalin, adderall, vyvsnse) and find in the beginning, they are a lot more social, happy, and fulfilled. As time goes on, these effects wane considerably. And so people think that just because these effects diminish or disappear, that the medication isn't working how it's supposed to. So, for example, while at the start stimulants make things so interesting that very little effort is required to focus, they eventually make it so that it's still easier to focus, but that is requires a considerable greater effort.

I do get that, though, the "magic" of MDMA probably lessesn more than that of more dopaminergic stimulants. Not sure why.


----------



## aced126

When people talk about SRAs having "affinity to SERT", what does this actually mean? Does it suggest that when the SRA binds onto SERT, SERT is reversed? I thought SRAs would have their action similar to amphetamine where they go into the neuron through SERT and then increase cytosolic 5HT concentration, and then through some other mechanism reverse SERT. If all an SRA does is bind onto SERT and either block it (which would make it an SSRI) or reverse it, then where does the cytosolic 5HT come from?


----------



## Dresden

The magic of methamphetamine does not wane.  I've been using it off but mostly on for 19 years, and the magic as good as ever.

* * *

Why haven't more peptide drugs been developed?


----------



## aced126

If you're talking about neuroactive peptide drugs, well they probably can't cross the gut, let alone the BBB.

On another note, when MAO metabolizes phenethylamine in the brain into phenylacetic acid (more polar), won't the PAA just be stuck in the brain because it can't cross the BBB back into the blood? Thus does MAO serve just to deactivate the neuromodulator rather than excrete it?


----------



## Neithman

Hey all

Do more potent(per mg)drugs have the tendency to be less neurotoxic because there is less of the chemical that has to be metabolized(in total weight) or doesnt work it this way.
i know you cant generalize this thesis on all drugs because there just too many drugs with different pharmacological action but im just wondering if its more likewise for a drug to be less neurotoxic if its more potent per mg than say a analog with same effects that is 1/10th of the potency


----------



## aced126

That depends on the cause of the (neuro)toxicity. For example paracetamol hepatotoxicity is dependant on metabolism of paracetamol to NAPQI. Your statement is correct if the drug in its unmetabolized form is itself neurotoxic. However it seems that neurotoxicity seems to correlate with amount of neurotransmission release in some hypotheses. For example a hypothesis for SRA (eg. MDMA) induced serotonergic neurotoxicity is that after all the serotonin is depleted within the neuron, dopamine then enters the serotonergic neuron. If this hypothesis was true then that would mean a more potent drug releasing and depleting more serotonin would cause more neurotoxicity. So in answer to your question it really depends on the mechanism of neurotoxicity. 

However, I do think that more potent drugs are theoretically better drugs because they are more likely to be selective to their appropriate target. What I mean by this is: if a drug whose dose was say 10mg interacted with target A and target B, the latter being the desired target, and if an analogue of the drug was found to make it require only 0.1mg for desired effect at target B, then it is unlikely that such a big change will occur at target A, especially if A was vastly different to B, and so 0.1mg will have approximately x100 less effect on A and the same effect on B as 10mg of the other analogue. Thus by making the drug more potent, then by probability you have increased selectivity. 

Practically though, especially for recreational drugs, greater potency is bad bad bad, even if the drug has increased selectivity (which could increase therapeutic index eg sufentanyl), as stupid people will be stupid and fuck themselves up. But from a pharmaceutical standpoint it seems good to make a drug more potent, and they can accordingly dose the tablets accordingly, even to small microgram amounts.


----------



## clubcard

No simple rule to apply. Nitromethaqualone is x4 as potent as it's parent, but in that para position, it's ripe to be reduced to an amine... and as a very general rule, aromatic amines are bad (BUPO).

The fact that it's all fentanyl analogues and WHICH analogues speaks volumes. These joker have read 'The Seigfried Route' and are not real chemists. Sufentanil is a lot more work. No sign of 3-methyl analogue (Kolokol) so they can't access a wide range of chemicals as does the missing beta hydroxy derivatives. However you read it, I've seen too many good people lose it all to fentanyl. People getting a 20-minute habit where, day & night, they have to take another spray from the solution. One chemist I know was busted & put straight into jail while his assistant wasn't charged but a year later & he's still in withdrawal. Opioids with an N-(aryl)ethyl group bind to a part of the receptor that endorphins don't and by the looks of it, it's a 1-way street. You get a fentanyl habit and no amount of juice is going to fix you. Look at the guy who made etonitazine. That's another strong opiate that binds to that extra point on the receptor. He had money but no amount of juice could fix him... so he killed himself. Worked at Morton Thiokol... Thomas K Highcliff. Etonitazine is only 60x M in man but that's still far, far too much and more evidence that addiction to that class is a 1-way street.


----------



## crOOk

clubcard said:


> No simple rule to apply. Nitromethaqualone is x4 as potent as it's parent, but in that para position, it's ripe to be reduced to an amine... and as a very general rule, aromatic amines are bad (BUPO).
> 
> The fact that it's all fentanyl analogues and WHICH analogues speaks volumes. These joker have read 'The Seigfried Route' and are not real chemists. Sufentanil is a lot more work. No sign of 3-methyl analogue (Kolokol) so they can't access a wide range of chemicals as does the missing beta hydroxy derivatives. However you read it, I've seen too many good people lose it all to fentanyl. People getting a 20-minute habit where, day & night, they have to take another spray from the solution. One chemist I know was busted & put straight into jail while his assistant wasn't charged but a year later & he's still in withdrawal. Opioids with an N-(aryl)ethyl group bind to a part of the receptor that endorphins don't and by the looks of it, it's a 1-way street. You get a fentanyl habit and no amount of juice is going to fix you. Look at the guy who made etonitazine. That's another strong opiate that binds to that extra point on the receptor. He had money but no amount of juice could fix him... so he killed himself. Worked at Morton Thiokol... Thomas K Highcliff. Etonitazine is only 60x M in man but that's still far, far too much and more evidence that addiction to that class is a 1-way street.


Thanks for the insights!


----------



## Dresden

aced126 said:


> On another note, when MAO metabolizes phenethylamine in the brain into phenylacetic acid (more polar), won't the PAA just be stuck in the brain because it can't cross the BBB back into the blood? Thus does MAO serve just to deactivate the neuromodulator rather than excrete it?



I suppose phenylacetic acid is pumped out of the brain via some kind of active transport mechanism?  But I never studied in biology as much as I should have.  I just really didn't care to subject my brain to all that rote memorization when the rave scene was just starting to burgeon (1996-1997), and I had lots of really good drugs to do.  Sad, isn't it?


----------



## clubcard

The rave scene began 10 years earlier. I was there...providing 'ambiance' to proceedings. Still have the 1000 capping board.


----------



## Dresden

Are you British?


----------



## neurotic

why would dopamine entering a serotonergic neuron cause damage but entering a dopaminergic neuron not cause it? thinking of that dopamine getting inside 5HT neurons explanation for neurotoxicity of MDMA and MDAI + amphetamine combo


----------



## Dresden

The whole DA entering the 5-HT neuron and damaging it was just a never proven hypothesis that Nichols or one of the early MDMA researchers once threw out there.  It has since been disproven by mephedrone, which simultaneously releases tons of DA and 5-HT but yet does not cause "MDMA type neurotoxicity."


----------



## Cotcha Yankinov

Idk, I think the SERT can transport dopamine into the serotonin terminal http://www.ncbi.nlm.nih.gov/m/pubmed/2413404/ http://www.ncbi.nlm.nih.gov/m/pubmed/8016192/  I also don't know if I would compare mephedrone and MDMA :3 Especially if mephedrone doesn't produce "MDMA type neurotoxicity", though it might be a metabolite specific to MDMA that is getting into the neurons through SERTs and causing damage or could even be MDMA itself. 

 But Neurotic I could be remembering wrong but I was under the impression it was catecholamines being metabolized by MAO-B that might've damaged the serotonin axons to an extent https://www.erowid.org/references/refs_view.php?ID=974  The damage was attenuated by MAO-B inhibitors and increased by more dopamine, while lack of dopamine through different methods meant less to no serotonin damage. Although I should mention a great portion of the increase in neurotoxicity with more dopamine is probably from increased temperature. But I do wonder what the consequence is of having dopamine inside a serotonin axon if that is indeed a thing. One study said even dopamine itself is toxic to serotonin neurons, hydrogen peroxide aside.


----------



## aced126

Does methylphenidate/derivatives enter the dopaminergic neuron at all? If it does, what effects does it have? Does anyone have any good studies on the (Q)SAR of DAT,TAAR1 or VMAT2?


----------



## aced126

Can someone knowledgeable on opioid SAR shed some light as to why none of the nitrogens in endogenous opioid peptides are tertiary? I thought a tertiary nitrogen was key for opioid activity.


----------



## adder

As a matter of fact tertiary amine is not necessary for opioid activity and secondary amines, like normorphine, don't necessarily have lower affinity or efficacy than tertiary amines. This paper has some useful information on normorphine and its analgesic potency and what might affect it. I suppose it's less potent in vivo due to increased hydrophilicity (unlike tertiary amines secondary amines can function as hydrogen bond donors aside from acceptors) which makes it cross the blood-brain barrier less effectively. Norbuprenorphine has a comparable affinity to buprenorphine at MOP receptors but it's a substrate for P-gp which transports it out of the brain (source, source).

BTW, almost all essential aminoacids bear a primary amine so when they're bound via a peptide bond in a peptide, the resulting amide ends up secondary. The only essential aminoacid with a secondary amine is proline.


----------



## aced126

Fair enough, I just think that morphine is a rather lipophilic molecule if you consider it as a whole. (Meth)amphetamine still crosses the BBB effectively. I can't see how one methyl group can increase diffusion across BBB that much. Is lipophilicity the only factor in question? I thought having a tertiary amine had something to do with the binding interactions, maybe I was wrong.


----------



## neurotic

Dresden said:


> It has since been disproven by mephedrone, which simultaneously releases tons of DA and 5-HT but yet does not cause "MDMA type neurotoxicity."



yeah, i was wondering about that. if that theory (the one i mentioned) made sense then mephedrone should be brain destroying. i was gonna mention mephedrone but then i gave it a google search and found this article here which claimed it was neurotoxic to both DA and 5-HT neurons. they fed rats with some apparently pretty hardcore mephedrone regimens and found reduced paroxetine and DA uptake binding sites 3 and 7 days afterwards. the numbers did raise from rats examined at day 3 to day 7, which is a different pattern than neurotoxic drugs like pCA and MDMA which cause a more sustained reduction... i guess mephedrone shows it is not simultaneous dopamine and serotonin release which is the villain



Cotcha Yankinov said:


> But Neurotic I could be remembering wrong but I was under the impression it was catecholamines being metabolized by MAO-B that might've damaged the serotonin axons to an extent https://www.erowid.org/references/refs_view.php?ID=974  The damage was attenuated by MAO-B inhibitors and increased by more dopamine, while lack of dopamine through different methods meant less to no serotonin damage. Although I should mention a great portion of the increase in neurotoxicity with more dopamine is probably from increased temperature. But I do wonder what the consequence is of having dopamine inside a serotonin axon if that is indeed a thing. One study said even dopamine itself is toxic to serotonin neurons, hydrogen peroxide aside.



pretty complicated stuff... don't know what to make all of that information hah, but i guess that mephedrone, releasing huge amounts of serotonin, comparable to MDMA, and even higher amounts of dopamine, not causing 'neurotoxicity' in the same fashion as MDMA does pretty much leaves it up to metabolites or some other nuance that MDAI shares, and are 'enhanced' by dopamine release... idk...


----------



## Cotcha Yankinov

I think it might indeed be something more compound specific with MDMA.. from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997268/ -- "MDMA is metabolized to catechol metabolites which can undergo oxidation to o-quinones that are highly redox-active molecules and produce free reactive oxygen species or nitrogen species radicals (Capela _et al_., 2006). It is widely believed that it is these oxidation products which may be responsible for the toxicity exerted by MDMA (Capela _et al_., 2009; Song _et al_., 2010; Green _et al_., 2012a), a view supported by the observation that administration of the free radical trapping agent α-phenyl-N-tert-butyl nitrone attenuated the long-term loss of 5-HT in the rat brain induced by MDMA (Colado and Green, 1995).* In contrast to MDMA, catechol and quinone metabolites do not appear to be formed as the result of mephedrone metabolism* (Figure 2). This distinction may explain why most studies have failed to observe any similar mephedrone-induced neurotoxicity in rat brain. No active metabolites of mephedrone have yet been identified." 

