# Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II



## Epsilon Alpha

Link to previous thread:
http://www.bluelight.ru/vb/threads/...rotoxicity-and-Tolerance-Reduction-Prevention
*The Basic Stack.*​


> - ~250mg elemental magnesium at bed. Why: magnesium deficiency is extremely common and known to worsen neurotoxic measures in mouse models. May also help with bruxism (jaw clenching)
> - ~1-5mg sublingual melatonin 3 hours before bed. Why: helps regulate sleep cycle, potent antioxidant, several neuroprotective mechanisms.
> - Stay hydrated, preferably with high quality fruit juices (such as 100% blueberry) Why: do I really need to explain this?
> - Eat a balanced diet rich in dark fruits and vegetables. Why: Why: do I really need to explain this? Make sure you eat period.
> - Avoid overheating. Why: Elevated body temperature has been linked to increased neurotoxicity in mouse models
> - Coenzyme Q10 at 100mg/day in a softgel or oil based formulation (preferably taken with food). Why: extremely long half life antioxidant, various beneficial effects on mitochondrial function.
> - Avoid sleep deprivation. Why: your body needs sleep whether you want to or not.
> - A good multivitamin, or at the very least vitamins A,C,E, and D as well as selenium at a significant portion of the RDA value. Malnutrition is a very real concern with amphetamine use,
> -Low dose ASA ~81mg/day, anti-inflammatory drugs have shown to reduce neurotoxic measures in several models, also might give your cardiovascular system a break.
> - Keep your dose as low as possible.



Now to sum up what we were talking about before:
*Epigenetics*:
 There are various animal studies that suggest amphetamine produces a large portion of its sensitization via epigenetic changes primarily through CREB and histone deacetylase (HDAC) activity. However, if the mouse studies are to be applied to humans the picture becomes complicated. Co-administration of HDACI’s and amphetamine produces increased sensitization and conditioned place preference http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03321.x/full
Curcumin provides an interesting approach to this by inhibiting virtually every epigenetic mechanism under the sun, though the exact concentrations needed for significant inhibition of the various pathways in humans is still unknown at this point. CREB inhibition would stop the immediate-early response gene (IERG) activation and in turn long term epigenetic changes, while HDAC inhibition (a process downstream of CREB) would theoretically lead to an acute increase in sensitization and production of IERG proteins.  Now during a “tolerance break” repeated HDACI application post amphetamine was shown to decrease sensitization which may be a relevant process in humans.
But, then there’s the possibility of histone acetyl transferase (HAT) playing a large role in the equation. Curcumin is a pretty bitching inhibitor of HAT, more so than HDAC in rats at least.  This suggests that the potential negative effects of HDAC acutely on sensitization may not be an issue. http://www.ncbi.nlm.nih.gov/pubmed/20383415
But, going back to the IERG’s it appears that they also play a role in the NMDA antagonist mechanism of action via CREB http://www.jneurosci.org/content/16/13/4231.short.  And, curcumin appears to have a effect on NMDA calcium influx too http://www.ncbi.nlm.nih.gov/pubmed/20015232.
So to sum it all up: curcumin is kind of like the sawn off shotgun of epigenetic modulators, showing promise on several fronts but with its 9/21 positive response rate we’d need better controlled anecdotal or actual clinical trials to make more sense out of it. Also, there may be glaring species differences with the various proteins curcumin binds between humans and rats/mice that I’m too lazy to check out (hint hint).  Also, don’t be afraid of trialling more selective inhibitors of epigenetic mechanisms as long as you’re smart and methodical about it.
http://www.ncbi.nlm.nih.gov/pubmed/21466474

*Sensitization vs Tolerance*. 
This is a particularly interesting issue, as it involves both epigenetics and the strengthening/weakening of a ton of pathways in the brain. I’ll fully admit that I’m not that well versed on the topic (somebody grab Ex Dubio ) but it plays into the idea that a portion of "tolerance" may be specific pathways in the brain adapting to amphetamine use.



> A very interesting study came out a couple weeks ago, and though it's hard to say how relevant the implications are to humans, the study nonetheless puts forth some very intriguing ideas.
> 
> First, a quick refresher. Sensitization is a rather complex process that occurs when rodents are given [strongly] DAergic drugs or, as they are commonly known, "drugs of abuse". Sensitization refers to the phenomenon in which responding to a drug (measured typically by means of locomotor activity) is increased with repeated administration. For example, locomotor responding to amphetamine tends to increase -- not decrease, as would be expected with tolerance -- when amphetamine is given repeatedly, assuming a few technical criteria are met. What is particularly important, though, is that sensitization persists after months -- and even years -- of abstinence from a given drug.
> 
> Now, the catch is that we don't really even know if sensitization occurs in humans, but sensitization is nonetheless often taken as a model for the maladaptive neurological changes that occur in addiction. (Note that it may be that sensitization and tolerance happen simultaneously, but are expressed differently, in humans. It's not clear to me how well we can judge tolerance (i.e. to rewarding effects) in rodents.) So, assuming that sensitization -- or something like it -- occurs in humans, being able to quickly "break" sensitization -- which seems to otherwise persist indefinitely -- could completely change the landscape of addiction treatment. If fact, if the link between sensitization and addiction is correct, then "breaking" sensitization could be a rapid "cure" for addiction. Note that it is quite possible that this is precisely what compounds like ibogaine do.
> 
> As if that weren't enough, I have a pet theory that sensitization may be related to the development of motor complications like bruxism with extended use of amphetamine, cocaine, MDMA, and similar drugs. As many an MDMA user can attest, being able to prevent the bruxism that often accompanies frequent MDMA use would be a major boon.
> 
> And "breaking" sensitization is precisely what these researchers claim they have accomplished, with a rather unorthodox combination of a D1/D2 agonist (pergolide) and either a 5-HT3 antagonist (ondansetron) or a 5-HT2A/2C antagonist (ketanserin). Though the protocol might be tricky to adapt to humans, and suitable drugs might be hard to obtain, if it can truly reverse what we believe to be the manifestations of sensitization in humans, it would be game-changing. So without further ado, I present the study:
> 
> Behav Brain Res. 2011 Sep 30;223(1):227-32. Epub 2011 May 7.
> Reversal of long-term methamphetamine sensitization by combination of pergolide with ondansetron or ketanserin, but not mirtazapine.
> 
> Bhatia KS, Szabo ST, Fowler JC, Wetsel WC, Lee TH.
> Source
> 
> Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
> 
> Abstract
> 
> Psychostimulant abuse represents a psychiatric disorder and societal concern that has been largely unamenable to therapeutic interventions. We have previously demonstrated that the 5-HT₃ antagonist ondansetron or non-selective 5-HT(₂A/₂C) antagonist ketanserin administered 3.5 h following daily pergolide, a non-selective DA agonist, reverses previously established cocaine sensitization. The present study was conducted to evaluate whether the same treatments or delayed pairing of pergolide with the antidepressant mirtazapine can also reverse consolidated methamphetamine (METH) behavioral sensitization. Sprague-Dawley rats received METH infusion via osmotic minipumps (25 mg/kg/day, s.c.) for 7 days, with accompanying daily injections of escalating METH doses (0-6 mg/kg, s.c.). This regimen takes into account the faster elimination of METH in rats, and is designed to replicate plasma METH concentrations with superimposed peak drug levels as observed during METH binging episodes in humans. Following a 7-day METH withdrawal, ondansetron (0.2 mg/kg, s.c.), ketanserin (1.0 mg/kg, s.c.), or mirtazapine (10mg/kg, i.p.) was administered 3.5 h after pergolide injections (0.1 mg/kg, s.c., qd) for 7 days. Behavioral sensitization as a model of METH abuse was assessed 14 days after the combination treatment cessation (i.e., day 28 of METH withdrawal) through an acute challenge with METH (0.5 mg/kg, i.p.). Pergolide combined with ondansetron or ketanserin reversed METH behavioral sensitization, but pergolide-mirtazapine combination was ineffective. The role of reactivation of addiction "circuit" by a non-selective DA agonist, and subsequent reconsolidation blockade through 5-HT₃ or 5-HT₂ antagonism in reversal of METH sensitization and treatment of METH addiction is discussed.
> Copyright © 2011 Elsevier B.V. All rights reserved.
> 
> PMID:21571009 [PubMed - indexed for MEDLINE]
> PMCID: PMC3113440 [Available on 2012/9/30]
> http://www.mindandmuscle.net/forum/neuroscience-nootropics/40750-sensitization-breakthrough-2.html



To discuss: TAAR, MGluR, NAChR, 5HT3R, long term potentiation, and further mechanism of cell death/dysfunction.


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## atrollappears

Good to see you back, Epsilon Alpha. Your contributions are a huge asset to ADA.

A few points:
1. I believe we talked about about magnesium's effect on neurotoxicity in a thread a while back, using MPTP as a crude model for amphetamine. The studies I posted mostly leaned toward (normal amounts of) magnesium being protective against neurotoxicity, but there was still that one study which seemed to indicate a pretty big exacerbation of MPTP toxicity in a not-too-ridiculous dosage of magnesium (and there was the matter of another study referenced in that study which supposedly claimed that magnesium exacerbated l-amph neurotoxicity, though I don't believe we ever accessed that study and looked at the amounts used). So, did you find anything new?
2. I would recommend acetyl-L-carnitine and (if you have a buffering agent) alpha lipoic acid as supplements for amphetamine users as well. ALC has been shown to protect against amphetamine (and I think MDMA too) neurotoxicity, and has also been shown to substantially improve cognitive function (in a perhaps biased study) when administered in conjunction with ALA, which is also a potent antioxidant.
3. As far as effects outside the brain go, some studies say ASA isn't really that effective for helping your heart, and can increase the risk of hemorrhagic stroke and ulcers. It's also unclear how the vasoconstriction caused by aspirin in some areas would combine with that already caused by amphetamine. Just some things to bear in mind if you're starting to take aspirin daily.

I'll give this the in-depth reading it deserves later, but for now I've got some work to do.


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## atrollappears

Careful messing with epigenetics---it may be the brain's defense mechanism. In one study rats exposed to amph in adolescence were resistant to neurotoxicity in adulthood due to epigenetic changes.


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## Nagelfar

atrollappears said:


> ...In one study rats exposed to amph in adolescence were resistant to neurotoxicity in adulthood due to epigenetic changes.



Perhaps why I myself am so overly prone to amphetamine psychosis; I never touched it until nearly 30 years old.


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## atrollappears

Could be. It's unclear what the human correlates of neurotoxicity are (can't cocaine cause psychosis?), but clearly, when introduced during development, the body is able to make some protective changes against the effects of amphetamines.

http://onlinelibrary.wiley.com/doi/10.1002/syn.20902/abstract


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## i are spectre

blueberries


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## Epsilon Alpha

atrollappears said:


> Good to see you back, Epsilon Alpha. Your contributions are a huge asset to ADA.



A few points:


> 1. I believe we talked about about magnesium's effect on neurotoxicity in a thread a while back, using MPTP as a crude model for amphetamine. The studies I posted mostly leaned toward (normal amounts of) magnesium being protective against neurotoxicity, but there was still that one study which seemed to indicate a pretty big exacerbation of MPTP toxicity in a not-too-ridiculous dosage of magnesium (and there was the matter of another study referenced in that study which supposedly claimed that magnesium exacerbated l-amph neurotoxicity, though I don't believe we ever accessed that study and looked at the amounts used). So, did you find anything new?


Well massive doses of magnesium will do far more than just mess up your response to amphetamine, its a inverse U shaped curve with NMDA activity and magnesium concentration. Magnesium is probably only a good idea to supplement if you have a deficiency in it (and chances are you do).



> 2. I would recommend acetyl-L-carnitine and (if you have a buffering agent) alpha lipoic acid as supplements for amphetamine users as well. ALC has been shown to protect against amphetamine (and I think MDMA too) neurotoxicity, and has also been shown to substantially improve cognitive function (in a perhaps biased study) when administered in conjunction with ALA, which is also a potent antioxidant.


 Interesting, I'd like to see some links for that. CoQ10 is my staple just because its stupidly safe and has a ~31 hour half life. 



> 3. As far as effects outside the brain go, some studies say ASA isn't really that effective for helping your heart, and can increase the risk of hemorrhagic stroke and ulcers. It's also unclear how the vasoconstriction caused by aspirin in some areas would combine with that already caused by amphetamine. Just some things to bear in mind if you're starting to take aspirin daily.


It may just be COX inhibition in general that causes the sparing of DA neurons in the studies I've been reading, but ASA seems to have a favorable risk/benefit ratio to me. But as far as vasodilators go, Ginkgo has some promise in amphetamine useage but I haven't fully evaluated its safety.
http://www.nature.com/npp/journal/v25/n4/full/1395696a.html




i are spectre said:


> blueberries


Fucking this :D

But, as far as the epigenome goes we're only now beginning to understand it. However, a curry and speed binge hasn't killed anyone yet (dispite 12.5g of curcumin and 90mg D-AMP...). But, I've seen a lot of evidence suggesting that things like deltaFosB and genome wide methylation are both protective and harmful at the same time.

Here's a really interesting paper on sensitization in humans from Nature.
http://www.nature.com/npp/journal/v25/n4/full/1395696a.html

Buuuuut, sensitization has way way too many links to bipolar disease and schizophrenia for my liking. Granted it may also be involved in some of the benefits seen in long term stimulant treatment of ADHD.
D1 antagonists in monkeys seem to reverse it http://www.sciencedirect.com/science/article/pii/S0091305710001899
Amp sensitization looks a lot like schizophrenia http://archpsyc.ama-assn.org/cgi/content/abstract/68/6/545
Looks to me like ADHD could predispose someone to sensitization  http://archpsyc.ama-assn.org/cgi/content/abstract/63/12/1386
And a little info on the sensitization-bipolar link. http://www.sciencedirect.com/science/article/pii/S0166432809005841

I'm beginning to think that by looking into schizophrenia and bipolar/epilepsy we can begin to find some significant findings for all these conditions.


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## atrollappears

Yeah, did you ever figure out how high concentrations of Mg act as a Ca agonist? Or locate any studies that used amphetamine with reasonable concentrations of magnesium?

And here's some stuff on acetyl-L-carnitine, looks very promising IMO. In the MDMA study, note the essentially _complete lack_ of 5-HT depletion in the ALC + MDMA group.
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2002.tb04164.x/abstract
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2003.tb07530.x/abstract
http://www.sciencedirect.com/science/article/pii/S0306452208015947
Couldn't find anything on alpha lipoic acid for amphetamine, but here's a study where it also _fully prevents_ MDMA induced 5-HT depletion.
http://www.ncbi.nlm.nih.gov/pubmed/10619665
And a study of the combination in age-associated memory impairment:
http://juvenon.com/pdfs/juvenon_memory.pdf


Edit: That paper on sensitization is, as you say, interesting. Funny that drug liking and the rating of "euphoria" don't go hand in hand. How much is known about the neurochemical basis for sensitization? Between that odd relationship of drug liking to euphoria (mGluR5 antagonists, anyone?) and the link to schizophrenia/bipolar, it screams glutamate to me...


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## Epsilon Alpha

Well at normal levels magnesium prevents excessive activation of NMDA, no big surprises there.
http://www.nature.com/nature/journal/v307/n5950/abs/307462a0.html

However, higher doses may antagonize the actions of endogenous NMDA channel blockers. IIRC at really high doses it also increases NE efflux which would explain the l-amphetamine bit. http://www.ncbi.nlm.nih.gov/pubmed/22261381

Your study showing increased stereotyping in response to l-amp and apomorphine, is in the discussion linked to increased cAMP production and NE/DA binding, and the doses are pretty high. http://www.sciencedirect.com/science/article/pii/0091305790901207

So it all kind of comes back to the inverted U curve with magnesium as far as I can tell. Stuff will bind to literally anything given high enough concentrations, much like lead.


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## atrollappears

Ah okay. The MPTP study that led me to that l-amp study said that the latter study showed an increase in neurotoxicity; did they measure DA/DA metabolite content or did they mean something different by "neurotoxicity"?


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## atrollappears

Also, why do we want to block sensitization anyway? It seems like a positive to me, I want to experience increased "euphoria" and "vigor" from amphetamine without feeling as much as though the drug has rewarded me


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## Vaya

Nice to see you back, EA.

~ vaya


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## chaultistic

How would this apply to methylphenidate's neurotoxicity or tolerance? What doses would causes mild to severe changes by low to high doses of methylphenidate, I would think that they the synapses would be spread further apart and a lot less because of down regulation. Is this down regulation permanent if taken during your childhood and adolescence's developing brain, and if it's not just down regulation that is in effect with methylphenidate, what other things come into play that would create long-term changes?


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## Amu

Eplison Alpha and atrollappears, what do you two think of of the possibility of an anti-oxidant stack turning pro-oxidant in presence of MDMA/METH? Also, are you aware daily anti-oxidants will likely DOWNREGULATE endogenous production of the brain's own anti-oxidants? This means if one day you skip those anti-oxidants and something in your brain causes damage that requires internal protection, _*we're fucked*_. Selegiline I believe up-regulates said production, one reason why it's so interesting.


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## Vaya

Amu said:


> Eplison Alpha and atrollappears, what do you two think of of the possibility of an anti-oxidant stack turning pro-oxidant in presence of MDMA/METH?



Melatonin has been shown to turn pro-oxidant in the presence of chronic moderate to large doses of methamphetamine. Not sure if this is specifically something you were addressing, but, FWIW.

~ vaya


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## Epsilon Alpha

Now this is the kind of discussion I'm talkin' about!

Well my take on the antioxidant supplementation bit is that at the point when your body's endogenous defense mechanism are overloaded, at the point when oxidative stress is great enough to begin with to turn things like CoQ10 pro-oxidant I feel that having them mop up the significant amount of ROS and RNS before they themselves become pro-oxidant produces a net benefit. There's also several studies showing excessive oxidative stress in amphetamine users on the greater scale which I'd take as evidence for the use of antioxidants.

http://onlinelibrary.wiley.com/doi/10.1111/j.1369-1600.2009.00176.x/full
Also, by no means do I expect oxidative stress to be the sole mechanism through which amphetamine exerts its toxic effects and as such antioxidants may only provide partial protection.
http://www.sciencedirect.com/science/article/pii/S0892036209002001



> Melatonin has been shown to turn pro-oxidant in the presence of chronic moderate to large doses of methamphetamine. Not sure if this is specifically something you were addressing, but, FWIW.
> 
> ~ vaya


 I'd be very interested in seeing that study if you could bring it up.

I'd also be up for seeing some studies showing selegiline upregulates your brains protective systems if you can dig them up.


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## Nagelfar

chaultistic said:


> How would this apply to methylphenidate's neurotoxicity



From my understanding methylphenidate, being a DRI unlike methamphetamine, is neuro_protective_ and not neurotoxic. Tolerance & down-regulation are different issues.


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## Amu

Epsilon Alpha said:


> I'd also be up for seeing some studies showing selegiline upregulates your brains protective systems if you can dig them up.



But that doesn't address the down-regulation supplements cause, and also how the brain quickly and effectively builds a defense against even the most potent neurotoxins, at least at recreational doses, we aren't IV'ing MPTP here, and it does it on it's own.

http://www.ncbi.nlm.nih.gov/pubmed/15959853


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## chaultistic

Nagelfar said:


> From my understanding methylphenidate, being a DRI unlike methamphetamine, is neuro_protective_ and not neurotoxic. Tolerance & down-regulation are different issues.



With that being said, are there no danger's associated with prolonged therapeutic high doses of Methylphenidate from childhood to adolescents and onwards? Also, if your brain is used to having this for prolonged periods during development, when it's stopped, would you not be left blunted in terms of development of the brain? What I'm trying to say is, would someone be cognitively better or worst from this treatment, or would it predispose one to some other mental illness?


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## Vaya

Epsilon Alpha said:


> I'd be very interested in seeing that study if you could bring it up.



Exacerbation of methamphetamine-induced neurochemical deficits by melatonin.

There's a start, but there was a specific Google Books reference I'd read up on about two months ago that I'm still looking for. Bear with me.


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## Epsilon Alpha

Amu said:


> But that doesn't address the down-regulation supplements cause, and also how the brain quickly and effectively builds a defense against even the most potent neurotoxins, at least at recreational doses, we aren't IV'ing MPTP here, and it does it on it's own.
> 
> http://www.ncbi.nlm.nih.gov/pubmed/15959853


 
Very interesting, any info on the relevant dosage conversion for humans? I've always avoided looking at MAO-B inhibitors because there's the potential for serious adverse reactions. This might also address the issue of continued cell death days or weeks after the last dose in a binge type situation.

As for the melatonin though, I'm tempted to say it might have more to do with it binding to receptors elsewhere in the body at the 25mg/kg doses they gave. I'll have to check out how this weighs in with the larger body of evidence suggesting melatonin exerts a protective role in vivo and in vitro. But still, this is very unexpected to say the least.

http://www.ncbi.nlm.nih.gov/pubmed/20738755
http://www.ncbi.nlm.nih.gov/pubmed/20374443
http://www.ncbi.nlm.nih.gov/pubmed/19386024
http://www.ncbi.nlm.nih.gov/pubmed/19409439


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## Epsilon Alpha

chaultistic said:


> How would this apply to methylphenidate's neurotoxicity or tolerance? What doses would causes mild to severe changes by low to high doses of methylphenidate, I would think that they the synapses would be spread further apart and a lot less because of down regulation. Is this down regulation permanent if taken during your childhood and adolescence's developing brain, and if it's not just down regulation that is in effect with methylphenidate, what other things come into play that would create long-term changes?



I recall MPH is generally associated with improved long term measures of focus in humans but increased anxiety and depression if given to children. MPH is a lot more than a DRI, infact it increases DA concentrations in the synapse faster than DAT blockade alone would predict, so its quite a different can of worms.

Also, there is some info suggesting it may promote apoptosis at clinically used levels in rats at least.


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## chaultistic

Epsilon Alpha said:


> I recall MPH is generally associated with improved long term measures of focus in humans but increased anxiety and depression if given to children. MPH is a lot more than a DRI, infact it increases DA concentrations in the synapse faster than DAT blockade alone would predict, so its quite a different can of worms.
> 
> Also, there is some info suggesting it may promote apoptosis at clinically used levels in rats at least.



So does it cause release of dopamine like amphetamine, but differently? You say even at low doses it can causes apoptosis, does MPH only cause this, and does AMPH also cause this? If so, which one would be cause more apoptosis? I feel very slow and dumb now after taking it for so long, and I don't know if I should get Focalin or get on Dexedrine as the Ritalin is not doing anything for me. I was part of the Ritalin generation, and being honest, would you say I don't have much of a brain left after being on them for so long, and in a moderately high dose? Don't have to sugar coat it, I already feel as if my brain is empty and brain damaged beyond repair. Would you think moving up to amphetamines would only speed up the damage already done, or do you think I could find a dose that would be able to be maintained for a long while so I can continue without being useless?


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## atrollappears

Epsilon Alpha said:


> I recall MPH is generally associated with improved long term measures of focus in humans but increased anxiety and depression if given to children.



Eh there are somewhat conflicting reports. The study you referred to found decreased cocaine self-administration, but another study, giving ritalin in adolescence, found an increase.

Edit:
And chaultistic, I too often wonder about what long-term effects being medicated and doing drugs in adolescence have had on me. But the fact of the matter is that we are who we are now, and nothing will be gained from trying to discern how the past may have affected the present. Treat your brain well and become a person you are happy with---the brain is an amazing thing, and you certainly still have the ability to do so.


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## ebola?

Thanks, EA, for consolidating these data!  The prior thread was getting slightly unwieldy to read through.

ebola


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## atrollappears

Epsilon Alpha, you may find this interesting:

http://onlinelibrary.wiley.com/doi/10.1196/annals.1403.019/full
(if that link doesn't work for you, try this http://onlinelibrary.wiley.com/doi/10.1196/annals.1403.019/abstract)

Edit: Some research suggests that ALC should actually decrease the response to amphetamine (though paradoxically it increases it to cocaine) so I'm going to remove it from my stack tomorrow and see if I notice a difference. Hardly empirical, but oh well.
Update: Skipped my ALC dose today, and I noticed an increase in the effects of the amph, both in terms of behavioral activation and inhibition. So, looks like ALC may block amphetamine, probably from its effects on cell membranes. I still recommend alpha lipoic acid though, if you have some tums xD

Edit 2: To those who use cocaine or MPH, you might find ALC of interest, because as I mentioned ALC increases the response to cocaine, but I neglected to mention the surprising magnitude of the difference: dopamine increase due to cocaine was *doubled* and serotonin increase was also increased by some similarly surprising factor I forget.


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## Nagelfar

atrollappears said:


> Edit: Some research suggests that ALC should actually decrease the response to amphetamine (though paradoxically it increases it to cocaine)



Perhaps ALCAR has some role in the increased versus decreased instances of Alzheimer's in chronic amphetamine users as opposed to life long cocaine users.


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## atrollappears

Nagelfar said:


> Perhaps ALCAR has some role in the increased versus decreased instances of Alzheimer's in chronic amphetamine users as opposed to life long cocaine users.



Yeah, it does increase acetylcholine release, and it shows promise in age-related cognitive impairment (20% increase in working memory when combined with a-lipoic acid). I wonder, though, how the administration of amphetamine/cocaine would affect ALC levels rather than ALC affecting the response to those chemicals... 
Maybe people with low endogenous ALC levels prefer amph and those with high prefer cocaine? xD Or more generally (and more probably) the basic metabolic processes, which are affected by ALC and influence cognitive function esp. with respect to aging, affect the response to cocaine and amphetamine in such a way that those more prone to Alzheimer's prefer amphetamine and vice versa.


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## chaultistic

atrollappears said:


> Yeah, it does increase acetylcholine release, and it shows promise in age-related cognitive impairment (20% increase in working memory when combined with a-lipoic acid). I wonder, though, how the administration of amphetamine/cocaine would affect ALC levels rather than ALC affecting the response to those chemicals...
> Maybe people with low endogenous ALC levels prefer amph and those with high prefer cocaine? xD Or more generally (and more probably) the basic metabolic processes, which are affected by ALC and influence cognitive function esp. with respect to aging, affect the response to cocaine and amphetamine in such a way that those more prone to Alzheimer's prefer amphetamine and vice versa.



Again, although methylphenidate is similar to both amphetamine and cocaine, does this mean that people who respond well to methylphenidate instead of amphetamine have high ALC levels, (since it works as a DNRI, and cocaine is a DNSRI) and would cocaine or methylphenidate predispose someone to Alzheimerz as well?? What would methylphenidate replicate more between cocaine and amphetamine? I think this thread should include all RX'D amphetamine-like substances (and cocaine) , unless the reason you haven't is because that they're too different, but they generally do a few of the same things.


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## atrollappears

chaultistic said:


> Again, although methylphenidate is similar to both amphetamine and cocaine, does this mean that people who respond well to methylphenidate instead of amphetamine have high ALC levels, (since it works as a DNRI, and cocaine is a DNSRI) and would cocaine or methylphenidate predispose someone to Alzheimerz as well?? What would methylphenidate replicate more between cocaine and amphetamine? I think this thread should include all RX'D amphetamine-like substances (and cocaine) , unless the reason you haven't is because that they're too different, but they generally do a few of the same things.



My comment about ALC levels was mostly meant to be a joke, because of how common it is that people say X condition is due to deficiency of Y-ine, and how rare it is that it's anywhere close to that simple. If I understood Nagelfar correctly, he was saying that cocaine (so *possibly* methylphenidate by extension, because methylphenidate and cocaine work similarly) users have a lower risk of Alzheimer's. Note that this does not mean cocaine decreases the risk of Alzheimer's, because as I theorized, it's possible that cocaine users simply have some trait that would make them less vulnerable to Alzheimer's whether or not they did cocaine. Amphetamine and methylphenidate/cocaine actually work very differently, since amphetamine actually releases the neurotransmitter while MPH or cocaine only stop it from being stored (so obviously the answer to your question is that MPH is more like cocaine). As far as we have observed, methylphenidate and cocaine do not have neurotoxic effects, so there's really no reason to discuss their neurotoxicity. They may have adverse effects, some of which may be neurological, but that's not necessarily neurotoxicity, which includes actual damage to the neurons.

Also, more personally, I read your thread, and you're not going to get anywhere by worrying about what may have affected you in the past. Maybe MPH or seroquel or what-have-you affected your brain permanently to some significant degree (and it's entirely possible that they didn't). But, the human brain is very resilient (more resilient than rats' brains, from what I can tell). Even if you think that you've been impaired to some degree, you should remember that your brain is constantly working to repair and recover, so you should treat it well and start working toward the person you want to be, rather than dwelling on the past. I'd bet that things will get a lot better than you think they will.


----------



## atrollappears

Amu said:


> Eplison Alpha and atrollappears, what do you two think of of the possibility of an anti-oxidant stack turning pro-oxidant in presence of MDMA/METH? Also, are you aware daily anti-oxidants will likely DOWNREGULATE endogenous production of the brain's own anti-oxidants? This means if one day you skip those anti-oxidants and something in your brain causes damage that requires internal protection, _*we're fucked*_. Selegiline I believe up-regulates said production, one reason why it's so interesting.



Alpha lipoic acid is now believed to exert most of its antioxidant effects by activating the body's own antioxidant defense mechanisms, so that might avoid that issue of down-regulation. It doesn't seem to form large amounts of pro-oxidative metabolites, but supposedly it activates the body's antioxidative mechanisms through somehow being pro-oxidative (though I can't seem to get access to the article which supposedly says this), but if that's true, then even if it did go pro-oxidative then it wouldn't be a problem. There aren't any studies on ALA and amphetamine, but it does completely block long-term serotonin depletion due to MDMA.

Edit: On a side note, you have to munch a lot of antacids to take ALA with amphetamine (acidity inhibits absorption and such). Stuff's pretty damn hard on the stomach.


----------



## Nagelfar

atrollappears said:


> ...your brain is constantly working to repair and recover, so you should treat it well and start working toward the person you want to be, rather than dwelling on the past. I'd bet that things will get a lot better than you think they will.



Good advice atrollappears.

chaultistic, MPH, to my knowledge & like cocaine, shows neuroprotective traits & possibly mechanisms. Though it causes acute anhedonia after long bouts of use, recovery (years of abstinence) *may* put you in a better situation than you were before using for all that is known. Amphetamines however, seem to indicate the opposite and put one in a more thorough-goingly compromised condition and be less well neurologically tolerated after chronic use.


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## atrollappears

Nagelfar said:


> Amphetamines however, seem to indicate the opposite and put one in a more thorough-goingly compromised condition and be less well neurologically tolerated after chronic use.



Hahah, but don't we love 'em anyway...
And that's after chronic use, unless you use it in adolescence, in which case you were resistant to neurotoxic damage then (though not cortical impairment) and will continue to be resistant to it into adulthood, if rats are any indication. xD But in what sense do you mean a chronic user is more vulnerable? More vulnerable to psychosis, certainly, but I think tolerance/sensitization/whatever-the-hell-actually-happens-in-humans is protective against neurotoxicity, correct?


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## Nagelfar

atrollappears said:


> I think tolerance/sensitization/whatever-the-hell-actually-happens-in-humans is protective against neurotoxicity, correct?



Sensitization, I believe, is an exacerbation of neurotoxicity (in its own case) as per definition. At least if I recall correctly studies show as much.


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## atrollappears

Nagelfar said:


> Sensitization, I believe, is an exacerbation of neurotoxicity (in its own case) as per definition. At least if I recall correctly studies show as much.



At least as far as dopaminergic neurotoxicity goes, it looks like tolerance develops rather than sensitization. http://www.sciencedirect.com/science/article/pii/S0006899397005428


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## Epsilon Alpha

http://www.sciencedirect.com/science/article/pii/S0014299998008516 THC increases sensitization.
http://www.sciencedirect.com/science/article/pii/S0165017399000491 Evidence supporting a developmental theory of schizophrenia, and gating issues in the limbic system.
http://www.sciencedirect.com/science/article/pii/S003193840800379X Sensitization to amphetamines appears to require a certain biological basis, and rats resistant to sensitization actually show reduced movement relative to sensitized rats. Also, interestingly enough apparently ~40% of SD rats do not sensitize. High corticosterone and low 5HT in the mPFC appear to be involved in sensitization

http://www.springerlink.com/content/y13g4j7287330848/ And some sweet reading on mGlu5 vs DA mediated reward


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## Epsilon Alpha

atrollappears said:


> Epsilon Alpha, you may find this interesting:
> 
> http://onlinelibrary.wiley.com/doi/10.1196/annals.1403.019/full
> (if that link doesn't work for you, try this http://onlinelibrary.wiley.com/doi/10.1196/annals.1403.019/abstract)
> 
> Edit: Some research suggests that ALC should actually decrease the response to amphetamine (though paradoxically it increases it to cocaine) so I'm going to remove it from my stack tomorrow and see if I notice a difference. Hardly empirical, but oh well.
> Update: Skipped my ALC dose today, and I noticed an increase in the effects of the amph, both in terms of behavioral activation and inhibition. So, looks like ALC may block amphetamine, probably from its effects on cell membranes. I still recommend alpha lipoic acid though, if you have some tums xD
> 
> Edit 2: To those who use cocaine or MPH, you might find ALC of interest, because as I mentioned ALC increases the response to cocaine, but I neglected to mention the surprising magnitude of the difference: dopamine increase due to cocaine was *doubled* and serotonin increase was also increased by some similarly surprising factor I forget.



I find this *very* interesting, would you mind going into a bit more detail for those who simply browse this thread? I'm mulling over some reading trying to figure out whats going on on during my breaks for my term paper. You know you're a future Ph.D when your breaks are going from one pubmed topic to another...