I think temperature is incredibly important too, mephedrone seems to cause more hypothermia interestingly. But the only other thing I could think of is an 5-HT2B interaction, seeing as its involved with the SERTs and MDMA and MDMA's toxicity does seem to be associated with SERTs carrying some molecule into the serotonin terminal, and maybe not other amphetamines have as much interaction with 5-HT2B?? Idk though I know 5-HT2B is supposed to be important for substituted amphetamines it sounds like.. Whenever I think 5-HT2B I just think heart valvular disease and not brain serotonin lol, wish I knew more about what it did in the brain.


----------



## immad

Would these catechol and quinone metabolites be expected from Methylone metabolism as well?


----------



## aced126

Very likely yes, although less so than MDMA because the beta ketone is prone to metabolism as well.


----------



## clubcard

Interesting that UK law leaves 1-(2H-1,3-benzodioxol-5-yl)-3-fluoro-N-methylpropan-2-amine legal due to this f**kup in classifying amphetamines:

(c) any compound (not being methoxyphenamine or a compound for the time being specified in sub-paragraph (a) above) structurally derived from phenethylamine an N-alkylphenethylamine, a methylphenethylamine, an N-alkyl-α-methylphenethylamine, an ethylphenethylamine, or an N-alkyl-α-ethylphenethylamine by substitution in the ring to any extent with alkyl, alkoxy, alkylenedioxy or halide substituents, whether or not further substituted in the ring by one or more other univalent substituents.

I mean - HOLES man!


----------



## sekio

Does it? I think it's covered, as a "N-alkyl-a-methylphenethylamine" substituted with an alkylenedioxy and halide substituent.

"to any extent with ... or" is inclusive, not exclusive, language. Doesn't mean you can avoid it by having BOTH an alkylenedioxy and halide sub.

Besides, the UK lawyers have no sense of humor anyway. I would not be suprised if they "mistakenly" "swapped" the GC traces for one of methamphetamine during the customs inspection...

(Or, wait, shit, _you're talking about a halide on the alpha-carbon_, not the ring! Sneaky! You trickster!)


----------



## Doc Aliquot

In the US, at least, there is no parenteral formulation available of amphetamine, d-amphetamine, methamphetamine, methylphenidate, dexmethylphenidate....nada.

 The last injectable amphetamine product legally manufactured was Methedrine HCl. Injection, 5mg./ml. 2ml. ampoules, made by Burroughs-Wellcome, (now part of GSK). The FDA recalled 'em all on Jan. 1, 1970.


----------



## Dresden

Mephedrone has since been shown to be metabolized by N-dealkylation to the primary amine, by reduction of the keto group to an alcohol, and by oxidation of the aromatic methyl to a aromatic methanol then to an aldehyde and finally to the carboxylic acid.  Indeed, no catechols or quinones form or would be expected to form.


----------



## Dresden

sekio said:


> That's because it's just plain ibuprofen as the free acid, it's not a salt.



Nope, check out the new bottle labels.  It's ibuprofen sodium.


----------



## belligerent drunk

After a fairly quick search, I didn't find any suggestions that grapefruit inhibits CYP2D6, only 3A4. So according to my understanding, 3A4 is responsible for N-dealkylation of codeine producing the inactive norcodeine while 2D6 is responsible for 3-dealkylation producing morphine. This should mean that if 3A4 is inhibited, more codeine will follow the 3-dealkylation path resulting in more morphine, thus increased opioid effect. My question is, why do people suggest against using grapefruit to potentiate codeine and why do some people say that in their experience grapefruit actually decreases the effects of codeine?


----------



## crOOk

belligerent drunk said:


> After a fairly short search, I didn't find any suggestions that grapefruit inhibits CYP2D6, only 3A4. So according to my understanding, 3A4 is responsible for N-dealkylation of codeine producing the inactive norcodeine while 2D6 is responsible for 3-dealkylation producing morphine. This should mean that if 3A4 is inhibited, more codeine will follow the 3-dealkylation path resulting in more morphine, thus increased opioid effect. My question is, why do people suggest against using grapefruit to potentiate codeine and why do some people say that in their experience grapefruit actually decreases the effects of codeine?


I can't give an answer, but you definitely have the enzymes right. The mechanism you describe would be the same as the one causing Tramadol to be potentiated through grapefruit juice. 3A4 metabolizes to N-Desmethyltramadol, 2D6 to O-Desmethyltramadol, resulting in higher plasma levels of the latter which is a much stronger mu opioid receptor agonist.


----------



## aced126

Can anyone with a good chemistry knowledge explain the mechanism by which an aliphatic carbon chain is hydroxylated? Also, if someone could explain the enzymatic reaction mechanism by which phenethylamine is metabolised into phenylacetic acid, that would be very much appreciated.


----------



## aced126

Is there any way to separate the relative importances of logP and target (receptor, enzyme etc) binding interactions. Both obviously effect how efficacious the drug is. Someone here said a while ago that MDMA injected directly into the brain requires x140 less of a normal dose (in rats at least). I think seeing how big of a role each of these 2 important properties play could be very useful in understanding the mode of action of the drug. Furthermore, wouldn't it be in the better interest of a molecule to actually have a (relatively low) lipophilicity and a high affinity and selectivity for its target. If the opposite were the case, as in the drug was very lipophilic and got into the brain in large amounts, surely there is more of a chance it interacts with undesirable targets causing side effects etc.


----------



## Weltmeister

Does anyone know how exactly Gramine mediates its toxicity ? Wikipedia says : "Gramine is a norepinephrine reuptake inhibitor in synaptic vesicles.[citation needed] Resulting effects of extra norepinephrine raise blood pressure and heart rate."

What i dont get is why the inhibition of norepinephrine reuptake is considered toxic in this case but not when its stuff like methylphenidate that inhibits the reuptake.


----------



## belligerent drunk

Without reading much about gramine, I think this is a case of "the difference between medicine and poison is in concentration" so to speak. Stimulants of all kinds could be considered toxic because an overdose can lead to death. In this case though it's not considered a medicine, only a toxin, hence the wording "mechanism of toxicity" rather than "mechanism of action".


----------



## Cotcha Yankinov

Hmmm if it's not sometime specific to this chemical Gramine (a toxic metabolite for example) the mechanism of toxicity could be excitotoxicity from increased adrenaline transmission at a high dose? This should be possible with methylphenidate if the dose is high enough?

 Excitotoxicity is typically dose dependent (you won't get enough excitability at a low dose to cause damage) where as other kinds of metabolism toxicity could be possible at any dosage but the extent of the toxicity correlates with the dosage.


----------



## Weltmeister

I guess i just have to try it myself. Just gotta start very low and work my way up. I dont think its that toxic because if you compare the molecules its almost identical to dmt just with a shorter sidechain.

Fortunately i already have experience with noradrenalin overloads and know what it feels like.

This just pisses me off because in literature the pharmacology seems to be well known but you cant find anything about it on the internet.


----------



## belligerent drunk

It's actually closer to phenethylamines if you look at it - a 2 carbon spacer between the tertiary nitrogen and "benzene ring" if you ignore the fact that it's an indole derivative, which also explains why it has NE reuptake inhibiting properties.

I'd be cautious if I were you though. Just because there's little information on the possible toxicity outside of NERI doesn't mean it isn't dangerous/harmful. Maybe someone with more knowledge about gramine could chime in as I'm only speculating. But yes, start very low.


----------



## aced126

A few questions about Shulgin. 

1. How did he know the compounds he made were actually the compounds he made. I guess he had an NMR machine but I can't see anywhere in pictures of his lab. 
2. Speculations on his dosing method/schedule to trial out a completely novel compound which could be active at 10 micrograms or 10 grams. 
3. How did he tackle purification of compounds which might have a few impurities in them e.g overbromination of 2-CB?


----------



## belligerent drunk

NMR machine is not really something you keep in your lab. It's usually in a separate room if your institution has one. Anyway, there are many ways to identify a compound's structure, I'm sure he had that under control.

Not many substances are active in the nanogram range so I guess one could start from the low end of micrograms and (on separate occasions) move up from there increasing the dosage slowly. This is what I would have done if I had no idea how active the compound is. Usually the active dosage is at least somewhat similar to the compounds close relatives, so you can predict whether it'll be more of a microgram or milligram range. I don't know what he actually did though, but I do believe he didn't just blindly eat grams of new product.


----------



## aced126

belligerent drunk said:


> NMR machine is not really something you keep in your lab. It's usually in a separate room if your institution has one. Anyway, there are many ways to identify a compound's structure, I'm sure he had that under control.
> 
> Not many substances are active in the nanogram range so I guess one could start from the low end of micrograms and (on separate occasions) move up from there increasing the dosage slowly. This is what I would have done if I had no idea how active the compound is. Usually the active dosage is at least somewhat similar to the compounds close relatives, so you can predict whether it'll be more of a microgram or milligram range. I don't know what he actually did though, but I do believe he didn't just blindly eat grams of new product.



I said micrograms lol, anyway though I don't think predicting from similar compounds a dosage range is completely safe either as there are many examples to prove this. For example, alpha methylation substitution increases potency of some compounds by an order of magnitude, like the DOX series, likely because of much increased resistance to enzymatic oxidation. If one had assumed just a slight increase in potency from this substitution and took a slightly smaller dose of the methylated version than usual, that person would be in for a long ride.


----------



## belligerent drunk

I was just saying that starting from the nanogram range would be redundant in my opinion, didn't mean that you suggested it. Anyway, you're right. Just assuming the potency of a compound could prove to be dangerous especially in substances that can be lethal in OD. My point was that if you account for the known changes (like the example you gave, methylation) and the active dosage of a related compound, you can get an estimate. If a very similar compound is active at 500 mg, there's a very big chance that your new compound won't be active at 5 µg. What I had in mind was more like starting from 2 orders of magnitude lower than the "possible estimated" active range.

What would you do?

EDIT: a good example to counter my argument is phenibut and baclofen. A para-chloro addition shifts the active dosage 2 orders of magnitude lower. Still though, baclofen is active in the milligram range so start from micrograms would not be problematic.


----------



## aced126

If it's a completely novel compound which no one has ever ingested before, I'd probably first examine it to see the potential causes of toxicity, then go 3 orders of magnitude lower than the expected range and then double the dosage every say 24 hours assuming the molecule has reasonably metabolically labile to have a half life way shorter than 24 hours. I think there are only very few drugs which are inactive at one dose and then toxic or lethal at double the inactive dose. Any thoughts on the purification question?


----------



## belligerent drunk

How would you examine the potential toxicity? I'm not a pharmacology expert, but I think there are (even recent) examples of compounds with unexpected toxicity which went by unnoticed until some people messed up their body/receptors. Unless you have rodents or primates to torture, I think just looking at the structure will give you less information about its possible human toxicity. Correct me if I'm mistaken.

Regarding purification, there are many ways to separate compounds. Column chromatography? I personally haven't worked with compounds of different degree of halogenation on an aromatic ring, but I guess you could separate them chromatographically as that's a pretty convenient way of purifying synthesis products. Cheap and fairly easy too.


----------



## aced126

I was actually thinking rodents would be a good indicator of at least acute fatal toxicity, although some people will definitely object to this morally. If a rodent can survive x amount of compound then a human is very likely to survive that (or even 10 times that amount) for the most part. By examining potential toxicity I meant doing nothing too in-depth as with these novel compounds they are totally unpredictable, but for example if it has a phenethylamine skeleton in it, you could predict that it'll have vasoconstrictive properties at extremities, pulmonary hypertension etc. So you could obtain a rough indication of what risks definitely exist. That is not to say there are unpredictable risks.


----------



## pharmakos

shulgin morally objected to testing on lab animals -- its the reason why he did things the way he did


----------



## belligerent drunk

pharmakos said:


> shulgin morally objected to testing on lab animals -- its the reason why he did things the way he did



Would you elaborate on the way he did things then?