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## Epsilon Alpha

*Arguments for various antioxidants*

*CoQ10 related compounds*​


> The antioxidant nature of CoQ10 derives from its energy carrier function. As an energy carrier, the CoQ10 molecule is continually going through an oxidation-reduction cycle. As it accepts electrons, it becomes reduced. As it gives up electrons, it becomes oxidized. In its reduced form, the CoQ10 molecule holds electrons rather loosely, so this CoQ molecule will quite easily give up one or both electrons and, thus, act as an antioxidant.[9] CoQ10 inhibits lipid peroxidation by preventing the production of lipid peroxyl radicals (LOO). Moreover, CoQH2 reduces the initial perferryl radical and singlet oxygen, with concomitant formation of ubisemiquinone and H2O2. This quenching of the initiating perferryl radicals, which prevent propagation of lipid peroxidation, protects not only lipids, but also proteins from oxidation. In addition, the reduced form of CoQ effectively regenerates vitamin E from the a-tocopheroxyl radical, thereby interfering with the propagation step. Furthermore, during oxidative stress, interaction of H2O2 with metal ions bound to DNA generates hydroxyl radicals and CoQ efficiently prevents the oxidation of bases, in particular, in mitochondrial DNA.[9] In contrast to other antioxidants, this compound inhibits both the initiation and the propagation of lipid and protein oxidation. It also regenerates other antioxidants such as vitamin E. The circulating CoQ10 in LDL prevents oxidation of LDL, which may provide benefit in cardiovascular diseases.



Pros: half life longer than that of amphetamine, known to cross the BBB, well studied at doses up to several grams a day, known side effect profile, reduction in expression of pro-inflammatory genes, documented reductions in systolic blood pressure, and has been shown in vivo to prevent the progress of Parkinson's disease.
Cons: Unknown if constant dosage will cause downregulation of endogenous antioxidant mechanisms, GI disturbances possible, possible absorption issues.
http://en.wikipedia.org/wiki/Ubiquinol
http://en.wikipedia.org/wiki/Coenzyme_Q10

*alpha lipoic acid *​Pros: iron chelator (would help prevent DA auto-oxidation), improvements in cardiovascular disease, upregulation of body's antioxidant defense mechanisms, possible protection against stim dick (no joke), easily, crosses BBB, and reduction of inflammation.
Cons: high doses may prevent benefits of CR diet on longevity, very short half life.
http://en.wikipedia.org/wiki/Lipoic_acid
http://msj.sagepub.com/content/16/4/387.full.pdf+html

Up next: PQQ


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## Amu

Epsilon Alpha, any similar info on ALCAR/NAC/Selenium/Melatonin? Especially whether they up-regulate or down-regulation endogenous mechanisms?


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## atrollappears

Epsilon Alpha said:


> I find this *very* interesting, would you mind going into a bit more detail for those who simply browse this thread? I'm mulling over some reading trying to figure out whats going on on during my breaks for my term paper. You know you're a future Ph.D when your breaks are going from one pubmed topic to another...



Going into detail about what exactly? The studies I read indicated that the researchers seemed to believe that ALC was inhibiting the action of amphetamines via its actions on cell membranes. As far as its diminishing effect on the amphetamine experience, I can elaborate on that as needed (it especially diminishes 4-FA I've found, such that while I am not on ALC I find 4-FA extremely enjoyable, and while I am on ALC I find 4-FA not worth taking).





Epsilon Alpha said:


> *alpha lipoic acid *​Pros: iron chelator (would help prevent DA auto-oxidation), improvements in cardiovascular disease, upregulation of body's antioxidant defense mechanisms, possible protection against stim dick (no joke), easily, crosses BBB, and reduction of inflammation.
> Cons: high doses may prevent benefits of CR diet on longevity, very short half life.
> http://en.wikipedia.org/wiki/Lipoic_acid
> http://msj.sagepub.com/content/16/4/387.full.pdf+html
> 
> Up next: PQQ



I believe that ALA's plasma concentration is not necessarily correlated with respect to time with its effectiveness. I've heard that the upregulation of endogenous antioxidant mechanisms lasts longer than ALA itself in the body, though I can't find evidence for that. Also, what's "CR diet"?


----------



## atrollappears

A note about curcumin which is a little concerning: It seems to activate enzymes involved in glutathione-mediated antioxidation. This is potentially counterproductive, as the agent currently thought to mediate MDMA-induced neurotoxicity is an oxidant MDMA metabolite bound to glutathione. If a similar mechanism is at work with (meth)amphetamine, to increase the activity of those enzymes could increase neurotoxicity.


----------



## Epsilon Alpha

atrollappears said:


> A note about curcumin which is a little concerning: It seems to activate enzymes involved in glutathione-mediated antioxidation. This is potentially counterproductive, as the agent currently thought to mediate MDMA-induced neurotoxicity is an oxidant MDMA metabolite bound to glutathione. If a similar mechanism is at work with (meth)amphetamine, to increase the activity of those enzymes could increase neurotoxicity.


 
Mind posting the study in question? I'm interested to see what enzymes are involved and what the extent of the effects are, curcumin in reasonable doses is in itself a potent antioxidant so depending on the situation may prevent some of the potential oxidative stress.

Also, I'll post more antioxidant info when I get some free time. Been crazy busy lately.


----------



## atrollappears

Epsilon Alpha said:


> Mind posting the study in question? I'm interested to see what enzymes are involved and what the extent of the effects are, curcumin in reasonable doses is in itself a potent antioxidant so depending on the situation may prevent some of the potential oxidative stress.
> 
> Also, I'll post more antioxidant info when I get some free time. Been crazy busy lately.



http://www.sciencedirect.com/science/article/pii/S1357272598000156
http://online.liebertpub.com/doi/abs/10.1089/ars.2005.7.32

I think that metabolite model of MDMA neurotoxicity theorizes that oxidative stress causes the damage indirectly by inducing glutathione activity. Certainly, something more than oxidative stress is needed to explain what's going on, since alpha-methyldopamine, itself an oxidant, can be injected directly into a rat brain in concentrations sufficient to release and deplete 75% of dopamine, but not cause any long-term depletion.
Still, it's entirely possible that glutathione or metabolites have nothing to do with DAergic toxicity.

Edit: Except apparently glutathione is still protective against MDMA neurotoxicity? http://www.sciencedirect.com/science/article/pii/S0028390802004112
I'm confused.


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## Epsilon Alpha

atrollappears said:


> http://www.sciencedirect.com/science/article/pii/S1357272598000156
> http://online.liebertpub.com/doi/abs/10.1089/ars.2005.7.32
> 
> I think that metabolite model of MDMA neurotoxicity theorizes that oxidative stress causes the damage indirectly by inducing glutathione activity. Certainly, something more than oxidative stress is needed to explain what's going on, since alpha-methyldopamine, itself an oxidant, can be injected directly into a rat brain in concentrations sufficient to release and deplete 75% of dopamine, but not cause any long-term depletion.
> Still, it's entirely possible that glutathione or metabolites have nothing to do with DAergic toxicity.
> 
> Edit: Except apparently glutathione is still protective against MDMA neurotoxicity? http://www.sciencedirect.com/science/article/pii/S0028390802004112
> I'm confused.



Well I did some reading and here's my take on this issue:
-Oxidative stress is one of or the primary mediators of cell damage in MDMA and (Meth)AMP
-Glutathione conjugation up to a point where the body can not remove the resulting conjugates from circulation is good, as it reduces oxidative stress.
-Excess glutatione conjugates act in a unique fashion to cause apoptosis, perhaps recognition by death receptors/ increased uptake/ novel binding affinities?
-While your study is on epithelial cells in the lung, there is the distinct possibility that this may happen in vivo but there is no way in hell I'm paying $59.00 to check the concentrations they used in that study.
-The rat liver study showed only a 1.4x increase in GST, granted its a very small measure of a complex system. My thoughts are that there is only mild effects at relevant human dosage.

But keep up the good work man, ain't no review but peer review =)

But as for a brief summery of what I saw for the antioxidant stuff:
-NAC is *really* bad long term
-PQQ is too novel to really give a solid review, but has the potential to be stunning so far.
-Selenium is actually required for proper antioxidant defenses, but for the love of god don't megadose it.
-Melatonin is safe up to a gram a day from a few studies I found, no real info on it downregulating anything at reasonable doses.


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## Amu

NAC is really bad long-term!? That comes as a shock, why is that so?


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## atrollappears

Epsilon Alpha said:


> Well I did some reading and here's my take on this issue:
> -Oxidative stress is one of or the primary mediators of cell damage in MDMA and (Meth)AMP
> -Glutathione conjugation up to a point where the body can not remove the resulting conjugates from circulation is good, as it reduces oxidative stress.
> -Excess glutatione conjugates act in a unique fashion to cause apoptosis, perhaps recognition by death receptors/ increased uptake/ novel binding affinities?
> -While your study is on epithelial cells in the lung, there is the distinct possibility that this may happen in vivo but there is no way in hell I'm paying $59.00 to check the concentrations they used in that study.
> -The rat liver study showed only a 1.4x increase in GST, granted its a very small measure of a complex system. My thoughts are that there is only mild effects at relevant human dosage.
> 
> But keep up the good work man, ain't no review but peer review =)



Thanks!
Yeah, ultimately I guess it's not a huge concern, it looks like enhancing glutathione-related processes is actually protective.

Those glutathionyl-alpha-methyldopamine compounds are confusing though. For example, they manage to mimic MDA pharmacologically, even though they have the entire glutathione peptide attached to them. No way that fits through the transporter. So obviously they are being changed into one or more compounds that aren't just alpha-methyldopamine (no SERT affinity, no neurotoxicity injected intracranially), which then account for the neurotransmitter release and probably toxicity.
It seems that this neurotoxicity pathway actually requires the pharmacological action of amphetamines to occur. After all, amphetamines are preferentially toxic to the neurotransmitter system they have a higher affinity for, and AFAIK none are at all toxic to a system they don't activate. Considering the emergent 5-HT toxicity with MDAI + amph, maybe the release leaves neurons vulnerable to toxic metabolites. And since meth causes neurotoxicity even when DA is depleted, it's probably something in the pathway of transporter phosphorylation which causes that, although here I'm assuming DA and 5-HT toxicity are the same.
So we have glutathione, oxidation, glutamate, and microglia. They're very related, and they seem to rely on the direct neurochemical effects of stimulants. Epsilon Alpha (or anyone else), do you have any guesses as to how stimulants might make cells more vulnerable? Or an alternative explanation?


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## Epsilon Alpha

Amu said:


> NAC is really bad long-term!? That comes as a shock, why is that so?



Well a large part of it is unrelated to its antioxidant action and is more a toxic metabolite issue. NAC is also ridiculous at sequestering NO which may cause future vascular issues at very high doses. So the take home message is don't eat spoonfuls of this stuff, and probably take occasional breaks from it as well.
http://en.wikipedia.org/wiki/Acetylcysteine#Adverse_effects

But, with antioxidants in general, its also an issue of the dose makes the poison. I can find tons of studies showing that reasonable (low) dosing patterns are protective, but also studies showing that higher doses prevent needed upregulation of antioxidant defense mechanisms.
http://www.sciencedirect.com/science/article/pii/S0167488900000367


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## Epsilon Alpha

http://www.mindandmuscle.net/forum/41838-amphetamine-sensitization-possible-implications-humans
Hey, started a bit of a side discussion on the sensitization bit over at M&M last week if you want to keep up with what I'm researching. But, this stuff has a lot to do with opioids as well...a

And Redman if you're reading this: Hello my friend!
And J. Foley if you're reading this: get off the drugs man holy fucking Christ.


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## atrollappears

Decreased dopamine, tyrosine hydroxylase, and DAT, but normal VMAT (!) and DOPA decarboxylase levels in human methamphetamine users.
http://www.nature.com/nm/journal/v2/n6/abs/nm0696-699.html

VMAT is decreased by meth administration in mouse/rat/primate. This is definitely a major difference that calls into question the validity of extrapolating from these models...

Epsilon Alpha, you mentioned in that thread that immune response is related to amph's effects on the brain. Isn't that a given, though, with amph's microglia activation?


----------



## Nagelfar

atrollappears said:


> Decreased dopamine, tyrosine hydroxylase, and DAT, but normal VMAT (!) and DOPA decarboxylase levels in human methamphetamine users.



I wonder what the decrease in DAT is for DRA (meth) users versus DRI (cocaine) users.


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## Epsilon Alpha

atrollappears said:


> Decreased dopamine, tyrosine hydroxylase, and DAT, but normal VMAT (!) and DOPA decarboxylase levels in human methamphetamine users.
> http://www.nature.com/nm/journal/v2/n6/abs/nm0696-699.html
> 
> VMAT is decreased by meth administration in mouse/rat/primate. This is definitely a major difference that calls into question the validity of extrapolating from these models...
> 
> Epsilon Alpha, you mentioned in that thread that immune response is related to amph's effects on the brain. Isn't that a given, though, with amph's microglia activation?



...the hell?
http://www.springerlink.com/content/p6753g35n6521230/
http://www.ncbi.nlm.nih.gov/pubmed/18815269
http://www.jneurosci.org/content/22/20/8951.abstract
http://neuro.cjb.net/content/28/39/9850.short

Looks like VMAT2 is initially downregulated (bad) then upregulated (good) in humans. But this study (comparing VMAT2 in amphetamine vs cocaine in rats) suggests that the localization of vesicles may change with acute or subacute usage. http://www.sciencedirect.com/science/article/pii/S0014299902019854
Well we'll get a better idea when this study comes out http://search.engrant.com/project/y...of_brain_vmat2_in_human_methamphetamine_users

I could be wrong here, but maybe VMAT2 is only implicated in toxicity because of a secondary effect on vesicle transport within the cell. That would explain some of the weirder results, but I'm not 100% on it. Methamphetamine appears to keep vesicles away from the synapse, while cocaine appears to lead to more vesicles being close to the synapse. Not sure if MPH could have the same effect as cocaine, but if so it might be a good idea to cycle AMP and MPH at least on paper...

However there are also a giant stew of other proteins and signals involved in long term amphetamine use. One thing I'm still trying to figure out is how amphetamine but not MCAT activates glial cells, hopefully someone with more expertise in the field of immunology can help me out here.


----------



## atrollappears

Epsilon Alpha said:


> However there are also a giant stew of other proteins and signals involved in long term amphetamine use. One thing I'm still trying to figure out is how amphetamine but not MCAT activates glial cells, hopefully someone with more expertise in the field of immunology can help me out here.



Activation of glial cells is a specific marker for neurotoxicity, right? If so, then I'd look toward the metabolites. There's a very specific SAR for what does and does not cause neurotoxicity: amphetamines (not cathinones), but only amphetamines which can be para-hydroxylated (if I may extrapolate from 4-FA and conflate 5-HT and DA toxicity).



Epsilon Alpha said:


> I could be wrong here, but maybe VMAT2 is only implicated in toxicity because of a secondary effect on vesicle transport within the cell. That would explain some of the weirder results, but I'm not 100% on it. Methamphetamine appears to keep vesicles away from the synapse, while cocaine appears to lead to more vesicles being close to the synapse. Not sure if MPH could have the same effect as cocaine, but if so it might be a good idea to cycle AMP and MPH at least on paper...



This is very interesting... that sort of opposite behavior suggests to me involvement of DAT (downregulated by amph but upregulated by cocaine), which would make a lot of sense. (Maybe an attempt by the cell to maintain normal intracellular (non-vesicular) DA levels?) What are your thoughts on how this could affect toxicity?


----------



## Amu

Are there any agents that specifically prevent *excito*toxicity besides memantine?


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## atrollappears

Amu said:


> Are there any agents that specifically prevent *excito*toxicity besides memantine?



You mean anything besides DXM or other voltage independent NMDA antagonists?
How about taurine? http://www.fasebj.org/content/18/3/511.full


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## Amu

Memantine at some unknown low-dose only blocks extra-synaptic NMDA receptors which are involved in neurotoxicity, leaving post-synaptic ones alone, the question is at what dosage does this occur in humans? I'm guessing around 20 mg, any estimates? Also, it is annoying how it blocks nicotine/acetylcholine's action on alpha-7 receptors otherwise it would be a great drug


----------



## Epsilon Alpha

Hey, been really busy with midterms lately.

From what I've seen in a few papers I'm mulling over is that stress breeds the kind of conditions for amphetamine neurotoxicity or negative aspects of sensitization to take place. There is also a lot more evidence piling for amphetamine sensitization sharing a similar foundation as schizophrenia or bipolar disorder.
http://www.ncbi.nlm.nih.gov/pubmed/18757738


----------



## chaultistic

atrollappears said:


> Activation of glial cells is a specific marker for neurotoxicity, right? If so, then I'd look toward the metabolites. There's a very specific SAR for what does and does not cause neurotoxicity: amphetamines (not cathinones), but only amphetamines which can be para-hydroxylated (if I may extrapolate from 4-FA and conflate 5-HT and DA toxicity).
> 
> 
> 
> This is very interesting... that sort of opposite behavior suggests to me involvement of DAT (downregulated by amph but upregulated by cocaine), which would make a lot of sense. (Maybe an attempt by the cell to maintain normal intracellular (non-vesicular) DA levels?) What are your thoughts on how this could affect toxicity?



Is that necessarily a good thing to switch back and forth? Wouldn't you want upregulation instead of downregulation? Or are you trying to say if you're on AMPH and you get a tolerance, that going on cocaine/MPH will make the AMPH work better? Would this cause more or less damage to be switching, or is that something difficult to answer, even on paper?


----------



## atrollappears

chaultistic said:


> Or are you trying to say if you're on AMPH and you get a tolerance, that going on cocaine/MPH will make the AMPH work better? Would this cause more or less damage to be switching, or is that something difficult to answer, even on paper?



Yes I think that's what he's saying. As far as amph 'neurotoxicity' goes, I don't know how this would affect it. However, if redistribution of VMAT were permanent and somehow negative (maybe increased parkinson's risk or something) then it could be considered a type of damage. So, if it is indeed a bad thing, which it very well may be, then this would be a way of causing less damage.

In general though, I'd caution against using oneself as a guinea pig to test things which are thus far only theories. Honestly, if you were to use non-meth amphetamine regularly and not become heavily dependent on it, without any supplements or whatever, it doesn't seem like it would really be _that_ bad for you. Even if it does do a few mild negative things, I'd take that over potentially creating some terrible emergent side-effect which left me a retarded akinetic zombie.


----------



## atrollappears

Amu said:


> Memantine at some unknown low-dose only blocks extra-synaptic NMDA receptors which are involved in neurotoxicity, leaving post-synaptic ones alone, the question is at what dosage does this occur in humans? I'm guessing around 20 mg, any estimates? Also, it is annoying how it blocks nicotine/acetylcholine's action on alpha-7 receptors otherwise it would be a great drug



Maybe huperzine, since its known to block excitotoxicity while being nootropic/not causing dissociation. Might not be a pharmacological specificity at NMDAR though so much as acetylcholinesterase inhibition.


----------



## chaultistic

I'm a little confused, I wasn't talking about methamphetamine. I was talking about regular amphetamine mix switched back and forth between cocaine/mph. Does levo/dextroamphetamine itself cause redistribution of VMAT?

*edit* I'm not very savvy about all this stuff, so bear with me on my questions.


----------



## atrollappears

chaultistic said:


> I'm a little confused, I wasn't talking about methamphetamine. I was talking about regular amphetamine mix switched back and forth between cocaine/mph. Does levo/dextroamphetamine itself cause redistribution of VMAT?
> 
> *edit* I'm not very savvy about all this stuff, so bear with me on my questions.



No problem. Yes, levo/dextroamphetamine should in theory also cause redistribution of VMAT. Amphetamine and methamphetamine act virtually the same in the brain, besides slightly different affinities for the different transporters and the latter being more neurotoxic; so, the study that epsilon alpha cited _should_ apply to amphetamine as well.
If it was my comment about being a guinea pig that confused you, all I was saying was 'better the devil you know' and such 


By the way, anyone have an idea of what effect phosphatidylserine might have on amph neurotoxicity? It seems to be protective against NDMA-excitotoxicity related pathways such as ischemic cell death, but on the other hand D-serine itself potentiates excitotoxicity so I'm hesitant to add phosphatidylserine to my stack.
Edit: Nevermind, the supplement version is phosphatidyl-L-serine


----------



## Renz Envy

Are there any ways to decrease NE augmentation and increase the serotonin and dopamine release with basic amphetamine?


----------



## chaultistic

Renz Envy said:


> Are there any ways to decrease NE augmentation and increase the serotonin and dopamine release with basic amphetamine?



Wouldn't Dextroamphetamine be the key here? I think I've read somewhere that is has very little effect on NE, and much greater effect on DA, not sure about SERT, but possibly.


----------



## Nagelfar

chaultistic said:


> Wouldn't Dextroamphetamine be the key here? I think I've read somewhere that is has very little effect on NE, and much greater effect on DA, not sure about SERT, but possibly.



'Basic amphetamine' (though a loose term) is what is meant by dextroamphetamine, since it has to be an isomer and 'dextro-' is the active one.


----------



## Renz Envy

chaultistic said:


> Wouldn't Dextroamphetamine be the key here? I think I've read somewhere that is has very little effect on NE, and much greater effect on DA, not sure about SERT, but possibly.



I do mean dextro amphetamine.
D-amp does have quite the potency on NE compared to its meth brother.


----------



## MaxTTR

I agree that antioxidants very beneficial

alfa lipioc acid and L-glutamin would be two most effective in my books.

also neurotoxicity of amphetamine may need some revision. result of neurotoxicity is always a loos of some particular type of neuronal cells, if something toxic to cells then cells are gone.

Like in case with MDMA it is believed that serotonegic neurons are lost. I would like to see similar information regarding amphetamine.

In one case described in New Concepts of Psychostimulants Induced Neurotoxicity 2009 four chronic amph users brains been examined on postmortem - no any degeneration been reported. 

I think that kind of hard evidence may be crucial in establishing of concept of neurotoxicity, similar evidence been demonstrated in many cases of neurodegenerative diseases, but not in case of amphetamin as far as I know.


----------



## Epsilon Alpha

MaxTTR said:


> I agree that antioxidants very beneficial
> 
> alfa lipioc acid and L-glutamin would be two most effective in my books.
> 
> also neurotoxicity of amphetamine may need some revision. result of neurotoxicity is always a loos of some particular type of neuronal cells, if something toxic to cells then cells are gone.
> 
> Like in case with MDMA it is believed that serotonegic neurons are lost. I would like to see similar information regarding amphetamine.
> 
> In one case described in New Concepts of Psychostimulants Induced Neurotoxicity 2009 four chronic amph users brains been examined on postmortem - no any degeneration been reported.
> 
> I think that kind of hard evidence may be crucial in establishing of concept of neurotoxicity, similar evidence been demonstrated in many cases of neurodegenerative diseases, but not in case of amphetamin as far as I know.



From what I've seen so far, gross cell death isn't often seen but diffuse damage and inflammation is. Not to mention potential "wiring" problems.
Still climbing midterm mountain...


----------



## atrollappears

Epsilon Alpha said:


> From what I've seen so far, gross cell death isn't often seen but diffuse damage and inflammation is. Not to mention potential "wiring" problems.
> Still climbing midterm mountain...



IIRC in the case of MDMA the loss of 5-HT cell bodies is not observed, but rather axons are destroyed, while in the case of (meth)amp the entire DA neuron is lost. I'm not 100% on this though.

MaxTTR, that's very interesting, and if you could provide a link to that source I'd be grateful. That seems to further evince what appears to be the case with most (human, non-meth) amph users: that no significant damage occurs. One study I saw found that high-dependence amphetamine users were cognitively impaired, while low-dependence users were indistinguishable from controls besides that they scored _higher_ in verbal memory. The study was very well controlled and such. And as far as the high dependence users go, it's hard to say whether the impairment they showed was the result of neurotoxicity or simply downregulation.


----------



## bremes

What about monoamine transporter activators?
Apigenin, Luteolin and IMO few other flavonoids seems to be MaT activators.


> Functional activation of monoamine transporters by luteolin and apigenin isolated from the fruit of Perilla frutescens (L.) Britt.
> Zhao G, Qin GW, Wang J, Chu WJ, Guo LH.
> Source
> 
> Cell Star Bio-Technologies Co., Limited, Shanghai, PR China.
> Abstract
> 
> Monoamine transporters playing major roles in regulating normal and abnormal synaptic activity are associated with various neuropsychological disorders. In spite of the discovery of a series of structurally different monoamine transporter antagonists for the therapy approach, no practical pharmaceutical can act as a transporter activator. Here, we isolated luteolin and apigenin from the fruit of Perilla frutescens (L.) Britt by using an activity-guided extraction technique, and proved that the two compounds possess actions of enhancing monoamine uptake either upon monoamine-transporter transgenic Chinese hamster ovary (CHO) cells or upon wild dopaminergic cell lines, with higher specificity for dopamine (DA) uptake than for norepinephrine (NE)- and serotonin (5HT)-uptake, as well as with more potency and greater efficacy for luteolin than for apigenin. Further, in the transgenic cells, the principal NE/DA uptake activation by luteolin was significantly prevented by respective transporter inhibitor, and the transmitter-uptake-enhancing action was independent of its ligands, which is in support of the compounds as monoamine transporter activators. Furthermore, luteolin evoked a marked disinhibition of cocaine-targeted effect in CHO cells overexpressing dopamine transporter. Thus, luteolin and apigenin function as monoamine transporter activators, which would improve several hypermonoaminergic neuropsychological disorders, especially cocaine dependence, through up-regulating monoamine transporter activity.


http://www.ncbi.nlm.nih.gov/pubmed/19815045



> Bioorg Med Chem. 2010 Nov 15;18(22):7842-8. Epub 2010 Sep 25.
> Discovery and synthesis of novel luteolin derivatives as DAT agonists.
> Zhang J, Liu X, Lei X, Wang L, Guo L, Zhao G, Lin G.
> Source
> 
> Department of Medicinal Chemistry, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China. jgzhang5500@hotmail.com
> Abstract
> 
> Luteolin, 5,7-dihydroxy-2-(3,4-dihydroxyphenyl)-4H-chromen-4-one, has been proposed and proved to be a novel dopamine transporter (DAT) activator. In order to develop this potential of luteolin, a series of novel luteolin derivatives were designed, synthesized, and evaluated for their DAT agonistic activities, utilizing constructed Chinese hamster ovary (CHO) cell lines stably expressing rat DAT. Biological screening results demonstrated that luteolin derivatives 1d, 1e, and 4c carry great DAT agonistic potency (EC(50)=0.046, 0.869, and 1.375μM, respectively) compared with luteolin 8 (EC(50)=1.45±0.29μM). Luteolin derivative 1d, notably, exhibited a 32-fold-higher DAT agonistic potency than luteolin. These luteolin derivatives represent a novel DAT agonist class, from which lead compounds useful for exploration of additional novel DAT agonists could be drawn.



http://www.ncbi.nlm.nih.gov/pubmed/20971650

Meal rich in parsleys, broccoli, apples, oranges and many other vegetables and fruits was able to shutdown compltetly high doses of 2-DPMP, Ethylphenidate or 6-APB. 

I thinking about taking NDRI(methylphenidate or ethylphenidate) during the day and eating really alot fruits in the evening. How it would affect neurotoxicity?


----------



## atrollappears

bremes said:


> I thinking about taking NDRI(methylphenidate or ethylphenidate) during the day and eating really alot fruits in the evening. How it would affect neurotoxicity?



It wouldn't, with NDRI's there is no neurotoxicity to affect. They actually block amphetamine neurotoxicity. I think some studies suggest MPH/cocaine promote apoptosis, but I don't think it occurs in relevant doses.


----------



## bremes

Then why people are using amph instead of NDRI's? You think even heavy use of NDRI shouldn't lead to any toxicity?

How would this MaT agonists affect amphetamine neurotoxicity?


----------



## chaultistic

atrollappears said:


> It wouldn't, with NDRI's there is no neurotoxicity to affect. They actually block amphetamine neurotoxicity. I think some studies suggest MPH/cocaine promote apoptosis, but I don't think it occurs in relevant doses.



Would you say the apoptosis from cocaine/mph is worst than the neurotoxicity of amph? What doses would you say of MPH or AMPH would cause a low to high amount of toxicity, or apoptosis, would AMPH also cause apoptosis?


----------



## Nagelfar

chaultistic said:


> Would you say the apoptosis from cocaine/mph is worst than the neurotoxicity of amph? What doses would you say of MPH or AMPH would cause a low to high amount of toxicity, or apoptosis, would AMPH also cause apoptosis?



Cocaine & MPH are NDRIs, what atrollappears was saying is that they, unlike DRAs & amphetamines, are not known to be neurotoxic. In-fact I have read evidence of them being quite neuroprotective.

...

It is interesting that VMAT is normal in methamphetamine users. I wonder what a compound that is selective for release at VMAT but acts as a DRI at MAT would do, if possible.


----------



## MaxTTR

*New.Concepts.of.Psychostimulants.Induced.Neurotoxi city.2009*



atrollappears said:


> IIRC in the case of MDMA the loss of 5-HT cell bodies is not observed, but rather axons are destroyed, while in the case of (meth)amp the entire DA neuron is lost. I'm not 100% on this though.
> 
> MaxTTR, that's very interesting, and if you could provide a link to that source I'd be grateful. That seems to further evince what appears to be the case with most (human, non-meth) amph users: that no significant damage occurs. One study I saw found that high-dependence amphetamine users were cognitively impaired, while low-dependence users were indistinguishable from controls besides that they scored _higher_ in verbal memory. The study was very well controlled and such. And as far as the high dependence users go, it's hard to say whether the impairment they showed was the result of neurotoxicity or simply downregulation.


 
here it is, this review is a real milestone in this direction.

http://www.datafilehost.com/download-023bc943.html

more correct would be to call it as alteration of brain function.


----------



## bremes

> Cocaine & MPH are NDRIs, what atrollappears was saying is that they, unlike DRAs & amphetamines, are not known to be neurotoxic. In-fact I have read evidence of them being quite neuroprotective.



Do you have any paper about it?


----------



## atrollappears

bremes said:


> Do you have any paper about it?



They're neuroprotective in that they block AMPH or MPTP neurotoxicity. I don't know how useful that is for people or rats who are not being exposed to MPTP or large doses of AMPH. This is pretty much common knowledge; it's the same principle that makes SSRIs protective against MDMA neurotoxicity.


----------



## Nagelfar

atrollappears said:


> They're neuroprotective in that they block AMPH or MPTP neurotoxicity. I don't know how useful that is for people or rats who are not being exposed to MPTP or large doses of AMPH. This is pretty much common knowledge; it's the same principle that makes SSRIs protective against MDMA neurotoxicity.



I think I've read that chronic lifetime cocaine users also have lower overall instances of alzheimer's, etc.


----------



## atrollappears

Nagelfar said:


> I think I've read that chronic lifetime cocaine users also have lower overall instances of alzheimer's, etc.



Hmm so then NDRIs may have some general neuroprotective effects, but that doesn't prove a cause-effect relationship with NDRI action or even cocaine.


----------



## Epsilon Alpha

Wish I could contribute at this time but you guy's are doing great!


----------



## atrollappears

Phosphatidylserine acts directly on microglia to decrease the release of pro-inflammatory molecules. Because exactly that is believed to be a necessary step in the pathway of amphetamine neurotoxicity, phosphatidylserine supplementation could be extremely useful, and in any case I don't see it hurting.

http://journals.lww.com/jneuropath/...ion_of_Phosphatidylserine_Receptor_and.6.aspx


----------



## atrollappears

I've been thinking about the potential mechanisms behind amph DA neurotoxicity, and I've come up with a very speculative theory on the pathway. I haven't abandoned my hunch that the metabolism of the drug itself plays a role, so I began with that. So, (meth)amph is oxidized by MAO into something which is then necessary for damage to occur (since MAOIs are protective). Well, this metabolite is oxidated so it's probably an oxidant, especially when concentrated in nerve terminals, so glutathione possibly reacts to reduce this molecule. However, if the concentration of this metabolite is high enough to oxidize a significant portion of the glutathione, perhaps this disrupts glutathione's important natural reduction of nitric oxide (with reduced glutathione conc. NO becomes toxic at usually trophic levels). (Edit: Methamp-induced neurotoxicity seems to accelerate the oxidation of NADPH [probably because of oxidative conditions], which is required in reduced form to reclaim oxidized glutathione, likely further depleting glutathione's antioxidant efficacy.) Meanwhile, calcium influx from neuronal excitation induces the synthesis of NO. The resulting excess of NO could then activate microglia (with resulting oxidant/excitotoxin release aggravating the effect) and thereby cause cell damage, whether through apoptosis, necrosis, or whatever.

This accounts for several features of (meth)amp toxicity:
-Protection by MAOIs
-Partial protection by NMDA antagonists/induction of nitric oxide synthase
-Partial protection by antioxidants, since the oxidation would occur in a concentrated fashion in the nerve terminal, while with MDMA, whose toxicity is completely blocked by antioxidants, oxidative metabolites must diffuse through the periphery
-Specific neurotoxicity of non-keto amphetamines, due to specific metabolic pathways
-Reduction in glutathione observed in some studies, using sufficient dosages. Other studies find increases, but note that the depletion of glutathione need only occur in the nerve terminal, not everywhere, so to find a general increase in GSH doesn't mean it isn't being depleted where it counts.

Critiques?


----------



## m060mm

I'm a little over my head so bear with me: 

My understanding is that DXM prevents the glutamatergic influx of calcium ions via voltage-gated agonist ligands. It does this by antagonizing the NMDAR.

Magnesium will have similar results, but will only prevent excess (abnormal, due to amphetamines) influx; it will not prevent the typical influx generated from an action potential. If this is correct, how does this work - the magnesium is blocking the calcium channel? So the NMDAR is agonized, it just has no effect of calcium gradients?

Assuming this (please correct me as necessary), what are the practical implications of this distinction?