----------



## pharmakos

essentially the way described above... started out at microgram doses and doubled every day or three until he reached the active dosage.  then once he found the active dosage, he would share the chemical with his "research team" (not all of the qualitative comments in PiHKAL are written by ann and sasha).  the research team wouldn't titrate up in the same way.  which led to problems a time or two... (check the qualitative comments under... i forget if its one of the TOMs or one of the TOETs but its one of 'em.  one of the research crew ended up being unusually sensitive to one of those chemicals).

his goal was to create more potent drugs, the mindset being that the physical sideeffects aren't necessarily caused by the 5HT2A activation.  so in theory drugs that are psychedelic at lower doses would be less likely to have peripheral action.  he admitted that this is not a foolproof theory, but in the absence of anything else to go on it seemed to him to be the most sensible way to proceed.  so, many of the drugs in PiHKAL and TiHKAL that don't have active dosages listed may actually be active at higher doses -- shulgin just never hit the active dosages in his titration procedure and gave up once he realized that they were going to be less potent than the parent compounds.

particularly a lot of the MDxx analogues in PiHKAL are probably active at the sub-1gram range, but since they were so much less active than MDMA/MDA and their cousins that he never bothered reaching the active dosage.

and probably a lot of the mescaline analogues are active but at rather large dosages.


----------



## un kle fukka

you know rodents  to test on?


----------



## Dresden

He had an NMR machine.  He often used re-crystallization as a means of purifying both intermediates and finished products.


----------



## aced126

A calculator estimates trigonometric functions by using many terms in the Taylor series for the respective function.

Similarly, how does a computer energy minisiming a structure? How do you even calculate the potential energy for a structure?


----------



## aced126

Why is it that if a molecule is taken up by SERT, there is a good chance it'll be taken up by DAT. In other words, lots of substituted phenethylamines are taken up by both. So surely we would expect BOTH the endogenous ligands to be similar in structure to phenethylamines. Dopamine is similar, but 5HT seems way different with an indole ring instead.


----------



## belligerent drunk

aced126 said:


> Why is it that if a molecule is taken up by SERT, there is a good chance it'll be taken up by DAT. In other words, lots of substituted phenethylamines are taken up by both. So surely we would expect BOTH the endogenous ligands to be similar in structure to phenethylamines. Dopamine is similar, but 5HT seems way different with an indole ring instead.



Well serotonin isn't THAT different. There's basically one extra methylene group between the basic nitrogen and the benzene ring, the other ring with the aromatic nitrogen could be viewed as a ring and aliphatic chain substitution, which is often done on phenethylamines. Of course, indole is quite different from benzene, but structurally tryptamines look quite similar to phenethylamines. Gramine is a good example, imo, because it lacks the extra methylene group and seems to behave like a phenethylamine despite looking closer to tryptamines at first glance.


----------



## ...

Incredibly trivial question.  What is the best way to pronounce "moiety"?

I've usually heard MOY-e-tee (sounds like "boy Eddie" but with stress on the first syllable).  But today I heard moo-EYE-e-tee and I like that better.


----------



## Cotcha Yankinov

Anyone familiar with sodium valproate care to take a guess at how much of its effects are related to sodium channel/Neurotrophic effects vs. GABA? I'm hoping most of its efficacy (for mania) is stemming from sodium channel/neurotrophic factor mediated effects and not GABA...


----------



## ...

The 2 other major bipolar drugs--lithium and carbamazepine--owe their efficacies to some type of fuckery with sodium.  I would imagine Depakote to be the same.

I certainly didn't feel any baseline anxiolysis from Depakote.  I would expect that from a gabaergic drug.


----------



## Cotcha Yankinov

Thank you. How did you sleep on depakote?


----------



## ...

^I don't remember it being sedating.  It was fairly side-effect free for me.  TBPH it had such a faint presence that I suspected it was placebo. But I didn't really have hypomanic episodes while on it, so I suppose it worked as intended.

Lamotrigine was added a few months later and my mood was very stable.  I think lamotrigine is an excellent prophylaxis for bipolar depression.


----------



## Dresden

Depakote--placebo.  Lamictal--worthelss for me.  I now take benadryl, cogentin, haldol, trazodone, and gabapentin at bedtime for my bipolar, and that combination seems to work pretty well for me.  I used to take Restoril too, which was nice, but one time I got my prescription for it filled, took five or so, went to sleep, woke up, blacked out, ended up taking all 30 x 30mg capsules, ended up in the psych ward for a week, and was lucky I didn't die.  I stopped getting scripts for benzodiazepines after that, for obvious reasons.


----------



## ...

^Haldol can be bad news, even with Cogentin on board.  Have you tried any atypicals, or even lithium?


----------



## Dresden

Yes, I've been on all the atypicals pretty much.  Risperdal was largely without effect for me, though is good for stopping an unwanted trip I found.  Abilify did fuck all nothing for me.  Thorazine (not an atypical, I know) caused akasthisia a lot, but was at least somewhat sedating/helpful under the right circumstances.  Zyprexa was quite good; I took it for years.  However, when the generic came out, I tried it again, and this time it did almost nothing.  Seroquel had a tendency to cause dry mouth, and a steadily building tolerance to its therapeutic effects caused me to have to go off of it.  Geodon does NOT control my schizoaffective delusionsal thoughts and behavior effectively at all.  Latuda, I hate; it puts me in a dysphoric mood.  Stelazine (another typical) I can't remember much about.  Idk, I may be forgetting a couple.  I hate lithium; it makes me dumb and gives me flat affect.  But Haldol works well for me.  At 10mg per day, I don't get extrapyramidal symptoms, even without Cogentin, which I find largely worthless but take anyway for some reason.  The weight gain for the two antipsychotics I respond best to, Zyprexa and Haldol, are equally horrific (about 50 lbs. consistent weight gain for either one for me), but it beats being psychotic and locked away in a psych ward or personal care home with the other unwanted, mentally ill derelicts.


----------



## ...

fuck wow.  I hope you can find a way to reverse the weight gain. Lorcaserin?


----------



## SKL

Lorcaserin in my experience is overrated
The weight gain operates on two levels
first, altering metabolism
second, altering appetite
it is really a matter of willpower and choices

to randomly reply to other posts

VPA does indeed have some effect on GABA but our understanding is limited
zyprexa is OK especially for schizoaffective type situations but metabolic effects suck
Geodon is crap although sometimes useful together with Ativan for acute agitation (i.m.)
some people don't take their Geodon with food though which renders it worthless
I prefer to stick to the tried and true, Haldol yes but I favor Prolixin
Cogentin shouldn't be the be all and end all to deal with side effects the are other options
Lamictal is a great drug for bipolar (II) especially those with a tendency towards depression
it is a good augmentation for depression but not only that for clozapine & other antipsychotics as well
but for real bipolar (I) pts who tend towards psychotic mania it is often not enough
good thing about Lamictal is it is very transparent subjectively
there are of course really nasty potential side effects but they are quite rare
VPA has added benefits in that it helps control impulsivity and stuff
but has a higher side effect burden but is better in bipolar(I) with a tendency towards mania IM(C)E
but actually it turns out the research support for all that is less objectively factual than we think
but really
psychiatry is about finding empircally the best choice to manage symptoms
more art than science vs what some would have you believe
and yes I do this for a living
but no nothing here is medical advice


----------



## pharmakos

did they change the name of "noradrenaline" to "norepinephrine" for marketing reasons?


----------



## SKL

_ad_ + _renus_ = _ἐπί_ + _νεφρός_

Latin and Greek for the same thing, above the kidney
don't think it is a marketing thing
Epinephrine is the more American term
Adrenaline is more British
but they are the same


----------



## Dresden

Oh yeah, the worst extrapyramidal symptoms that I've ever had were caused by Serentil, an old typical antipsychotic.  Don't ever let them give you that shit!  Atypicals don't work any better than typicals.  But yeah, prescribing psych medicine is more of an art than a science and needs to be tinkered with to tailor the right drug regimen to the individual patient because, well, people have different brains and everything.


----------



## aced126

Why don't dopamine receptor agonists have the same effect as dopamine releasing agents or reuptake inhibitors?


Not recommending this at all, but hypothetically if one were to take a MAOb inhibitor along with phenethylamine, what would happen?


----------



## AlphaMethylPhenyl

Can you give some examples? My intuition is to say that there are other factors that go into whether or not a drug produces euphoria. Are you talking about anti-parkinsonian medications versus something like methylphenidate? I think that's a good question, but again things like what brain region a drug targets, how fast it's absorbed, what other mechanisms other than dopaminergic agonism may be at play, and how long it lasts all play a decent role.

As for your second question, likely that would result in a hypertensive crisis, and possibly a stroke and death. A warning sign is a powerful headache in the back of the head. I was stupid enough to do it anyway. The feeling is just too powerful and transient to be worth it. Of course I'm drawing on anecdotes here, but when you read about people taking MAOIs with phenethylamine for a period, you read about a very high degree of addiction, as in at least on par to that of amphetamine. Eventually when the person decides to stop for whatever reason, they go through a long-ass time, we're talking months or years, before they start to feel more normal.

I didn't find it good for concentration even.


----------



## aced126

My question also applies to serotonin releasers and agonists. Why do agonists of serotonin receptors (like DMT) differ in subjective effects from serotonin releasers? Obviously DMT is selective for certain receptors, but what if one were to administer a load of agonists such that all types and subtypes of 5HT receptors were agonised; would this produce a response akin to serotonin releasers?


----------



## Cotcha Yankinov

Hmmm correct me if I'm mistaken but  seeing as I think releasers usually reverse the transporter it might possibly have something to do with variability of transporter density across different serotonin types? Is there variability of SERT density across different neurons or brain regions? 

I know MDMA is kind of a weird one because it's a 5-HT2B agonist as well and 5-HT2B is necessary for both its serotonin and dopamine effects (I guess due to 2B being necessary for the function of SERT). Apparently most SSRIs are 5-HT2B agonists as well. 

On that note does anybody know why these things that have affinity for SERT also have affinity for 5-HT2B? Do they somehow access the SERT through 2B or is there a similar binding site between the two?


----------



## Dresden

Neuroscience and pharmacology are such sophistry at this point.


----------



## neurotic

aced126 said:


> My question also applies to serotonin releasers and agonists. Why do agonists of serotonin receptors (like DMT) differ in subjective effects from serotonin releasers? Obviously DMT is selective for certain receptors, but what if one were to administer a load of agonists such that all types and subtypes of 5HT receptors were agonised; would this produce a response akin to serotonin releasers?



if i'm understanding right, i've asked myself the same question. i remember one claim that agonists like DMT and other psychedelics agonized the 5HT2a receptor in a different manner than serotonin or lisuride (stimulated PLA2 vs. PLC, or both to different degrees), though this doesn't match the data from one study where they measured efficacy of different psychedelics and serotonin to stimulate these pathways (this review on hallucinogens from Nichols has a nice section on functional selectivity on page 13 / 143)

i think the current model doesn't cut it, or i'm missing something...


----------



## Dresden

What I said.


----------



## nAON

There's something to do with receptor colocalization too, involving mGluR's forming complexes with 5HT2A, which switches it toward a different pathways often involving transcription rather than direct G-signalling. And then Glu receptors themselves can change affinities/ligand bias based on bonding with shit like Neto's. Wouldn't say it's sophsitry so much as an incomplete science (along with the rest of them  )


----------



## aced126

Possibly the weirdest ever use of amphetamine: https://en.wikipedia.org/wiki/1,1'-Bi-2-naphthol

They use S-amphetamine as a chiral ligand to synthesize S-BINOL.


----------



## sekio

Amphetamine has a lot of usage as a chiral base, I don't know why it's suprising.


----------



## aced126

sekio said:


> Amphetamine has a lot of usage as a chiral base, I don't know why it's suprising.



I'd have thought there would be difficulty obtaining it/getting any licensing required but then again I'm not a chemist.

***

https://en.wikipedia.org/wiki/SCH-50911

It is a GABA-b antagonist, reverses a GHB overdose and precipitates convulsions in GHB-dependant animals. Yet it apparently is an anticonvulsant, which I find unusual. Any thoughts or explanations?


----------



## sekio

There's CDSA paperwork to be filed out for sure, but it doesn't limit a company like Glaxo from using it.

Think about it, there are in fact companies that use safrole and benzaldehyde and the like - controlled chemcials - but yet they still keep accepting deliveries. You just have to be serious enough about controlling access to the "hot" compounds.



> Yet it apparently is an anticonvulsant, which I find unusual. Any thoughts or explanations?



Maybe there's other sites it acts on?

The study doesn't seem very kind to the rats, though. 


> Thirteen of 30 rats died during the intoxication procedure, likely due to overdose



At that level of GHB administration... you're talking about the human equivalent of consuming several hundred mL of GHB a day. They report killing all the GBL rats with overdoses. Something tells me the study could hav e been done a little better.


----------



## Cotcha Yankinov

aced126 said:


> Why do agonists of serotonin receptors (like DMT) differ in subjective effects from serotonin releasers?



http://biopsychiatry.com/5ht2a.htm


----------



## aced126

Cotcha Yankinov said:


> http://biopsychiatry.com/5ht2a.htm



Thanks for linking, interesting article.

***

This compound shows that the nitrogen is not needed for reuptake inhibition. I was really really surprised when I saw this: https://en.wikipedia.org/wiki/O-2172






Also similar things have been done for cocaine analogues:https://en.wikipedia.org/wiki/Tropoxane

Changing the N-methyl for CH2 results in only a less than 6 fold loss in activity. I would've thought it would utterly kill any activity...


----------



## neurotic

This just reinforces that the phenidates should be put together with pipradrol or cocaine rather than amphetamines, and that the amphetamine backbone in it is just a mere coincidence...


----------



## aced126

Although there are some cocaine analogues lacking the carbomethoxy group and they still retain activity. This suggests: 1) the carbomethoxy group is not necessary and 2) the nitrogen is not necessary and it doesn't even need to be replaced with an electronegative atom, a carbon suffices.

If a simple carbon skeleton suffices, then maybe steric factors play a way  bigger role than originally thought.


----------



## neurotic

i can't really understand your first sentence, that "although" is confusing me, but anyway there are active phenidate analogues (loosely) which are without the carbomethoxy too, such as 2-benzylpiperidine and desoxypipradrol. benzylcyclohexane (would that be the name) is definitely inactive though...

a study testing these drugs for affinity at the cocaine site at DAT would be interesting


----------



## aced126

Is 2-benzylpiperidine a reuptake blocker only though? It could very well act as a releasing agent. For desoxypipradol the phenyl ring could in some ways act as a bioisostere for the carbomethoxy group?


----------



## Dresden

I'm the one who got them to invent 2-BzP (2-benzylpiperidine) way back, as I was sure its uncanny similarities to MPH (with an amphetamine benzyl methylene to boot) would make it an utter shoo in for research chemical of the year.  Imagine my chagrin when somebody makes it, and it's utterly and widely deplored as utter shiite!!!  How embarrassing.

But yeah, as far as MPH and desoxypipradrol relate to each other, wouldn't their carbomethoxy and phenyl rings be the definition of bioisosteric?


----------



## aced126

Dresden said:


> But yeah, as far as MPH and desoxypipradrol relate to each other, wouldn't their carbomethoxy and phenyl rings be the definition of bioisosteric?



Only if they had the same mode of action, which seems to be disputed.


----------



## Dresden

Is seems like to me that it should mean they are 'bioisosteric' if they have the same biological effect as each other with the same two different functional groups in the same places in two otherwise identical molecules.  Clearly, they are both powerful CNS stimulants.  But, upon closer inspection, MPH may be a pure NT reuptake inhibitor, while desoxypipadrol may be a NT releaser.

Is the mode of that action really the deciding factor?  Mightn't it depend on how close you are splitting hairs when settling on a definition for "biological effect" (i.e., in a general sense, yes, they are both powerful CNS stimulants, but on a more hair splitting level, one is possibly a releaser while the other is a reuptake inhibitor?).  

Which leads me to the question:  Is it possible for a molecule to be both a releaser and a reuptake inhibitor in varying degrees at the same time?  In other words, why (or does) this dichotomy have to a be an all or nothing proposition?  Seems like I remember reading here somewhere maybe by you, aced126, that releasers are also reuptake inhibitors in so far as they have to fill DAT or SERT or whatever long enough to reverse NT flow anyway.

Must the means and ends match?  Why not just the ends?  I guess I'm just the kind of guy who focuses on the end results and tries his best to ignore the intermediary mechanism which gives rise to that end.  To me, the ends often justify the means, but maybe I'm a Machiavellian psychopath with a small penis, a psychiatric diagnosis or two, an inability to currently procure real MDMA or LSD (which was once my forte of sorts back when we still bought Schedule I drugs on the streets, at rave parties, and in dorm rooms) and a fairly robust ice methamphetamine habit, I dunno.


----------



## aced126

Dresden said:


> Is seems like to me that it should mean they are 'bioisosteric' if they have the same biological effect as each other with the same two different functional groups in the same places in two otherwise identical molecules.  Clearly, they are both powerful CNS stimulants.  But, upon closer inspection, MPH may be a pure NT reuptake inhibitor, while desoxypipadrol may be a NT releaser.
> 
> Is the mode of that action really the deciding factor?  Mightn't it depend on how close you are splitting hairs when settling on a definition for "biological effect" (i.e., in a general sense, yes, they are both powerful CNS stimulants, but on a more hair splitting level, one is possibly a releaser while the other is a reuptake inhibitor?).
> 
> Which leads me to the question:  Is it possible for a molecule to be both a releaser and a reuptake inhibitor in varying degrees at the same time?  In other words, why (or does) this dichotomy have to a be an all or nothing proposition?  Seems like I remember reading here somewhere maybe by you, aced126, that releasers are also reuptake inhibitors in so far as they have to fill DAT or SERT or whatever long enough to reverse NT flow anyway.
> 
> Must the means and ends match?  Why not just the ends?  I guess I'm just the kind of guy who focuses on the end results and tries his best to ignore the intermediary mechanism which gives rise to that end.  To me, the ends often justify the means, but maybe I'm a Machiavellian psychopath with a small penis, a psychiatric diagnosis or two, an inability to currently procure real MDMA or LSD (which was once my forte of sorts back when we still bought Schedule I drugs on the streets, at rave parties, and in dorm rooms) and a fairly robust ice methamphetamine habit, I dunno.



I think finding out the intermediate mechanism which results in the observed effect is important if we want to build upon and improve on what we have currently. As a brief example, if we wanted to make a non-neurotoxic stimulant but we did not even know how the stimulant precisely acted upon us to exert its effect, how are we even going to get close to finding out the mechanism of neurotoxicity?


----------



## Dresden

Yeah, I agree but I approach pharmacology from a drug's subjective effects as a function of its Kekule structure first and foremost, mainly because I can study those variables because I can see or change its structure and feel what it does for me subjectively but haven't the foggiest notion of how to elucidate any important biochemical markers of a drug with or without a sophisticated biochemistry lab and years of training I don't have.  

Yes, I know I could make a pilgrimage to my old university's science library to brush up on the proprietary drug studies (it has been, after all, 20 years!), but I get off more intellectually on coming up with disparate chemical structural commonalities rather than the latest ED50 binding data for sertraline or what not.  In other words, I am both basically crazy and lazy, I guess.  Not really, though.  I mean, I do try to read the stuff you and a couple others have to say about biopharmacology, but still, I don't know what ampakines do or anything still, for example.  That's just not the side of the science I find most fascinating.  Furthermore, I don't feel the importance of finding out whether a particular stimulant is a NT releaser or reuptake inhibitor as long as they seem pretty much indistinguishable chemically and all feel pretty much great to me.  It's a rather narrow approach, yes.


----------



## aced126

But there are so so many factors in determining a drug's subjective effects. What you're talking about is structure activity relationship within a set of very similar compounds, which, to an extent, can be predicted without a deep understanding of the mechanism of the drug. For example, 4-lipophilic substituents are *observed* to increase activity in the 2-CX series, and so one could predict that increasing the lipophilicity will increase activity (we can speculate why this is so but until proper binding studies are done and pk data is obtained, it will always be speculation) but correlation does not imply causation, as the saying goes.


----------



## ...

Why is "dimenhydrinate" (Dramamine) considered a generic drug name?  I can find no other instance of a two-drug combination being given a single generic name, but I also know of no other pharmaceutical salt in which both ions are active.  Oh except for morphine valerate o whatever.

edit: wait, is it a salt?

Incidentally, is 8-chlorotheophylline more stimulating than caffeine?


----------



## Cotcha Yankinov

Do antagonists/inverse agonists ever get close to increasing neural activity because the amount of auto receptors out number the regular receptors? It seems at some times a partial agonist can work as an antagonist because it's displacing a more efficacious ligand..


----------



## belligerent drunk

A very common example of a partial agonist working like an antagonist is buprenorphine, which can produce precipitated withdrawal if taken while some other opioid (full agonist) is still active.


----------



## aced126

Cotcha Yankinov said:


> Do antagonists/inverse agonists ever get close to increasing neural activity because the amount of auto receptors out number the regular receptors? It seems at some times a partial agonist can work as an antagonist because it's displacing a more efficacious ligand..



To your second point, I'd say that it'd depend on some factors including concentration of the partial agonist (which results in the specific receptor saturation). The endogenous ligand is by definition a full agonist, and so assuming that all the receptors are saturated with endogenous ligands, introducing a partial agonist in necessary concentrations to achieve complete displacement of all the endogenous ligands to the receptor (we're of course assuming the partial agonist has a much higher affinity for the receptor so that displacement takes place easily) would mean that the overall response is reduced, and in that case the partial agonist would actually kind of be an antagonist (assuming the antagonist doesn't achieve full receptor saturation; if so, then by definition there would be 0 response overall; if partial saturation is achieved then only partial response is suppressed). As belligerent mentioned, this can happen if the "endogenous ligand" is something one continually administers in high concentrations (full mu opioid agonists).

But in most situations, I think the endogenous ligand is in concentrations such that most of the receptors are not occupied, and so introducing a partial agonist will bind to the unoccupied receptors (and occupied ones if the affinity is high enough) will result in an overall increased response.


----------



## belligerent drunk

aced126 said:


> But in most situations, I think the endogenous ligand is in  concentrations such that most of the receptors are not occupied, and so  introducing a partial agonist will bind to the unoccupied receptors (and  occupied ones if the affinity is high enough) will result in an overall  increased response.



As far as I know that's true, most partial agonists I've heard of do produce an agonist-like effect rather than the opposite in an individual who hasn't taken anything for a while. If I'm not mistaken THC (what about other major cannabinoids?) is also a partial agonist.


----------



## aced126

What are people's thoughts on the legitimacy of this claim? 

https://en.wikipedia.org/wiki/Tramadol#Pin_cushion_tree


----------



## SKL

aced126 said:


> What are people's thoughts on the legitimacy of this claim?
> 
> https://en.wikipedia.org/wiki/Tramadol#Pin_cushion_tree



The "bullshit" theory (sorry, I couldn't resist) sounds kind of far fetched to me, doesn't it?


----------



## neurotic

aced126 said:


> Is 2-benzylpiperidine a reuptake blocker only though? It could very well act as a releasing agent. For desoxypipradol the phenyl ring could in some ways act as a bioisostere for the carbomethoxy group?



i mentioned it based on the assumption that MPH itself isn't a reuptake blocker only, from that study dopa posted a while ago proposing 'transporter inverse agonism'. MPH and coke are very different than bupropion


----------



## Dresden

Why hasn't






O-METHYL EPHEDRA

been explored yet?  Or has it been?  I realize it might be expected to be a nerve racking adrenergic high, but you never know, and its synthesis from ephedra appears to me to be facile.


----------



## aced126

I suggested that a while a go. It should technically have decent dopaminergic activity. O-demethylation will reduce BBB penetration and increase affinity for adrenergic receptors around the body and heart. That's why I suspect it won't be that great.


----------



## P T Green 21-83046

Know technique to make from a wizard of a master of bakin' flash methods and in around 8 mins (I personally know this works) and out of sudafed pe to make Seth-or- D methMethamphetamine or D Meth-methamphetamine in 8 minutes with and one chemicals/ 2 products at chemist with just a microwave and electric stove and metal pan with water. I guarantee and done research into this myself and apart from microwave (tricky)lol you'll know why when I say the need of chemical and water to super fused to be heated adding two products to heat at a half max if that but getting a bit to fusr two more times and then smell the wizadry methamphetamine exactly like the true pseudeo gear fruity smell chemical 'yet still' fruity and will if anyones interested help explainr how to.from Sudafed PE to ????wizadry D Seth Methamphetamine? ?