----------



## atrollappears

m060mm said:


> I'm a little over my head so bear with me:
> 
> My understanding is that DXM prevents the glutamatergic influx of calcium ions via voltage-gated agonist ligands. It does this by antagonizing the NMDAR.
> 
> Magnesium will have similar results, but will only prevent excess (abnormal, due to amphetamines) influx; it will not prevent the typical influx generated from an action potential. If this is correct, how does this work - the magnesium is blocking the calcium channel? So the NMDAR is agonized, it just has no effect of calcium gradients?
> 
> Assuming this (please correct me as necessary), what are the practical implications of this distinction?



DXM blocks the NMDAR in a voltage _independent_ fashion. Magnesium blocks the NMDAR in a voltage dependent fashion.
The implication of this is that when magnesium is present, normal cell signaling is preserved, whereas with DXM obviously it is not. So, magnesium will prevent excess Ca++ influx while preserving cognition, whereas DXM will not preserve cognition but block Ca++ influx more effectively.


----------



## m060mm

atrollappears said:


> DXM blocks the NMDAR in a voltage _independent_ fashion. Magnesium blocks the NMDAR in a voltage dependent fashion.
> The implication of this is that when magnesium is present, normal cell signaling is preserved, whereas with DXM obviously it is not. So, magnesium will prevent excess Ca++ influx while preserving cognition, whereas DXM will not preserve cognition but block Ca++ influx more effectively.


 
Boom. Everything I needed. You're truly lovely. And I like your hair.


----------



## eeklekins

atrollappears said:


> Phosphatidylserine acts directly on microglia to decrease the release of pro-inflammatory molecules. Because exactly that is believed to be a necessary step in the pathway of amphetamine neurotoxicity, phosphatidylserine supplementation could be extremely useful, and in any case I don't see it hurting.
> 
> http://journals.lww.com/jneuropath/...ion_of_Phosphatidylserine_Receptor_and.6.aspx



You'd be better off just taking fish oil. All the phosphatidylserine we need is readily synthesized in the body, and there's no real evidence showing a benefit from supplementation except for a few flawed studies by a sports supplement company.


----------



## bremes

What about 5-ht3 antagonists? I've heard they are neuroprotective. Ginger is wide available and is quite potent 5-ht3 antagonist.


----------



## Epsilon Alpha

bremes said:


> What about 5-ht3 antagonists? I've heard they are neuroprotective. Ginger is wide available and is quite potent 5-ht3 antagonist.


5HT3 antagonists are a promising method of breaking sensitization, however its exact role hasn't been figured out. Mind posting some studies on the ginger 5HT3 antagonist bit though


----------



## atrollappears

Epsilon Alpha said:


> 5HT3 antagonists are a promising method of breaking sensitization, however its exact role hasn't been figured out. Mind posting some studies on the ginger 5HT3 antagonist bit though



What exactly is the problem with sensitization anyway? And why do researchers think its a useful model for schizophrenia/bipolar/addiction/basically everything they're trying to figure out? On paper, in humans, it looks pretty good to me. I wish I sensitized, I don't think I do :/


----------



## atrollappears

eeklekins said:


> You'd be better off just taking fish oil. All the phosphatidylserine we need is readily synthesized in the body, and there's no real evidence showing a benefit from supplementation except for a few flawed studies by a sports supplement company.



I agree that fish oil is good, and I take it myself. However, for the same reason that the SSRIs superseded tryciclics I prefer to use the most pharmacologically specific agent to be sure that I am fully accomplishing what I want, and also not inadvertently causing some other potentially counterproductive effect. (Maybe SSRIs are a bad example... Imagine effective SSRIs xD)
Also, the literature does support phosphatidylserine.
For ADHD: http://www.whathealth.com/phosphatidylserine/references.html
For stress and mood: http://www.ncbi.nlm.nih.gov/pubmed/11842886
That it's more effective than fish oil: http://www.ajcn.org/content/87/5/1170.abstract


----------



## Epsilon Alpha

Well in ADHD individuals without a predisposition to addiction/depression/mania/OCD/psychosis its probably involved in the increased focus even after medication is withdrawn following long term treatment. But, in some individuals it may be involved in negative psychological changes and tics.

I'm mainly interested in it as a mechanism behind that "first time use" feeling most users report. Also, its just interesting as sin :D


----------



## atrollappears

From what I've read, people with ADHD who were medicated with ritalin in childhood, matched with people with ADHD who were not medicated, are virtually indistinguishable as adults besides having had a better experience in school while on the medication and having slightly higher self-esteem. So I'm doubtful about direct long-term benefit, if ritalin sensitization is analogous to amphetamine's.

I bet the first time thing has to do with that VMAT redistribution you mentioned 
Edit: What do you mean by sensitization playing a role in that first time feeling? Are you suggesting that the development of sensitization blocks that feeling? That seems kind of counterintuitive considering sensitization increases feelings of "vigor" and "euphoria." Do you think, then, that the feeling is a function of drug reward, which does decrease even as sensitization develops? (Although I'd more readily ascribe that to classic tolerance.)

Also, are there any agents which increase the development of sensitization?


----------



## Clickety

*NSAIDS as neuroprotective agents*

Inflammation is thought to play a role in amphetamine toxicity as well.

What about NSAIDS such as ibuprofen taken before/during/after stimulant use to reduce or attenuate any neurotoxicity mediated by inflammation?

REF: http://www.ncbi.nlm.nih.gov/pubmed/18946735


----------



## atrollappears

Clickety said:


> Inflammation is thought to play a role in amphetamine toxicity as well.
> 
> What about NSAIDS such as ibuprofen taken before/during/after stimulant use to reduce or attenuate any neurotoxicity mediated by inflammation?
> 
> REF: http://www.ncbi.nlm.nih.gov/pubmed/18946735



Yup. We've talked about using aspirin in this thread before, but this study finds it ineffective so perhaps we should switch over to ibuprofen 

Speaking of which, apparent anti-inflammatory effects of phosphatidylserine in vivo: http://ebm.rsmjournals.com/content/200/4/548.abstract


----------



## Epsilon Alpha

Clickety said:


> Inflammation is thought to play a role in amphetamine toxicity as well.
> 
> What about NSAIDS such as ibuprofen taken before/during/after stimulant use to reduce or attenuate any neurotoxicity mediated by inflammation?
> 
> REF: http://www.ncbi.nlm.nih.gov/pubmed/18946735



I don't think you realize how mind blowing that study is to me!



> , these results imply that the protective effects of ibuprofen against METH-induced neurotoxicity may be based, in part, on its anti-inflammatory PPAR gamma agonistic properties, but not on its COX-inhibiting property or hypothermic effect.


I've been thinking that COX inhibition was one of the major pathways these drugs worked through, but I guess now its more of an artifact caused by the fact that most of the compounds I'm looking at inhibit it anyways. COX has previously been identified as a target for preventing DA cell damage in several studies, but I'll have to mull over more data to figure out exactly what is significant in preventing neurotoxic effects.

The author of that paper also has some earlier work on ketoprofen and it shows much the same promise.
http://www.ncbi.nlm.nih.gov/pubmed/14615038


----------



## raybeez

atrollappears said:


> From what I've read, people with ADHD who were medicated with ritalin in childhood, matched with people with ADHD who were not medicated, are virtually indistinguishable as adults besides having had a better experience in school while on the medication and having slightly higher self-esteem. So I'm doubtful about direct long-term benefit, if ritalin sensitization is analogous to amphetamine's.


 
I'm going to assume that when you say "virtually indistinguishable", you're talking about behavioral metrics. The reason for this finding is because ADHD persistence into adulthood is very low - only 40% of children with ADHD continue to have symptoms, and only 0.9% of children meet the full diagnostic criteria as adults [1]. 

Interestingly this decline in ADHD rates is only seen on behavioral studies - these former children with ADHD still have abnormal brain scans [2]. Afiak there haven't been studies looking at the effect of ritalin use as a child on brain scans in adults, which would be the type of study needed to properly back up that claim you cite.


----------



## atrollappears

raybeez said:


> Interestingly this decline in ADHD rates is only seen on behavioral studies - these former children with ADHD still have abnormal brain scans [2]. Afiak there haven't been studies looking at the effect of ritalin use as a child on brain scans in adults, which would be the type of study needed to properly back up that claim you cite.



As far as I'm concerned, how the brain looks on a brain scan only matters insofar as it affects the physical or psychological well-being of the person.

Also, I don't know if I've mentioned this before, it's probably a good idea to avoid too much caffeine while using amphetamine (especially if using it recreationally). Here's a source, and I'd love if someone could get me full access: http://jpet.aspetjournals.org/content/271/3/1320.short

Edit: Almost forgot to mention, the flipside of this is that regular caffeine use is protective against amphetamine neurotoxicity because of tolerance mechanisms, as long as you have allowed time for the caffeine to leave your body before taking an amphetamine.


----------



## atrollappears

Evidence that you should eat healthy, trans fat increases neurotoxicity and fish oil (unsaturated) decreases it:
http://www.sciencedirect.com/science/article/pii/S0091305710003424

Fish oil itself is a concern if oxidized, but it looks like the gelcaps are OK:
http://www.ncbi.nlm.nih.gov/pubmed/22101881

The unknown level of oxidation in available fish oil products is a concern, but regularly buying small quantities in gelcaps from a reputable manufacturer would ensure maximum freshness.


----------



## bremes

D2 agonists seems to be neuroprotective.


> Biochem J. 2003 Jul 1;373(Pt 1):25-32.
> Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines.
> Nair VD, Olanow CW, Sealfon SC.
> Source
> 
> Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
> Abstract
> 
> Whereas dopamine agonists are known to provide symptomatic benefits for Parkinson's disease, recent clinical trials suggest that they might also be neuroprotective. Laboratory studies demonstrate that dopamine agonists can provide neuroprotective effects in a number of model systems, but the role of receptor-mediated signalling in these effects is controversial. We find that dopamine agonists have robust, concentration-dependent anti-apoptotic activity in PC12 cells that stably express human D(2L) receptors from cell death due to H(2)O(2) or trophic withdrawal and that the protective effects are abolished in the presence of D(2)-receptor antagonists. D(2) agonists are also neuroprotective in the nigral dopamine cell line SN4741, which express endogenous D(2) receptors, whereas no anti-apoptotic activity is observed in native PC12 cells, which do not express detectable D(2) receptors. Notably, the agonists studied differ in their relative efficacy to mediate anti-apoptotic effects and in their capacity to stimulate [(35)S]guanosine 5'-[gamma-thio]triphosphate ([(35)S]GTP) binding, an indicator of G-protein activation. Studies with inhibitors of phosphoinositide 3-kinase (PI 3-kinase), extracellular-signal-regulated kinase or p38 mitogen-activated protein kinase indicate that the PI 3-kinase pathway is required for D(2) receptor-mediated cell survival. These studies indicate that certain dopamine agonists can complex with D(2) receptors to preferentially transactivate neuroprotective signalling pathways and to mediate increased cell survival.




Memantine, Ketamine and probably Methoxetamine are D2 agonists.


----------



## Epsilon Alpha

Atrollappears, mind summing up that childhood stimulant treatment paper you got yesterday? I'm interested in the findings


----------



## atrollappears

Epsilon Alpha said:


> Atrollappears, mind summing up that childhood stimulant treatment paper you got yesterday? I'm interested in the findings



The stimulant treated kids were basically the same as untreated kids, but were more emotionally healthy, had better self-esteem, and a better view of their childhoods.
I saw no evidence of increased depressed/anxious behavior like that seen with rats treated with MPH in childhood; if anything, it was the opposite.

Edit: Forgot to mention, the stimulant treatment was exclusively MPH, so I guess the study is relevant to amphetamine only insofar as you're looking at long-term effects that are exclusively the consequence of elevated DA/NE.


----------



## Epsilon Alpha

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2009.05911.x/full Glutamate receptors do not change in rat NAcc during sensitzation
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202508/ Role of changes in glutamate systems in stimulant treatment (good old review)


----------



## atrollappears

Epsilon Alpha, or anyone else who can provide an answer, how much do we know about the mechanism behind amphetamine (DA) toxicity? Also, what is the speculated role of nitric oxide, and how might amphetamines generate it? I ask because nitric oxide synthase knockout is the only thing I've seen that can actually completely block neurotoxicity (besides blocking the DAT), so it seems pertinent.


----------



## processofmind

Epsilon Alpha said:


> I don't think you realize how mind blowing that study is to me!
> 
> 
> I've been thinking that COX inhibition was one of the major pathways these drugs worked through, but I guess now its more of an artifact caused by the fact that most of the compounds I'm looking at inhibit it anyways. COX has previously been identified as a target for preventing DA cell damage in several studies, but I'll have to mull over more data to figure out exactly what is significant in preventing neurotoxic effects.
> 
> The author of that paper also has some earlier work on ketoprofen and it shows much the same promise.
> http://www.ncbi.nlm.nih.gov/pubmed/14615038



i also find this very interesting as well the study Epsilon Alpha posted on stimulant induced glutamate changes and plasticity. curcumin seems to hit many angles on this, iNOS inhibition, cox inhibition, NMDA antagonist.


----------



## atrollappears

processofmind said:


> i also find this very interesting as well the study Epsilon Alpha posted on stimulant induced glutamate changes and plasticity. curcumin seems to hit many angles on this, iNOS inhibition, cox inhibition, NMDA antagonist.



Except COX inhibition apparently isn't helpful, and iNOS inhibition might block the effects of amphetamine.


----------



## kfluxsake

I'd like to thank the contributors to this thread for doing such a wonderful job. As a smoker, I'd also like to add this study.

*Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin*

Karine Paraina, 1,
Céline Hapdeya, 1,
Estelle Rousseleta,
Véronique Marchandb,
Bernard Dumeryb,
Etienne C Hirscha,

Abstract

Epidemiological studies have found a negative association between cigarette smoking and Parkinson’s disease (PD). In order to analyze the putative neuroprotective effect of cigarette smoke and nicotine, one of its major constituents, we examined their effects in an animal model of PD provoked by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. Two groups of mice were chronically exposed to cigarette smoke (a low exposure subgroup and a high exposure subgroup; 5 exposures per day at 2-h intervals), two other groups received nicotine treatment (two doses tested 0.2 and 2 mg/kg, 5 injections i.p. per day at 2-h intervals) and one group placebo. On day 8 after the beginning of the treatment, 4 injections of MPTP hydrochloride (15 mg/kg, i.p., at 2-h intervals) or saline were administered to these animals. Nicotine and cotinine plasmatic concentration was quantified by the HPLC method, and degeneration of the nigrostriatal system was assessed by tyrosine hydroxylase (TH) immunohistochemistry. The loss of dopaminergic neurons induced by MPTP in the substantia nigra was significantly less severe in the chronic nicotine treatment groups (at 0.2 and 2 mg/kg) and the low exposure to cigarette smoke group than in the high exposure to cigarette smoke subgroup and the placebo treated subgroup. In contrast, no preservation of TH immunostaining of nerve terminals was observed in the striatum in any group. This suggests that nicotine and low exposure to cigarette smoke may have a neuroprotective effect on the dopaminergic nigrostriatal system by an as yet unknown mechanism.



http://www.sciencedirect.com/science/article/pii/S0006899303031950


----------



## Dysphoric

I read somewhere that Methamphetamine at lower doses can actually be neuroprotective. After looking around I found this http://www.ncbi.nlm.nih.gov/pubmed/21635908

I'm curious just how low of a dose is considered neuroprotective, would anywhere from 10-25mgs be in this area?

I'm mainly curious because I've been reluctant on taking Desoxyn, but after hearing this I might get back into taking it every so often.


----------



## ShAYZoN

If it was Nero protective I'd be inclined to take it again as well lol.


----------



## Epsilon Alpha

atrollappears said:


> Epsilon Alpha, or anyone else who can provide an answer, how much do we know about the mechanism behind amphetamine (DA) toxicity? Also, what is the speculated role of nitric oxide, and how might amphetamines generate it? I ask because nitric oxide synthase knockout is the only thing I've seen that can actually completely block neurotoxicity (besides blocking the DAT), so it seems pertinent.


 
Well its a very multifaceted issue, particularly the toxicity that is observed days after last administration. But, this excerpt from the ketoprofen paper does a good job of explaining some of nitric oxide's acute effects.



> In a previous report, we showed that METH injections (×4 with 2 h-interval) caused dose-dependent activation of striatal NF-κB which is a transcription factor activated by ROS, and that the activation of NF-κB was significantly attenuated in Cu,Zn-SOD-Tg mice [2]. NF-κB promotes induction of iNOS to generate NO, and consequently induce inflammatory cytokines. The generation of NO is involved in METH-induced neurotoxicity in dopaminergic neurons [11] and [12]. NSAIDs exert inhibitory effects against inflammatory mediators-induced increases in NF-κB and iNOS activities, to inhibit NO production [1] and [8]. It is well known that activated microglial cells produce various inflammatory cytokines, i.e. interleukin-1β (IL-1β), IL-6, and NO radicals. Indeed, METH induced expression of IL-1β mRNA in the rat brain [17]. Cadet and his colleagues reported that METH-induced neurotoxicity and gliosis were attenuated in IL-6 knockout mice [14], suggesting involvement of inflammatory cytokines in METH-induced neurotoxic cascade. Therefore, the present results suggest the possibility that ketoprofen might suppress production of inflammatory cytokines and NO, or suppress them indirectly through inhibition of microglia activation, with consequent amelioration of METH-induced neurotoxicity and microgliosis. Further study will be required to clarify mechanism of this protective effects.





kfluxsake said:


> I'd like to thank the contributors to this thread for doing such a wonderful job. As a smoker, I'd also like to add this study.
> 
> *Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin*
> 
> Karine Paraina, 1,
> Céline Hapdeya, 1,
> Estelle Rousseleta,
> Véronique Marchandb,
> Bernard Dumeryb,
> Etienne C Hirscha,
> 
> Abstract
> 
> Epidemiological studies have found a negative association between cigarette smoking and Parkinson’s disease (PD). In order to analyze the putative neuroprotective effect of cigarette smoke and nicotine, one of its major constituents, we examined their effects in an animal model of PD provoked by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. Two groups of mice were chronically exposed to cigarette smoke (a low exposure subgroup and a high exposure subgroup; 5 exposures per day at 2-h intervals), two other groups received nicotine treatment (two doses tested 0.2 and 2 mg/kg, 5 injections i.p. per day at 2-h intervals) and one group placebo. On day 8 after the beginning of the treatment, 4 injections of MPTP hydrochloride (15 mg/kg, i.p., at 2-h intervals) or saline were administered to these animals. Nicotine and cotinine plasmatic concentration was quantified by the HPLC method, and degeneration of the nigrostriatal system was assessed by tyrosine hydroxylase (TH) immunohistochemistry. The loss of dopaminergic neurons induced by MPTP in the substantia nigra was significantly less severe in the chronic nicotine treatment groups (at 0.2 and 2 mg/kg) and the low exposure to cigarette smoke group than in the high exposure to cigarette smoke subgroup and the placebo treated subgroup. In contrast, no preservation of TH immunostaining of nerve terminals was observed in the striatum in any group. This suggests that nicotine and low exposure to cigarette smoke may have a neuroprotective effect on the dopaminergic nigrostriatal system by an as yet unknown mechanism.
> http://www.sciencedirect.com/science/article/pii/S0006899303031950


 
Interesting, the smoke group likely is benefiting from MAO inhibition but the nicotine group I'm interested in. There is some research suggesting NAChR binding and presumably agonism by amphetamine being implicated in ROS generation, so I'd hazard a guess it may be due to receptor desensitization or upregulation of some sort of protective factor. Should be an interesting area to watch how the research develops.



Dysphoric said:


> I read somewhere that Methamphetamine at lower doses can actually be neuroprotective. After looking around I found this http://www.ncbi.nlm.nih.gov/pubmed/21635908
> 
> I'm curious just how low of a dose is considered neuroprotective, would anywhere from 10-25mgs be in this area?
> 
> I'm mainly curious because I've been reluctant on taking Desoxyn, but after hearing this I might get back into taking it every so often.



Assuming that study translates to humans, and there is a strong chance it doesn't given how different species are affected by amphetamines, it would be around 4-8mg for a 140lb or 70ish kg human. Its also worth noting that this is under stroke conditions, so its relevance to normal conditions might be minimal. Interesting nevertheless though, it points to downregulation of dopamine receptors being a possible contributing factor to the continued apoptosis seen days after the last dose given to rats.


----------



## Dysphoric

Epsilon Alpha said:


> Assuming that study translates to humans, and there is a strong chance it doesn't given how different species are affected by amphetamines, it would be around 4-8mg for a 140lb or 70ish kg human. Its also worth noting that this is under stroke conditions, so its relevance to normal conditions might be minimal. Interesting nevertheless though, it points to downregulation of dopamine receptors being a possible contributing factor to the continued apoptosis seen days after the last dose given to rats.


 

well, assuming that it's around the 4-8 mgs. Would 15-25mg's make that much of a difference? I would think the neurotoxicity would be fairly benign at a dose a little over double the "neuroprotective" dose. Right?


----------



## Epsilon Alpha

Dysphoric said:


> well, assuming that it's around the 4-8 mgs. Would 15-25mg's make that much of a difference? I would think the neurotoxicity would be fairly benign at a dose a little over double the "neuroprotective" dose. Right?


 
Well assuming it applies to humans who aren't having strokes, using the roughly 16mg measure for humans showed mixed results in preventing the neurotoxic measures in intact mice. Some brain areas showed reduced toxicity due to the stroke and others showed more, at the lowest tested doses it was uniformly positive in the measured categories. This study isn't really applicable to human usage sorry to say, but who knows what further research in the topic turns out. But, benign? Defining benign is hard, but will it cause major issues before you're 50. Probably not, but talk that kind of thing over with a doctor, for all I know you're an obese diabetic with a heart problem or an Olympic athlete with ADHD. Its more of a quality of life thing though if you're not using it recreationally, and only you and your doctor can decide that.

Wish I could be more definitive, but the data doesn't give me anything I can reasonably apply to humans.


----------



## atrollappears

Epsilon Alpha said:


> Well its a very multifaceted issue, particularly the toxicity that is observed days after last administration. But, this excerpt from the ketoprofen paper does a good job of explaining some of nitric oxide's acute effects.



IIRC, the behavioral effects of meth were attenuated or blocked in iNOS knockout mice... presumably meth need not generate reactive oxygen species (other than NO) to carry out its stimulant effects, so I'm guessing that the NO is created at some stage in its dopamine releasing action. But does this mean that the neurotoxicity of meth actually contributes to its behavioral effects, by generating additional NO? (Or is NO only related in that it's needs to be present for meth to work, but is not generated by meth's pure pharmacological action?)

Oh, by the way, I remember reading a study where tobacco smoke attenuated meth toxicity in mice.


----------



## golden1

Why exactly is NAC "really" bad? You seem to have just said that when many of the other substances listed also have possible side effects...

"The implications of these findings for long-term treatment with acetylcysteine have not yet been investigated. The dose used by Palmer and colleagues was dramatically higher than that used in humans;[24] nonetheless, positive effects on age-diminished control of respiration (the hypoxic ventilatory response) have been observed previously in human subjects at more moderate doses.[25]" from the wiki page on it that you linked..

However even after reading the abstract [25] I'm not sure if by "positive effects" which way they mean it. For example gasoline has a positive effect on a forest fire's growth, however many would consider that a negative.. if that helps anyone understand my confusion on the wording.

also "The dose used by Palmer and colleagues was dramatically higher than that used in humans," does mean anything? Where are the studies showing that it is _really bad_?

I'm asking because I've looked up all about the metabolite and it's adverse effects, however a low dose(300mg) when comparing the benefits to the negatives at much higher doses doesn't seem bad at all...
especially if you are taking it every so often and not daily(and I know you mentioned chronic dosing as worse, obviously, but I'm really curious why you labeled it so negatively mostly for my own knowledge)


----------



## Epsilon Alpha

Well I don't have any refs at the moment, but chronically NAC may downregulate the body's antioxidant defense mechanisms in a manner unique to its GSH mimicking properties. Not to mention I recall seeing a few studies showing it increased measures of sensitization chronically while being protective acutely. So is it safe every once in a while? Yeah. Is it safe every day, eating spoonfuls of the stuff? Not going to take my chances.
Part of it is also that glutathione seems to play a important role in INCREASING MDMA toxicity at higher doses and I don't want the science illiterate raver to come through this thread and think its a good idea to take MDMA or any of its RC counterparts with it.

More me just avoiding a small possible issue


----------



## golden1

Epsilon Alpha said:


> Well I don't have any refs at the moment, but chronically NAC may downregulate the body's antioxidant defense mechanisms in a manner unique to its GSH mimicking properties. Not to mention I recall seeing a few studies showing it increased measures of sensitization chronically while being protective acutely. So is it safe every once in a while? Yeah. Is it safe every day, eating spoonfuls of the stuff? Not going to take my chances.
> Part of it is also that glutathione seems to play a important role in INCREASING MDMA toxicity at higher doses and I don't want the science illiterate raver to come through this thread and think its a good idea to take MDMA or any of its RC counterparts with it.
> 
> More me just avoiding a small possible issue



ok I completely understand, safety first 

I understand you do not recommend it with mdma and such(I've read same study(studies? probably, I forget) about the conjugations being more neurotoxic/a neurotoxic component. Do you remember if it applied to straight amphetamine? It does right? So me taking 300mg, say after the main effects of amphetamine wear off, is possibly(probably?) doing more harm than good? (my thoughts were that the extra gsh would have a net effect being positive due to all the other anti-oxidant effects+nac's anti-oxidant effects, and amphetamine use probably depletes gsh).

I realize you could easily have no idea(like me), since it's really all up in the air when looking at so many studies, but maybe you have an opinion on that? Maybe I should take the 300mg(every so often) only on days that I don't take amphetamine? That seems most reasonable right? I mean I also use ~500mg NA-R-ALA, ~1g alcar, 1g vitamin c(2-5 times spaced about an hour apart), vit E(not sure how much), 250mg magnesium, 500mg-1g cdp-choline, and fresh blueberry shakes(sooo good, also like the study that shows some constant % of diet containing blueberries raises BDNF levels(which I see as good, others might say messing with those are bad.. I disagree esp. if its caused by blueberries  )). Oh and I smoke weed during lots of it, which I read seems to help, although it also sensitizes you(not quite sure on the meaning, but I assume thats why I feel much more euphoric smoking on amphetamine, that it is partly enhancing the action of the amphetamine.. not sure if that is an issue since I can just take less amphetamine and smoke and it feels like more, I don't think it's permanent sensitation and I'm not sure where I read that weed does this, but I think this thread or the last one. I also don't really understand sensitization, if someone wants to link to post explaining it better or explain for me the reason it's negative.. is it because only some parts you are sensitized to? so you have to take the same dose, yet some actions of the amphetamine are enhanced causing potentially more neurotoxicity? or some completely different reason?)

Thanks for making me remember about the gsh conjugates being neurotoxic, I think I let that slip or forgot it applied to straight amp(?) I probably would have come to the conclusion to take only on off days already(I don't use amp chronically, but enough I would like to protect my brain as much as possible haha. 

If you see anything wrong with the other things I'm taking, please let me know :O I realize the na-r-ala dose is decently high, but it gives a rather fast subjective mind cleaning/fixing feeling at that dose compared to 100-400mg.


----------



## Epsilon Alpha

golden1 said:


> ok I completely understand, safety first
> If you see anything wrong with the other things I'm taking, please let me know :O I realize the na-r-ala dose is decently high, but it gives a rather fast subjective mind cleaning/fixing feeling at that dose compared to 100-400mg.



By any chance are you bipolar? Insanely positive responses to antioxidants are something I've noted people mention online.
Like virtually all the positive responses I've heard for PQQ were from people with diagnosed or suspected (on their end) bipolar disease.


----------



## golden1

Epsilon Alpha said:


> By any chance are you bipolar? Insanely positive responses to antioxidants are something I've noted people mention online.
> Like virtually all the positive responses I've heard for PQQ were from people with diagnosed or suspected (on their end) bipolar disease.



I'm naturally an extremely happy person, with dips here and there(I'd consider it almost normal, except that weed might be helping to keep me so happy since If I don't smoke for a 1-2 days I start feeling depressed about anything possible(not all the time, but in bouts)...however I think that is just "withdrawal" from vape/smoking weed too much, since it will go away if I refrain getting high for like 4+ days). 

I have much more reason to believe that I have some light form of ADD, mostly a lack of energy and inability to focus or do tasks that require too much thought(sometimes much worse than others and sometimes I have complete clarity).
I only call it ADD because it fits most, I have friend with much worse ADD symptoms, so I know I am not nearly full on ADD at all(his memory is also shit, way less attention span, and much more severe versions of my symptoms.. must be so shitty for him).

It's hard to tell if it's made worse by using drugs(long term) or if it's part of me(I suspect it's partly both because I remember the same symptoms in middleschool/highschool). Amphetamines make a huge difference, but then again for almost everyone they do. So does getting high, almost as effective, except energy wise.

I definitely have clarity that comes and goes, however if it's just due to a cycle such as not eating well when I feel fine and then eating extra well when I'm not etc, I don't know.


I'd also like to add that CDP-Choline makes a world of a difference to me, the onset feels like a small euphoric dopamine rush and the time after my wellbeing is greatly increased. When I took it daily I felt like I was cured of everything! I stopped when I ran out and my life got a bit more stressful to keep up on it, but I'm going to try it out again. I am wondering, wikipedia has abstract saying it increases specifically the d2 receptor(probably others d receptors too I'm guessing, but the test they used was only d2) density in rats with chronic dosing(also muscarinic acetylcholine receptor, I believe), I'm thinking either that or the effects on whatever else are the cause... only because I've taken alpha-gpc(no effect), choline citrate(no effect), choline bitartrate(extra sweating and fish smell all day LOL), and centrophenoxine(which gave me a hypomaniac-like mood lift and then sometimes depression the next day). 

Anyway doesn't amphetamine internalize d2 receptors or something I read here? So cdp-choline could possibly help maybe through that mechanism?(my attempt to try to bring my post back to the topic lol)


----------



## Dysphoric

golden1 said:


> I'd also like to add that CDP-Choline makes a world of a difference to me, the onset feels like a small euphoric dopamine rush and the time after my wellbeing is greatly increased.


 


I'm interested in this now. Can anyone else vouch for this?


----------



## MeDieViL

Epsilon Alpha said:


> Well I don't have any refs at the moment, but chronically NAC may downregulate the body's antioxidant defense mechanisms in a manner unique to its GSH mimicking properties. Not to mention I recall seeing a few studies showing it increased measures of sensitization chronically while being protective acutely. So is it safe every once in a while? Yeah. Is it safe every day, eating spoonfuls of the stuff? Not going to take my chances.
> Part of it is also that glutathione seems to play a important role in INCREASING MDMA toxicity at higher doses and I don't want the science illiterate raver to come through this thread and think its a good idea to take MDMA or any of its RC counterparts with it.
> 
> More me just avoiding a small possible issue


Its a good idea to cycle nac with curcumin; curcumin in fact thrives on low glutathione and may work better after a nac cycle.


----------



## MeDieViL

Id say a racetam combined with a nmda antagonist is ideal in the scenario this thread is about this combination will help tolerance; potentiate amphetamine; offer neuroprotection and minimalise the comedown.


----------



## Jabberwocky

i've heard that methylphenidate has some neuroprotective elements to it, after doing quite a bit of research on the topic i am still puzzled as to how it does so. according to this study its binding on DAT receptors is what causes this to occur, but can kill the effects of an amphetamine high as excess dopamine is not pushed into the synapses. there is also another neuroprotective feature of mph is due to indirect use of VMAT-2. the study concludes that it is neuroprotective while being toxic at the same time. left me a little puzzled - as surely cocaine with also regulates dopamine is said to be highly neurotoxic and mph acts on the same principle just at a much lower level. the seizure threshold also increases vastly while using methylphenidate so i assume that that would always be a possibly especially if co-administered with amphetamines. receptors could be over stimulated using both together, it doesn't seem very promising but could be an alternative.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701286/

i've also heard that alprazolam is neuroprotective at low doses but for stress related illness. amphetamine increases gluthathione and catalytic activity in the brain under which alp reduces. i could be wrong so i wait to stand corrected of this.

personally what interests me vastly at the moment is selegine. although it is used for parkisons disease i think there is a world of potential to be gained from this drug especially when co-administered with l-dopa, both essentially cancelling out each others neurotoxic effects. as shown in parkisons suffers it can delay onset by up to 14 months but this shows that it is not a long term effective treatment.

as amphetamines can produce parkinson like features at higher doses or long term abuse i have been looking into the use of selegine too which is meant to provide neuroprotection through MAO-B inhibition. i have looked for further conclusive studies regarding the mechanism of action of selegine and no further studies have been taken to demonstrate its secondary course of action. as cigarettes also inhibit MAO-B i believe that this could also be a method of preventing neurotoxicity but the other chemicals involved in smoking a cigarette damage the neurones too giving a hit and miss situation. it also provides protection from 6-OHDA in vivo when used on animals, but possibly is not concurrent with humans. levo-dopa and Selegine has shown when used together to increase triatal superoxide levels or something along those lines too. it also increases the amount of n-acetylserotonin by the pineal gland although serotonin levels are not really of a concern regarding amphetamine abuse, it was shown to be a strong anti-oxidant which could stop amphetamine oxidising.

i'm also giving a brief guess as i haven't researched it but L-dopa is meant to stimulate dopamine response and help regain lost dopamine through the use of amphetamines. as amphetamines have been shown to provide oxidative stress amongst its users, it also seems that ,l-dopa has shown increase hydroxyl radicals as well so in a way it is also neuroprotective by increasing the levels of dopamine in the brain while being destructive at the same time hence why selegine or even possibly cigarettes could block these radicals due to the MAO abilities of it

thats my best bet on the subject of neuro protection regarding amp abuse, now where do i buy these compounds? 

being a heavy amphetamine abuser myself, using l-tyrosine on days off seems to alleviate some of the psychological symptoms of not taking them along with a vitamin b6 complex. as it is a precursor to dopamine and in fact l-dopa it could provide some help in my opinion as the dopamine receptors can regenerate more quickly although i'm not really interested in l-tyrosine as i think amino acids are all a big gimic anyway. fish oils are meant to provide some sort of neuroprotectivity too but once again have done no research in the matter and that is fairly old. 

from all concurrent research there has been no real major breakthrough in a drug which is neuroprotective fully that we have tested and know about to the present day which a bit upsetting. of course heading down using parkinson drugs to help with amphetamine damage is not really productive either.

Tianeptine is said to be an anti-depressant with neuroprotective features too, although it could be potentially deadly as NMDA receptors are opened at an extreme level leading to possible cell damage, but at a lower dosage have shown to be effective in increasing dopamine and boosting d2/d3 receptors as well. along with boosting serrortonin which will likely be lowered in the brain of a long term amphetamine user it also enhances the most damaged receptors in the brain of an amps user too.


----------



## Epsilon Alpha

Well L-DOPA and a MAO-B inhibitor is likely going to make you a writhing gambling addict far easier than it will fix stim tolerance. 
Tianeptine is a interesting as hell drug, but its going to be something I WOULD NOT SUGGEST to stimulant users until more research comes out. NMDA potentiation and upregulation of D3 receptors would be the last thing any stimulant abuser needs, that just spells out worsened addiction.

MPH is protective through a few mechanisms in amphetamine toxicity, but one of its primary advantages is it blocks reactive DA metabolites from entering the synapse. Co-administration in humans might work out as a protective mechanism, but figuring out the doses would be an absolute bitch.



MeDieViL said:


> Id say a racetam combined with a nmda antagonist is ideal in the scenario this thread is about this combination will help tolerance; potentiate amphetamine; offer neuroprotection and minimalise the comedown.



Sauce?


----------



## Jabberwocky

Epsilon Alpha said:


> Well L-DOPA and a MAO-B inhibitor is likely going to make you a writhing gambling addict far easier than it will fix stim tolerance.
> Tianeptine is a interesting as hell drug, but its going to be something I WOULD NOT SUGGEST to stimulant users until more research comes out. NMDA potentiation and upregulation of D3 receptors would be the last thing any stimulant abuser needs, that just spells out worsened addiction.
> 
> MPH is protective through a few mechanisms in amphetamine toxicity, but one of its primary advantages is it blocks reactive DA metabolites from entering the synapse. Co-administration in humans might work out as a protective mechanism, but figuring out the doses would be an absolute bitch.
> 
> 
> 
> Sauce?



why do you think that about l-dopa and selegine? selegine in itself is not a pure MAO-B inhibitor and has other effects on the brain, which are still being looked into. i've heard such good reports of stimulant tolerance being dissolved relatively easily and quickly with just one dose, as it potentiates the high as well as reducing outstanding tolerance, but you are at risks of psychosis due to all the excess dopamine being available, if we are going on the basis that this what causes it.

indeed tianeptine is fascinating, and i also agree more research is needed to be done. it would most likely potentiate stimulants to a vast effect due to its effect on the nmda receptors. 

as for MPH, i have been thinking hard about this one. surely the effects of it being a reuptake inhibitor would cancel out all the positive effects of an amphetamine? what if you were to use cocaine at the same level? why would dosage need to be finely tuned? so that some dopamine can be produced by the receptors but not too much?? 

oh how i wish our brains could provide themselves with neuroprotective features.


----------



## Tussmann

EA, MeD and all the others...now that M&M is dead, I'd still like to get my amphetamine fix --scholarly that is. 



I've read through Reduction/Prevention threads I & II and am happy to see new theories. I will hopefully be able to contribute some in the future. 


For those who don't know me, here's a pretty basic summary: http://www.mindandmuscle.net/forum/38990-memantine-overrated-amphetamine-tolerance


----------



## Epsilon Alpha

Tussmann said:


> EA, MeD and all the others...now that M&M is dead, I'd still like to get my amphetamine fix --scholarly that is.
> 
> 
> 
> I've read through Reduction/Prevention threads I & II and am happy to see new theories. I will hopefully be able to contribute some in the future.
> 
> 
> For those who don't know me, here's a pretty basic summary: http://www.mindandmuscle.net/forum/38990-memantine-overrated-amphetamine-tolerance



Welcome to bluelight


----------



## Epsilon Alpha

synthetix said:


> why do you think that about l-dopa and selegine? selegine in itself is not a pure MAO-B inhibitor and has other effects on the brain, which are still being looked into. i've heard such good reports of stimulant tolerance being dissolved relatively easily and quickly with just one dose, as it potentiates the high as well as reducing outstanding tolerance, but you are at risks of psychosis due to all the excess dopamine being available, if we are going on the basis that this what causes it.
> ....
> as for MPH, i have been thinking hard about this one. surely the effects of it being a reuptake inhibitor would cancel out all the positive effects of an amphetamine? what if you were to use cocaine at the same level? why would dosage need to be finely tuned? so that some dopamine can be produced by the receptors but not too much??



Well cocaine is a whole different can of worms than MPH, but on a very theoretical only basis it might work. 

L-DOPA is something I can't stress enough that people should avoid if they don't have Parkinson's. Unless administered with a decarboxylase inhibitor, its peripheral actions alone will just have you violently vomiting with extremely low blood pressure...

I've seen that first hand, turns out generic Canadian L-DOPA looks just like cheap European asprin. She was ok after though


----------



## Tussmann

Epsilon Alpha said:


> L-DOPA is something I can't stress enough that people should avoid if they don't have Parkinson's. Unless administered with a decarboxylase inhibitor, its peripheral actions alone will just have you violently vomiting with extremely low blood pressure...



What doses of L-DOPA are you referring to here? I have had my fair share in proprietary blends and standalone supplements over the years. I've never really experienced anything too drastic, if at all.


----------



## atrollappears

Epsilon Alpha, you posted this a couple weeks ago when I asked about the mechanism of meth-induced neurotoxicity. I have a few questions though.



> In a previous report, we showed that METH injections (×4 with 2 h-interval) caused dose-dependent activation of striatal NF-κB which is a transcription factor activated by ROS, and that the activation of NF-κB was significantly attenuated in Cu,Zn-SOD-Tg mice [2]. NF-κB promotes induction of iNOS to generate NO, and consequently induce inflammatory cytokines. The generation of NO is involved in METH-induced neurotoxicity in dopaminergic neurons [11] and [12]. NSAIDs exert inhibitory effects against inflammatory mediators-induced increases in NF-κB and iNOS activities, to inhibit NO production [1] and [8]. It is well known that activated microglial cells produce various inflammatory cytokines, i.e. interleukin-1β (IL-1β), IL-6, and NO radicals. Indeed, METH induced expression of IL-1β mRNA in the rat brain [17]. Cadet and his colleagues reported that METH-induced neurotoxicity and gliosis were attenuated in IL-6 knockout mice [14], suggesting involvement of inflammatory cytokines in METH-induced neurotoxic cascade. Therefore, the present results suggest the possibility that ketoprofen might suppress production of inflammatory cytokines and NO, or suppress them indirectly through inhibition of microglia activation, with consequent amelioration of METH-induced neurotoxicity and microgliosis. Further study will be required to clarify mechanism of this protective effects.



This paragraph seems to claim that NO is toxic in this case by inducing inflammatory cytokines, but I can't seem to find any research which says NO does induce inflammatory cytokines; what I've read actually says the opposite. So presumably this effect would occur with abnormally high concentrations, but is this an established effect of nitric oxide? Also, at what point does microglial activation come in? As the synthesis of nitric oxide is induced or as a result of it?

Edit: On somewhat of a side note, is it safe to take american ginseng with amphetamine? Ginseng seems to affect nitric oxide, but if I'm interpreting this research correctly it seems that ginseng would be protective against amph neurotoxicity.


----------



## Infinite1

Perhaps I missed it but I'm rather surprised that bupropion hasn't been mentioned as it has some potential for redistributing VMAT2 protein. 



> Bupropion increases striatal vesicular monoamine transport
> 
> Abstract
> 
> The vesicular monoamine transporter-2 (VMAT-2) is principally involved in regulating cytoplasmic dopamine (DA) concentrations within terminals by sequestering free DA into synaptic vesicles. This laboratory previously identified a correlation between striatal vesicular DA uptake through VMAT-2 and inhibition of the DA transporter (DAT). For example, administration of methylphenidate (MPD), a DAT inhibitor, increases vesicular DA uptake through VMAT-2 in a purified vesicular preparation; an effect associated with a redistribution of VMAT-2 protein within DA terminals. The purpose of this study was to determine if other DAT inhibitors, including bupropion, similarly affect VMAT-2. Results revealed bupropion rapidly, reversibly, and dose-dependently increased vesicular DA uptake; an effect also associated with VMAT-2 protein redistribution. The bupropion-induced increase in vesicular DA uptake was prevented by pretreatment with eticlopride, a DA D2 receptor antagonist, but not by SCH23390, a DA D1 receptor antagonist. We previously reported that MPD post-treatment prevents persistent DA deficits associated with multiple methamphetamine (METH) administrations. Although bupropion attenuated the METH-induced reduction in VMAT-2 activity acutely, it did not prevent the long-term dopaminergic toxicity or the METH-induced redistribution of VMAT-2 protein. The findings from this study demonstrate similarities and differences in the mechanism by which MPD and bupropion affect striatal dopaminergic nerve terminals.


----------



## Epsilon Alpha

atrollappears said:


> Epsilon Alpha, you posted this a couple weeks ago when I asked about the mechanism of meth-induced neurotoxicity. I have a few questions though.
> 
> This paragraph seems to claim that NO is toxic in this case by inducing inflammatory cytokines, but I can't seem to find any research which says NO does induce inflammatory cytokines; what I've read actually says the opposite. So presumably this effect would occur with abnormally high concentrations, but is this an established effect of nitric oxide? Also, at what point does microglial activation come in? As the synthesis of nitric oxide is induced or as a result of it?
> 
> Edit: On somewhat of a side note, is it safe to take american ginseng with amphetamine? Ginseng seems to affect nitric oxide, but if I'm interpreting this research correctly it seems that ginseng would be protective against amph neurotoxicity.



I'm kind of lost on that as well, while we know inflammation is bad in regards to neurotoxicity I haven't been able to deduce which step in the process is directly toxic. NO production produces peroxynitrite which is known to induce apoptosis, but I haven't had the time between the move and work to look too deep into the system.  

Ginseng and amphetamine is a weird combo with all the reports saying "potentiates this, inhibits that", but so long as you dose reasonably you should be safe. I've seen it done first hand without any issues. Herbs with as many actives as ginseng (gingko as well) are a hard thing to recommend to people, as frankly for every compound that does something in one direction it probably has one that does something in opposition. If you'd like to dig up some studies on ginseng I think that would be a great way to further discussion though 



Infinite1 said:


> Perhaps I missed it but I'm rather surprised that bupropion hasn't been mentioned as it has some potential for redistributing VMAT2 protein.



Welcome to Bluelight 
Well I'm glad you've brought this up, it does counteract VMAT2 uptake deficiencies however in humans it seems the issue is more VMAT2 localization changes. I don't have journal access off campus so I can't look into its effects on vesicle localization (amphetamines seem to localize them towards the cell body, away from the synapse). Could you check if they mention it in the paper?



Tussmann said:


> What doses of L-DOPA are you referring to here? I have had my fair share in proprietary blends and standalone supplements over the years. I've never really experienced anything too drastic, if at all.



Like 1970's farmer Parkinson's doses, so pretty high (+200mg). Still, if someone gets a non-bunk batch and is really sensitive to it they're going to have a bad time.


----------



## MeDieViL

Korean ginseng seems to block sensitization of opiates and stimulations; alpha do you think it might be effective for tolerance related issues?


----------



## foolcoolguy

*How long for dopamine receptors to return to normal after long term Rx Amp Use?*

Ok, so I have been abusing adderall at about 250mg a day for 7 days on, 21 days off for about 3 years. Then I took a long break, and have used it only about 10x since then. I no longer get high from the drug. I realize that the dopamine system will re-regulate itself. The last time I used amphetamines was 120mg last wednesday, so about 10 days ago.

I am on 300mg wellbutrin and 20mg ritalin er per day.

How long until my dopamine regulates itself back to normal? I feel fine, but I don't really know because I haven't been off drugs for a while.

I have read many conflicting reports on the internet, but I was hoping someone here could give me a concrete answer.

edit: Ok, so I realize that the dopamine receptors will return to normal, I was just hoping someone could give me a timeline. I have been researching in medical books and it looks like rats return to normal physical activity from 23-27 days after amphetamine injections.


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## Epsilon Alpha

foolcoolguy said:


> Ok, so I have been abusing adderall at about 250mg a day for 7 days on, 21 days off for about 3 years. Then I took a long break, and have used it only about 10x since then. I no longer get high from the drug. I realize that the dopamine system will re-regulate itself. The last time I used amphetamines was 120mg last wednesday, so about 10 days ago.
> 
> I am on 300mg wellbutrin and 20mg ritalin er per day.
> 
> How long until my dopamine regulates itself back to normal? I feel fine, but I don't really know because I haven't been off drugs for a while.
> 
> I have read many conflicting reports on the internet, but I was hoping someone here could give me a concrete answer.
> 
> edit: Ok, so I realize that the dopamine receptors will return to normal, I was just hoping someone could give me a timeline. I have been researching in medical books and it looks like rats return to normal physical activity from 23-27 days after amphetamine injections.



Well DA receptor densities will return to normal after about a month as you found, but things like tyrosine hydroxylase and various transcriptional changes will last much longer. So I'm not sure what kind of answer you want, but from recent literature it looks like it takes about 2 years for things to go back to normal, but as far as getting high again that might be out of the question.

The brain kind of "learns to counteract drugs" which is why tolerance builds so much faster in former users than drug naive individuals, and its a very very complex process.


----------



## Epsilon Alpha

MeDieViL said:


> Korean ginseng seems to block sensitization of opiates and stimulations; alpha do you think it might be effective for tolerance related issues?



Mind linking some studies? I've never really given ginseng more than a customary glance because of the variability of extracts.


----------



## MeDieViL

Here's a couple of study's: (i got other compounds in the back of my mind as well but lets take a look at ginseng first.

Wild ginseng attenuates repeated morphine-induced behavioral sensitization in rats.

Lee B, Kwon S, Yeom M, Shim I, Lee H, Hahm DH.
Source

Acupuncture and Meridian Science Research Center, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Korea.

Abstract


Many studies have suggested that the behavioral and reinforcing effects of morphine are induced by hyperactivation of the mesolimbic dopaminergic system, which results in increases in locomotor activity, c-Fos expression in the nucleus accumbens (NAc), and tyrosine hydroxylase (TH) in the ventral tegmental area (VTA). In order to investigate the effect of wild ginseng (WG) on treating morphine addiction, we examined the behavioral sensitization of locomotor activity and c-Fos and TH expression in the rat brain using immunohistochemistry. Intraperitioneal injection of WG (100 and 200 mg/kg), 30 min before administration of a daily injection of morphine (40 mg/kg, s.c.), significantly inhibited morphine-induced increases in c-Fos expression in NAc and TH expression in VTA as well as in locomotor activity, as compared with Panax ginseng. It was demonstrated that the inhibitory effect of WG on the behavioral sensitization after repeated exposure to morphine was closely associated with the reduction of dopamine biosynthesis and postsynaptic neuronal activity. It suggests that WG extract may be effective for inhibiting the behavioral effects of morphine by possibly modulating the central dopaminergic system and that WG might be a useful resource to develop an agent for preventing and treating morphine addiction.

Inhibitory effects of ginseng total saponin on up-regulation of cAMP pathway induced by repeated administration of morphine.

Seo JJ, Lee JW, Lee WK, Hong JT, Lee CK, Lee MK, Oh KW.
Source

College of Pharmacy, Chungbuk National University, Cheongju, 360-763, Korea.

Abstract


We have reported that ginseng total saponin (GTS) inhibited the development of physical and psychological dependence on morphine. However, the possible molecular mechanisms of GTS are unclear. Therefore, this study was undertaken to understand the possible molecular mechanism of GTS on the inhibitory effects of morphine-induced dependence. It has been reported that the up-regulated cAMP pathway in the LC of the mouse brain after repeated administration of morphine contributes to the feature of withdrawals. GTS inhibited up-regulation of cAMP pathway in the LC after repeated administration of morphine in this experiment. GTS inhibited cAMP levels and protein expression of protein kinase A (PKA). In addition, GTS inhibited the increase of cAMP response element binding protein (CREB) phosphorylation. Therefore, we conclude that the inhibitory effects of GTS on morphine-induced dependence might be mediated by the inhibition of cAMP pathway.

Ginsenoside Rg1 restores the impairment of learning induced by chronic morphine administration in rats.

Qi D, Zhu Y, Wen L, Liu Q, Qiao H.
Source

Neuroscience Program, Shandong University of Traditional Chinese Medicine, Jinan, China.

Abstract


Rg1, as a ginsenoside extracted from Panax ginseng, could ameliorate spatial learning impairment. Previous studies have demonstrated that Rg1 might be a useful agent for the prevention and treatment of the adverse effects of morphine. The aim of this study was to investigate the effect of Rg1 on learning impairment by chronic morphine administration and the mechanism responsible for this effect. Male rats were subcutaneously injected with morphine (10 mg/kg) twice a day at 12 hour intervals for 10 days, and Rg1 (30 mg/kg) was intraperitoneally injected 2 hours after the second injection of morphine once a day for 10 days. Spatial learning capacity was assessed in the Morris water maze. The results showed that rats treated with Morphine/Rg1 decreased escape latency and increased the time spent in platform quadrant and entering frequency. By implantation of electrodes and electrophysiological recording in vivo, the results showed that Rg1 restored the long-term potentiation (LTP) impaired by morphine in both freely moving and anaesthetised rats. The electrophysiological recording in vitro showed that Rg1 restored the LTP in slices from the rats treated with morphine, but not changed LTP in the slices from normal saline- or morphine/Rg1-treated rats; this restoration could be inhibited by N-methyl-D-aspartate (NMDA) receptor antagonist MK801. We conclude that Rg1 may significantly improve the spatial learning capacity impaired by chonic morphine administration and restore the morphine-inhibited LTP. This effect is NMDA receptor dependent.

Pharmacological action of Panax ginseng on the behavioral toxicities induced by psychotropic agents.

Kim HC, Shin EJ, Jang CG, Lee MK, Eun JS, Hong JT, Oh KW.
Source

Neurotoxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Korea.

Abstract


Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (mu-receptors) and mouse vas deferens (delta-receptors) are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine A2A/ delta-opioid receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.

[Pharmacological and physiological effects of ginseng on actions induced by opioids and psychostimulants].

[Article in Japanese]
Tokuyama S, Takahashi M.
Source

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. stoku@pharm.showa-u.ac.jp

Abstract


Pharmacological and physiological effects of ginseng on actions induced by opioids and psychostimulants were summarized. Analgesic effects of opioids, such as morphine and U-50,488H, were blocked by ginseng in a non-opioid dependent manner. Furthermore, ginseng inhibited the tolerance to and dependence on morphine, and prevented the suppressive effect on the development of morphine tolerance caused by co-exposure to foot-shock stress, but not psychological stress. On the other hand, behavioral sensitization (reverse tolerance to ambulation-accelerating effect) to morphine, methamphetamine (MAP) and cocaine was also inhibited by ginseng. Interestingly, ginseng also inhibited the appearance of the recurrent phenomenon (reappearance of the sensitized state was observed at the time of readministration of MAP and cocaine even after a 30-day discontinuation of drug administration) of the effect of MAP and cocaine. The conditioned place preference of MAP and cocaine was completely blocked by ginseng. These findings provide evidence that ginseng may be useful clinically for the prevention of abuse and dependence of opioids and psychostimulants.

Inhibition by ginseng total saponin of the development of morphine reverse tolerance and dopamine receptor supersensitivity in mice.

Kin HS, Kang JG, Oh KW.
Source

Department of Pharmacology, College of Pharmacy, Chungbuk National University, Cheongju, Korea.

Abstract


1. Ginseng total saponin (GTS), 200 mg/kg i.p. 3 hr prior to morphine, inhibited the development of reverse tolerance to the ambulatory-accelerating effect of morphine. 2. GTS, 200 mg/kg, also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of morphine, 10 mg/kg a day for 7 days. 3. These results suggest that GTS may be useful for the prevention and therapy of the adverse action of morphine.

The effect of Panax ginseng on the development of tolerance to the pharmacological actions of morphine in the rat.

Bhargava HN, Ramarao P.
Source

Department of Pharmacodynamics University of Illinois, Chicago 60612.

Abstract


1. The effect of intraperitoneal administration of Panax ginseng on the development of tolerance to the analgesic and hyperthermic actions of morphine was determined in male Sprague-Dawley rats. Rats were rendered tolerant to morphine to different degrees by the subcutaneous implantation of either four pellets of morphine over a 3-day period or six pellets over a 7-day period. Each pellet contained 75 mg of morphine free base. Rats serving as controls were implanted with placebo pellets. 2. Daily administration of ginseng extract (6.25-50.0 mg/kg) for 3 days inhibited the development of tolerance to the analgesic effect but not to the hyperthermic effect of morphine in the four pellet schedule. 3. In six pellet schedule, daily administration of ginseng extract (25 and 50 mg/kg) for 7 days also inhibited the development of tolerance to the analgesic effect of morphine, but the 100 mg/kg dose had no effect. On the other hand, in six pellet schedule, the administration of ginseng extract (50 and 100 mg/kg) once daily for 7 days inhibited the development of tolerance to the hyperthermic effect of morphine. 4. It is concluded that in appropriate doses,ginseng extract has inhibitory activity on the development of tolerance to the pharmacological actions of morphine.

The effect of ginseng extract on locomotor sensitization and conditioned place preference induced by methamphetamine and cocaine in mice.

Tokuyama S, Takahashi M, Kaneto H.
Source

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki University, Japan.

Abstract


Repeated i.p. injections of 2 mg/kg methamphetamine (MA) or 20 mg/kg cocaine at 48-h intervals induced reverse tolerance to their ambulation-enhancing effects (behavioral sensitization). Furthermore, the reappearance of the sensitized state was observed at the time of readministration of MA or cocaine even after a 30-day discontinuation of drug administration. A concomitant injection of ginseng extract (GE), 200 mg/kg, i.p., suppressed the development of reverse tolerance and the reappearance of sensitization to MA and cocaine. Conditioned place preference to MA (1, 2, and 4 mg/kg, i.p.) and cocaine (1, 4, 10, and 20 mg/kg, i.p.), was completely blocked by GE, 200 mg/kg, i.p. combined treatment with MA of cocaine. Meanwhile, spontaneous motor activity and place preference were not affected by GE alone. These results provide evidence that GE may be useful clinically for the prevention of adverse actions of MA and cocaine.


----------



## Epsilon Alpha

Hey, I know I haven't been too active in this thread of late, but here's some of the more interesting topics I've found so far
http://www.sciencedirect.com/science/article/pii/S0028390801001654 5HT6 and amphetamine, interestingly enough 5HT6 antagonists are procognitive in animal studies
http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2011.07356.x/full Curcumin and 5HT pathway responses to stress
http://www.springerlink.com/content/h69677w064755083/?MUD=MP A WTF paper on 5HT2A and amphetamine
http://onlinelibrary.wiley.com/doi/10.1111/j.1460-9568.2004.03805.x/full A good paper on how amphetamine sensitization isn't all about the dopamine

Been mainly looking at genomic effects on 5HT and mGluR regulation. Ginseng appears to work partly through these pathways too.


----------



## Tussmann

EA I can't access those full-texts, even with my University login  Mind posting up some of the key excerpts when you get the chance?


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## thikal

A friend of mine said to me that if you begin to take L-DOPA, your natural dopaminergic system won't live more than 15/20 years. The body can recognise exogenous dopamine or what?


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## alkap555

> A friend of mine said to me that if you begin to take L-DOPA, your natural dopaminergic system won't live more than 15/20 years. The body can recognise exogenous dopamine or what?



I don't know if your body can determine the _source _of the L-DOPA, but it certainly knows when there is too much, and alters enzyme activity, receptor density, sensitivity and a whole bunch of up/downstream factors in the DAergic system. I certainly wouldn't recommend supplementing L-DOPA long-term for no particular reason. 

Also, without co-administration of a peripheral DDCI (carbidopa etc), you are gonna get vasodilation (hypotension) and probably tachycardia (it acts as a positive inotropic and chronotropic via B1 receptor activation on the heart) and lots of other nasty side effects, depending on the dose.


----------



## Aetherius Rimor

Epsilon Alpha said:


> Buuuuut, sensitization has way way too many links to bipolar disease and schizophrenia for my liking. Granted it may also be involved in some of the benefits seen in long term stimulant treatment of ADHD.
> 
> <snip>
> 
> I'm beginning to think that by looking into schizophrenia and bipolar/epilepsy we can begin to find some significant findings for all these conditions.


 
Ok this seems to be almost a recurring theme in stuff I read about, as far as addiction goes, so I'm wondering if you have any further knowledge on this subject or have articles I could learn more from.

Everyone that I know who has been diagnosed bi-polar, seems to have one of two extremes with drug addiction. Either they're like me, and the couple bi-polar people I actually will associate with, and have it seems no reward response from taking drugs that normally induce rewards. Or they have the exact opposite and have extreme addiction issues, where they -have to have it- and get easily addicted.

Growing up, I always got the "bi-polar people have huge issues with drug abuse fact" ingrained into my head, so I was always nervous about ever experimenting with drugs.

When I finally started experimenting however, all the addictive drugs I've done I have no compulsion to or desire to keep doing if I decide not to. I usually have almost a "reverse tolerance" when I first start using, or after extended breaks from using. When I started using cocaine, I started at ~80 to 100mg lines, and usually on the second day I was down to 30 to 40mg lines because it would get to strong (never doing more than 1 or 1.5 g in a 24hr period). I never have more than a 2 day binge, because I get absolutely sick of it and don't want to touch it again for at least a week or two.

MDMA had a reverse tolerance at first, but I seemed to gain a tolerance until I stopped using it. I only use it once every 2 to 3 months though it's same potency I expect whenever I do, so not sure if reverse tolerance would kick in again.

Ampehtamines similarly have no compulsion to do unless I have a use for them.

After a few months without adderall, and no desire to use cocaine, and the caffeine triggered hypermanic states were starting to cause problems, I finally tried oral meth. Usually 15 to 35mg range. No desire to redose, or use when not necessary. A gram of meth lasts me 6 months easily using one or two days a week.

Opiate and benzo tolerance seems to work as expected, and I usually just stop using them when the regular dose stops working. Have no desire to keep using when it no longer gives me a euphoria.

Another thing I've noticed, is that almost every time I take a drug, a usually make a comment like "I forgot how good this feels", even if I used it a few days prior.

It's as if my body stores no recollection of the euphoria given by a drug. When I'm in a depression phase, I'll be sitting at my computer, needing to work, having absolutely no desire to work, and absolutely no desire to do a line of coke even though I know it would help. The depression completely overrides even the "want" to do it to help me do my job.

The only other people I've ever spoken to with similar experiences as me also are diagnosed bi-polar. Never met anyone who admitted to being schizophrenic, and I've definitely seen some bi-polar people with drug abuse issues. However there seems to be a link in my eyes between bi-polar and addiction at both extremes. Another pattern I noticed is that bi-polar people who have more depression phases, and rarely or never get hypermania are the ones who don't get addicted, while the ones who are more often hypermanic and less often depressed seemed to easily get addicted.

The only drug I've ever had a problem quitting is nicotine. Quit once for 3 months, and a few times for a couple weeks. But if I decide to smoke 1 after going a couple weeks, it's back to smoking daily.

I know I've brought this up at bluelight before in other threads, but I still haven't gotten a satisfactory conclusion to this curiosity. It's a great trait to have, but with how confusing it is, I have an insane desire to know -why-.

Edit: Side note, is there a link you can share that goes more in depth of the differences between sensitization and tolerance, or would you be willing to describe them a little more? I'm not sure I follow, but as I currently interpret what you're saying, sensitization is an increased desire for it, and tolerance is a reduced effectiveness of it? If that's the correct meanings, it would explain my experience with opiate/benzo to say that I gain no sensitization, but do gain tolerance, correct?


----------



## Epsilon Alpha

Tussmann said:


> EA I can't access those full-texts, even with my University login  Mind posting up some of the key excerpts when you get the chance?



Well they're more just background reading for 5HTR modulation of stimulant responses, but I'll post the pubmed id's for you 
http://www.ncbi.nlm.nih.gov/pubmed/11804613

http://www.ncbi.nlm.nih.gov/pubmed/21689105

http://www.ncbi.nlm.nih.gov/pubmed/17510759 Basically 5HT2A is involved in "liking" but not sensitization according to this one

Couldn't find ANYTHING else for the last article, but this one covers much the same points. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1464364/


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## Epsilon Alpha

Aetherius Rimor said:


> Ok this seems to be almost a recurring theme in stuff I read about, as far as addiction goes, so I'm wondering if you have any further knowledge on this subject or have articles I could learn more from.


If I find a solid paper on it I'll post it, but try google'ing around the topic. There's a lot of good evidence, just no good review article 



> Everyone that I know who has been diagnosed bi-polar, seems to have one of two extremes with drug addiction. Either they're like me, and the couple bi-polar people I actually will associate with, and have it seems no reward response from taking drugs that normally induce rewards. Or they have the exact opposite and have extreme addiction issues, where they -have to have it- and get easily addicted.


I hear you man, its kind of like schizophrenics and autistic kids (google "I told you I was hardcore" for a suspected case)



> I know I've brought this up at bluelight before in other threads, but I still haven't gotten a satisfactory conclusion to this curiosity. It's a great trait to have, but with how confusing it is, I have an insane desire to know -why-.
> 
> Edit: Side note, is there a link you can share that goes more in depth of the differences between sensitization and tolerance, or would you be willing to describe them a little more? I'm not sure I follow, but as I currently interpret what you're saying, sensitization is an increased desire for it, and tolerance is a reduced effectiveness of it? If that's the correct meanings, it would explain my experience with opiate/benzo to say that I gain no sensitization, but do gain tolerance, correct?



Same here, and I wish I had a good link for it. Sensitization is weird in humans in the fact that its a completely separate process from tolerance, and mainly manifests as behavioural changes as far as I know. There's a link near the start of the thread I posted regarding amphetamine sensitization in humans after 3 uses if you want some reading.


----------



## crestfallen

This is a really interesting thread. I recently found a study at my uni that correlates the # of DA receptors and impulsivity to increased addictive behavior in rats. It was a short summary but the interesting part is this ": 





> impulsive rats, which had never before been exposed to cocaine, self-administered more of the drug than non-impulsive rats. Moreover, the higher the rats’ pre-drug impulsivity levels, the fewer dopamine D2/3 receptors they had in the nucleus accumbens, a brain structure known to have a role in motivation and reward.



That's pretty cool shit to me. It provides more basis for the belief that impulsive people, particularly the ADD population, are theoretically more inclined to have an addictive personality. The first line of treatment is usually stimulants and since most stims I know are dopaminergic, It could be safe to assume that is the reason most medicated ADD'ers are less likely to self-medicate with other drugs. And the fact that depression is a comorbidity very commonly observed with people with ADD, its plausible to hypothesize the 2 are related to having low dopamine levels/receptors

I hope that made sense lol


----------



## DexterMeth

n-acetyl-cystiine (NAC).  Has using this with amps been discussed?

IIRC, it's used as a first line "antidote" for APAP poisoning in hospitals.
A friend said it seemed to tune down a certain number of negative effects and crash associated with methamp and amp, but not at all with 2-FMA.  

I'm still reading about it, so I know very little atm.

Edit - He also said that it removes hangovers from alcohol and/or prevents them.


----------



## Epsilon Alpha

crestfallen said:


> This is a really interesting thread. I recently found a study at my uni that correlates the # of DA receptors and impulsivity to increased addictive behavior in rats. It was a short summary but the interesting part is this ":
> 
> That's pretty cool shit to me. It provides more basis for the belief that impulsive people, particularly the ADD population, are theoretically more inclined to have an addictive personality. The first line of treatment is usually stimulants and since most stims I know are dopaminergic, It could be safe to assume that is the reason most medicated ADD'ers are less likely to self-medicate with other drugs. And the fact that depression is a comorbidity very commonly observed with people with ADD, its plausible to hypothesize the 2 are related to having low dopamine levels/receptors
> 
> I hope that made sense lol



Lol no worries it made sense, its pretty interesting looking at the roles of D2 like receptors (D2, D3, and D4) in impulsiveness and social roles. Here's some interesting info on it that pretty much damns the whole "amphetamine for social anxiety" movement as well (sorry MeD, D2 downregulation is a bitch :/).

http://www.nature.com/neuro/journal/v5/n2/abs/nn798.html


----------



## Epsilon Alpha

Aetherius Rimor said:


> Edit: Side note, is there a link you can share that goes more in depth of the differences between sensitization and tolerance, or would you be willing to describe them a little more? I'm not sure I follow, but as I currently interpret what you're saying, sensitization is an increased desire for it, and tolerance is a reduced effectiveness of it? If that's the correct meanings, it would explain my experience with opiate/benzo to say that I gain no sensitization, but do gain tolerance, correct?



http://www.ncbi.nlm.nih.gov/pubmed/18486243 Review of rat amphetamine model of schizophrenia
http://www.sciencemag.org/content/207/4428/329.short
Most of it seems to stem from inadvertent activation of the stress response rather than activation of the reward pathways 


> Functional Magnetic Resonance Imaging Investigation of the Amphetamine Sensitization Model of Schizophrenia in Healthy Male Volunteers



Amphetamine kind of seems to mimic intense longterm stress in abuse settings which seems to be similar to intense negative experiences seen commonly in the onset of bipolar/schizophrenia. Interestingly enough, it appears to be a more corticosteroid/5HT/NE/Glu mediated process to me than the traditional dopamine theories.