----------



## SKL

basically if you can bake a cake, you can make MA
but we do not discuss synthesis here
however the level of coherence in the above post suggests the MA has already been made and consumed, however


----------



## Dresden

Sometimes methoxies are quite metabolically resistant, for example on the 2Cx's and DOx's.


----------



## aced126

True, although I think phenyl methoxies are more metabolically stable than just alkyl methoxies.


----------



## belligerent drunk

Why is it that way though? You'd think that an aromatic -oxy group would be a better leaving group than an aliphatic one.


----------



## Dresden

It's an ether.  They are quite strong.  Anyway, why can't this molecule






be used as a false neurotransmitter?  (Perhaps "improved NT" would be a better name for it.)  Why don't our bodies produce this N-methyl-DA on their own already?  Too pleasurable?


----------



## aced126

Yes Belligerent, however I think that protonation on the oxygen occurs first before leaving, which in that case phenyl methoxies would be less labile than aliphatics; it is harder for the phenyl methoxy to be protonated due to pi delocalisation of a lone pair.


----------



## sekio

generally speaking ethers are awful leaving groups, aromatic or aliphatic

also N-methyl dopamine i'd bet can be used as a surrogate for dopamine, but good luck getting it past the BBB


----------



## Solipsis

Could you extend it with a methylene so that you get:






_3-Amino-4-(3,4-dihydroxyphenyl)butanoic acid_

to still get it through the BBB with LAT and have it decarboxylated to N-methyl dopamine, or do you suppose it would not be 'recognized' well enough to bind? (i.e. does LAT only transport alpha amino acids or also beta?)


----------



## sekio

> i.e. does LAT only transport alpha amino acids


I would suspect that's the case, even if LAT moves them past BBB there is the issue of them being recognized at L-amino acid decarboxylases.


----------



## Dresden

sekio said:


> generally speaking ethers are awful leaving groups, aromatic or aliphatic
> 
> also N-methyl dopamine i'd bet can be used as a surrogate for dopamine, but good luck getting it past the BBB



I'd wager this molecule






would cross the blood brain barrier intravenously.


----------



## sekio

Sure, if it weren't going to be rapidly deacetylated....


----------



## Dresden

Yes, but that's what the intravenous administration is for.  For example, IV heroin (diacetylmorphine) gets past the BBB 3x better than morphine.


----------



## SKL

Yeah, heroin immediately came to mind. The metaphor I always used is that it is an "arrow" to better "pierce" the BBB.


----------



## aced126

Can someone with expertise please chime in on the latest comment I made in this thread about 4-fluoro-MPH? http://www.bluelight.org/vb/threads/769052-Novel-stimulant-4-Fluoromethylphenidate-(4F-MPH)/page4


----------



## aced126

http://www.bluelight.org/vb/threads...-The-White-Bull-Bucked-Into-Deep-Space-Read-m

This compound, and not any metabolites, is active on its own. How is this so? Could this operate on a basis akin to the pyrovalerones?


----------



## clicheguy

aced126 said:


> Why don't dopamine receptor agonists have the same effect as dopamine releasing agents or reuptake inhibitors?
> 
> 
> Not recommending this at all, but hypothetically if one were to take a MAOb inhibitor along with phenethylamine, what would happen?



Old post, but this may be of interest to someone.



> Ironically, while selegiline can't be mixed with cheese or Prozac, it can be mixed with methamphetamine and cocaine.  A small placebo controlled study found that concomittant administration of methamphetamine (15 or 30mg) with selegiline (oral) caused no EKG, lab, or vital sign changes.  The clearance and half-life of methamphetamine was also unchanged.  Similarly, 10mg PO can be safely mixed with up to 40mg cocaine, should you be into that.  An earlier study found that 10mg/d could reduce the high of cocaine and reduced the activity of the amygdala (as defined as glucose utilization on PET scan) and not cause any negative interactions.


----------



## Nagelfar

http://www.filedropper.com/gatley1996

Anybody know what is meant by "Hill slope" as per:

_e.g._ pg. 4 @ 





> temperature on the IC50s values for o-bromomethylphenidate binding to the dopamine transporter. However, methylphenidate at 37 degrees had a higher IC50 value* and a lower Hill slope than at* 0 or 22 degrees. A possible explanation is a significant degree of hydrolysis of the methyl ester during incubations at the higher temperature.



The above link to the article.


----------



## aced126

A few pages ago, Shulgin's method of trialing drugs was discussed. Here is an excerpt from the 2,5-dimethoxy-4-methylthioamphetamine entry in Pihkal:

This specific compound is probably the first sulfur-containing phenethylamine to have been evaluated as apotentially active CNS stimulant or psychedelic. It was a complete, total, absolute unknown. The first trials were made at the sub-microgram level,specifically at 0.25 micrograms, at 11:30 AM on September 3, 1975. Part of this extreme precaution was due to the uniqueness of a new heteroatom ina phenethylamine system. But part was due to the strange manic excitement that occurred at the time of the isolation and characterizing of the finalproduct in the laboratory. Although it was certainly all placebo response, I was jumpy and unable to stay in the lab for more than a few minutes at atime. Maybe dust in the air? Maybe some skin contact with the free base? Now, I know there was nothing, but the possibility of extraordinary potencywas real, and I did indeed wash everything down anyway. In fact, it took a total of 18 trials to work the experimental dosage up to as much as a singlemilligram. In retrospect, overly cautious. But retrospection, as they say, is cheap.


----------



## Dresden

The power of Sasha's mind's belief that ALEPH-1 (DOT) would be phenomenal likely produced a placebo like effect.  It was later found to be "boring."


----------



## TheBlackPirate

PiHKAL said:
			
		

> This specific compound is probably the first sulfur-containing phenethylamine to have been evaluated as a potentially active CNS stimulant or psychedelic. It was a complete, total, absolute unknown. The first trials were made at the sub-microgram level,specifically at 0.25 micrograms, at 11:30 AM on September 3, 1975. Part of this extreme precaution was due to the uniqueness of a new heteroatom in a phenethylamine system. But part was due to the strange manic excitement that occurred at the time of the isolation and characterizing of the final product in the laboratory. Although it was certainly all placebo response, I was jumpy and unable to stay in the lab for more than a few minutes at a time. Maybe dust in the air? Maybe some skin contact with the free base? Now, I know there was nothing, but the possibility of extraordinary potency was real, and I did indeed wash everything down anyway. In fact, it took a total of 18 trials to work the experimental dosage up to as much as a single milligram.



Shulgin was an expert. Years of experience and education resulted in these procedures. They are effective. Utilizing this procedure with newly received chemicals has saved my life. If you're interested, PiHKAL and TiHKAL have more.


----------



## aced126

Might have already addressed this before but...

Should hyperthymic temperament be considered a disorder or rather something we should strive towards?

https://en.wikipedia.org/wiki/Hyperthymic_temperament


----------



## Cotcha Yankinov

Hey aced, you should check out some of this person's writings http://biopsychiatry.com 

engineering pharmacological utopia isn't necessarily a bad thing but if it caused apathy/contentment to stare at a wall all day it could be bad, I mean maybe there are benefits to having pain/sadness and being able to understand other people's suffering. Maybe a permanent state of an MDMA type experience would at least have enough empathy to it that hyperthymic people wouldn't disregard normal people's troubles.


----------



## aced126

I read that a while ago actually. I don't think complete utopia would be ideal for reasons you discussed. But it seems to me that hyperthymic temperament is considered not really a disorder, but more of a bad thing than a good thing by the psychiatric community and I'm not sure why.


----------



## Cotcha Yankinov

Well my theory would be that hyperthymia is usually associated with hypomanic/bipolar and my theory on the cycling between depression and mania is that it's really receptor homeostasis - during a state of hypomania or hyperthymia the receptors down regulate and this eventually leads into depression/dysthymia. Then the receptors up regulate and lead back into hyperthymia.

To avoid the depression which is clearly pathological you might have to avoid the hyperthymia, which at first glance doesn't appear pathological. 

Of course this does not apply if there are people out there who are 100% hyperthymic and don't actually cycle.


----------



## aced126

Cotcha Yankinov said:


> Well my theory would be that hyperthymia is usually associated with hypomanic/bipolar and my theory on the cycling between depression and mania is that it's really receptor homeostasis - during a state of hypomania or hyperthymia the receptors down regulate and this eventually leads into depression/dysthymia. Then the receptors up regulate and lead back into hyperthymia.
> 
> To avoid the depression which is clearly pathological you might have to avoid the hyperthymia, which at first glance doesn't appear pathological.
> 
> Of course this does not apply if there are people out there who are 100% hyperthymic and don't actually cycle.



Do you think many people like this exist? Could one live a long period of their life (say, the first 25 years of their life) as a hyperthymic and then finally cycle into the dysthymic phase? If your theory about receptor up & down-regulation is true, then if someone was hyperthymic for a long period of their life, they would very slowly transition into a dysthymic phase?

I feel as though I have been hyperthymic all my life (and still am, although I have admittedly not lived very long) but I sometimes fear if I will eventually transition phases.


----------



## Lulolanda

Hi, it's my first post. Do you know something about 3-diethylamine-carbazole (don't know how to attach a pic)? It is active? does anybody tried?


----------



## Cotcha Yankinov

aced126 said:


> Do you think many people like this exist? Could one live a long period of their life (say, the first 25 years of their life) as a hyperthymic and then finally cycle into the dysthymic phase? If your theory about receptor up & down-regulation is true, then if someone was hyperthymic for a long period of their life, they would very slowly transition into a dysthymic phase?
> 
> I feel as though I have been hyperthymic all my life (and still am, although I have admittedly not lived very long) but I sometimes fear if I will eventually transition phases.



Well many people are indeed happy people, though whether that's related to them being in a good situation or having a good temperament is hard to say. Some people are happy with very little - Sam Harris talks of how some people in history have found profound happiness by isolating themselves and meditating, which sounds like hell to some people. I can only assume if you remove stimulation (by isolation) that receptors up regulate and such. But maybe there's more to it, such as maybe with meditation and shutting off the thoughts comes a weakening of the glutamatergic inputs that inhibit the nucleus accumbens. 

So I'll start this off by highlighting two concepts that might be good to differentiate between later on - intense short term euphoria (you could think methamphetamine or intense mania/bipolar I) and long term mild euphoria (hyperthymia). 

I think my theory of receptor homeostasis leading to mood swings makes most sense in the context of "rapid cycling" bipolar with a consciousness (or "thought patterns") that lead to activation of brain regions important for euphoria like the nucleus accumbens, whereby after a lot of stimulation in a short period of time the receptors are down regulated, but if we ponder how sustainable a constant state of hyperthymia is I'd say a lot of it probably has to do with DeltaFosB and neurotrophic factors like BDNF, also essentially long term potentiation / long term depression. 

Even though all drugs of abuse induce DeltaFosB and will create a sensitization with that genetic expression through various routes (wiki has a good page on what DeltaFosB does), I think drugs like meth will cause receptor downregulation that will outpace the induction of DeltaFosB and from this you will get less and less euphoria from it. I theorize the same happens with intense mania - the receptor downregulation outpaces the expression of DeltaFosB's ability to sensitize the "euphoria brain regions" and so depression ensues. 

Long term mild euphoria is probably much more sustainable in the sense that there might be a better DeltaFosB to receptor downregulation ratio, or maybe even that the receptors always have enough time to up regulate during sleep to be able to sustain a daily mild euphoria. Sort of like bipolar but the "depression/upregulation" phase is always during sleep. 

The other thing to take into account is the specific mechanics of the nucleus accumbens - I'll use NMDA antagonists (known to induce DeltaFosB) as an example. The reason why NMDA antagonists cause dopamine release / euphoria / hallucinations is because NMDA provides a lot of input to inhibitory interneurons. So when you block that NMDA input you get release of monoamines downstream because you're inhibiting the inhibitors essentially. And apparently the reason why opoids cause euphoria is because there are opoid receptors on the GABA interneurons in the nucleus accumbens, and when opoids bind there they inhibit the GABA neurons and let the dopamine flow downstream. 