----------



## DexterMeth

Epsilon Alpha said:


> http://www.ncbi.nlm.nih.gov/pubmed/18486243 Review of rat amphetamine model of schizophrenia
> http://www.sciencemag.org/content/207/4428/329.short
> Most of it seems to stem from inadvertent activation of the stress response rather than activation of the reward pathways
> 
> 
> Amphetamine kind of seems to mimic intense longterm stress in abuse settings which seems to be similar to intense negative experiences seen commonly in the onset of bipolar/schizophrenia. Interestingly enough, it appears to be a more corticosteroid/5HT/NE/Glu mediated process to me than the traditional dopamine theories.



Excuse my ignorance, but what does "Glu" stand for.. Glucosamine?


----------



## Epsilon Alpha

DexterMeth said:


> Excuse my ignorance, but what does "Glu" stand for.. Glucosamine?



Glutamate


----------



## Dizmal

I am quite under-educated compared to most of you, but recently I have noticed that drinking a moderate amount of alcohol before, during and after a meth session can decrease the duration and effects of the amphetamine.  

Could this be due to the fact alcohol increases the speed of dopamine transmission thus speeding up effects of meth or is it more the anti-GABA effects?

EDIT: I do not read every bumped thread every day so soz if I have missed the answer to my question and you assume Im retarded.  UTFSEncylopedia I know


----------



## Aetherius Rimor

I'm assuming it's going to be a combination of both GABA/NMDA effects that Alcohol has.

Being a sedative due to GABA, and the neuroprotective qualities of NMDA. Speculation on my part based on what I've read so far, but that's my initial guess.


----------



## polymath

Dizmal said:


> I am quite under-educated compared to most of you, but recently I have noticed that drinking a moderate amount of alcohol before, during and after a meth session can decrease the duration and effects of the amphetamine.



Alcohol lowers the pH of your urine and is a diuretic. These effects increase the renal excretion of amphetamines and shorten the duration of action. Taking a lot of vitamin C to acidify your urine would have the same effect. (in fact for this reason, amphetamine overdose victims are given vitamin C or ammonium chloride through an IV drip in the hospital)


----------



## DexterMeth

Dizmal said:


> I am quite under-educated compared to most of you, but recently I have noticed that drinking a moderate amount of alcohol before, during and after a meth session can decrease the duration and effects of the amphetamine.
> 
> Could this be due to the fact alcohol increases the speed of dopamine transmission thus speeding up effects of meth or is it more the anti-GABA effects?
> 
> EDIT: I do not read every bumped thread every day so soz if I have missed the answer to my question and you assume Im retarded.  UTFSEncylopedia I know





DexterMeth said:


> n-acetyl-cystiine (NAC).  Has using this with amps been discussed?
> 
> IIRC, it's used as a first line "antidote" for APAP poisoning in hospitals.
> A friend said it seemed to tune down a certain number of negative effects and crash associated with methamp and amp, but not at all with 2-FMA.
> 
> I'm still reading about it, so I know very little atm.
> 
> Edit - He also said that it removes hangovers from alcohol and/or prevents them.



anyone?


----------



## Aetherius Rimor

polymath said:


> Alcohol lowers the pH of your urine and is a diuretic. These effects increase the renal excretion of amphetamines and shorten the duration of action. Taking a lot of vitamin C to acidify your urine would have the same effect. (in fact for this reason, amphetamine overdose victims are given vitamin C or ammonium chloride through an IV drip in the hospital)



Thanks! Wasn't aware of that. I'm sure the things I mention have some effect (even if negligible) on dampening the experience, but that definitely explains the shorter duration.


----------



## Epsilon Alpha

DexterMeth said:


> anyone?



We talked a little about NAC, and my take on it was its promising short term but has some potential to be negative long term at high doses.


----------



## DexterMeth

Not sure an "antidote" should ever be used long term, no?
Sounds like something good to on hand.

I was not thinking long term or high doses at all though.  If it works so well, I can see how it would quickly get out of hand and cause harm.


----------



## polymath

NAC prevents hangovers because it binds to acetaldehyde, the toxic metabolite of alcohol.

http://www.ncbi.nlm.nih.gov/pubmed/8833231


> All known pathways of ethanol metabolism result in the production of acetaldehyde, a highly reactive compound. N-acetyl cysteine, an analogue of the dietary amino acid cysteine, binds acetaldehyde, thus preventing its damaging effect on physiological proteins.


----------



## Tussmann

polymath said:


> NAC prevents hangovers because it binds to acetaldehyde, the toxic metabolite of alcohol.
> 
> http://www.ncbi.nlm.nih.gov/pubmed/8833231



Don't take it the morning after drinking though, or it actually does _MORE_ damage.


----------



## Tussmann

Epsilon Alpha said:


> We talked a little about NAC, and my take on it was its promising short term but has some potential to be negative long term at high doses.



Here's an abstraction for you, Epsilon: What if you had to advocate the most effective NAC supplement protocol -- what would that entail?

Without going into explicit details, I take NAC for a WIDE variety of reasons, and have nestled it in as a top 10 health supplement of mine over the last 1.5 years. I want to (or maybe I don't) continue taking it at ~1200 mg a day.


----------



## Epsilon Alpha

Tussmann said:


> Here's an abstraction for you, Epsilon: What if you had to advocate the most effective NAC supplement protocol -- what would that entail?
> 
> Without going into explicit details, I take NAC for a WIDE variety of reasons, and have nestled it in as a top 10 health supplement of mine over the last 1.5 years. I want to (or maybe I don't) continue taking it at ~1200 mg a day.



To be honest man, I hardly have any time to research any more but I haven't seen any data either way. If you've figured out something that works for you for several reasons, by all means keep on it. I just wouldn't advocate long term use of it for amphetamine toxicity only, and I'd also maybe advocate for taking it before your amp just to make sure it gets absorbed prior.


----------



## DexterMeth

Tussmann said:


> Don't take it the morning after drinking though, or it actually does _MORE_ damage.



How so


----------



## Tussmann

DexterMeth said:


> How so



Actually causes MORE oxidation stress. Basically NAC after a night of drinking turns into a Pro-oxidant.


----------



## Epsilon Alpha

Probably posted this paper before, but its such a good read!
http://www.nature.com/nrn/journal/v12/n11/full/nrn3111.html#B107

It pretty much states that CREB -> DeltaFosB -> NF-kb -> epigenetic changes (though each step in the above appears to mediate changes).
Multiple myocyte-specific enhancer factor 2 (MEF2) is likely a mechanism for NMDA mediated epigenetic changes as it is regulated by Ca2+ sensitive proteins.



> By contrast, a very different cascade mediates chronic amphetamine-induced repression of the Fos gene. Here, ΔFOSB binds to the Fos promoter and recruits HDAC1 and SIRT1, and presumably numerous other proteins90.


 Not sure I like the fact amphetamine treatment modulates SIRT1... Its heavily involved in the ageing process :/


----------



## totally81

Epsilon Alpha said:


> .
> 
> Not sure I like the fact amphetamine treatment modulates SIRT1... Its heavily involved in the ageing process :/



Bummer. Well, I believe amph is *highly* pro-aging, so maybe take SIRT1 'nutrients' like resveratrol, pterostilbene, and what else? Vit D?  
Sry if this has already been discussed, nice thread.


----------



## Epsilon Alpha

totally81 said:


> Bummer. Well, I believe amph is *highly* pro-aging, so maybe take SIRT1 'nutrients' like resveratrol, pterostilbene, and what else? Vit D?
> Sry if this has already been discussed, nice thread.



They've been mentioned but not discussed in depth, that would be a good place to turn the discussion to. I looked at ginseng and it appears that the doses of even the active constitute (RG-1) would be in the grams unless it has some sort of synergistic actions I'm missing.

Interestingly enough SIRT1 appears to be responsible for both gene silencing (presumably involved in the downregulation of many proteins by amphetamine, which may be a key point in tolerance) and the strangely low rates of dementia found in stimulant users.

Weird... I'm going to have to do more digging


----------



## _Olon_

Here is a nice article about the mechanism of NAC and cefriaxone in treatment of drug addiction.
http://www.ncbi.nlm.nih.gov/pubmed/19717140


----------



## Epsilon Alpha

_Olon_ said:


> Here is a nice article about the mechanism of NAC and cefriaxone in treatment of drug addiction.
> http://www.ncbi.nlm.nih.gov/pubmed/19717140



Interesting, I wasn't aware of that transporter being so important in addiction. Does it have any actions in the VTA?


----------



## _Olon_

Epsilon Alpha said:


> Does it have any actions in the VTA?


Sorry, I am not so much into the addiction topic. This is just something I accidentally stumbled upon on my search for the effects of glutamate transporters in schizophrenia and treatment with clozapine.


----------



## enduin

I know this is slightly off topic but I posted about it few months ago and you didn't tear me a new one, so I assume it's ok.

In my previous post I asked about suggestions on how to minimize the racing heart and palpitations I usually get from my Dexedrine because I take it as needed and not every day (have ADD but just got recently diagnosed so I'm used to deal with it and prefer to not take medications when it's not too bad).

I started using propanolol and so far it's been amazing! I just take a quarter of a pill (10mg) with the Dexedrine pill and I don't experience any acceleration in my heartbeat, and only an acceptable increase in blood pressure (not different than without the propanolol). If I add one aspirin to the mix I can also avoid the increase in blood pressure.

I know this thread is about neurotoxicity and tolerance, but I'm also concerned about the effects on the cardiovascular system, so I figured I'd share.

I actually don't really understand why beta blockers are not more widely used, I know there's a lot of talk about them not being good with stimulants but I couldn't really find a lot of evidence, besides the theory that since they only block the beta adrenergic receptors more drug would activate the alpha receptors with an increased rise in blood pressure from vasoconstriction. Is there any actual evidence against the use of beta blockers and stimulants (in particular amphetamines) that you guys can share?


----------



## Epsilon Alpha

enduin said:


> I know this is slightly off topic but I posted about it few months ago and you didn't tear me a new one, so I assume it's ok.


*grabs fisting gloves as a precaution and starts Rammstein playlist*



> I know this thread is about neurotoxicity and tolerance, but I'm also concerned about the effects on the cardiovascular system, so I figured I'd share.
> 
> I actually don't really understand why beta blockers are not more widely used, I know there's a lot of talk about them not being good with stimulants but I couldn't really find a lot of evidence, besides the theory that since they only block the beta adrenergic receptors more drug would activate the alpha receptors with an increased rise in blood pressure from vasoconstriction. Is there any actual evidence against the use of beta blockers and stimulants (in particular amphetamines) that you guys can share?



Well beta blockers are stellar drugs, they're generic to the extreme and can produce some rather unpleasant side effects in some populations. Not to mention the "anxiety crowd" just seems to be hell bent on benzo's, so this class of drug is even further overlooked. So in short, its more of a marketing issue than a efficacy issue.

The issues with amphetamine use is that its much like MAO-B inhibitors in the fact if dosed carefully it can have a positive effect on the user yet improper dosing can result in sudden severe distress (think massive doses of either drug during a meth binge ). I can't recall any solid studies on it off the top of my head, but its been covered before.


----------



## Tussmann

I love propanolol too but I now use it sparingly (10-30 mg at a time). Beta blockers can cause depressive symptoms with chronic use as well as unwanted fat gain.

40-60 mg is almost recreational in those with high bodily anxiety.


----------



## Epsilon Alpha

Well looks like piracetam increases stimulant response in rats in a distinctly non-placebo manner. And, before everyone comes rushing in asking "is it safe to mix?" I will answer with a resounding "don't know,probably not". Piracetam's known pharmacology suggests that it would boost several processes known to worsen amphetamine tolerance (weak NMDA/AMPA positive allosteric modulation, no radical scavenging ability, and weird weird effects on membranes) but who knows what else it can do. Small molecule drugs like piracetam are notoriously dirty, binding to everything at low concentrations yet requiring doses so high its ridiculous.
http://www.ncbi.nlm.nih.gov/pubmed/22607774
http://hightowerpharmacology.blogspot.ca/2012/01/pharmacology-of-nootropics-volume-1.html


----------



## DexterMeth

> _Similarly, positively modulating the AMPA receptor itself increases the activation of the NMDA receptor, and so piracetam can be considered to be somewhat self-potentiating._


 ^From the hightowerpharm link.
--------------------

I don't understand this.  How can a compound be self-potentiating?
------------------

Same link: 





> _One of the advantages of allosteric activation is that it supports receptor activation even in the presence of physiological receptor antagonists (barbiturates, benzodiazepines, alcohol). Similarly, allosterism prevents receptor over-activation in the presence of excessive agonist (glutamate)_.


^Does this mean that piracetam prevents receptor over-activation when using amphetamines?
----------------------


> n addition to enhancing glutaminergic neurotransmission, piracetam also effects, and is effected by, the cholinergic system. This system consists of 2 families of receptors (metabotropic & ionotropic) and its ligand, acetylcholine (Ach). In dementia and cognitive decline, both types of receptors are diminished along with the production of acetylcholine. The reason for the latter is due to a generalized death of acetylcholine producing neurons in the hippocampus, and due to diminished production of the enzyme choline acetyl transferase. The latter is responsible for the reason that supplementing with acetylcholine precursors has little impact on cognition in dementia, whereas compounds that prevent the degredation of acetylcholine (Acetylcholinesterase Inhibitors) markedly improve dementia symptoms.


Couldn't one just take choline? Even if you did, I take it that has nothing to do with preventing acetylcholine from degrading.  Again, I don't believe I understand this.  Guess I should read more into acetylcholine and acetylcholinesterase inhibitors.  Something tells me choline bitartate (cheaper yes), should always be taken with piracetam.
------------------



> _Coenzyme Q10 (CoQ10) is a fat soluble compound which participates in the ETC as an electron acceptor from Complex I and II. Relative deficiencies of CoQ10 have generalized deleterious effects on the body, mostly as a result of mitochondrial dysfunction. Supplemental CoQ10 has a multitude of health benefits including limiting membrane peroxidation, and reducing ROS formation. The latter two mechanisms would naturally support mitochondrial longevity and function, and synergize well with piracetam. Co-supplementing with Vitamin E helps to regenerate the active form of CoQ10, ubiquinol from its oxidized form, ubiquinone. There is also some evidence that the combination increases tissue retention of CoQ10 (14). Keep in mind that these effects would require chronic supplementation in order to be observed, and that the effects will be much more pronounced in those experiencing progressive memory decline._


Ok.. so I should get CoQ10, Vitamin E, and ALCAR.

I guess this is off topic from amp toxicity, but I found that an informative read.  Not sure what the 2nd link had to do with this thread though.. because of the talk of AMPA?


----------



## MeDieViL

Epsilon alpha whats your opinion on quercetin?

Its been shown in rodents to atenuate morphine tolerance due to its ability to supress nos; nos is implicated in tolerance to opiates; benzo's and sensitization to amphetamine and cocaine (possibly tolerance too).
It may also work on other pathways involved in tolerance but our mod probably knows more about this.
It is a SIRT1 Antagonist tough not a agonist as first tought.

Im also interested in its ability to supress PDE4 and raise camp wich potentiates LTP.
On imminst people had very interesting results by combining a PDE4 inhibitor; forskolin to increase cAMP further and a stimulant (drastic tolerance reduction has been reported too wich may be attributed to cAMP's ability to upregulate D2)



> Evidence for involvement of ventral tegmental area cyclic AMP systems in behavioral sensitization to psychostimulants.
> Tolliver BK, Ho LB, Reid MS, Berger SP.
> Source
> Department of Psychiatry, University of California at San Francisco, USA.
> Abstract
> The present study investigated the role of ventral tegmental area (VTA) cyclic AMP (cAMP) systems in the behavioral sensitivity to psychostimulants in male Sprague-Dawley rats. Bilateral microinjections of cholera toxin (CTX) into the VTA (50-500 ng/500 nl/side) dose-dependently sensitized animals to the locomotor stimulant effects of systemic d-amphetamine, cocaine and apomorphine, but were without effects on morphine-induced locomotion 24 hr after microinjection. The CTX-induced behavioral sensitization to amphetamine was even greater 72 hr after microinjection, but was no longer present 14 days after intra-VTA CTX pretreatment. Coadministration of the cAMP-dependent protein kinase inhibitor H8 into the VTA blocked CTX-induced sensitization to amphetamine, suggesting that the sensitization is dependent on phosphorylation events in the VTA mediated by cAMP-dependent protein kinase. Pretreatment with CTX did not enhance amphetamine-induced dopamine release in the nucleus accumbens relative to saline controls 24 hr after microinjection. A single bilateral injection of d-amphetamine into the VTA (5 micrograms/side) produced a significant sensitization to systemic amphetamine challenge 72 hr later, and this effect was also blocked by coadministration of H8 into the VTA. These results extend previous studies which have established the importance of the VTA in the development of behavioral sensitization and suggest that cAMP systems may play a crucial role in this neuroadaptive process.


Dont know wheter this has been discussed before.

Also i have posted before how DAA has been reported to reverse stimulant tolerance; while nmda downregulation seemed a reasonable explanation one of the anecdotes reported tolerance reversal straight away; increases in cAMP can explain this.



> D-Aspartic acid is a novel endogenous neurotransmitter.
> D'Aniello S, Somorjai I, Garcia-Fernàndez J, Topo E, D'Aniello A.
> Source
> Departament de Genètica, Institut de Biomedicina, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
> Abstract
> D-aspartic acid (D-Asp) is present in invertebrate and vertebrate neuroendocrine tissues, where it carries out important physiological functions and is implicated in nervous system development. We show here that D-Asp is a novel endogenous neurotransmitter in two distantly related animals, a mammal (Rattus norvegicus) and a mollusk (Loligo vulgaris). Our main findings demonstrate that D-Asp is present in high concentrations in the synaptic vesicles of axon terminals; synthesis for this amino acid occurs in neurons by conversion of L-Asp to D-Asp via D-aspartate racemase; depolarization of nerve endings with K(+) ions evokes an immediate release of D-Asp in a Ca(2+) dependent manner; specific receptors for D-Asp occur at the postsynaptic membrane, as demonstrated by binding assays and by the expansion of squid skin chromatophores; D-aspartate oxidase, the specific enzyme that oxidizes D-Asp, is present in the postsynaptic membranes; and stimulation of nerve endings with D-Asp triggers signal transduction by increasing the second messenger cAMP. Taken together, these data demonstrate that D-Asp fulfills all criteria necessary to be considered a novel endogenous neurotransmitter. Given its known role in neurogenesis, learning, and neuropathologies, our results have important implications for biomedical and clinical research.





> D-aspartate: an atypical amino acid with neuromodulatory activity in mammals.
> Errico F, Napolitano F, Nisticò R, Centonze D, Usiello A.
> Source
> Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, Naples, Italy.
> Abstract
> Within the pool of endogenous amino acids, serine and aspartate are the only two residues occurring at significant concentrations in free D-form in mammalian tissues. D-Serine (D-Ser) is mainly localized in the forebrain structures of the CNS throughout embryonic development and postnatal phase. Compelling evidence demonstrates that D-Ser has a functional role as an endogenous co-agonist at N-methyl-D-aspartate receptors (NMDARs) and shows its beneficial involvement in psychiatric disorders including schizophrenia. On the other hand, knowledge concerning the role of free D-Asp in mammals has so far been less extensive. D-Asp occurs in the brain as well as in peripheral tissues including the endocrine glands. In endocrine glands, D-Asp levels increase during the postnatal period in concomitance with their functional maturation. The involvement of D-Asp in the regulation of the synthesis and/or release of different hormones has been clearly demonstrated. However, its biological significance in the brain is still obscure. D-Asp appears with a peculiar temporal pattern of localization, being abundant during embryonic development and strongly decreasing after birth. This phenomenon is the result of the postnatal onset of D-Asp oxidase (DDO) expression, the only known enzyme that strictly controls the endogenous levels of D-Asp. The pharmacological affinity of D-Asp for the glutamate site of NMDARs has raised the intriguing question whether this D-amino acid may have some in vivo influence on responses mediated by this subclass of glutamate receptors. In order to unveil the physiological function of D-Asp and of its metabolizing enzyme, genetic and pharmacological approaches have been recently developed. It has now become possible to generate animal models with abnormally elevated levels of D-Asp in adulthood based on the targeted deletion of the Ddo gene and on the oral administration of D-Asp. These animal models have thus highlighted that D-Asp has a neuromodulatory role at NMDARs in brain areas where they regulate crucial nervous functions. Indeed, abnormally high D-Asp levels in the hippocampus are able to strongly enhance NMDAR-dependent LTP and, in turn, to facilitate spatial memory of mice. Moreover, in both mutant and treated animals, this deregulated D-Asp content completely suppresses striatal LTD, most likely via overactivation of NMDARs. The later synaptic plasticity alteration resembles that produced by chronic administration of haloperidol and is probably the neurobiological substrate responsible for the attenuation of prepulse inhibition deficits induced by amphetamine and MK-801 in Ddo knockout and D-Asp-treated mice. These in vitro and in vivo findings, together with others reported in this review, support a neuromodulatory action for D-Asp at glutamatergic synapses. In addition, they suggest that this D-amino acid may play a potential beneficial role in conditions related to a pathological hypofunctioning of NMDARs in the mammalian brain.


----------



## MeDieViL

Epsilon Alpha said:


> Not sure I like the fact amphetamine treatment modulates SIRT1... Its heavily involved in the ageing process :/



It actually appears that SIRT1 isnt that much involved as first tought (compounds that activate this dont extend the lifespan of rodents wich supports this) but sirt3 plays a much more important role. But there are so many genes involved its hard to know whats going on; another example resveratrol wich inhibits telemorase also involved in aging doesnt reduce lifespan either.

@Dextermeth
Piracetam appears to act on nmda but not only that also on AMPA; because of acting on AMPA it increases the activation of the nmda receptor so basicly it potentiates itself by acting on AMPA too.


----------



## MeDieViL

Epsilon Alpha said:


> Lol no worries it made sense, its pretty interesting looking at the roles of D2 like receptors (D2, D3, and D4) in impulsiveness and social roles. Here's some interesting info on it that pretty much damns the whole "amphetamine for social anxiety" movement as well (sorry MeD, D2 downregulation is a bitch :/).
> 
> http://www.nature.com/neuro/journal/v5/n2/abs/nn798.html


Its a bitch but it can be overcome however i dont think memantine really is ideal as it impairs LTP; so im trialling alternatives. (Stimulants still work for my social anxiety after using them for damn ages as an aside.)


----------



## Epsilon Alpha

MeDieViL said:


> It actually appears that SIRT1 isnt that much involved as first tought (compounds that activate this dont extend the lifespan of rodents wich supports this) but sirt3 plays a much more important role. But there are so many genes involved its hard to know whats going on; another example resveratrol wich inhibits telemorase also involved in aging doesnt reduce lifespan either.
> 
> @Dextermeth
> Piracetam appears to act on nmda but not only that also on AMPA; because of acting on AMPA it increases the activation of the nmda receptor so basicly it potentiates itself by acting on AMPA too.



Damn MeD you did your homework! And, spot on with the explanation 

As for my opinion on quercetin: its a steller in vitro substance though its oral bioavailability makes me wonder if direct supplementation has any sort of benefit over a natural source, say a bowl of blueberries and walnuts. It certainly won't hurt if its known pharmacology pans out, but I'd say for now its just another reason to cook with as many spices as possible and eat berries/leafy greens.

cAMP is a weird weird thing to look at on a gross scale as its more of a where/when/how much type messenger than the neurotransmitters we're more accustomed to discussing here. I'm not familiar with PDE4 expression, but I'll have to look into that. Mind going more in depth on the role of cAMP? I've kind of pigeon holed my research on it into CREB and PKA only.


----------



## MeDieViL

Im fully researching it at the moment so cant say much but i think especially PDE inhibition is extremely interesting and of therapeutic value.

cAMP is extremely important in LTP and combined with a PDE4 wich inhibits its breakdown and a stimulant there seems to be some very potent cognitive enhancement going on.
I have to research this more as PDE's and cAMP can have implications in anhedonia; tolerance; addiction; ADHD; social impairment but not all those are relevant to this forum.


----------



## Tussmann

MeDieViL said:


> Im fully researching it at the moment so cant say much but i think especially PDE inhibition is extremely interesting and of therapeutic value.



So should I pop some more cialis?


----------



## MeDieViL

If youv been hanging weights on your dick like ubiya you wont need any.


----------



## Tussmann

Dude that was a serious question MeD. Also, what is your gmail, I'm sick of you popping up every other month.


----------



## MeDieViL

I dont see any reason for you to take viagra.

Just pm your msn im to lazy to reply to pm's most of the time.


----------



## Tussmann

Well, I do get the impression that PDE5 inhibitors are great for the amph comedown. I feel like my blood is flowing again, maybe its purely psychological, but I think not.

I don't have MSN you douche, and I know you're lazy. You're telling me you don't have a gmail account?...If not you better get one.


----------



## MeDieViL

Ok epsilon alpha help me out on this shit.

I may be completely off but:
Dopamine doesnt cause reward itself; DRI's do cause reward wich is trough the mu opiate receptors.

I know from my shizo past that opiates dont work unless combined with a DRI.
I also know that cGMP is required for reward and is rewarding itself.

How does this all fit togheter?
I think PDE inhibitors may be the key for anhedonia and sa related issues as they modulate both dopamine and cGMP so mu is able to operate.

Srry for all this scattered shit; again may be completely off but have been compiling some shit here; its another of my too optimistic posts where you cant make def conclusions off but optimism often wins.
http://www.longecity.org/forum/topic/56694-pde10-inhibitor-and-its-potential-uses/

Ill pm you
Well gCMP is rewarding atleast according to cpp study's and all the shit.


----------



## MeDieViL

> Brain Res Bull. 2010 Apr 5;81(6):549-51. Epub 2009 Dec 14.
> Selective D1 agonism but not D2 antagonism is reflected in cAMP and cGMP levels in rat CSF.
> Torremans A, Van Hemelrijck A, Straetemans R, Vanhoof G, Van Den Kieboom G, Drinkenburg WH.
> Source
> Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica NV, 2340 Beerse, Antwerp, Belgium. antorremans@hotmail.com
> Abstract
> Cyclic adenosine 3'5'-monophosphate (cAMP) and cyclic guanosine 3'5'-monophosphate (cGMP) serve as second messengers in several cellular pathways within the central nervous system. In various neurological and psychiatric disorders with known deficits in neurotransmission function, CSF levels of cAMP and/or cGMP in patients were studied. Very little information is currently available on cAMP and cGMP levels in CSF of animals. Moreover, this is the first study on the effects of pharmacological treatment on cAMP and cGMP levels in rat CSF. Effect of systemic treatment with a D1 receptor agonist SKF82958 and a D2 receptor antagonist haloperidol on cAMP and cGMP levels, as well as baseline cAMP and cGMP levels in CSF of rats was determined. A significantly increased cAMP and cGMP level in cisternal CSF of rats systemically treated with the D1 receptor agonist SKF82958 was observed, while when treated with the D2 antagonist haloperidol, no effect on cAMP and only a slight decrease of cGMP was observed after treatment with the highest dose. Determining cAMP and/or cGMP in CSF of experimental animals can serve as a useful tool to study neural processes affected by disease and treatment.


Shizo --> hypo D1 and hyper D2 --> Depleted levels of camp and cgmp --> Immume to mu related pleasure. However opiates witch induce cGMP and cAMP still arent working and research shows da needs to be active before reward can take place.

PDE inhibition may normalise all this, perhaps...
Its interesting studying pde; camp and cgmp tough they are implicated in alot of things.


----------



## DexterMeth

MeDieViL said:


> @Dextermeth
> Piracetam appears to act on nmda but not only that also on AMPA; because of acting on AMPA it increases the activation of the nmda receptor so basicly it potentiates itself by acting on AMPA too.



Is piracetam the only nootropic racetam that exerts this action?


----------



## DexterMeth

"Amphetamine effect on the choline concentration of human cerebrospinal fluid'
-----

_Abstract
The choline concentration of the lumbar cerebrospinal fluid of amphetamine dependent subjects has been measured during amphetamine intoxication and after detoxification. It was found that the choline level was significantly higher during the intoxication period than after. The results are discussed in view of the known amphetamine effect on the acetylcholine release from brain cortex._

So is choline to be avoided while on amps or what?


----------



## sekio

Not neccesarily, amphetamine releases lots of norepinephrine etc. but tyrosine supplementation doesn't seem to have any harm.

Your body has lots of feedack mechanisms to help it keep the right levels of neurotransmitters derived from dietary nutrients, like choline and the monoamines. This explains why you can eat things like soy lecithin and not have them be directly psychoactive.


----------



## Epsilon Alpha

Does anyone have the free fulltext for the MDMA+viagra in rats/mice study?
I really want to see what it has to say.

NO. appears to be rather central in the whole process from NDMA to epigenetic CNS changes.


----------



## polarbearsarecool

Epsilon, the histone deacetylase inhibition has led me to a frightening conclusion, you focus mainly on curcumin but..

Psychiatry and neurology

HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics. The prime example of this is valproic acid, marketed as a drug under the trade names Depakene, Depakote, and Divalproex. In more recent times, HDIs are being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.[11] Enhancement of memory formation is increased in mice given the HDIs sodium butyrate or SAHA, or by genetic knockout of the HDAC2 gene in mice.[12] While that may have relevance to Alzheimer's disease, it was shown that some cognitive deficits were restored in actual transgenic mice that have a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins.[13]
Cancer treatment

from wikipedia


this has connected a few puzzle pieces regarding why I was able to continue on just a 1mcg ULD NLTX, ~15mg dxm 300mg gabapentinx3 daily (later pregbalin 100mg x3) and 120 mg codeine which kept my tolerance and the euphoria at a minimum, with discontinuation of the pregbalin I was no longer able to even get remotely close euphoric effects from opiates without much higher levels. 

And the reason being? anti epileptics, benzos, ethanol, all appear to affect histone activity thus stopping these epigenetic changes.. it doesnt make sense though, because the study is claiming HDI action increases memory formation with sodium butyrate- but we all know these drugs have the opposite effect from another mechanism of action ?

What is going on exactly..


----------



## Epsilon Alpha

Sorry for the brief reply I'm on my phone , but it appears to me that all the commonly available HDAI's are dirty as hell. Curcumin was my main focus as its easily available and has a stellar safety record. 

Most of the mood stabilizers and ethanol have significant effects on the GABAgenic system which would explain some of their negative cognitive effects. I'm extremely interested in NO's effect on the epigenome right now.


----------



## Epsilon Alpha

So my laptop is currently in for repairs, hence the whole link free replies lately. But, it looks like the KEY or at the very least central component to the whole amphetamine tolerance and neurotoxicity issue is NO.

Literally every other major pathway from epigenetic changes, to NMDA dependent tolerance appears to worth through it or be effected by NO.
Currently chipping away at my MCAT and the next thread's OP's

And with that I ask you all to please dump free full texts for me :D


----------



## sekio

Here you go


----------



## Epsilon Alpha

Yet another big ol link dump! Epigenetics, NMDA, gap junctions, and NOS! Oh my!

http://www.jneurosci.org/content/20/6/2332.full.pdf
http://onlinelibrary.wiley.com/doi/10.1196/annals.1316.027/abstract
http://www.ncbi.nlm.nih.gov/pubmed/10482402
http://www.sciencedirect.com/science/article/pii/S0301008299000386 (basal cNOS vs iNOS)
http://www.sciencedirect.com/science/article/pii/S001429990302524X
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2000.tb05193.x/abstract (author directly looks at methamphetamine)
http://www.ncbi.nlm.nih.gov/pubmed/15337264 (points to a microglial connection)
http://www.landesbioscience.com/journals/cbt/NottCC8-5.pdf (details how NO modifies the epigenome in developing neurons, implications for stem cells? Also, details CREB interaction)
http://www.ncbi.nlm.nih.gov/pubmed/11585554 (It appears to be mediated via dopagenic transmission and produces biphasic effects on nNOS expression)
http://www.nature.com/ncb/journal/v3/n2/abs/ncb0201_193.html (some reading on a potentially relevant additional NO signalling pathway)

And, to show I'm not totally biased towards my own hunches: 
http://csbn.concordia.ca/faculty/amir/docs/Stewart-Brain Res 641 (1994).pdf
Not entirely sure I like how it was conducted, L-NAME has a really really short effective half life in the body which could explain the results


----------



## Tussmann

Epsilon Alpha said:


> Yet another big ol link dump! Epigenetics, NMDA, gap junctions, and NOS! Oh my!
> 
> http://www.jneurosci.org/content/20/6/2332.full.pdf
> http://onlinelibrary.wiley.com/doi/10.1196/annals.1316.027/abstract
> http://www.ncbi.nlm.nih.gov/pubmed/10482402
> http://www.sciencedirect.com/science/article/pii/S0301008299000386 (basal cNOS vs iNOS)
> http://www.sciencedirect.com/science/article/pii/S001429990302524X
> http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2000.tb05193.x/abstract (author directly looks at methamphetamine)
> http://www.ncbi.nlm.nih.gov/pubmed/15337264 (points to a microglial connection)
> http://www.landesbioscience.com/journals/cbt/NottCC8-5.pdf (details how NO modifies the epigenome in developing neurons, implications for stem cells? Also, details CREB interaction)
> http://www.ncbi.nlm.nih.gov/pubmed/11585554 (It appears to be mediated via dopagenic transmission and produces biphasic effects on nNOS expression)
> http://www.nature.com/ncb/journal/v3/n2/abs/ncb0201_193.html (some reading on a potentially relevant additional NO signalling pathway)
> 
> And, to show I'm not totally biased towards my own hunches:
> http://csbn.concordia.ca/faculty/amir/docs/Stewart-Brain Res 641 (1994).pdf
> Not entirely sure I like how it was conducted, L-NAME has a really really short effective half life in the body which could explain the results




So, how can we use this information to reduce or prevent tolerance to amphetamines?