So knowing what we know about those mechanics, you might make a prediction - too much long term potentiation (that strengthens the NMDA/glutamate signal that inhibits the GABA interneurons) is bad, and too much GABA is bad. Now I'd have to dig up my textbook, but I recall very specifically it said that BDNF over expression in the nucleus accumbens is implicated in depression - which at first makes no sense (and the authors noted this) because normally BDNF is a great thing that strengthens neurons, but in light of the nucleus accumbens mechanics I think it makes sense how BDNF over expression might lead to depression. 

In my mind, assuming there isn't too much BDNF or LTP strengthening the inhibition of the nucleus accumbens, and you have enough long term depression to keep those glutamatergic inhibitory inputs weak, your hyperthymia could definitely be sustainable. With the exception that there are more hormonal reasons for your sense of well being (that might decline with age). Sorry for the wall of text lol


----------



## aced126

Which receptors do you refer to when talking about downregulation and, is up & down-regulation a process which can really take place over the time frame of hours? I thought it was a much longer process. Which textbook are you using?


----------



## Cotcha Yankinov

Dopamine is mostly implicated when talking about feelings of wellbeing, serotonin is important as well but some of dopamine release is via serotonin. Regarding the time frame, from what I understand there are pathways downstream of the receptor like beta arrestin (if I recall correctly) that signal receptor internalization (serotonin can signal through either G proteins or beta arrestin, and it sounds like inverse agonists are really agonists that are selective for beta arrestin) so I would assume that down regulation can occur rapidly. At least I would assume that you can signal through beta arrestin at the same speed that you would signal through G proteins... I don't know how immediate the receptor internalization is. Not too sure about upregulation - I imagine that there are factors that influence the rate of upregulation but it might be genetically predetermined to some extent. I suppose hyperthymia could be explained by having a high basal rate of up regulation. 

I liked molecular neuropharmacology by Nestler, got it for cheap used on Amazon. Introduction to neuropsychopharmacology by Iversen has been good too. 

I was thinking about making a thread about receptor homeostasis and hoping serotonin2A would chime in - my textbooks didn't go very into detail at all on the subject and I bet you serotonin knows a bunch. Cus I mean I could be horribly wrong on all of this lol


----------



## aced126

https://en.wikipedia.org/wiki/Alfentanil

Why is the pKa of alfentanil only 6.5? I thought the piperidine nitrogen would mean that the pKa is at least 8 or 9


----------



## TheBlackPirate

The significance of Brain-Derived Neurotrophic Factor and other similar chemicals have piqued my interest. I recently noticed Brain-Derived Neurotrophic Factor was mentioned on William Leonard Pickard's Twitter page.



			
				William Leonard Pickard said:
			
		

> Researchers determine that "Dihexa" is more active than Brain-Derived Neurotrophic Factor (BDNF) in enhancing cognitive function



https://twitter.com/scalable_mind


----------



## AlphaMethylPhenyl

I was hoping that someone could give an elaborate explanation of how opiates are so addictive. Sorry a lot of this is noob knowledge. I know that they inhibit Substance P and further cause depolarization of the cell so that it's less likely to fire. They also seem to inhibit GABA efflux, but I'm assuming in parts of the brain where such would somehow be more pleasurable than not...somehow. Is mu stimulation a better indicator of euphoria/abuse potential than D2 activation in the striatum and associated regions? Are there delta opiate agonists in clinical trials for depression (heard buprenorphine is making some headway but as I remember it's not a delta agonist)? I'm assuming that part of the allure of opiates has to do with volume/non-direct transmission so that they essentially have very far reach wherever they're released. Are beta-endorphin and friends also hormones? If so, and this is a long-shot, but might the opiate user be more liked by others by virtue of this? Just spitballing here.


----------



## Cotcha Yankinov

Hi Ho, I was under the impression that the main reason why opiates are so addicting outside of the withdrawal sense of the word is because they induce DeltaFosB in the nucleus accumbens, my textbook said that there are opiate receptors on the GABA neurons that inhibit the nucleus accumbens, and that when opoids bind there they inhibit the GABA and that results in release of neurotransmitters downstream / activation of the nucleus accumbens. 

I've also been told that addiction related DeltaFosB is induced mainly in D1 type medium spiny neurons - I don't think D2 is playing as big of a role in addiction but D2 in the striatum could be playing a role in locomotive sensitization seen with amphetamine and such. Antipsychotics apparently even induce DeltaFosB in D2 type MSNs if I recall correctly. Hope this was helpful.


----------



## AlphaMethylPhenyl

Hey Cotcha,

Thanks! I recall when of your other threads about DeltaFosB, which I'm assuming is a transcription factor. Are there any drugs out there that inhibit COMT? I haven't come across any.


----------



## Cotcha Yankinov

Yes sir a transcription factor that strengthens the dopamine signal. The COMT inhibitors I'm aware of besides EGCG (which is probably extremely weak) are the ones used in Parkinson's such as entacapone. 

They might have some use in depression but I would assume for most they would be psychosis inducing - COMT malfunction is implicated in schizophrenia.

COMT is especially important for dopamine breakdown in the PFC where there is no DAT to clear dopamine.


----------



## AlphaMethylPhenyl

Can someone explain how positive calcium ion influx when the action potential reaches the terminal button works to fuse vesicles to the presynaptic membrane and cause excytotosis?


----------



## Cotcha Yankinov

The whole SNARE protein thing?


----------



## aced126

Ho-Chi-Minh said:


> Can someone explain how positive calcium ion influx when the action potential reaches the terminal button works to fuse vesicles to the presynaptic membrane and cause excytotosis?



I think they bind to a protein on the cytoskeleton and that induces the cytoskeleton to bind to and move the vesicles towards the membrane. Then for the actual fusion, SNARE proteins are involved.


----------



## BobbyDick

[h=1]"Muscimol induces state-dependent learning" What is SDL.[/h]http://www.sciencedirect.com/science/article/pii/0006899395003038


----------



## Bagseed

a video some here might dig...


----------



## aced126

Does L-DOPA bind to the tRNA for tyrosine, and as a result get incorporated into proteins, at least in some cells?


----------



## InterestingFACT

aced126 said:


> Does L-DOPA bind to the tRNA for tyrosine, and as a result get incorporated into proteins, at least in some cells?


Yes, it's been observed in Parkinson's patients. 

In vitro studied have shown serious implications of these substitutions, including mitochondrial dysfunction and the formation of autophagic vacuoles. I don't think these effects have ever been traced specifically back to L-DOPA containing proteins in Parkinson's patients, but it's quite likely that this is a significant factor in L-DOPA's toxicity. 

There's probably not much L-DOPA around in the cell nuclei of individuals not undergoing exogenous therapy.


----------



## Solipsis

Can someone explain a bit to me about one of the morphine rules and opioid SAR, particularly the quaternary carbon?

It doesn't seem like the quaternary carbon itself can get involved in much interaction with the receptor site, but I assume that instead the carbon being any less than quaternary in that part of the pharmacophore would preclude proper binding somehow?

Or does the Q carbon somehow determine the overall geometry of the molecule in an important way, is it rather that a neopentylene (do I get that right?) moiety must be present sterically?

And what are some examples of the boundaries of this rule? Heteroatomic substitution? What are curious opioids that defy this morphine rules, or others for that matter?


----------



## Neithman

This shit looks crazy
The 3 D Picture actually looks like a dog with a tennis racket in his mouth LOL


----------



## aced126

Solipsis said:


> Can someone explain a bit to me about one of the morphine rules and opioid SAR, particularly the quaternary carbon?
> 
> It doesn't seem like the quaternary carbon itself can get involved in much interaction with the receptor site, but I assume that instead the carbon being any less than quaternary in that part of the pharmacophore would preclude proper binding somehow?
> 
> Or does the Q carbon somehow determine the overall geometry of the molecule in an important way, is it rather that a neopentylene (do I get that right?) moiety must be present sterically?
> 
> And what are some examples of the boundaries of this rule? Heteroatomic substitution? What are curious opioids that defy this morphine rules, or others for that matter?



I'm not too sure the quarternary carbon is off much importance to opioid SAR. The more polar groups are much more significant factors that affect the affinity of a compound to the mu opioid receptor. For example, several open chain opioid analogues exist, some with several times the potency of morphine itself (e.g. fentanyl), implying that the rings in morphine are not THAT important. We would call morphine a rigidified structure, and rigidified structures often have incredibly high affinities at receptors because they exist in a conformation close to the conformation an open chain analogue would bind to in the receptor. If an open chain analogue has to change its conformation to one different from its energy minimised conformation, then it is less likely to bind as it spends less time in higher energy conformations. So fixing a drug to a certain conformation (often done by nature with many toxins) can result in very strong binding. I think that it just so happens that the conformation of morphine is pretty good, but nowhere near the optimal conformation for strongest binding to mu. We know this because there exist several open chain opioid analogues with several times the potency of morphine (e.g. fentanyl analogues and methadone analogues to name a few). This suggests that functional groups play a much greater role in SAR than shape of molecule. I will briefly discuss the main points in opioid SAR.

The nitrogen in morphine plays an important part in SAR. First of all, if the nitrogen has 4 alkyl groups on it, and is thus charged (for example in methylnaltrexone), then it is too polar to cross the blood brain barrier and will have no psychoactive effects. It still binds strongly to peripheral opioid receptors, and this tells us that when the opioid is bound to the receptor, the nitrogen is charged (and thus protonated in the brain) when it binds to mu. It forms an ionic bridge with a negatively charged amino acid residue (such as aspartate). It's observed that making the nitrogen secondary in morphine (https://en.wikipedia.org/wiki/Normorphine) significantly reduces potency. I think this is because normorphine can act has a H-bond donor, which disrupts the ionic bridge by changing its angle or something. So a tertiary nitrogen is important for good opioid activity. And as you will see, almost all opioids in clinical use have a tertiary nitrogen.

The 3-OH group in morphine plays an important role in binding. It acts as a H-bond donor. Adding a methyl group at this position (codeine) significantly reduces potency.

The 6-OH group in morphine is not involved in binding very much at all and is not significant. It can be replaced by (long) alkyl substituents and still retain potency. Thus one can add lipophilic substituents on this group, like in heroin, to increase concentration of the blood reaching the brain.

The ether bridge is not important for binding to mu, but removing it increases the time taken for the blood to reach the brain. Ethers are weird in that they slightly increase polarity but not massively. Diethyl ether is a non polar solvent, of course. I think, to cross the BBB most effectively, you need in general a pretty lipophilic compound, with a few hydrophilic spots to stabilise it initially as it approaches the phosphate head (someone correct me if I'm wrong, I'm not too sure on all that logic). Ethers suit this purpose best. Alcohols, less so, and carboxylic acids cross the BBB in very small proportions. I think it is something to do with ethers not having a labile hydrogen, and thus it is not that unfavourable for them to be surrounded completely by alkyl chains in the phospholipid bilayer, at least less unfavourable than alcohols and carboxylic acids. 

Hydrogenating the double bond in morphine increases potency. It relieves some strain on the molecule, and lets the molecule conform to a slightly more optimal binding conformation. More evidence that the morphine conformation is by no means the best opioid conformation for strongest binding. 

Adding an alcohol group on carbon 14 increases potency (e.g oxycodone, oxymorphone). This is likely because this group acts as a H bond donor or acceptor while bound to the receptor.


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## Solipsis

Thanks very much, I forgot to say that I was very interested to read this.


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## crOOk

Neithman said:


> This shit looks crazy
> The 3 D Picture actually looks like a dog with a tennis racket in his mouth LOL


It's clearly an ant, at best an ant with a dog's head in it's mouth.



aced126 said:


> Could this operate on a basis akin to the pyrovalerones?


You've got me wondering which property of provalerones you may be refering to. Please do tell.


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## Nagelfar

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469479/figure/F10/






Anyone understand what is meant by "Fo-Fc densities for ligands complexed with (fruit fly) DAT"? Surprisingly, N-methyl-amphetamine is less dense than simple dextro-amphetamine.


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## DotChem

Nagelfar said:


> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469479/figure/F10/
> 
> 
> 
> 
> 
> 
> Anyone understand what is meant by "Fo-Fc  densities for ligands complexed with (fruit fly) DAT"? Surprisingly,  N-methyl-amphetamine is less dense than simple  dextro-amphetamine.