----------



## Epsilon Alpha

Tussmann said:


> So, how can we use this information to reduce or prevent tolerance to amphetamines?



This like most of the stuff I'm still sitting on isn't refined enough for me to give any suggestions right now, but it does help tie in NMDA antagonists in with epigenetic changes as well as neuro-inflammation/microglial activation. What it does show its that if we start digging around NO we may find a central piece of the puzzle for both tolerance and toxicity. 

Other than that amphetamine may change gap junction function so that groups of neurons are more likely to fire in all-or-nothing bursts, potentially giving another reason to look at modafinil for amphetamine withdrawal. It also suggests that low dose modafinil might be a place to look, hell the stuff is even neuroprotective in combination with methamphetamine according to some animal studies.

Some reading on the role of the NMDA-NOS connection: http://www.jbc.org/content/269/17/12645.short
Cholecystokinin-NMDA-NOS relationship: http://www.anesthesia-analgesia.org/content/91/1/110.short


----------



## ProphetofProfit

Would anyone mind educating me on what is so special about blueberries please. They have been mentioned a few times in this thread but my knowledge of them was that their antioxidant content was less than that of coffee and cacao. Is there a magical ingredient that I don't know about?


----------



## ProphetofProfit

There is much I do not understand about these substances and I would like to know a little more because there are some possible issues with consuming the 2/3/4-fluoroamphetamines. There is little information on available on the specific drugs but perhaps by applying some psychopharmacological principles it's is possible to assess their long term safety. I have read every thread on bluelight concerning 2-fa but my lack of knowledge makes the process of putting all the jigsaw puzzle pieces together problematic. 

2-fluoroamphetamine:





Wikipedia is telling me that



> The high reactivity of fluorine means that once it does react with something, it bonds with it so strongly that the resulting molecule is very inert and non-reactive to anything else.



Now does this make 2-fa just dextroamphetamine with a fluorine added? Would you consider 2-fa safe because of the strength of the C-F bond? Am I committing unintentional suicide if I consume 2-fa regularly?

tyvm


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## trance in fraance

Quick question:
I'm prescribed Wellbutrin 300mg/day for depression and from what I've read it's apparently an amphetamine? If anyone could clarify it'd be much appreciated. And if it is, should I be worried about neurotoxicity?


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## sekio

Re: Fluoroamphetamine toxicity, fluorine bonds are incredibly hard to remove on organic compounds without essentially burning the molecule down. Fluorocarbons are actually often praised for their non-reactivity.

Even if, through some freak process, your body removed fluoride from the amphetamine, a dose of amphetamine would have something like 1-10mg of fluoride. You get more than that in a dose of toothpaste.

Re: Wellbutrin, buproprion is a lot closer to a cathinone and shouldn't be considered an amphetamine.


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## Epsilon Alpha

sekio said:


> Re: Fluoroamphetamine toxicity, fluorine bonds are incredibly hard to remove on organic compounds without essentially burning the molecule down. Fluorocarbons are actually often praised for their non-reactivity.
> 
> Even if, through some freak process, your body removed fluoride from the amphetamine, a dose of amphetamine would have something like 1-10mg of fluoride. You get more than that in a dose of toothpaste.
> 
> Re: Wellbutrin, buproprion is a lot closer to a cathinone and shouldn't be considered an amphetamine.



The biggest issue with the fluoroamphetamines is that they might have some weird toxicity that the SAR just doesn't predict. Look at the toxicity gap between methamphetamine and regular amphetamine and all the various other derivatives.

The amphetamine backbone is a very gifted structure, so relatively small changes in it can result in say an antidepressant/psychedelic/stimulant/toxic nightmare ala PMMA.


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## ebola?

pro(phet)(fit) said:
			
		

> Now does this make 2-fa just dextroamphetamine with a fluorine added? Would you consider 2-fa safe because of the strength of the C-F bond? Am I committing unintentional suicide if I consume 2-fa regularly?



Given that the para-halogenated amphetamines exhibit neurotoxicity not fully explained by their potency as trimonoamine releasers, some hesitancy with ring-halogenated compounds in general seems warranted.  However, when the halogen in question is fluorine and when affinity for SERT is nearly nil, we should expect reduced toxicity.

ebola


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## golden1

Just to add, subjectively of course, of 2-fa, 3-fa, 4-fa, and 2-fma that 3-fa feels much more stressful on both the brain and body and leaves me feeling uncomfortably stimulated and then very drained of mental energy the day after. The other 3 have no sort term side effects for me or negative comedown and I feel fine for any amount of time afterwards(I would say even less of a rebound effect than vyvanse, which is hardly anything). Of course this doesn't prove anything toxicologically, but to me it is kind of telling that 3-fa is much more subjectively toxic feeling. Might be one to stay away from, maybe they are all better to stay away from.. of any of them though 4-fa has the most use record and research by far and I've used it at low doses for a week or so with no negative except getting used to not being stimulated after stopping.

Also, how do you guys think piracetam effects neurotoxicity? I mean I know several studies where it's shown to be neuroprotective(unless my memory is failing me..) particularly for glutamate/nmda excitability(I wish I had the non-lazyness to find them atm, but maybe i will edit post if I find them). I mean I know when I take piracetam while on any sort of stimulant all the positives are greatly increased, it also makes me less laser focused(you know where you are _just too busy and focused on finishing something_ to even stop for a minute and use the bathroom) hahah.

It also brings back mental energy and mood days after taking stimulants(well.. and in general, but much more so when needed like that), so I don't know what to think.

I get the feeling it might be making the toxicity worse, yet I've taken it many times and in general it seems like I've had less after effects when I've done so... I'll get looking on the sources on piracetam unless someone chimes in beforehand


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## Epsilon Alpha

I posted the one study on piractam and stimulants out there to my knowledge a few weeks back. It potentates them, but we have no clue how aside from possible membrane effects and AMPA/NMDA allosteric modulation it exerts those effects.

My take on it is it might worsen outcomes by enhancing pathways associated with tolerance, but even that is just a shot in the dark and me being cautious.

I've come to see that a few of the more knowledgeable people on sites like this have their word taken without question. So, we need to be very careful about what we say. 

Hell, PQQ looked like a solid place to start, yet it seemed to lead to binges and mental health problems in some individuals with pre-existing issues. That's why I'm focusing more on the hard science and well known compounds now. 

I've got a few things in mind for the NO, NAChR, and MAOB angles, but I don't dare mention them now lest someone under informed hurt themselves. 

I'm just that hardcore harm reduction mod haha


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## Quercetin

Acute Hypoglycemia Presenting as Methamphetamine psychosis
http://www.bluelight.ru/vb/threads/632242-Acute-Hypoglycemia-Presenting-as-Methamphetamine-psychosis

Evidence based methamphetamine research on cessation
http://www.bluelight.ru/vb/threads/...research-on-cessation?p=10750516#post10750516


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## Limpet_Chicken

Epsilon alpha, I find it a real shame, when on a harm reduction and general drug user's forum you feel as though you can't post research that might allow people in need of it to (and meth/stimulant users in general are, along with benzo/sedative users, in need of more help than most IMO) come up with a protocol to minimize the potentially long lasting, and serious damage done.

I do see where you are coming from, but I have to question weather its the right decision to make. Then again I haven't seen what you haven't thus far posted. PM me?


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## Epsilon Alpha

Limpet_Chicken said:


> Epsilon alpha, I find it a real shame, when on a harm reduction and general drug user's forum you feel as though you can't post research that might allow people in need of it to (and meth/stimulant users in general are, along with benzo/sedative users, in need of more help than most IMO) come up with a protocol to minimize the potentially long lasting, and serious damage done.
> 
> I do see where you are coming from, but I have to question weather its the right decision to make. Then again I haven't seen what you haven't thus far posted. PM me?



Well some of the tamer bits are Viagra and various polyphenols. But, for the most part we're looking at stuff that's just made it into rat studies within the last 3 years. The potential for side effects outweighs the possible benefits for most of them. As for the MAO-B angle I think you know what I'm talking about though, and why its not a good idea to promote its use in individuals who aren't too well versed in biology. 

Also let's just say that quercetin's looking at one of the same angles I am with stimulants effects on basal metabolism. 
Hopefully that's just obscure enough, PM me if you need any clarification.


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## Quercetin

Vinpocetine enhance glucose uptake by brain neurons _
Vinpocetine is a slightly altered form of vincamine, an alkaloid extracted from the Periwinkle plant, vinca minor. In use for almost 30 years, research has gradually shown vinpocetine to be the superior vinca alkaloid, having few and minor if any side effects, with a greater range of metabolic and clinical benefits than vincamine. Vinpocetine has been shown to be a cerebral metabolic enhancer and a selective cerebral vasodilator. Vinpocetine has been shown to enhance oxygen and glucose uptake from blood by brain neurons, and to increase neuronal ATP energy production. Both animal and human research has shown vinpocetine to restore impaired brain carbohydrate/energy metabolism._

Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs.
4-Aminopyridine (4-AP) is a convulsing agent that in vivo preferentially releases Glu, the most important excitatory amino acid neurotransmitter in the brain. Here the ionic dependence of 4-AP-induced Glu release and the effects of several of the most common antiepileptic drugs (AEDs) and of the new potential AED, vinpocetine on 4-AP-induced Glu release were characterized in hippocampus isolated nerve endings pre-loaded with labelled Glu ([3H]Glu). 4-AP-induced [3H]Glu release was composed by a tetrodotoxin (TTX) sensitive and external Ca2+ dependent fraction and a TTX insensitive fraction that was sensitive to the excitatory amino acid transporter inhibitor, TBOA. The AEDs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine at the highest dose tested only reduced [3H]Glu release to 4-AP between 50-60%, and topiramate was ineffective. Vinpocetine at a much lower concentration than the above AEDs, abolished [3H]Glu release to 4-AP. We conclude that the decrease in [3H]Glu release linked to the direct blockade of presynaptic Na+ channels, may importantly contribute to the anticonvulsant actions of all the drugs tested here (except topiramate); and that the significantly greater vinpocetine effect in magnitude and potency on [3H]Glu release when excitability is exacerbated like during seizures, may involve the increase additionally exerted by vinpocetine in some K+ channels permeability.

_Excitability linked to glutamate modulation is exacerbated by methamphetamine administration. Glutamate signaling plays a significant role in regards to DAergic deficits. Glutamate also contributes to the persistent deficits, as suggested by the inhibition of these deficits when NMDA antagonist are administered. Dopaminergic cells within the striatum possess AMPA and NMDA receptors. Glutamate-induced activation of these receptors promotes Ca 2+ influx into the DAergic neuron. This effect, when excessive, can result in mitochondrial damage and neurotoxicity. _

Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation.
Brain injuries are common in professional American football players. Finding effective rehabilitation strategies can have widespread implications not only for retired players but also for patients with traumatic brain injury and substance abuse problems. An open label pragmatic clinical intervention was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated brain damage and cognitive impairment. The study included weight loss (if appropriate); fish oil (5.6 grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that included nutrients to enhance blood flow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain SPECT imaging. In the retest situation, corrected for practice effect, there were statistically significant increases in scores of attention, memory, reasoning, information processing speed and accuracy on the Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study demonstrates that cognitive and cerebral blood flow improvements are possible in this group with multiple interventions.

_Vinpocetine impact on blood flow may decrease BBB permeability. Significant increases in blood pressure is often experienced post-admisnistration. Vasodilatation and (PDE) type-1 inhibition may cause the effect on smooth muscle tissue.  _
_
Glucose Regulation 
Glucose is the principal brain fuel. Most other cells and organs of the body are able to "burn" fat as well as glucose to produce ATP bioenergy, but brain neurons can only burn glucose under normal, non-starvation/ketogenic conditions. The brain is only 2% of the body mass, yet typically consumes 15-20% of total body ATP energy. The brain is dependent on a second-by-second delivery of glucose from the bloodstream, as neurons can only store about a 2-minute supply of glucose (as glycogen) at any given time. The brain must have access to a large portion of the glucose flowing through the bloodstream.

Unlike most other body tissues, the brain does not require insulin to absorb glucose from the blood. The effect of insulin on the brain is less well defined. Elevations of circulating insulin can alter brain function, augmenting the counterregulatory response to hypoglycemia, altering feeding behavior. Thus, the optimal blood status for the brain to acquire its disproportionately large share of blood sugar is a normal blood sugar level, combined with low blood insulin. When insulin is low or absent in the bloodstream, the rest of the body will ignore the blood sugar and burn fat or amino acids for their fuel.

Methamphetamine is known to stimulate production of insulin, leaving the brain with less then adequate amount of glucose. This will cause a rapid glucose uptake by almost all body tissues, leaving far less than optimal supplies for the brain._

Methamphetamine-induced insulin release.
Administration of methamphetamine or amphetamine to rats and mice produces a rapid increase in the level of immunoassayable plasma insulin not attributable to hyperglycemia. While in the mouse this release of insulin is followed consistently by a profound hypoglycemia, in the rat this response is variable. Studies in vitro demonstrate that insulin is released by a direct effect of methamphetamine on the pancreas.

_Profound hypoglycemia is observed in the human subjects as well_

_Physiologic response to hypoglycemia
The physiologic response to hypoglycemia is a complex and well-coordinated process. In healthy humans, there is an ordered, failsafe response system that begins with a reduction in insulin secretion while blood glucose concentration is still in the physiologic range. As blood glucose concentration declines further, peripheral and central glucose sensors relay this information to central integrative centers to coordinate the secretion of counterregulatory hormones (glucagon, epinephrine, norepinephrine, growth hormone and cortisol, respectively) and avert the progression of hypoglycemia. Type 1 diabetes perturbs these counterregulatory responses: circulating insulin levels cannot be reduced (due to exogenous insulin); glucagon secretion is blunted or absent; and epinephrine secretion is blunted and shifted to a lower plasma glucose concentration. It is also observed in methamphetamine induced hyperinsulinemia.

Counterregulation has also been shown to be impaired in type 2 diabetes. In this setting, the glucagon response to hypoglycemia may be normal or blunted, while epinephrine response remains intact, if not augmented. Patients affected by type 1 and type 2 diabetes can develop the syndrome of hypoglycemia unawareness. 

Hypoglycemia unawareness develops as recurrent iatrogenic hypoglycemia shifts the glycemic threshold for counterregulation and development of hypoglycemic symptoms to lower plasma glucose concentrations. In this setting, neurogenic symptoms, which are usually the initial warning symptoms of hypoglycemia, are blunted and the first manifestation of hypoglycemia becomes neuroglycopenia. The mechanisms underlying the development of hypoglycemia unawareness may be related to both altered central sensing of hypoglycemia and impaired coordination of responses to hypoglycemia. Neuroglycopenia is a medical term that refers to a shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia. Glycopenia affects the function of neurons, and alters brain function and behavior.

*Signs and symptoms of neuroglycopenia*
Abnormal mentation, impaired judgement
Nonspecific dysphoria, anxiety, moodiness, depression, crying, fear of dying, suicidal thoughts
Negativism, irritability, belligerence, combativeness, rage
Personality change, emotional lability
Fatigue, weakness, apathy, lethargy, daydreaming, sleep
Confusion, amnesia, dizziness, delirium
Staring, "glassy" look, blurred vision, double vision
Automatic behavior
Difficulty speaking, slurred speech
Ataxia, incoordination, sometimes mistaken for "drunkenness"
Focal or general motor deficit, paralysis, hemiparesis
Paresthesia, headache
Stupor, coma, abnormal breathing
Generalized or focal seizures

Not all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by the severity of the hypoglycemia. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects or a hard-to-define malaise. The symptoms of a single person do tend to be similar from episode to episode.

Most neurons have the ability to use other fuels besides glucose (e.g., lactic acid, ketones). Our knowledge of the "switchover" process is incomplete. The most severe neuroglycopenic symptoms occur with hypoglycemia caused by excess insulin because insulin reduces the availability of other fuels by suppressing ketogenesis and gluconeogenesis.

A few types of specialized neurons, especially in the hypothalamus, act as glucose sensors, responding to changing levels of glucose by increasing or decreasing their firing rates. They can elicit a variety of hormonal, autonomic, and behavioral responses to neuroglycopenia. The hormonal and autonomic responses include release of counterregulatory hormones. There is some evidence that the autonomic nervous system can alter liver glucose metabolism independently of the counterregulatory hormones.

*Compensatory responses to neuroglycopenia*
Adjustment of efficiency of transfer of glucose from blood across the blood–brain barrier into the central nervous system represents a third form of compensation which occurs more gradually. Levels of glucose within the central nervous system are normally lower than the blood, regulated by an incompletely understood transfer process. Chronic hypoglycemia or hyperglycemia seems to result in an increase or decrease in efficiency of transfer to maintain CNS levels of glucose within an optimal range.

*Neuroglycopenia without hypoglycemia*
In both young and old patients, the brain may habituate to low glucose levels, with a reduction of noticeable symptoms, sometimes despite neuroglycopenic impairment. In insulin-dependent diabetic patients this phenomenon is termed hypoglycemia unawareness and is a significant clinical problem when improved glycemic control inefficient. Frequent in methamphetamine user, neuroglycopenia is observed after repeated hypoglycemic episode._


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## Quercetin

Dentate gyrus, stress, psychosis and depression
_The dentate gyrus is part of the hippocampal formation. It is thought to contribute to the formation of new memories, as well as possessing other functional roles. It may also have a functional role in stress and depression. However, the physiological effects of stress, often characterized by release of glucocorticoids such as cortisol, as well as activation of the sympathetic division of the autonomic nervous system, have been shown to inhibit the process of neurogenesis in primates. Both endogenous and exogenous glucocorticoids are known to cause psychosis and depression, implying that neurogenesis in the dentate gyrus may play an important role in modulating symptoms of stress and depression. Recent studies indicate that poor glucose control can lead to deleterious effects on the dentate gyrus._

Diabetes increases brain damage caused by severe hypoglycemia.
Insulin-induced severe hypoglycemia causes brain damage. The hypothesis to be tested was that diabetes portends to more extensive brain tissue damage following an episode of severe hypoglycemia. Nine-week-old male streptozotocin-diabetic (DIAB; n = 10) or vehicle-injected control (CONT; n = 7) Sprague-Dawley rats were subjected to hyperinsulinemic (0.2 U.kg(-1).min(-1)) severe hypoglycemic (10-15 mg/dl) clamps while awake and unrestrained. Groups were precisely matched for depth and duration (1 h) of severe hypoglycemia (CONT 11 +/- 0.5 and DIAB 12 +/- 0.2 mg/dl, P = not significant). During severe hypoglycemia, an equal number of episodes of seizure-like activity were noted in both groups. One week later, histological analysis demonstrated extensive neuronal damage in regions of the hippocampus, especially in the dentate gyrus and CA1 regions and less so in the CA3 region (P < 0.05), although total hippocampal damage was not different between groups. However, in the cortex, DIAB rats had significantly (2.3-fold) more dead neurons than CONT rats (P < 0.05). There was a strong correlation between neuronal damage and the occurrence of seizure-like activity (r(2) > 0.9). Separate studies conducted in groups of diabetic (n = 5) and nondiabetic (n = 5) rats not exposed to severe hypoglycemia showed no brain damage. In summary, under the conditions studied, severe hypoglycemia causes brain damage in the cortex and regions within the hippocampus, and the extent of damage is closely correlated to the presence of seizure-like activity in nonanesthetized rats. It is concluded that, in response to insulin-induced severe hypoglycemia, diabetes uniquely increases the vulnerability of specific brain areas to neuronal damage.

Withdrawal from chronic amphetamine produces persistent anxiety-like behavior but temporally-limited reductions in monoamines and neurogenesis in the adult rat dentate gyrus.
Acute amphetamine administration activates monoaminergic pathways and increases systemic corticosterone, both of which influence anxiety states and adult dentate gyrus neurogenesis. Chronic amphetamine increases anxiety states in rats when measured at 24 h and at 2 weeks of withdrawal. However, the effects of chronic amphetamine exposure and withdrawal on long term anxiety-like behavior and adult neurogenesis in the dentate gyrus are unknown. Adult male rats were administered amphetamine (2.5 mg/kg, ip.) daily for two weeks. Anxiety-like behaviors were increased markedly in amphetamine-treated rats following four weeks of withdrawal from amphetamine. Plasma corticosterone level was unaltered by amphetamine treatment or withdrawal. However, norepinephrine and serotonin concentrations were selectively reduced in the dentate gyrus 20 h following amphetamine treatment. This effect did not persist through the four week withdrawal period. In separate experiments, rats received bromodeoxyuridine to label cells in S-phase, prior to or immediately following amphetamine treatment. Newly generated cells were quantified to measure extent of progenitor cell proliferation and neurogenesis following treatment or withdrawal. Progenitor cell proliferation and neurogenesis were not significantly affected by amphetamine exposure when measured 20 h following the last amphetamine treatment. However, neurogenesis in the dentate gyrus was reduced after four weeks of withdrawal when compared to saline-pretreated rats. Overall, our findings indicate that withdrawal from chronic amphetamine leads to persistent anxiety-like behavior which may be maintained by reduced neurogenesis in the dentate gyrus at this protracted withdrawal time point. However, neurogenesis is unaffected at earlier withdrawal time points where anxiety states emerge, suggesting different mechanisms may underlie the emergence of anxiety states during amphetamine withdrawal.

Hypothesis
_Methamphetamine induced hypoglycemia/neuroglycopenia, caused by insulin secretion have deleterious impact on the dentate gyrus, part of the hippocampus, which is also observed with diabetic experiencing hypoglycemia from exogenous insulin. The functional role in stress and depression play an important role in modulating symptoms causing relapse. An educated guess tend to make me believe that a dysfunctional dentate gyrus, could potentially explain poor emotional intelligence often observed with methamphetamine abuser._


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## Quercetin

N-Acetylcysteine prevent metabolic changes 
_Acetylcysteine has been shown to reduce the symptoms of both schizophrenia and bipolar disorder in two placebo controlled trials conducted at Melbourne University. It is thought to act via modulation of NMDA glutamate receptors or by increasing glutathione. Pilot data suggests potential efficacy in autism, cocaine craving, smoking, and obsessive symptoms._

N-Acetylcysteine (NAC) Prevents the Impairment of the Counter-Regulatory Response Following Recurrent Hypoglycemia
Hypoglycemia is a severe side effect of intensive insulin therapy. Recurrent hypoglycemia (RH) impairs the counter-regulatory response (CRR) which restores euglycemia. The ventromedial hypothalamus (VMH) detects hypoglycemia and initiates the CRR. VMH nitric oxide (NO) production and activation of it's receptor soluble guanylyl cyclase (sGC) is necessary for the CRR. When NO is produced in the presence of reactive oxygen species (ROS) protein S-nitrosylation occurs. S-nitrosylation of sGC impairs its function and desensitizes NO signaling. We hypothesize that during hypoglycemia, the interaction between NO and ROS increases S-nitrosylation levels. This reduces NO activation of sGC and impairs the CRR. In support of this, insulin-hypoglycemia increases VMH ROS levels by 49.66 ± 18.37% (P<0.05). Moreover, 3 consecutive daily episodes of insulin-hypoglycemia (RH model) increase VMH sGC S-nitrosylation. We then determined whether preventing ROS production, and consequently S-nitrosylation of sGC prevents the impaired CRR after RH by treating rats with the antioxidant N-acetylcysteine (NAC) in their drinking water (5 g/l) for 9 days before and during RH (NAC pre-treatment). After RH, glucose levels fell further and epinephrine production was reduced by 50% in response to insulin-hypoglycemia compared to controls (glucose nadir RH: 39.3 ± 1.1 mg/dl; single hypoglycemia [SH]: 53.5 ± 1.8 mg/dl; epinephrine 120 min RH: 611.2 ± 108.3 ng/l; SH: 1350.6 ± 95 ng/l; p<0.05). After NAC pre-treatment there were no significant differences in glucose nadir between RH and SH animals (glucose nadir RH + NAC: 39.6 ± 3 mg/dl; SH + NAC: 35 ± 3 mg/dl). Moreover, after NAC pre-treatment the RH epinephrine response was restored to that of the SH group (RH + NAC: 1390 ± 148.4 ng/l vs SH, p>0.05). NAC also reversed sCG S-nitrosylation. Next we determined whether NAC reverses the impaired CRR by injecting NAC (200mg/kg; i.p). into RH rats 4 hours after the 3rd episode of insulin hypoglycemia. NAC significantly increased glucagon production following RH (RH+NAC: 140 ± 9.2 vs RH: 102.4 ± 8.4; p<0.05). Interestingly, following RH insulin-hypoglycemia produced no further increase in ROS production suggesting that ROS–induced S-nitrosylation is sustained in the absence of further ROS production. These data suggest that NAC prevention of ROS production during hypoglycemia may be clinically useful in preventing impaired CRR in patients undergoing intensive-insulin therapy.

_After recurrent insulin-hypoglycemia, NAC significantly increased glucagon secretion and epinephrine response was restored. NAC prevention of ROS production during hypoglycemia may prevent metabolic changes causing dysfunction in counter-regulatory response. During hypoglycemia, the interaction between NO and ROS increases S-nitrosylation levels. This reduces NO activation of sGC and impairs the counter-regulatory response. Soluble guanylate cyclase (sGC) is a mammalian nitric oxide (NO) sensor. When NO binds to the sGC heme, its GTP cyclase activity markedly increases, thus generating cyclic GMP, which serves to regulate several cell signaling functions. A good deal is known about the kinetics and equilibrium of binding of NO to sGC, leading to a proposed multistep mechanism of sGC activation that involves at least two NO-binding sites._

Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome.
To evaluate the clinical, endocrine and metabolic effects of metformin and N-acetyl-cysteine (NAC) in patients with polycystic ovary syndrome (PCOS). In this prospective trial, 100 women with PCOS were randomly divided to receive metformin (500 mg p.o. three times daily) or NAC (600 mg p.o. three times daily) for 24 weeks. Hyperandrogenism, lipid profiles, hirsutism scores, menstrual irregularity, insulin sensitivity and tumour necrosis factor-α (TNF-α) levels were measured at baseline and after the treatment period. Both treatments resulted in a significant decrease in fasting insulin, body mass index, hirsutism score, HOMA index, free testosterone and menstrual irregularity compared with baseline values, and both treatments had equal efficacy. NAC led to a significant decrease in both total cholesterol and low-density lipoprotein levels, whereas metformin only led to a decrease in total cholesterol level. Although TNF-α levels increased following treatment for both groups, the difference from baseline was not significant. Metformin and NAC appear to have comparable effects on hyperinsulinaemia, hyperandrogenismand menstrual irregularity in women with PCOS. The effects of metformin and NAC on insulin sensitivity are not associated with TNF-α.

_Polycystic ovary syndrome is one of the most common female endocrine disorders with insulin resistance, hyperinsulinaemia for symptoms. _

Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine.
http://www.ncbi.nlm.nih.gov/pubmed/15234256
Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-L-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kg x 4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

_Addiction may also be related to increased (sensitized) drug craving when environmental stimuli associated with drug taking, or drug cues, are encountered. This process may contribute to the risk for relapse in addicts attempting to quit. Such sensitization involves changes in brain mesolimbic dopamine transmission, as well as a molecule inside mesolimbic neurons called delta FosB._


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## Epsilon Alpha

I love you so much right now 
Do you think the metabolic effects of NAC are unique or could be found to various extents in other antioxidants?


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## Quercetin

Epsilon Alpha said:


> I love you so much right now
> Do you think the metabolic effects of NAC are unique or could be found to various extents in other antioxidants?



_Carnosine may be. _


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## Tussmann

I'm not really understanding this NAC discussion - could someone cliff it for me, please?


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## plexx92

*Neurotoxic effects of stimulants mitigated by NMDA antagonists.*

Found under the Glutamate section. I found this while looking for experimental VMAT2 inhibitors. In particular compounds that work on the serotonin systems.

Glutamate signaling is another important component of METH-induced DAergic deficits. Parenteral administration of METH evokes striatal glutamate release37,38 via the “direct” pathway.47 Glutamate likely contributes to the persistent deficits caused by METH treatment, as evidenced by findings that administration of the N-methyl-D-aspartate (NMDA) antagonist, MK801, prevents these deficits.48-52 One confounding feature of these studies is that MK801 prevents METH-induced hyperthermia, and this may contribute to the neuroprotection. On the other hand, posttreatment with NMDA antagonists attenuates the persistent deficits caused by amphetamine analogs, suggesting a protective effect independent of body temperature.53 Further evidence for a role of glutamate independent of temperature includes findings that mGluR5 antagonists prevent METH-induced deficits in a temperature-independent manner.54 However, the mechanism by which mGluR5 antagonists prevent METH toxicity may simply be via the inhibition of glutamate release.55

Dopaminergic cells within the striatum possess α-amino-5-hydroxy-3-methyl-4-isoxazde propionic acid (AMPA) and NMDA receptors.56 Glutamate-induced activation of these receptors promotes Ca2+ influx into the DAergic neuron, an effect, when excessive, that can result in mitochondrial damage and neuronal toxicity.39 In addition, glutamate-induced activation of NMDA receptors increases NO production via nNOS.40 Dopaminergic neurons can be regulated by NO generated from DAergic, non-DAergic neurons, or glia since NO is a diffusible gas. NO alters DAT function57 and can lead to reactive species production (by reacting with superoxide to produce peroxynitrite),32,58 each of which may contribute to persistent DA deficits.

Of interest, central administration of METH does not promote striatal glutamate release (or hyperthermia) and does not produce DAergic deficits45 demonstrating that areas distant from the site of toxicity are an important component of METH toxicity.

Source:http://www.aapsj.org/view.asp?art=aapsj080248

Also, I don't think it would be safe to take MK801 but other NMDA antagonists probably have the same effect.


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## Quercetin

The role of glutamate signaling
_Reduced glutathione (GSH, L-gamma-glutamyl-L-cysteinylglycine, glutathione that has its hydrogen atom) is the predominant anti-oxidant in the aqueous cytoplasm of cells. Virtually all cells require glutathione for viability and function. Glutathione is synthesized from three amino acids in a two-step process, beginning with the combination of glutamic acid & cysteine and ending with the addition of glycine. The liver & lungs are the primary sites of glutathione synthesis. Glycine & glutamic acid are plentiful in cells, so it is the availability of cysteine that controls the reaction rate. Cysteine competes with glutamate for transport into cells such that conditions of elevated extracellular glutamate can lead to glutathione depletion, worsened oxidative stress and cell death. 

Reduced glutathione (GSH) can scavenge peroxynitrite & hydroxyl radicals as well as convert hydrogen peroxide to water. Although a glutathione radical (GS.) is formed, it is readily neutralized by combining with another glutathione radical to produce GSSG. GSSG can be converted back to GSH by NADPH-dependent glutathione reductase enzyme (making the process dependent upon production of the NADPH energy-storing molecule).
_
N-Acetyl Cysteine, a Glutamate-Modulating Agent, in the Treatment of Pathological Gambling: A Pilot Study
http://www.ncbi.nlm.nih.gov/pubmed/17445781
Although pathological gambling (PG) is relatively common, pharmacotherapy research for PG is limited. N-acetyl cysteine (NAC), an amino acid, seems to restore extracellular glutamate concentration in the nucleus accumbens and therefore offers promise in reducing addictive behavior. Twenty-seven subjects (12 women) with DSM-IV PG were treated in an 8-week open-label trial of NAC with responders (defined as a ≥ 30% reduction in Yale Brown ObsessiveCompulsive Scale Modified for Pathological Gambling [PG-YBOCS] total score at end point) randomized to 6 weeks of double-blind NAC or placebo. The PG-YBOCS scores decreased from a mean of 20.3 ± 4.1 at baseline to 11.8 ± 9.8 at the end of the open-label phase (p < .001). Sixteen of 27 subjects (59.3%) met responder criteria. The mean effective dose of NAC was 1476.9 ± 311.3 mg/day. Of 16 responders, 13 entered the double-blind phase. Of those assigned to NAC, 83.3% still met responder criteria at the end of the double-blind phase, compared with only 28.6% of those assigned to placebo. The efficacy of NAC lends support to the hypothesis that pharmacological manipulation of the glutamate system might target core symptoms of reward-seeking addictive behaviors such as gambling. Larger, longer, placebo-controlled double-blind studies are warranted.

N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044191/
There is an expanding field of research investigating the benefits of alternatives to current pharmacological therapies in psychiatry. N-acetylcysteine (NAC) is emerging as a useful agent in the treatment of psychiatric disorders. Like many therapies, the clinical origins of NAC are far removed from its current use in psychiatry. Whereas the mechanisms of NAC are only beginning to be understood, it is likely that NAC is exerting benefits beyond being a precursor to the antioxidant, glutathione, modulating glutamatergic, neurotropic and inflammatory pathways. This review outlines the current literature regarding the use of NAC in disorders including addiction, compulsive and grooming disorders, schizophrenia and bipolar disorder. N-acetylcysteine has shown promising results in populations with these disorders, including those in whom treatment efficacy has previously been limited. The therapeutic potential of this acetylated amino acid is beginning to emerge in the field of psychiatric research.

*Glutamate*
In addition to the effects on oxidative balance, alterations in cysteine levels have also been shown to modulate neuro-transmitter pathways, including glutamate and dopamine. Cysteine assists in the regulation of neuronal intra- and extracellular exchange of glutamate through the cystine–glutamate antiporter. Whereas this antiporter is ubiquitous throughout all cell types, in the brain it is preferentially located on glial cells. The dimer, cystine, is taken up by astrocytes and exchanged for glutamate, which is released into the extracellular space. This free glutamate appears to stimulate inhibitory metabotropic glutamate receptors on glutamatergic nerve terminals and thereby reduce the synaptic release of glutamate. Given that relation, the amount of cysteine in the system as well as the feedback via GSH production by neurons may directly regulate the amount of glutamate present in the extracellular space. Furthermore, GSH itself has been shown to potentiate brain N-methyl-d-aspartate receptor response to glutamate in rats. Changes in the levels of neuronal GSH may not only alter available glutamate levels, but also have direct consequences on glutamatergic function.