F = Fourier transform coefficient Factor used in X-ray  crystallography to determine electron density of a molecule: Fo-Fc  difference between observed Fo and calculated Fc (calculated) Factor. It  basically gives you a 3D map of electron density of your molecule under  X-ray.
Now that being said, you may be comparing apples and oranges  if you're comparing the PEAs and the tropanes. The former act by  activation of intracellular located trace amine associated receptor type  1 TAAR1 to induce DA release.. the latter block synaptic cleft DA  reuptake.  
nb: the PEAs are so flexible that actually the  corresponding crystal structure-determined electronic maps maybe  meaningless: they will crystallize in all sort of conformations  depending on all sort of conditions such as salt, temperature,  solvent....etc let alone in the presence of bunch of proteins, lipids,  ions ..etc. As like when you smoke'em (ie at their TAAR1 receptor).  The  best approximation of the "active" conformation would be co-crystallize  the PEA bound with its TAAR1 receptor. But that's a million dollar  question that could keep a PhD thesis student busy ...depending of how  many years it will take him to get the right conditions to crystallize  and get the protein-ligand complex Fo-Fc ..


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## Nagelfar

DotChem said:


> F = Fourier transform coefficient Factor used in X-ray  crystallography to determine electron density of a molecule: Fo-Fc  difference between observed Fo and calculated Fc (calculated) Factor. It  basically gives you a 3D map of electron density of your molecule under  X-ray.
> Now that being said, you may be comparing apples and oranges  if you're comparing the PEAs and the tropanes. The former act by  activation of intracellular located trace amine associated receptor type  1 TAAR1 to induce DA release.. the latter block synaptic cleft DA  reuptake.



I knew this, yes. My mention was comparing dextro-N-methyl-amphetamine with dextro-amphetamine.


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## aced126

Why does diastereomeric recrystallisation work?

What are the molecular reasons behind why 2 enantiomers can't be separated with chromotography but 2 diastereomers can?


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## SKL

BobbyDick said:


> [h=1]"Muscimol induces state-dependent learning" What is SDL.[/h]http://www.sciencedirect.com/science/article/pii/0006899395003038



State dependent learning is the idea that memories you form in an altered state (of various kinds, not necessarily just drug-induced altered states, this also has some applications in the study/potential therapy of PTSD) are better retrieved when in that altered state, i.e. a scientific spin on the old saw about getting drunk in order to find your keys which you lost when drunk. Kind of tangentially at best related but perhaps the inreverse of this is that the effects of drugs do also depend on external circumstances, i.e. overdosage being more likely in unfamiliar circumstances.


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## DotChem

aced126 said:


> Why does diastereomeric recrystallisation work?
> 
> What are the molecular reasons behind why 2 enantiomers can't be separated with chromotography but 2 diastereomers can?



It boils down to solvation: the solvation shell around a   diastereoisomer pairs is different for each of the diastereoisomer. So   their physical properties including their Rf is different. And also   because of that, they crystallize under different conditions hence they   can be separated by selective fractional recrystallization.
On the  other hand, solvation of an enantiomeric pair is the same for  both  enantiomers. So their physical properties will be the same in  solution  (ie for Rf: the eluting solvent and the stationary phase can't  tell the  difference so to speak). UNLESS the solvent used is chiral in  that case  the solvation will give 2 ( L(+)S(+) and L(-)S(+) not 1  solvated  entities (L(+)-S.  Kind of like the non-covalent (VanderWaals  only)  complex equivalent of diastereoisomers! chiral compound solvated  by  chiral solvent or complexed by chiral chromatographic media.   Hence  the  use of chiral stationary phase to separate enantiomers... does it  make  sense??


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## aced126

What are the molecular reasons behind why the solvation shell is different for 2 diastereomers but the same for 2 enantiomers?


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## Pomzazed

Ha aced, 

Enantiomer: u have exact mirror image of left and right gloves, same mass and u cant separate by shaking the box.

Now u form a diastereomer pair, u tie each glove with left shoe only. Now this got a shape different  (yo, solvation!)
A glob of "leftglove+leftshoe" is now different in space/shape requirement than "rightglove+leftshoe"

Make sense now?


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## aced126

Pomzazed said:


> Ha aced,
> 
> Enantiomer: u have exact mirror image of left and right gloves, same mass and u cant separate by shaking the box.
> 
> Now u form a diastereomer pair, u tie each glove with left shoe only. Now this got a shape different  (yo, solvation!)
> A glob of "leftglove+leftshoe" is now different in space/shape requirement than "rightglove+leftshoe"
> 
> Make sense now?



Enantiomers kind of have different shapes too, otherwise enantiomers of a compound wouldn't show wildly different pharmacological activity.


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## DotChem

aced126 said:


> What are the molecular reasons behind why the  solvation shell is different for 2 diastereomers but the same for 2  enantiomers?


What do you mean by "molecular reasons"? The solvation shell ie the  surface area (the solvent accessible area of the molecule) topography  will be different because the relative position of the atoms in the  diastereoisomeric pair is not the same.  So the solvated forms will give  physically different entities (ie relative positions of charged  groups in the molecule, heteroatoms..etc will be different). And that will make them  crystallize to a different crystal lattice or at different conditions. Or move at different speed in chromatograph media (Rf).  Question of geometrical shapes actually! (see crystal lattice system here ). 

On the other hand, the relative position of the atoms in an enantiomeric pair is the same.  As far as the solvent is concerned. Not so for a POLARIZED ray of light!!  The solvent approach, interact (vanDerWaals..salt.H-bond..etc) and  solvate the molecule from its right side or its left side equally.  So long as the solvent IS NOT chiral. So the shape of the "2" entities are the same.  Kind of  like those "ambidextrous" gloves where it doesn't matter whether the  right or the left hand, the glove will fit, it can't tell a difference. 

Another  way to look at this is the 3-point model of biological binding with chiral drugs sp3 carbon: 3 point 3-D pharmacophore (L1 interact with P1 AND  L1---P2 AND L3---P3) for optimum binding. L = pharmacophore group of  the drug, P = corresponding interaction pocket at the protein binding  site.  Only 1 enantiomer of a chiral sp3 carbon can satisfy the 3-point  interactions at the same time!! And that is because the  environment in proteins and other biomolecules is most often not  symmetrical. P1 P2 P3 arrangement in 3D.


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## Pomzazed

Aced, the above sentence is only true when environment is chiral. Like in biological system.
Enan hasnt got different shape, but they are flipped on other side (exact same shape)
But in chiral environment like receptor, these make difference.

What i stated is like you have a nonchiral (eg. Toluene) solvent/environment, then you dissolve racemic amphets fo example.
You cannot separate it with achiral ways cos they are so the same, (D-Amp, L-Amp)then you add ONE other compound with chirality
eg. Add L-Malic to it.
The "ion cage"(salt cage" structure of D-Amp/L-Malic and L-Amp/L-Malic is very different in shape thus solvation in toluene is difference, thus solubility, thus fractional crystallization is possible.

Let's say in achiral environment you cant distinguish the enantiomer by any means except light angle changing when pas thru it.
With more chiral environment (eg. Chiral HPLC column) the interaction for each enantiomer+chiralcolumnsurface will be diff so u can separate it.
With even more chiral-fixed environment like body, its no wonder why enan gives vastly diff pharma profile.

If still unclear ask out more i can try to answer (my english is bad, not main used language sorry for this)


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## aced126

Pomzazed said:


> Aced, the above sentence is only true when environment is chiral. Like in biological system.
> Enan hasnt got different shape, but they are flipped on other side (exact same shape)
> But in chiral environment like receptor, these make difference.
> 
> What i stated is like you have a nonchiral (eg. Toluene) solvent/environment, then you dissolve racemic amphets fo example.
> You cannot separate it with achiral ways cos they are so the same, (D-Amp, L-Amp)then you add ONE other compound with chirality
> eg. Add L-Malic to it.
> The "ion cage"(salt cage" structure of D-Amp/L-Malic and L-Amp/L-Malic is very different in shape thus solvation in toluene is difference, thus solubility, thus fractional crystallization is possible.
> 
> Let's say in achiral environment you cant distinguish the enantiomer by any means except light angle changing when pas thru it.
> With more chiral environment (eg. Chiral HPLC column) the interaction for each enantiomer+chiralcolumnsurface will be diff so u can separate it.
> With even more chiral-fixed environment like body, its no wonder why enan gives vastly diff pharma profile.
> 
> If still unclear ask out more i can try to answer (my english is bad, not main used language sorry for this)





DotChem said:


> What do you mean by "molecular reasons"? The solvation shell ie the surface area (the solvent accessible area of the molecule) topography will be different because the relative position of the atoms in the diastereoisomeric pair is not the same. So the solvated forms will give physically different entities (ie relative positions of charged groups in the molecule, heteroatoms..etc will be different). And that will make them crystallize to a different crystal lattice or at different conditions. Or move at different speed in chromatograph media (Rf). Question of geometrical shapes actually! (see crystal lattice system here ).
> 
> On the other hand, the relative position of the atoms in an enantiomeric pair is the same. As far as the solvent is concerned. Not so for a POLARIZED ray of light!! The solvent approach, interact (vanDerWaals..salt.H-bond..etc) and solvate the molecule from its right side or its left side equally. So long as the solvent IS NOT chiral. So the shape of the "2" entities are the same. Kind of like those "ambidextrous" gloves where it doesn't matter whether the right or the left hand, the glove will fit, it can't tell a difference.
> 
> Another way to look at this is the 3-point model of biological binding with chiral drugs sp3 carbon: 3 point 3-D pharmacophore (L1 interact with P1 AND L1---P2 AND L3---P3) for optimum binding. L = pharmacophore group of the drug, P = corresponding interaction pocket at the protein binding site. Only 1 enantiomer of a chiral sp3 carbon can satisfy the 3-point interactions at the same time!! And that is because the environment in proteins and other biomolecules is most often not symmetrical. P1 P2 P3 arrangement in 3D.



Thanks both, I understand now.


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## aced126

Have polar CB1 agonists and/or antagonists that do not cross the BBB been reported?


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## belligerent drunk

^ I'm not very familiar with cannabinoid receptor ligands, but are there not any basic nitrogen-containing ones? Because if there are, then I imagine it would not be too difficult to make an alkyl quaternary salt of the compound, and that would limit its BBB permeability greatly.


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## aced126

belligerent drunk said:


> ^ I'm not very familiar with cannabinoid receptor ligands, but are there not any basic nitrogen-containing ones? Because if there are, then I imagine it would not be too difficult to make an alkyl quaternary salt of the compound, and that would limit its BBB permeability greatly.



That is what I was thinking as well. For example, here is rimonabant, a BBB-permeable CB1 inverse agonist: https://en.wikipedia.org/wiki/Rimonabant






https://en.wikipedia.org/wiki/Canna.../File:Metabolic_effects_of_CB1_antagonism.png

The diagram linked indicates a major mechanism of action of Rimonabant is through antagonising CB1 receptors in the hypothalamus region. However it also clearly depicts peripheral means by which it could act. And as we all know CB1 receptors are expressed densely throughout the brain, not really contributing to the drug's selectivity. This fact, maybe amplified by the drug antagonising mu receptors, could be the reason why some patients experience negative CNS effects while on this, like depression or suicidal thoughts. If a quarternary salt derivatives of Rimonabant could be evaluated, they may show promise in this respect.

Likewise, CB1 and CB2 agonists have been shown to have therapeutic potential in treating peripheral disorders like inflammatory pain, so developing impermeable agonists could gain easier approval if it does turn out to be beneficial.


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## belligerent drunk

The compound you brought up has 2 nitrogen centres, of which I imagine the hydrazide nitrogen would have the highest basicity/nucleophilicity, and I don't see any reason why it would be difficult to methylate that nitrogen to produce a quaternary salt and effectively make it only peripherally-active. I also don't think that adding a methylene bridge (N-CH2-H+ vs. N-H+) would affect its affinity for CB receptors significantly, unless there's a specific reason for that.


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## DotChem

aced126 said:


> Have polar CB1 agonists and/or antagonists that do not cross the BBB been reported?