*Dopamine*
In addition to modulating glutamate levels through the cystine–glutamate antiporter, NAC has also been shown to alter DA release. Following amphetamine treatment to rat striatal slices, NAC has been shown to facilitate vesicular DA release at low doses in striatal neurons and inhibit release at millimolar concentrations. In monkeys, NAC has been shown to protect against reductions in DA transporter levels following repeated methamphetamine administration, suggesting one mechanism whereby increased DA release was facilitated in the previous study. Glutathione has also been shown to increase glutamate agonist–evoked DA release in mouse striatal neurons.


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## Tussmann

Quercetin said:


> *Dopamine*
> In addition to modulating glutamate levels through the cystine–glutamate antiporter, NAC has also been shown to alter DA release. Following amphetamine treatment to rat striatal slices, NAC has been shown to facilitate vesicular DA release at low doses in striatal neurons and inhibit release at millimolar concentrations. In monkeys, NAC has been shown to protect against reductions in DA transporter levels following repeated methamphetamine administration, suggesting one mechanism whereby increased DA release was facilitated in the previous study. Glutathione has also been shown to increase glutamate agonist–evoked DA release in mouse striatal neurons.




This might be a bit overblown. From what I understand, the doses of NAC were immense and were injected, no?


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## Quercetin

Tussmann said:


> This might be a bit overblown. From what I understand, the doses of NAC were immense and were injected, no?



Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine.
http://www.ncbi.nlm.nih.gov/pubmed/15234256
Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-L-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kg x 4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

Magnesium in drug dependences.
http://www.ncbi.nlm.nih.gov/pubmed/18557129
Magnesium decreases the intensity of some drug-induced dependences (e.g. opiates, nicotine, cocaine, amphetamine, ethanol, etc.). The main mechanism involved is a decreasing activity of central glutamatergic synapses, especially those involved in the reward system. There are many particularities of action for each drug dependence. Apart from the effects during emerging dependence, magnesium ions administered only during the withdrawal syndrome decrease the intensity of clinical symptoms. In some cases, Mg2+ decreased the relapse and reinstatement of cocaine and amphetamine intake. Administered alone, in the absence of any abused drug, Mg2+ has moderate stimulatory effects on the reward system and reinforcement, without inducing dependence. The existent data stress a modulatory role of Mg2+ in some drug-induced dependences. Therapeutic administration of magnesium decreases nicotine dependence and cocaine/amphetamine self-administration.

_I have decreased tolerance on 2 human subjects. Oral dosage of 3x 2 grams/day of NAC and 3x 150mg/day of magnesium 50mg glycinate, 50mg taurate, 25mg fumarate, 25mg orotate blend. Neuroglycopia symptoms entirely disappeared, acute psychosis and obsessive-compulsive episode was no longer occurring in hypoglycemic state. _


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## sekio

You might want to give your figures for the Mg blend, as the differing slats have various percentages of magnesium by weight.


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## Quercetin

Enhancement of learning and memory by elevating brain magnesium.
http://www.ncbi.nlm.nih.gov/pubmed/20152124
Learning and memory are fundamental brain functions affected by dietary and environmental factors. Here, we show that increasing brain magnesium using a newly developed magnesium compound (magnesium-L-threonate, MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. The pattern completion ability was also improved in aged rats. MgT-treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of hippocampus that were correlated with memory improvement. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced. Our findings suggest that an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.
_
Magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions. Upregulation of NR2B-containing NMDA receptors are involved in fear extinction/conditioning, also has clinical implications such as exposure and response prevention therapies for the treatment of variety of anxiety disorders, especially obsessive–compulsive disorder_

Acquisition of Fear Extinction Requires Activation of NR2B-Containing NMDA Receptors in the Lateral Amygdala
http://www.ncbi.nlm.nih.gov/pubmed/17213844
N-methyl-D-aspartate receptors (NMDARs) contribute to synaptic plasticity underlying learning in a variety of brain systems. Fear extinction, which involves learning to suppress the expression of previously learned fear, appears to require NMDAR activation in the .amygdala. However, it is unclear whether amygdala NMDARs are required for the acquisition of extinction learning, and it is unknown whether NR2B-containing NMDARs are required in fear extinction. Here, we assessed the effects of selective NR2B blockade with ifenprodil on fear extinction learning, and found that both systemic and intra-amygdala ifenprodil treatment, given before extinction training, impaired the initial acquisition, and subsequent retrieval of fear extinction. These results confirm previous evidence showing that NMDARs in the amygdala are involved in fear extinction, and additionally show that NR2B-containing NMDARs are required. Contrary to the conclusion of previous studies, our findings demonstrate NMDARs are required for the initial acquisition, rather than only the retention, of fear extinction learning. Thus, our results support a previously not known role for NMDA-dependent plasticity in the lateral amygdala during the acquisition of fear extinction.

_Extinction is the conditioning phenomenon in which a previously learned response to a cue is eliminated when the cue is presented in the absence of the previously paired aversive (unpleasant) or appetitive (pleasant) stimulus. Researchers have turned to investigations at the cellular level, most often in rodents to explore the specific brain mechanisms of extinction, in particular the role of the brain structures (amygdala, hippocampus, the prefontal cortex), and specific neurotransmitter systems (e.g., GABA, NMDA). Extinction is correlated with synaptic inhibition in the fear output neurons of the central amygdala. They infer that inhibition derives from the prefrontal cortex and suggest promising targets at the cellular level for new treatments of anxiety and drug addiction._

Glutamatergic Targets for Enhancing Extinction Learning in Drug Addiction
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080595/
Pharmacological agents that have shown potential efficacy include NMDA partial agonists, mGluR5 receptor positive allosteric modulators, inhibitors of the GlyT1 glycine transporter, AMPA receptor potentiators, and activators of the cystine-glutamate exchanger. These classes of cognition-enhancing compounds could potentially serve as novel pharmacological adjuncts to cue exposure therapy to increase success rates in attenuating cue-induced drug craving and relapse.

*Cystine-Glutamate Exchanger Activators*
Since NAC nonspecifically enhances glutamatergic transmission by increasing extracellular levels of this excitatory amino acid, it can potentially activate numerous postsynaptic glutamate receptors (i.e., AMPA, NMDA, mGluRs, etc.). It was recently demonstrated that the ability of NAC to restore LTP in the nucleus accumbens was due to actions of glutamate on presynaptic mGluR2/3 receptors, whereas the ability of NAC to restore LTD was due to stimulation of mGluR5 receptors, consistent with evidence that mGluR5 receptors mediate drug-induced alterations in synaptic plasticity. Although studies on the effects of NAC on enhancement on normal learning processes are lacking., Zhou and Kalivas demonstrated that NAC reduced extinction responding following intravenous heroin self-administration in rats, and produced lasting reductions in the reinstatement of heroin-seeking behavior. Similar inhibitory effects of NAC on extinction responding have recently been reported in rats with a history of cocaine self-administration. Thus, NAC may be a novel potential adjunct to cue exposure therapy to facilitate the extinction of cue-evoked cocaine craving as well as reducing cocaine and heroin-seeking behavior.

*Conclusion*
Pharmacological agents that enhance glutamatergic transmission via subtle mechanisms, including NMDA receptor partial agonism, mGluR5 and AMPA receptor potentiation, GlyT1 inhibition, and cystine-glutamate exchanger activation, may be of potential benefit in enhancing synaptic plasticity and thereby facilitating extinction learning.

_Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. Magnesium glycinate and magnesium taurinate treatment has been used to produce rapid recovery from depression.
_


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## huppim

I wanted to start my own thread on this particular idea but I guess I will throw it out here first. This is my first time posting here I think. Anyway, the idea is this in nature things come in molecular packages. I've heard that a "simple" tomato will have thousands of different chemicals. Anyway, my idea was that we should see were all these chemicals go into the body follow them and see their function. Then we can maybe design a drug database after the tomato model or whatever since tomato's are "safe". This is the general idea. Is this realistic? More "potent" food? An example is cocaine. It is in the leaf of the plant however we extract it and leave off the rest, why? Why not leave the original formulation intact?


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## Epsilon Alpha

huppim said:


> I wanted to start my own thread on this particular idea but I guess I will throw it out here first. This is my first time posting here I think. Anyway, the idea is this in nature things come in molecular packages. I've heard that a "simple" tomato will have thousands of different chemicals. Anyway, my idea was that we should see were all these chemicals go into the body follow them and see their function. Then we can maybe design a drug database after the tomato model or whatever since tomato's are "safe". This is the general idea. Is this realistic? More "potent" food? An example is cocaine. It is in the leaf of the plant however we extract it and leave off the rest, why? Why not leave the original formulation intact?



Well there are a couple reasons to go after one particular component, I'll list off a few:
1) expense, research is an expensive business to do any more "whole plant" research than an LD50 study in mice.
2) safety, if an adverse reaction happens with a purified extract, we learn what it does. If a adverse effect happens with a crude extract or whole plant, we're not as certain as to what happened.
3) dose/response/availability, dispite the rather shocking nutritional value of coca leaf, it is it's stimulant qualities most people are after. The rest of the plant doesn't really fit our goal strictly speaking. There are probably other active components in the plant, but we don't really go after the minor components. 

Hope this makes sense,
EA


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## Quercetin

Carnosine protects neurons against oxidative stress and modulates the time profile of MAPK cascade signaling.
http://www.ncbi.nlm.nih.gov/pubmed/22101981
Carnosine is a known protector of neuronal cells against oxidative injury which prevents both apoptotic and necrotic cellular death. It was shown earlier that carnosine serves as an intracellular buffer of free radicals. Using the model of ligand-dependent oxidative stress in neurons, we have shown that homocysteine (HC) initiates long-term activation of extracellular signal regulated kinase, isoforms 1 and 2 (ERK 1/2) and Jun N-terminal kinase (JNK) which corresponds to exitotoxic effect resulting in cellular death. L: -Carnosine (β-alanyl-L: -histidine) protects neurons from both excitotoxic effect of homocysteine and cellular death. Its analogs, β-alanyl-D: -histidine (D: -carnosine) and L: -histidyl-β-alanine, restricted accumulation of free radicals and delayed activation of ERK1/2 and JNK in neuronal cells, but did not promote neuronal viability.
_
Carnosine has a number of antioxidant properties that may be beneficial. Carnosine has been proven to scavenge reactive oxygen species (ROS) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress. Carnosine is also neuroprotective against permanent cerebral ischemia in mice. Ischemia is a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism often caused by hypoglycemia or stimulants vasoconstriction.

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division. The pathway includes many proteins, including MAPK (originally called ERK), which communicate by adding phosphate groups to a neighboring protein, which acts as an "on" or "off" switch. _

Stress, epigenetic control of gene expression and memory formation.
http://www.ncbi.nlm.nih.gov/pubmed/21466804

Amphetamine-evoked gene expression in striatopallidal neurons: regulation by corticostriatal afferents and the ERK/MAPK signaling cascade.
http://www.researchgate.net/publica...l_afferents_and_the_ERKMAPK_signaling_cascade
The environmental context in which psychostimulant drugs are experienced influences their ability to induce immediate early genes (IEGs) in the striatum. When given in the home cage amphetamine induces IEGs predominately in striatonigral neurons, but when given in a novel test environment amphetamine also induces IEGs in striatopallidal neurons. The source of the striatopetal projections that regulate the ability of amphetamine to differentially engage these two striatofugal circuits has never been described. We report that transection of corticostriatal afferents selectively blocks, whereas enhancement of cortical activity with an ampakine selectively augments, the number of amphetamine-evoked c-fos-positive striatopallidal (but not striatonigral) neurons. In addition, blockade of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling cascade preferentially inhibits the number of amphetamine-evoked c-fos-positive striatopallidal neurons. These results suggest that glutamate released from corticostriatal afferents modulates the ability of amphetamine to engage striatopallidal neurons through an ERK/MAPK signaling-dependent mechanism. We speculate that this may be one mechanism by which environmental context facilitates some forms of drug experience-dependent plasticity, such as psychomotor sensitization.

Regulation of mitogen-activated protein kinases by glutamate receptors.
http://www.ncbi.nlm.nih.gov/pubmed/17018022
Glutamate receptors regulate gene expression in neurons by activating intracellular signaling cascades that phosphorylate transcription factors within the nucleus. The mitogen-activated protein kinase (MAPK) cascade is one of the best characterized cascades in this regulatory process. The Ca(2+)-permeable ionotropic glutamate receptor, mainly the NMDA receptor subtype, activates MAPKs through a biochemical route involving the Ca(2+)-sensitive Ras-guanine nucleotide releasing factor, Ca(2+)/calmodulin-dependent protein kinase II, and phosphoinositide 3-kinase. The metabotropic glutamate receptor (mGluR), however, activates MAPKs primarily through a Ca(2+)-insensitve pathway involving the transactivation of receptor tyrosine kinases. The adaptor protein Homer also plays a role in this process. As an information superhighway between surface glutamate receptors and transcription factors in the nucleus, active MAPKs phosphorylate specific transcription factors (Elk-1 and CREB), and thereby regulate distinct programs of gene expression. The regulated gene expression contributes to the development of multiple forms of synaptic plasticity related to long-lasting changes in memory function and addictive properties of drugs of abuse. This review, by focusing on new data from recent years, discusses the signaling mechanisms by which different types of glutamate receptors activate MAPKs, features of each MAPK cascade in regulating gene expression, and the importance of glutamate/MAPK-dependent synaptic plasticity in memory and addiction.

_Conditioned Place Preference (CPP) is a form of Pavlovian conditioning used to measure the motivational effects of objects or experiences. This paradigm can also be used to measure conditioned place aversion with an identical procedure involving aversive stimuli instead. Both procedures usually involve mice or rats as subjects. This procedure can be used to measure extinction and reinstatement of the conditioned stimulus. This suggest that carnosine reduce cravings and neurotoxicity caused by amphetamine. _

Explore the Role of MAPK Signaling in Methamphetamine-Induced Place Preference: Acquisition, Extinction and Reinstatement by Stress
http://www.google.ca/url?sa=t&rct=j...6JXVCg&usg=AFQjCNFdbG1zFQdpiIEUyeVVQl1Pj8TeyA
Drug abuse could be considered as a chronic brain disease due to synaptic plasticity reformed after chronic drug-taking, hence reinforced to drug-craving is hardly withdrawn. However, the most severe follow-up problem of drug addiction is drug relapse, since neuronal circuitry has already been modified by chronic drug imbedding that makes drug reinstatement easily to trigger. Previous review has summarized the major triggers in reinstatement model of drug relapse, of which stress seems to be the major social factor or inducer to reinstate the drug-seeking in the present society. Hence, to explore the cellular mechanism of drug relapse, we first established an animal model of conditioned place preference (CPP) to paired methamphetamine (METH; 2 mg/kg) and demonstrated they could reinstate the METH relapse by physical restrainer stress after extinction training. Due to MAPK is a well studied signal that involves in drug addiction and its down-stream can be linked with tyrosine hydroxylase (TH) phosphorylation/activation, our current analyses revealed that phosphor-ERK1/2 signals in the nucleus accumbens enhanced after acquisition and relapse stages, but decreased during extinction. A similar change in phosphor-TH signals was also observed in the ventral tegmental area (VTA) of behaviorally distinct CPP stages. Further, to investigate the impact of CRF in stress-induced relapse, CRF2 receptor antagonist Avg-30 was microinjected bilaterally into the VTA prior to physical stress. We found that inhibition of CRF2 receptors in the VTA appeared to attenuate the drug reinstatement. These preliminary results suggest CRF2 receptors in the VTA appear to play a role in stress-induced drug reinstatement, while activation of MAPK in the nucleus accumbens might be viewed as a valid indicator for drug acquisition and/or reinstatement. The possible cross-talk between CRF and mesolimbic dopamine systems and underlying molecular mechanism are currently under investigation.
_
Glutamatergic drugs refer to drugs that interact with the glutamate-neurotransmitter system. This particular neurotransmitter system has been demonstrated to be an important part of reinstatement of the opiate-influenced CPP. Glutamatergic antagonists (such as memantine and dizocilpine) blocked the reinstatement of drug-produced CPP. The effect of glutamatergic antagonists on CPP may be on the disruption of processing of conditioned responses, therefore impairing drug-related associations and their reconsolidation._

Effect of memantine and CNQX in the acquisition, expression and reinstatement of cocaine-induced conditioned place preference.
http://www.ncbi.nlm.nih.gov/pubmed/17395352
The present study evaluates the effect of memantine, a non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist and CNQX, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist on the rewarding effects of cocaine in mice, using the conditioned place preference (CPP) paradigm. Cocaine-induced CPP was studied pairing this drug with different memantine or CNQX doses during either the acquisition or the expression phase of the procedure. Once CPP was established, and the preference extinguished, reinstatement was induced by a priming dose of cocaine. Both antagonists, which in themselves do not present motivational actions on the preference shown by the animals, abolished the acquisition and expression of the cocaine-induced CPP. Neither of the antagonists precipitated reinstatement of the preference induced by cocaine but memantine blocked the cocaine-primed reinstatement. Our results suggest that cocaine-induced CPP and reinstatement is largely dependent on glutamate neurotransmission, and confer a putative role for memantine among the tools useful for cocaine management and treatment.
_
The drug belongs to a class of drugs called NMDA receptor antagonists, which reduce certain types of brain activity by binding to NMDA receptors on brain cells and blocking the activity of the neurotransmitter glutamate. At normal levels, glutamate aids in memory and learning, but if levels are too high, glutamate appears to overstimulate nerve cells, killing them through excitotoxicity.

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity.

Glutamatergic antagonists have also been reported to have an effect on cocaine-induced CPP. Memantine was shown to block CPP produced by cocaine. In this study, animals did not approach cues that were associated with cocaine when NMDA receptors had glutamate transmission blocked. This suggests that glutamatergic antagonists can extinguishing drug-seeking behaviour._


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## Quercetin

NAChR induced neurotoxicity
_Nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression: muscle-type nicotinic receptors and neuronal-type nicotinic receptors. The neuronal subtypes are various homomeric or heteromeric combinations of twelve different nicotinic receptor subunits: α2 through α10 and β2 through β4. Examples of the neuronal subtypes include: (α4)3(β2)2, (α4)2(β2)3, and (α7)5. The neuronal forms of the receptor can be found both post-synaptically (involved in classical neurotransmission) and pre-synaptically where they can influence the release of multiple neurotransmitters.

The activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movement of cations causes a depolarization of the plasma membrane (which results in an excitatory postsynaptic potential in neurons), but also by the activation of voltage-gated ion channels. On the other hand, the entry of calcium acts, either directly or indirectly, on different intracellular cascades leading, for example, to the regulation of the activity of some genes or the release of neurotransmitters.
_
Memantine is a useful drug to prevent the spatial and non-spatial memory deficits induced by methamphetamine.
http://www.ncbi.nlm.nih.gov/pubmed/20553881
Methamphetamine (METH) is a street drug that is abused by young people. In previous studies, we demonstrated the effectiveness of alpha-7 nicotinic receptor antagonists in preventing the neurotoxicity induced by this amphetamine derivative. The present study seeks to determine whether pre-treatment with memantine (MEM) (an antagonist of both NMDA and alpha-7 nicotinic receptors) counteracts the memory impairment induced by METH administration in male Long Evans rats. Non-spatial memory was tested in the object recognition test and spatial learning memory was tested in the Morris water maze. In our experimental conditions, rats that received the MEM (5 mg/kg, intraperitoneally) pre-treatment recovered the ability to discriminate between a familiar and a novel object. This ability had been abolished by METH (10 mg/kg, subcutaneously) at 72 h and 1 week after treatment. Moreover, MEM pre-treatment also inhibited the thigmotaxis behaviour induced by METH. Rats treated with METH showed impaired learning in the Morris water maze. The results of the probe trial demonstrated that METH-treated rats did not remember the location of the platform, but this memory impairment was also prevented by MEM pre-treatment. Moreover, MEM by itself improved the learning of the task. Finally, MEM significantly improved the learning and memory impairment induced by METH. Therefore, MEM constitutes the first successful approach to prevent the cognitive deficits induced by amphetamine derivatives which are frequently abused in western countries.

*alpha-7 nicotinic receptors *
_Some centrally acting compounds such as bupropion, mecamylamine, and 18-methoxycoronaridine block nicotinic acetylcholine receptors in the brain and have been proposed for treating drug addiction._

The sensitizing effect of acute nicotine on amphetamine-stimulated behavior and dopamine efflux requires activation of β2 subunit-containing nicotinic acetylcholine receptors and glutamate N-methyl-D-aspartate receptors.
http://www.ncbi.nlm.nih.gov/pubmed/20971124

Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity
http://www.mdpi.com/1424-8247/4/6/822
Amphetamine derivatives such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) are widely abused drugs in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As far as neurotoxicity is concerned, increased reactive oxygen species (ROS) production seems to be one of the main causes. Recent research has demonstrated that blockade of a7 nicotinic acetylcholine receptors (nAChR) inhibits METH- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, a7 nAChR antagonists (methyllycaconitine and memantine) attenuated in vivo the neurotoxicity induced by METH and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to a7 and heteromeric nAChR, with MDMA showing lower Ki value.

*Dextromethorphan*
_*α3β4-, α4β2-, and α7-nACh receptor antagonist*. It inhibits the antinociceptive (pain killing) action of nicotine in the tail-flick test in mice, where mouse tails are exposed to heat, which makes the mouse flick its tail if it feels pain. _

*Mecamylamine *
_*α3β4 nicotinic receptors antagonist*. Sometimes used as an anti-addictive drug to help people stop smoking tobacco. _

*Varenicline*
_*Varenicline is a partial agonist of the α4β2 subtype of the nicotinic acetylcholine receptor.* In addition it acts on α3β4 and weakly on α3β2 and α6-containing receptors. A full agonism was displayed on α7-receptors. Partially stimulates, the α4β2 receptor without producing a full effect like nicotine. Varenicline does not greatly increase the downstream release of dopamine. It also acts as an agonist at 5-HT3 receptors, which may contribute to mood altering effects of varenicline._

*Possible varenicline-induced paranoia and irritability in a patient with major depressive disorder, borderline personality disorder, and methamphetamine abuse in remission. *http://www.ncbi.nlm.nih.gov/pubmed/19011454


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## Tussmann

Quercetin said:


> _Neuroglycopenia cause excessive glutamate release, causing neurotoxicity._




Not exactly the cliffs I was looking for. What exactly does NAC have to do with anything here in in regards to therapeutic co-usage with amphetamine?


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## Quercetin

Tussmann said:


> Not exactly the cliffs I was looking for. What exactly does NAC have to do with anything here in in regards to therapeutic co-usage with amphetamine?



*Hypoglycemia unawareness *
_I believe that recurrent hypoglycemic state from insulin-induced methamphetamine cause hypoglycemic unawareness which develop into neuroglycopenia. Often glucagon secretion is inhibited. Methamphetamine alters blood brain barrier permeability & GLUT1-GLUT3_
NAC prevents the impairment of the Counter-Regulatory response following recurrent Hypoglycemia.
NAC revert methamphetamine inhibition of glucose uptake by human neurons and astrocytes.
NAC revert glucose transporter impairment & blood-brain barrier dysfunction caused by methamphetamine.
NAC appear to reduce hyperinsulinaemia and promote insulin sensitivity.

*Glutamate - NMDA antagonist*
_I believe that neuroglycopenia inhibit GABA output, which trigger glutamate-induced neurotoxicity. NMDA receptor, a glutamate receptor, is the predominant pathway of control in synaptic plasticity and memory function. Glutamate system is the core of reward-seeking addictive behaviors and is the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis. _
NAC is exerting benefits by being a precursor to the antioxidant, glutathione, modulating glutamatergic, neurotropic and inflammatory pathways. 
NAC assists in the regulation of neuronal intra- and extracellular exchange of glutamate through the cystine–glutamate antiporter.
NAC is a decreasing activity of central glutamatergic synapses, especially those involved in the reward system.
NAC influence Acquisition, Extinction and Reinstatement behavior.
NAC has therapeutic value in treating obsessive-compulsive disorder. 
NAC reduce anxiety involved with dysfunctional GABA activity.

*Dopamine modulation*
NAC has been shown to protect against reductions in DA transporter levels following repeated methamphetamine administration

*Misc*
NAC inhibit hyperlocomotion, it is in my opinion ataxia induced by hypoglycemia and may be related to tolerence.
NAC reduce sensitization, important effect since it has been implied as a core mechanism in substance abuse and dependence.
NAC reduce amphetamine-related withdrawal symptoms and craving.
NAC reduce amphetamine seeking behavior.


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## Quercetin

MAOB in the regulation of GABA
_Tobacco smoke contains the monoamine oxidase inhibitors anatabine, harman and norharman. These beta-carboline compounds significantly decrease MAO activity in smokers. MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOI's and the nicotine is responsible for most of the addictive properties of tobacco smoking. _

GAD67: the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis
http://www.ncbi.nlm.nih.gov/pubmed/12811640
Decreases in the 67 kDa isoenzyme of brain glutamic acid decarboxylase (GAD67) expression have been consistently found in patients with bipolar disorder and schizophrenia. In animals GAD67 expression is diminished by chronic, but not acute stimulation of dopamine D2 receptors and by short-term blockade of NMDA receptors. In contrast, chronic treatment with D2 receptor antagonists enhances GAD67 expression. Thus, antipsychotic treatment cannot explain the reduction in GAD67 levels in patients with psychotic disorders. Rather, pathophysiological findings such as reduced viability of cortical glutamatergic neurones (in schizophrenia) or enhanced dopamine sensitivity (in bipolar disorder) might explain the observed reduction in GAD67. Since reduction in GAD67 expression leads to reduced levels of GABA, the GABAergic inhibitory control over glutamatergic cells is reduced. Psychosis could result from AMPA receptor activation caused by overactivity of the glutamatergic system. GAD67 levels would thus be a surrogate marker for psychosis liability. Pharmacological principles that raise GAD67 expression levels could represent novel targets for antipsychotic therapy.

*Amphetamine exposure down-regulated the levels of GAD.*
_*Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2.* 
Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity.

*MAO-B is an enzyme that metabolises the dopamine neurotransmitter.*
Monoamine Oxidase B inhibitors are used in the treatment of Parkinson's Disease. Nicotine, in tobacco addiction, has been shown to have weak addictive properties when administered alone, addictive potential increases after co-administration of an MAOI._

*Monoamine Oxidase inhibitors*
_Harmala alkaloids, Resveratrol, Curcumin, Rhodiola rosea, Ruta graveolens, Ginkgo biloba, Anthocyanins, Proanthocyanidin, Catechin, Desmethoxyyangonin, Epicatechin, Emodin, Hydroxytyrosol, Piperine, Gentiana lutea, Liquorice, Myristicin, Siberian Ginseng, Yerba Mate, Yohimbe_

Down-Regulated GABAergic Expression in the Olfactory Bulb Layers of the Mouse Deficient in Monoamine Oxidase B and Administered With Amphetamine
http://rd.springer.com/article/10.1007/s10571-009-9475-2
This study explores primarily the role of the activity of monoamine oxidase B (MAOB) in the regulation of glutamic acid decarboxylase67 (GAD67) expression in distinct layers of main olfactory bulb (OlfB), which links the limbic system. Moreover, the response of GAD67 was investigated to amphetamine perturbation in the absence of MAOB activity. Immunocytochemical analysis was performed on OlfB sections prepared from the adult wild type (WT) and the MAOB gene-knocked-out (KO) mice after receiving repeated intraperitoneal injections (two doses per day, total seven doses) of saline or amphetamine, 5 mg/kg. The levels of the GAD67 immunoreactivity were approximate 25 and 38% lower in respective glomerular (GloL) and mitral cell layers (ML) of saline-treated KO mice than that of WT, whereas similar in the external plexiform or granule cell layers (GraL) of the KO and WT. In the GloL, the level of tyrosine hydroxylase was 39% lower in the KO mice than WT, implicating different dopamine content in the KO from WT. The amphetamine exposure down-regulated the levels of GAD67 in the WT layers by 46 to 52%, and in KO layers 65 to 71%, except ML. The GraL GAD67 level may be regulated by the activation of CREB, as the phosphorylated (p) CREB coexisted with GAD67, and the percentage of GAD67-expressing pCREB neurons was decreased by the amphetamine exposure. The data indicate that the activity of MAOB could modulate the regular and amphetamine-perturbed expression of GAD67 and pCREB. Thus, interactions are suggested among the MAOB activity, GABA content of OlfB, and olfaction.

*CREB is a cellular transcription factor. *
_It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes. It play an important role in neuronal plasticity and long-term memory formation. It is a core mediator in late stage of long-term potentiation, a  long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. A major contributor in synaptic plasticity, causing synapse to change their strength a contributor in formation of memories. It has an important role in the development of drug addiction, emotional memory operate on fear conditioning, an amygdala-dependent behavior._


----------



## Quercetin

Menthol: κ-Opioid agonism is neuroprotective against hypoxia/ischemia. What do you guys think?


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## sekio

Doubtful, menthol is a poor K-opi agonist as evidenced from almost total lack of psychoactivity.

The monoterpenoids in general seem to be incredibly poor g-protein ligands.


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## Quercetin

I came across a study on _GLUT3 and Ascorbic Acid_ and was wondering what you guys think. 

I know that the decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3) which is the basis of my theory on acute psychosis. 
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019258

Anybody can explain to me the impact of ascorbic acid on GLUT3?

Ascorbic acid-dependent GLUT3 inhibition is a critical step for switching neuronal metabolism.
http://www.ncbi.nlm.nih.gov/pubmed/21321936
Intracellular ascorbic acid is able to modulate neuronal glucose utilization between resting and activity periods. We have previously demonstrated that intracellular ascorbic acid inhibits deoxyglucose transport in primary cultures of cortical and hippocampal neurons and in HEK293 cells. The same effect was not seen in astrocytes. Since this observation was valid only for cells expressing glucose transporter 3 (GLUT3), we evaluated the importance of this transporter on the inhibitory effect of ascorbic acid on glucose transport. Intracellular ascorbic acid was able to inhibit (3)H-deoxyglucose transport only in astrocytes expressing GLUT3-EGFP. In C6 glioma cells and primary cultures of cortical neurons, which natively express GLUT3, the same inhibitory effect on (3)H-deoxyglucose transport and fluorescent hexose 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was observed. Finally, knocking down the native expression of GLUT3 in primary cultured neurons and C6 cells using shRNA was sufficient to abolish the ascorbic acid-dependent inhibitory effect on uptake of glucose analogs. Uptake assays using real-time confocal microscopy demonstrated that ascorbic acid effect abrogation on 2-NBDG uptake in cultured neurons. Therefore, ascorbic acid would seem to function as a metabolic switch inhibiting glucose transport in neurons under glutamatergic synaptic activity through direct or indirect inhibition of GLUT3.


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## Quercetin

Glucagon secretion that is often inhibited in long-term methamphetamine user and came across this plant has the potential to restore production. It also has neuroprotective effects. Eucommia is a non-selective beta-blocker, it would modulate excessive adrenalin. 

Neuroprotective effects of Eucommia ulmoides Oliv. Bark on amyloid beta(25-35)-induced learning and memory impairments in mice.
http://www.ncbi.nlm.nih.gov/pubmed/20974223
Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
In the present study, we examined whether aqueous extract of Eucommia ulmoides Oliv. Bark (EUE) with graded doses exerted its neuroprotective effects on amyloid beta(25-35) (Aβ(25-35))-induced learning and memory impairments in mice. Mice received a single intracerebroventricular (i.c.v.) injection of Aβ(25-35) 6 nmol as the critical factor in Alzheimer's disease (AD), cognition was evaluated using Y-maze, passive avoidance, and Morris water maze tests. EUE significantly improved the Aβ(25-35)-induced memory deficit in the Y-maze test. Also, EUE increased step-through latency time with Aβ(25-35)-induced learning and memory deficits in the passive avoidance test. In addition, EUE decreased the escape latencies with Aβ(25-35)-induced cognitive impairments in the Morris water maze test. In the probe trial session, EUE increased time spent in the target quadrant. In the in vitro study, EUE was found to inhibit acetylcholinesterase (AChE) activity in a dose-dependent manner (IC50 value; 172 μg/ml). Ex vivo study, EUE significantly inhibited AChE activity in the hippocampus and frontal cortex. These results demonstrate that EUE possesses potent neuroprotective effects and that its beneficial effects are mediated, in part, by AChE inhibition, and therefore, might be a potential candidate in neurodegenerative diseases such as AD.


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## Epsilon Alpha

Hi Dane!


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## Tussmann

Just curious -what form are you guys using for your Magnesium? And, what dose are you taking?

I have always used 450 mg of citrate BID...but don't know if I want to place another order.


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## Epsilon Alpha

Tussmann said:


> Just curious -what form are you guys using for your Magnesium? And, what dose are you taking?
> 
> I have always used 450 mg of citrate BID...but don't know if I want to place another order.



300mg citrate myself, personally anything but oxide is ok in my opinion. I just get the cheapest stuff I can find.


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## Quercetin

I would go nothing that is not chelated. Magnesium glycinate, taurate, fumarate, orotate are the one you should be looking for. purebulk.com is a cheap source.


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## tenshu2k

I use chelated, "Doctors Best". I must be deficient, or getting used to it. Even after one pill at night, I have trouble waking in the morning. 

On the topic: What are thoughts on Aricept/Donepezil or Galantamine as an adjunct?


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## ebola?