> ...AM-6545 _does not cross the blood–brain barrier  to any significant extent_, it does not produce these kinds of side  effects[depression and sucidal thoights], but has still been shown to effectively reduce appetite and  food consumption in animal studies....https://en.wikipedia.org/wiki/AM-6545


Basic idea was to  increase hydrophilcity by replacing a CH2 of the piperidyl with a  sulfoxide or a sulfone: increase dramatically polarity while retaining  good binding since sulfoxide or sulfone are neutral.  That prevent its  crossing BBB while still antagonizing peripheral CB1Rs.


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## belligerent drunk

^ I think aced is asking for efficacious CB agonists that are non-CNS active, which is easily done by making the drug a methylated quaternary salt. I see no reason in making it a sulfoxide or sulfone, especially if it doesn't provide a charge.


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## DotChem

belligerent drunk said:


> ^ I think aced is asking for  efficacious CB agonists that are non-CNS active, which is easily done by  making the drug a methylated quaternary salt. I see no reason in making  it a sulfoxide or sulfone, especially if it doesn't provide a  charge.





aced126 said:


> agonists and/or antagonists that do not cross the BBB been reported?


.. but I am sure there must be CB agonists that do  not cross BBB too. But you're right: adding a permanently charge group will  prevent the molecule crossing BBB but you might kill receptor affinity in so doing.   This probably the reason the authors choose a sulfone is so you still  maintain CB1 activity! I don't know detailed SAR around CB1 ligands.  But in  general, quaternary ammonium salts with a positive charge may not like  the binding site where the part of the Cannabinoid molecule beeing replaced is  interacting. The site may be too  lipophilic to accommodate a charged ammonium. ie higher desolvation energy..Unless the quaternary  ammonium is located in some part of the molecule which is not involved  in interacting with the receptor CB1R. Detailed SAR can tell that.. But  yes of course it might work!


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## belligerent drunk

Typically binding occurs with a (partially) protonated quaternary amine salt, reight? Making it an alkyl quaternary salt will just decrease its BBB permeability, whereas its binding profile (a methyl group being not much different from a hydrogen as far as electronic structure is concerned) will be preserved - except its brain activity.

Methylating the nitrogen in the compound is both easier, and more logical than introducing sulfur moieties.


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## Pomzazed

^ That is not quite true for CB ligands.

Main interaction does not need the positively-charged species anywhere in the molecules which will destroy the activity.
Required pharmacophore for it is the 
1) Two hydrophobic bulky region, one must be planar and one does not need to. (eg. Phenol region and polycyclic alkyl in THC, or Indole and Naphthalene in JWHs)
2) One hydrophobic nonbulky region (aka. the "tail" of THC or JWHs), high electronegativity group at the tail-end enhance binding.
just that, and also
3) is not required, but H-bond acceptor somewhat increase affinity (phenolic OH in THC, or keto-group in JWHs)

There are several minor points that can increase/decrease binding affinity, but I wont go into detail yet in this post unless needed.


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## belligerent drunk

As I said before, I'm not very familiar with CB ligands, but I do know that there are quaternary alkyl salts used as peripherally-only active drugs (opioids for example), which would suggest that the compound binds to the receptor in the charged form. If that is not the case for CB ligands, then I'm sorry.


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## Pomzazed

You don't have to say sorry, what you said is absolutely correct for binding of anything with 'positively charged' at physiological pH,
which is mostly from alkaloidal nitrogen position. This is true for like opioid, muscarinics, nicotinics, etc.

Cannabinoids are just some strange guys which mostly rely on hydrophobic interaction, Maybe because itself is generated from fatty part in the cell membrane itself and firing 'backward' to presynaptic receptors or so.


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## DotChem

^ I agree. Main interactions involving CB receptors will be hydrophobic in nature. Considering the endogenous Cannabinoid ligand Anandamide is incredibly lipophilic! It is a fatty amide (fat basically!!). So CB receptors would be expected to bind mostly lipophlic ligands like THC and the JWs. 




Anandamide 

BTW I wonder why the natural CB ligand Anandamide is not used directly used as cannabinoid. It looks pretty stable, easy and cheap to synthesize from arachidonic acid (ie peanut oil !


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## sekio

> I wonder why the natural CB ligand Anandamide is not used directly used as cannabinoid. It looks pretty stable, easy and cheap to synthesize from arachidonic acid



All those double bonds mean it's not very stable compared to some other compounds, actually - they are all places for oxidation to happen, or rearrangement to a _trans-_ double bond. And the amide on the end tends to get hydrolysed in biological environments.

Besides all that, I don't know how potent it would be... oleamide is a structurally related compound that is a CB1 agonist but I've never heard of it being used on its own as an intoxicant.


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## aced126

Pomzazed, could you expand in more detail on the SAR of CB1 ligands. More importantly, what is required for antagonist activity. Afaik CB1 spontaneously switches between active and inactive states; rimonabant stabilises the inactive state of CB1, and thus could be considered an inverse agonist. 

https://en.m.wikipedia.org/wiki/Can...nist#/media/File:Rimonabant_Pharmacophore.png

Are the marked aa residues in the linked diagram also involved in active state agonist binding? Or are they completely different? If the latter is true, does this suggest an endogenous CB1 antagonist which enables more precise neuron signalling?


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## belligerent drunk

sekio said:


> All those double bonds mean it's not very stable compared to some other compounds, actually - they are all places for oxidation to happen, or rearrangement to a _trans-_ double bond. And the amide on the end tends to get hydrolysed in biological environments.
> 
> Besides all that, I don't know how potent it would be... oleamide is a structurally related compound that is a CB1 agonist but I've never heard of it being used on its own as an intoxicant.



Unsaturated fatty acids have plenty double bonds as well, but they're usually fine as far as biological degradation goes, no? Although there's definitely a lot more potential for oxidation/peroxidation with double bonds.

I've tried oleamide up to 500 mg per dose. Did jack shit.


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## seep

I'm pretty sure the answer is 8 but it's been so long since I've studied this.  How many stereoisomers does quinine have?






I count 3 stereocenters so to 2 to the 3rd power is eight, but I can't tell if some of them are the same isomer.

Also, if one drinks a liter of tonic water, how much quinidine will he be ingesting?  Quinidine is an antiarrhythmic drug that is one of the stereoisomers of quinine.


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## Dresden

Three chiral centers.  Don't drink tonic water.  It tastes terrible.


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## pharmakos

off topic, but something funny about tonic water... tonic water was used by european settlers in africa as a way to prevent getting malaria... the drink gin & tonic came about because tonic water tasted so bad that they mixed it with gin to make it taste better.

they mixed it with gin to make it taste _better_

that always blew my mind lol.  modern tonic water has very little quinidine compared to the stuff they used back then tho, and to answer your question, i think most tonic water manufacturers are pretty open about the amount of quinidine in their product.


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## seep

Say the manufacturer claims 80 mg of quinine per liter. How much quinidine is that? Is it 10 mg, or is quinidine a diastereomer of quinine (20 mg, 40 mg)?

As an antiarrhythmic this is a moot point because the effective dose is in the hundreds of milligrams. But as a cytochrome inhibitor, quinidine is efficacious even at 10 mg.


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## sekio

Tonic water contains quinine, not quinidine, although presumably "olde fashioned" tonic water was both, extracted from whatever bark...


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## seep

^thank you.  I had thought that "quinine" referred to the racemic mixture.


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## aced126

Can the tropane ring undergo inversion?

In other words, is (2R)-2-carbomethoxytropinone the same as (4R)-4-carbomethoxytropinone?

Opsin draws it badly but oh well:











My gut instinct is that ring inversion can't take place to a great degree, and if it does take place, it does so at a much slower conversion rate than say cyclohexane


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## sekio

Not easily, no. I'd imagine the etheno bridge would lock the ring.


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## DotChem

transition state energy too high! need C-C or C-N bond breaking.. unless you have catalyst to stabilized TS


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## TheBlackPirate

Here's a good link:

The Fundamentals of Neuroscience. A free Harvard nueroscience online class.


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## clubcard

http://www.vice.com/en_uk/video/dopesick-fentanyl-deadly-grip


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## Nagelfar

clubcard said:


> http://www.vice.com/en_uk/video/dopesick-fentanyl-deadly-grip



Library computer blocks me, says "pornographic content" :-f


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## Pomzazed

sekio said:


> Besides all that, I don't know how potent it would be... oleamide is a structurally related compound that is a CB1 agonist but I've never heard of it being used on its own as an intoxicant.



Oleamide is found in (former) spice synthcan blend of ancient time (during the boom of JWH-018 and -081 era long ago), in massive amount. But i don't believe it has central effect via smoking, too large molecule to vaporize and too easy to go thermal oxidation while heating.
There have been anecdotes of people trying oral oleamide (on different occasion, and 3-4 different group of people) without any central effect. Some reported slight nausea (i think its maybe the smell/fatty texture if oleamide itself) or slight 'calm' effect (maybe placebo).



aced126 said:


> Pomzazed, could you expand in more detail on the SAR of CB1 ligands. More importantly, what is required for antagonist activity.


Check your pm.


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## Jonneh

Some electron microscopic synaptic love for you all. Rotten membrane preservation to preserve epitopes for immunogold, but it is what it is.


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## 777prp

*This is 1 smart group of mofos.*

I just wanted to see if my use of ketamine might cause mental impairment but I think trying to understand this thread might be causing brain damage. I'm just sayin'.


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## vortech

Jonneh said:


> Some electron microscopic synaptic love for you all. Rotten membrane preservation to preserve epitopes for immunogold, but it is what it is.


It doesn't take much brain power to feel this image, regardless of damage from ketamine or this thread, lol..


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## Soulfake

Can anyone explain why there are no RC drugs similar made as esters from known drugs? Couldn´t you put practically on every drug that has either a free NH² or OH unit an ester of some form?
I know that some drugs are then simply hydrolized to release the components and others gain own medical effects in the ester form.

For example If one would take Morphine and esterfy it with GABA or Menthol, wouldn´t those molecules just hydrolize and according to the ratio you would just have to take a bit more? There are also things like Benzphetamine which is simply a Benzyl-ester of amphetamine with similar effects. The only downside I could imagine would be the "slow release" of effects, but for drugs like Oxycodone or Fentanyl this would´nt be that bad I think?


----------



## aced126

Soulfake said:


> Can anyone explain why there are no RC drugs similar made as esters from known drugs? Couldn´t you put practically on every drug that has either a free NH² or OH unit an ester of some form?
> I know that some drugs are then simply hydrolized to release the components and others gain own medical effects in the ester form.
> 
> For example If one would take Morphine and esterfy it with GABA or Menthol, wouldn´t those molecules just hydrolize and according to the ratio you would just have to take a bit more? There are also things like Benzphetamine which is simply a Benzyl-ester of amphetamine with similar effects. The only downside I could imagine would be the "slow release" of effects, but for drugs like Oxycodone or Fentanyl this would´nt be that bad I think?



Some drugs are formulated as esters and they result in time-release formulations. They often also improve oral bioavailability and (for neuroactive drugs) BBB penetration. 

https://en.wikipedia.org/wiki/BL-1020

The last molecule you displayed is an ether, not an ester, so esterases cannot separate the 2 molecules. The P450 system probably wouldn't be able to either.


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## TheAppleCore

Cross post:

http://www.bluelight.org/vb/threads...cPT-Thread?p=13828100&viewfull=1#post13828100


Also, while I'm at it, allow me to ask a n00b question. Are substitutions in the amino group in tryptamine symmetrical, in the sense that methyl-ethyl-tryptamine is identical to ethyl-methyl-tryptamine?


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## BobbyDick

What is downstream of every single muscarinic receptor?


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## Nagelfar

Soulfake said:


>





aced126 said:


> The last molecule you displayed is an ether, not an ester, so esterases cannot separate the 2 molecules. The P450 system probably wouldn't be able to either.



With the 6-position substitution place ethers (at least short ethers that don't displace the rest of the fit of the morphine derivative from the mu-receptor site) as shown, it doesn't need to be cleaved to be active, check out heterocodeine.

The bentley compounds have alcohols at the 7 position (7 alpha-oriented), so having a menthol which is a complex alcohol as an ether on the 6 position with one of those would be interesting, wonder if it'd fit into both mu sites & TRPM8 receptor sites, and how it would attenuate kappa opioid receptors since menthol affects that too.


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## sekio

This thread has passed 1000 posts, time for a new one!


----------