There is no reason that magnesium supplementation would cause extended drowsiness.

ebola


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## Quercetin

ebola? said:


> There is no reason that magnesium supplementation would cause extended drowsiness.
> 
> ebola



_Actually. It would cause in the presence of neuroglycopenia/hypoglycemia._

[Effects of magnesium intake on expression of insulin receptor in type 2 diabetes rats].

OBJECTIVE:
To investigate the effects of magnesium intake on expression of insulin receptor in type 2 diabetes rats.

METHODS:
The models of type 2 diabetes rats were established by feeding with high-fat-diet and injecting streptozotocin (STZ). Rats were randomly assigned to four groups. The high-fat-diets were administrated magnesium at a dose of 2000 (high magnesium group), 1000 (medium magnesium group) and 200 (low magnesium group). Model control group was only fed with high-fat-diet. Normal control group was fed with common diet. Rats ate freely for four weeks. Fasting blood glucose was detected by glucose oxidase method.. Insulin was detected by radio-immunity method. The expression levels of IR of pancreas and skeletal muscle were detected by immunohistochemistry method.

RESULTS:
The immunohistochemistry pictures were analyzed by Image-Pro Plus. Compared with model control group, the expression levels of IR of pancreas and skeletal muscle were 0.341 +/- 0.001 and 0.346 +/- 0.002, increased and fasting blood glucose decreased significantly in high magnesium group (P < 0.05 ).

CONCLUSION:
Magnesium intake may increase the expression levels of IR of pancreas and skeletal muscle, and decrease fasting blood glucose in type 2 diabetes rats.

_It is doing so by acutely reducing blood glucose in a dose-dependent manner.  Magnesium can cause hypoglycemia/Neuroglycopenia._


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## Epsilon Alpha

I f*cking love you. 
Wonder what the implications for this is for the extremely common magnesium and amphetamine coadministration?
Perhaps a case to coadministrater with a source of complex carbs or easily converted lipids?

I know CoQ10 has some interesting effects on sugar metabolism I'll have to dig up when I get home


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## Quercetin

Epsilon Alpha said:


> I f*cking love you.
> Wonder what the implications for this is for the extremely common magnesium and amphetamine coadministration?
> Perhaps a case to coadministrater with a source of complex carbs or easily converted lipids?
> 
> I know CoQ10 has some interesting effects on sugar metabolism I'll have to dig up when I get home



_Be very careful as a very strong *reactive hypoglycemia* may arise from a insuline spike caused by refined sugar or most free form amino acid. You have to make sure that the muscles are not glycogen depleted before you ingest any dose of NAC or Magnesium._


----------



## avcpl

atrollappears said:


> Edit: On a side note, you have to munch a lot of antacids to take ALA with amphetamine (acidity inhibits absorption and such). Stuff's pretty damn hard on the stomach.



I've wondered if plugging ALA would be an effective ROA?


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## Quercetin

avcpl said:


> I've wondered if plugging ALA would be an effective ROA?



I have made subq injection of Bio-enhanced Na RALA.  
Sorry no sourcing
Soluble in water: 1 g dissolves in 50 ml water at room temperature.
Significantly more bio-available than R-lipoic acid (RLA).


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## avcpl

Quercetin said:


> I have made subq injection of Bio-enhanced Na RALA.
> ...
> Soluble in water: 1 g dissolves in 50 ml water at room temperature.
> Significantly more bio-available than R-lipoic acid (RLA).



very interesting! I am primarily interested in neuroprotection from MDMA. How much of this would you recommend taking and at what point in the roll (pre-, during, post)? And anything else you recommend?

(We take 150mg MDMA with no re-dosing with 90day breaks between rolls, so we're pretty responsible users; not sure how much damage we are doing but always interested in harm reduction!)



.



.


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## sekio

Intravenous supplements = probably a bad idea in the long run

Which ALA are we talking about - alpha-lipoic acid, or alpha-linoleic acid?

Both should be extensively well-absorbed orally. Free acid lipoic acid is very much so, something like 93% bioavailiable orally after 2h.  No need to inject it but you can take it as a salt just as easily.


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## Ksa

This is a very interesting post, I never knew about it and to see that I have been doing everything that's in there point by point is highly reassuring. I have actually not developed any tolerance to amphetamines for 5 years now. More people should know about this post, I highly vouch it!

It's not just measures that slow down tolerance, like, by 5% or 10%. If you do everything that's in there, you might not develop any tolerance at all. This works guys, at least for me and the OP lol.

For example, I have long felt the need to take 100mg of Tylenol or aspirin with my daily dose. I could not explain it, I just felt it was better. To see it listed there on the first page came as a shock. Does anyone know why this works? I do it because I feel like it works but I don't know why.


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## Achten

I just stumbled upon this thread actually... . Could someone elaborate (in layman's terms perhaps) about the danger that may arise from magnesium supplementing ?
I take it when feeling some soreness or tension while tripping. With a regular trip (low/mid dose) it's mostly 300mg or nothing, but when doing larger amounts or releasers (aMT, MDMA, amphetamines too..) that could become 900 or 1200mg. Anything wrong with that? I always drop the compound on empty stomach (or just a piece of fruit) and try to eat fruit and drink lots of water during the trip.


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## Tussmann

Ksa said:


> This is a very interesting post, I never knew about it and to see that I have been doing everything that's in there point by point is highly reassuring. I have actually not developed any tolerance to amphetamines for 5 years now. More people should know about this post, I highly vouch it!




Tolerance, for the majority of users, never occurs to the pro-cognitive effect of amphetamine (due to properties of DA in the prefrontal cortex). For the pro-social, pro-motivational, appetite suppressing, and pro-energetic effects, however, (without drugs and other supplements) tolerance can settle in as few as days.


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## Ksa

Achten said:


> I just stumbled upon this thread actually... . Could someone elaborate (in layman's terms perhaps) about the danger that may arise from magnesium supplementing ?
> I take it when feeling some soreness or tension while tripping. With a regular trip (low/mid dose) it's mostly 300mg or nothing, but when doing larger amounts or releasers (aMT, MDMA, amphetamines too..) that could become 900 or 1200mg. Anything wrong with that? I always drop the compound on empty stomach (or just a piece of fruit) and try to eat fruit and drink lots of water during the trip.



I don't think it's a death risk. Once your blood sugar levels drop below 5mM, you'll blacken out and probably crouch to sit down. You regain vision after 5 or 10 seconds usually because your muscles no longer use glucose, temporarly. Otherwise, you pass out, with memory loss probably. In severe cases, you die but it almost never happens, unless you're being very stupid.

The problem occurs with people who don't know how to get high, read this topic, take magnesium with amphetamines and then pass out. This topic assumes you know how to get high in the first place. If you don't know how to get high, stay away from this topic! You need to take your magnesium when you're not using amphetamines, during the days when you eat and drink thoroughly.


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## Quercetin

Ksa said:


> The problem occurs with people who don't know how to get high, read this topic, take magnesium with amphetamines and then pass out. This topic assumes you know how to get high in the first place. If you don't know how to get high, stay away from this topic!



It must be amazing to know how to get high as much as you.. I wish I had such a skill.. Can you please teach me? 

Magnesium can be use while using meth/amphetamine anywhere between 150 to 450mg per serving post-meal, as long as it is not on empty stomach. Magnesium should  never be taken on empty stomach while using amph, or mixed with anything causing glucose uptake.


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## Quercetin

Achten said:


> I just stumbled upon this thread actually... . Could someone elaborate (in layman's terms perhaps) about the danger that may arise from magnesium supplementing ?
> I take it when feeling some soreness or tension while tripping. With a regular trip (low/mid dose) it's mostly 300mg or nothing, but when doing larger amounts or releasers (aMT, MDMA, amphetamines too..) that could become 900 or 1200mg. Anything wrong with that? I always drop the compound on empty stomach (or just a piece of fruit) and try to eat fruit and drink lots of water during the trip.



Why do you use drugs on an empty stomach? It sound risky to me.


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## Epsilon Alpha

I think we both know what this means, just watch your blood sugar on heroic doses of stims. A meal would enhance Mg uptake anyways


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## Quercetin

Epsilon Alpha said:


> I think we both know what this means, just watch your blood sugar on heroic doses of stims. A meal would enhance Mg uptake anyways



heroic doses of stims.. Is that the amount needed to see into the future?


----------



## avcpl

Quercetin said:


> Why do you use drugs on an empty stomach? It sound risky to me.



It's pretty standard practice for MDMA users to drop on an empty stomach. I have no idea where this came from, but if there is a better pre-roll intake that won't affect the roll (because really that is the most important thing! lol) please share?!!!


----------



## Quercetin

avcpl said:


> It's pretty standard practice for MDMA users to drop on an empty stomach. I have no idea where this came from, but if there is a better pre-roll intake that won't affect the roll (because really that is the most important thing! lol) please share?!!!



Why would a large meal affect the roll?


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## avcpl

Quercetin said:


> Why would a large meal affect the roll?





 I think the thinking is that food in the stomach will cause a slower absorption rate of the mdma and not reach the saturation levels needed to "flip the switch" ...



.


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## Quercetin

avcpl said:


> I think the thinking is that food in the stomach will cause a slower absorption rate of the mdma and not reach the saturation levels needed to "flip the switch" ...
> .



I really don't know what to say. I would eat the mdma and eat after.. I mean.. its such a small difference..


----------



## Epsilon Alpha

http://www.ncbi.nlm.nih.gov/m/pubmed/9128836/
Saw this on reddit, perhaps inhibiting a relevant P450 enzyme could be a way to prevent the formation of toxic metabolites assuming amphetamine undergoes a similar transformation.


----------



## MobiusDick

Quick comment about a few aspects of post: recent studies have shown that in at least 1/3 of people, 81 mgs of aspirin is a sub-therapeutic dose of the thrombolytic /antithromboembolic (the most common term for these medications is anticoagulant, but it is technically incorrect ; a compound like vampirin, which comes from the vampire bat, is an anticoagulant-the strongest one known, in fact, as it must be washed away before its activity stops). The full 325 mg dose is the ED50 for this subset of patients.

One of the reasons I want to comment on this is because I personally continue to witness too many cases of MI, CVA or other thromboembolic event that has resulted in mortality/morbidity due to the treating physician's lack of understanding of the concept of rebound phenomenon from drug discontinuation (I have heard this called bradyphylaxis, which is completely incorrect. Bradyphylaxis is the technical term for sensitization; tachyphylaxis is the technical term for habituation.) Patients should always be weaned off of thrombolytics when necessary (e.g., prior to elective surgery), including low dose aspirin; even Vitamin E ot Gingko should not be abruptly discontinued because almost all drugs have a period of excessive contra-efficacy when suddenly stopped. Thrombolytics have a period of hypercoagulability after discontinuation for 1-3 weeks depending on the drug, serious enough to be the primary cause of morbidity/mortality. The ME often rules theses death's primary causes as MI or CVA, when in fact, it was secondary to the primary cause of death, rebound phenomenon due to abrupt thrombolytic discontinuation.

Our physicians today, in general, have a very poor understanding of pharmaceutical science and are jeopardizing the lives of too many people by not keeping up with their reading and with CE credits resulting from ridiculously over-simplified course work designed more for the layman than a person the public goes to for their supposed medical, the average physician is far too often killing their patients by the medication they prescribe, and no one ever even realizes the patient was killed by their physician's ignorence


----------



## Epsilon Alpha

MobiusDick said:


> Quick comment about a few aspects of post: recent studies have shown that in at least 1/3 of people, 81 mgs of aspirin is a sub-therapeutic dose of the thrombolytic /antithromboembolic (the most common term for these medications is anticoagulant, but it is technically incorrect ; a compound like vampirin, which comes from the vampire bat, is an anticoagulant-the strongest one known, in fact, as it must be washed away before its activity stops). The full 325 mg dose is the ED50 for this subset of patients.
> 
> One of the reasons I want to comment on this is because I personally continue to witness too many cases of MI, CVA or other thromboembolic event that has resulted in mortality/morbidity due to the treating physician's lack of understanding of the concept of rebound phenomenon from drug discontinuation (I have heard this called bradyphylaxis, which is completely incorrect. Bradyphylaxis is the technical term for sensitization; tachyphylaxis is the technical term for habituation.) Patients should always be weaned off of thrombolytics when necessary (e.g., prior to elective surgery), including low dose aspirin; even Vitamin E ot Gingko should not be abruptly discontinued because almost all drugs have a period of excessive contra-efficacy when suddenly stopped. Thrombolytics have a period of hypercoagulability after discontinuation for 1-3 weeks depending on the drug, serious enough to be the primary cause of morbidity/mortality. The ME often rules theses death's primary causes as MI or CVA, when in fact, it was secondary to the primary cause of death, rebound phenomenon due to abrupt thrombolytic discontinuation.
> 
> Our physicians today, in general, have a very poor understanding of pharmaceutical science and are jeopardizing the lives of too many people by not keeping up with their reading and with CE credits resulting from ridiculously over-simplified course work designed more for the layman than a person the public goes to for their supposed medical, the average physician is far too often killing their patients by the medication they prescribe, and no one ever even realizes the patient was killed by their physician's ignorence



I've been looking at the NSAID bit too, it shows a lot of promise in non-human trials for various neurotoxic measures but fuck if I know the appropriate dose. I'd rather be too low than too high on something that inhibits bleeding.

But, thats good to know that if someone has been taking ASA for quite some time that they should ween themselves off rather than cold turkey it. Thanks man


----------



## Quercetin

Lets talk about histamine!

Drug interaction between methamphetamine and antihistamines: behavioral changes and tissue concentrations of methamphetamine in rats.
Methamphetamine is a psychomotor stimulant, whereas first generation antihistamines cause sedation. Several studies have demonstrated that first generation antihistamines potentiate methamphetamine-induced psychomotor activation and two possible mechanisms have been postulated. One is blockage of the central histaminergic neuron system and the other is inhibition of dopamine reuptake. However, the exact mechanism is still controversial. In this study, we examined in behavioral tests the effects of selected antihistamines on methamphetamine-induced psychomotor activation in rats, and measured plasma and brain tissue concentrations of methamphetamine. We found that some antihistamines significantly potentiate methamphetamine-induced psychomotor activation in rats and that plasma and brain tissue concentrations of methamphetamine in rats treated with methamphetamine in combination with D-chlorpheniramine were markedly higher than those in rats treated with methamphetamine alone. These results suggest that the potentiating effects of antihistamines are due to not only central effects but also the alteration of the pharmacokinetics of methamphetamine.


----------



## atrollappears

Hey everyone, it's been a while xD



Quercetin said:


> Lets talk about histamine!
> 
> Drug interaction between methamphetamine and antihistamines: behavioral changes and tissue concentrations of methamphetamine in rats.
> Methamphetamine is a psychomotor stimulant, whereas first generation antihistamines cause sedation. Several studies have demonstrated that first generation antihistamines potentiate methamphetamine-induced psychomotor activation and two possible mechanisms have been postulated. One is blockage of the central histaminergic neuron system and the other is inhibition of dopamine reuptake. However, the exact mechanism is still controversial. In this study, we examined in behavioral tests the effects of selected antihistamines on methamphetamine-induced psychomotor activation in rats, and measured plasma and brain tissue concentrations of methamphetamine. We found that some antihistamines significantly potentiate methamphetamine-induced psychomotor activation in rats and that plasma and brain tissue concentrations of methamphetamine in rats treated with methamphetamine in combination with D-chlorpheniramine were markedly higher than those in rats treated with methamphetamine alone. These results suggest that the potentiating effects of antihistamines are due to not only central effects but also the alteration of the pharmacokinetics of methamphetamine.



Well, we already know that H3 antagonists (H3 being an autoreceptor expresses exclusively in the brain) can potentiate methamphetamine induced monoamine release and subsequent hyperactivity. Judging by the fact that in that case an _increase_ in histamine signaling is increasing the effect of methamphetamine (which isn't surprising, considering H3 antagonists increase monoamine release on their own), I'm willing to chalk this up to a H3 antagonistic effect of chlorpheniramine.

Now, that bit about the tissue concentration is pretty interesting. I wonder: is methamphetamine degraded more quickly in the intracellular or extracellular environment? If there is a difference, would an increase or decrease in methamphetamine uptake affect the rate of change of the tissue concentration?


----------



## atrollappears

Oh, also, I recently came across something while reading about Olney's lesions which I thought might be relevant to this thread. The popular opinion on Olney's lesions at this point seems to be that the mouse studies in which Olney's lesions were discovered do not apply to humans. One of the justifications for this is that the metabolic rate of the mouse is higher, so the mouse mitochondria are much more liable to lose their proton gradient in response to toxic insults and/or release more free radicals upon losing their proton gradient. Considering that excitotoxic/oxidative damage definitely plays a role in amph neurotoxicity, I wonder if this same principle means that mouse studies overestimate the neurotoxicity of amphetamines?


----------



## blight12

Wow thank you all for this thread, went through it all and while not understanding any technical stuff, simply reading between the lines, conclusions, logic, assumptions based on recurring themes etc ensured i gained a ton of knowledge and insight and i would never have thought possible before actually going ahead and trying to interpret as much as possible. Firstly awesome insights as a recent high dose meth user and secondary:

I have been fascinated with Glutathione and direct supplementation, even just posted a new thread which was justly shut down due to no references and my overly enthusiastic claims/hopes etc. I was glad to see it mentioned often in this thread and to see known precursors to be highly valued, indicating that my conclusion of its value on topic seems justified. What i noticed was that the precursors (like NAC and ALA) where usually given credit for benefits directly and not increase in GSH itself. Is this accurate? Does NAC for example hold separate value beyond that provided by increased GSH?

I also noted a few comments where high levels would be negative. This seems very strange to me. My understanding of its value is antioxidant effects (the master antioxidant they call it), some sort of control over lesser antioxidants, a major role in the immune system and therefore noteworthy benefits in terms of autoimmune conditions as well as inflammatory conditions. My understanding that supplementation directly held major benefits as a deficiency here could be directly linked to aging and related issues. I reviewed many unconfirmed testimonials relating to massive benefits to difficult to treat diseases like many autoimmune concerns, cancers, parkinsons, altzhimers and many others.

I know the major consumer products with the most info and testimonials are based on increasing levels via precursors, the number 1 product via supplementing bonded cystine etc through undenatued whey and the other through a combination of NAC/ALA etc. Then recently I have seen liposomial delivered glutathione supplements as well.

Apparently maximizing blood GSH levels where possible, beyond the normal levels and also where levels are below the norm could produce some "amazing" results with claims against cancer and other things.

So really, i wanted to say that im a business, marketing persona and dont know the technical specifics and would really value confirmation, comments, etc of the above claims, inadequacies etc. I need the truth from you guys in the know, as i had planned to build a business around this product based on the claimed potential. results etc.

Appreciate any feedback, the more technical the better. Im certain this chemical has value but some of the claims are hard to believe, not matter how much i want to.

And then ofcourse the purpose of my other post and this one is determining any value to drug users through direct supplementation with the goal to maximize levels as it was understood that the more the better and low levels where closely linked to many illnesses and thus increasing levels could be the solution.


----------



## sekio

NAC is used as a prodrug for cystiene (and glutathione which is derived from cys.) because it is more bioavailiable than the unacetylated aminoa cid. Hence better oral absorbtion etc. Its main use is actually as an antidote for certain hepatotoxins like acetaminophen.

High doses of sulphur containing aminoa cids & prodrugs can cause side effects. Especially when large doses are administered orally, nausea is present with NAC sometimes at the very least.

Also, please be more specific when you refer to ALA. It can be one of three various chemicals (maybe more) - alpha-lipoic acid, a sulphur containing antioxidant; aminolevulinic acid, a chlorophyll precursor; or alpha-linolenic acid, an omega-3 fatty acid.

The "amazing" claims about glutathione supplementation I have yet to see. Best I can find is one pubmed study saying it slows the progression of untreated Alzheimers by ~40% versus placebo.Not really what I'd call a cure when you start looking at modern treatments like levo/carbidopa or segelegine.


----------



## polarbearsarecool

the secret of pre roll intake is a small meal 30-45 before, glucose levels man.


----------



## blight12

Long post warning:

I have reviewed this thread fully and attempted to understand as much as possible as a "layman". I have attempted to research the below answers but the technical data is very difficult to interpret in a useful way without the required skills. 

Can I confirm the accuracy of some conclusions? Any wording that i think may be perceived incorrectly, be inaccurate or i feel my not describe what i mean to satisfactory level will be in "". Dont go to any effort but if you know offhand...

1. Amphetamine Psychosis is in fact caused by physical "trauma", deficiencies and other easily explained physical conditions that would be considered unhealthy (for example hypoglycemia(hyper?)), and not the intended effect of the drug proceeding to a level where the experience is negatively perceived.
If so how does this explain experiences of similar psychosis presenting immediately through extreme doses as the first administration. Unless the physical conditions/requirements are created instantly by this, but it is my understanding that it will take some time to "deplete" the body to the point needed to cause psychosis.

2. Does the above conclusion also explain the perceived decreased mental faculties, paranoia, strange thoughts etc that can still be perceived as false, controlled etc. Basically the blatantly obvious negative mental states of mind that directly conflict with the expected effects of the drug. Can these be interpreted as an indication of the "beginnings" of an unhealthy physical state that would eventually progress to psychosis, or is this still subjective perception of your experience. Is there a perceived cut over point between subjective experienced based perceptions and mental states directly linked physical "trauma"? I have tried to repeat and reframe this to get my understanding across. Basically is there a functional way to interpret physical concerns during the experience.

3. Lastly where does the commonly accepted impact of sleep deprivation come into this? I understand it is a big part of the risk of psychosis. Does the sleep deprivation contribute to psychosis through exacerbating the physical "trauma" explanations for psychosis or does it impact in some other way. This was absent from this thread as far as i remember.

4. And at the risk of perhaps delving into the realm of pure theory: Any thoughts as to why the symptoms of psychosis in this regard, a seemingly chaotic unbalanced physical state of "unhealth" seem to present as rather surprisingly specific and consistent experiences which seem to follow some logical path. It would would seem the symptoms should present as they would with other forms of brain distress like random confusion, reduced mental function, memory loss, unconsciousness etc. Instead we see the same theme consistently. 
After reading many experiences of amp induced psychosis it seems to almost always present as a feeling of absolute certainty of impending danger from others or the environment which is perceived as being watched, followed etc. This feels like a hardwired specific instinctual response to a certain issue, but it doesn't seem to correlate to the root cause being physical distress.
My conclusions in an attempt to make sense of this:
1. The physical distress causes an appropriate mental sense of overall danger without a clear source, which we then imprint on our environment in a conscious effort to make sense of and identify the source of danger.
2. What is most likely more accurate is that the fight or flight response is at work here in extremes, which is what i always reasoned, but now i question this due to my new understanding of psychosis being caused by physical distress and not the SNS.
3. Lastly is it simply a result of the combination of physical distress and increased SNS activity logically resulting in the symptoms.

I am going to take this opportunity to risk the below questions which are more irrelevant and experience based, which I find interesting anyway. Feel free to ignore.

5. Can the perceived enhancement of certain mental tools during the experience be confirmed as accurate and explained technically/medically or would it be technically accurate to write off any perceived enhancement to a subjective perception of the experience? (EG. Enhanced creative writing abilities are simply due to enhanced confidence and not a physical effect for example improved access to the creative centers of the brain). This question is very broad and does not need answering directly. Let this rather be a clarification of context for the next more specific question.

5. I would like to know if the perceived enhanced senses (specifically smell and audio) during the experience can be technically explained, confirmed as accurate or reasonably concluded, even if just in theory using scientifically backed assumptions/methods, as in fact an enhancement of the senses for all intents and purposes. Or must we conclude this perception is always a purely subjective experience that is equivalent to a hallucinatory response, when considering this from a technical or scientific point of view.

To reframe: If i where to ask a medical/scientific professional with all the required knowledge whether I can logically accept, trust or assume that my senses are in fact enhanced and could therefore be theoretically useful on some way, what would they say? 
The sense enhancements are really the only perceived enhancement that i think *might *have some basis in fact but really i have no idea.

I hope none of the above makes no sense or is plain stupid but feel free to let me know if it is.

Lastly a random thought. I think it would be really awesome and interesting for somebody with all the knowledge and experience to take all the info in this thread and all relevant and confirmed as accurate data and do a write up or paper of some sort that explains the perfect process, requirements, actions etc for the use of amphetamines recreationally and functionally based on theoretical, technical and scientific conclusions etc. 
To clarify this would look like a detailed and step by step owners manual explaining exactly how to use amphetamines including everything that should be considered, physical defense strategies, supplementation, detailed dosage guides etc. A functional usable guide for anybody to understand.
I'm not asking or expect anybody to do this, simply thought that the whole concept of a functional summary of everything we know to date would be a worthy project and i dont think a well packaged and presented version of this idea exists anywhere, or does it?
Hell if i had the skills to do this responsibly, i would really enjoy this project i think. Also would be an awesome HR sticky for Other Drugs im sure. Anyways, just a random idea.

Love ADD and thanks to all the contributors, I could spam questions here all day, but I shall resist .


----------



## arohydro

I apologize for contributing nothing and only posing more questions:

I have pretty severe ADHD (by my account - I have been diagnosed but the severity modifier is MY addition) and am wondering if I should finally give low-dose adderall a proper trial. The only complication being that I am quite concerned about my brain and tend to stray away from anything that has the potential for long-term consequences. I drink once a month or so, and half of the time I go overboard, end up with a hangover, hate myself for having put my brain through dehydration, free radicals, potential excitotoxic rebound, etc, and swear off of it... until next time. That's another whole can of worms as far as my anxiety is concerned.

Anyway, I really only know one mechanism by which amphetamine may induce neurotoxicity in a primate, but I accept the likelihood of multiple tenets to this drug's toxic profile. For someone like me, that wants to use the drug therapeutically, and for a short trial (then, potentially, a longer one), is there any legitimate concern? I read frightening reports about reduced VMAT2, striatal dopamine, etc. *shivers* I know a fair amount, but not enough to understand brain pathways and metabolism.

I am getting my shit together in life either way, so if I skip out on this it may place more mechanical effort in the way of things, but ultimately I am going to the same place. It would be a major boon if I could garner some improved concentration from something relatively benign at the therapeutic level.


----------



## atrollappears

arohydro said:


> I apologize for contributing nothing and only posing more questions:
> 
> I have pretty severe ADHD (by my account - I have been diagnosed but the severity modifier is MY addition) and am wondering if I should finally give low-dose adderall a proper trial. The only complication being that I am quite concerned about my brain and tend to stray away from anything that has the potential for long-term consequences. I drink once a month or so, and half of the time I go overboard, end up with a hangover, hate myself for having put my brain through dehydration, free radicals, potential excitotoxic rebound, etc, and swear off of it... until next time. That's another whole can of worms as far as my anxiety is concerned.
> 
> Anyway, I really only know one mechanism by which amphetamine may induce neurotoxicity in a primate, but I accept the likelihood of multiple tenets to this drug's toxic profile. For someone like me, that wants to use the drug therapeutically, and for a short trial (then, potentially, a longer one), is there any legitimate concern? I read frightening reports about reduced VMAT2, striatal dopamine, etc. *shivers* I know a fair amount, but not enough to understand brain pathways and metabolism.
> 
> I am getting my shit together in life either way, so if I skip out on this it may place more mechanical effort in the way of things, but ultimately I am going to the same place. It would be a major boon if I could garner some improved concentration from something relatively benign at the therapeutic level.



Amphetamine is pretty benign, honestly. AFAIK well-controlled studies haven't found any negative effects (maybe slight positive ones) of even recreational amphetamine use... and there are a bunch of reasons I could give you for why neurotoxicity found in rodent studies is unlikely to apply to any reasonable human use. Amphetamine has been around a long time, so it's pretty safe to assume that its risks have been documented.


----------



## Renz Envy

Two things I've discovered while recovering my prescription to vyvanse.

The first thing is that L-tryptophan supposedly has minor-major antagonistic effects on d-amphetamine(Here). 

*However*, when I use L-tryptophan post D-amphetamine administration, it seems to intensify and enlongate the effects. There have been nights when I used L-tryptophan to go to bed and it lead to me standing right back up to clean my room or otherwise not sleep. Not necessarily in a bad way. The intensified effects seem to be centered more so around the pleasure center rather than excessive stimulation. I have been looking for a study that can give reason as to why this is in contrast to the previous study. 




*2nd thing* was a source I read via wikipedia about *buspirone, a D2 antagonist* and 5-ht1a partial selective agonist, when combined with melatonin has the ability to repair brain tissue.

Wikipedia

Source 1

Source 2



> A study of 142 patients showed positive results for the treatment of Depression when Buspirone was combined with Melatonin. It is suspected that the method of action differs from other SSRI medications. Preliminary research suggests that the combination of Buspirone and Melatonin stimulates the growth of new neurons in the brain, also known as neurogenesis



If this has been mentioned before, I apologize. After amphetamine use, this study was a god-send. I immediately tried it on myself. I woke 3 mornings later feeling normal. It was as if the "zombified" post-withdrawal use of amphetamine was non-existent. My anxiety and apathy were gone. I was back to the way I was before using any drug. I felt myself, able to socialize and connect easier with family and friends. Whereas in the past it would take close to 2-3 weeks without using my prescription to start coming back to normal.

Another thing I found was that each time I did it, it seemed to maintain D-amphetamine's strength the next day. The tolerance increase was far less than it would have been otherwise naturally.


----------



## campers

blight12, re glutathione.  

I've been researching glutathione a lot for a while now.  It's amazing how little mainstream attention it has given the massive amounts of published science on it (100,000+ search results on PubMed compared to under 50,000 for vitamin c/ascorbic acid), then again not so surprising given there hasn't been very effective glutathione supplement until recently.

Send me a pm, you've missed the new glutathione supp with a cysteine pro-drug that is far superior to whey or NAC.  For starters here is a number of studies relating methamphetamine neurotoxicity, low glutathione levels and glutathione supplementation.  My post I had written just got eaten so I'll write more again elaborating very soon.


http://www.ncbi.nlm.nih.gov/pubmed/15199373

These results suggest that NAC could attenuate the reduction of DAT (dopamine transporter ) in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/?tool=pubmed

The idea that oxygen-based free radicals are involved in METH neurotoxicity is further strengthened by reports that the drug can reduce the levels of glutathione

http://www.ncbi.nlm.nih.gov/pubmed/9839724

Our observations provide further evidence in support of the oxidative stress hypothesis of MA neurotoxicity and indirectly suggest that drugs designed to increase glutathione might protect against such damage.

http://www.ncbi.nlm.nih.gov/pubmed/10642830

 We have shown that dietary Selenium attenuated methamphetamine neurotoxicity and that this protection involves Glutathione Peroxidase-mediated antioxidant mechanisms

http://www.ncbi.nlm.nih.gov/pubmed/10913590

These findings indicate selectivity of methamphetamine for the glutathione system and a role for methamphetamine in inducing oxidative stress.

http://www.ncbi.nlm.nih.gov/pubmed/12018843

METH toxicity seems to be produced by oxidative stress, as it was attenuated by the antioxidant glutathione

http://www.ncbi.nlm.nih.gov/pubmed/21882243

We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons

http://www.ncbi.nlm.nih.gov/pubmed/11746378

 A dose-dependent depletion of total glutathione levels was detected in human brain microvascular endothelial cells exposed to METH

http://www.ncbi.nlm.nih.gov/pubmed/12230306

These results suggest that METH-induced disturbances in cellular redox status and that activation of AP-1 can play a critical role in signaling pathways leading to upregulation of inflammatory genes in vivo

http://www.ncbi.nlm.nih.gov/pubmed/15234256

These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

http://www.ncbi.nlm.nih.gov/pubmed/15111252

 It was found that acute administration of methamphetamine (5 and 15 mg kg(-1)) resulted in production of oxidative stress as demonstrated by decreased glutathione and increased oxidized glutathione levels

http://www.ncbi.nlm.nih.gov/pubmed/16038959

Enantiomers of trans-phenylpropylene oxide (Pyrolytic products of smoked methamphetamine) were stereoselectively and regioselectively conjugated in a Phase II drug metabolism reaction catalyzed by human liver cytosolic enzymes consisting of conjugation with glutathione

http://www.ncbi.nlm.nih.gov/pubmed/16760923

The levels of the reduced form of glutathione (GSH) in striatum, amygdala, hippocampus and frontal cortex were significantly lower in METH-treated mice compared to control during the period of conditioned place preference training. Acute and repeated administration of NAC to METH-treated mice restored the decreased brain GSH but had no effect on controls.

http://www.ncbi.nlm.nih.gov/pubmed/22354084

This suggests that METH induces oxidative stress in various organs and that a combination of N-acetylcysteine amide as a neuro- or tissue-protective agent, in conjunction with current treatment, might effectively treat METH abusers.


----------



## MeDieViL

So in conclusion methylene blue is what we are looking for, for tolerance issues:
It depletes glutamate and nitric oxide the main players in tolerance, besides that its neuroprotective but dunno wheter that apply's to amp, the 40% increase in mitochondrial function may make it easier for the body to handle amp's overdrive (dunno wheter thats true, just saying something).

MB will be a far better option then mem for tolerance as it doesnt impair some glut related issues like LTP, it actually enhances it, besides that its an antipsychotic something ppl may need on amp binges.


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## MeDieViL

Guanylate cyclase is another MB acts on and indeed seems implicated in tolerance:


> Guanylate cyclase inhibition by methylene blue as an option in the treatment of vasoplegia after a severe burn. A medical hypothesis.
> Farina Junior JA, Celotto AC, da Silva MF, Evora PR.
> Source
> Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil.
> Abstract
> Today it is known that severe burns can be accompanied by the phenomenon of vasoplegic syndrome (VS), which is manifested by persistent and diffuse vasodilation, hypotension and low vascular resistance, resulting in circulatory and respiratory failure. The decrease in systemic vascular resistance observed in VS is associated with excessive production of nitric oxide (NO). In the last 2 decades, studies have reported promising results from the administration of an NO competitor, methylene blue (MB), which is an inhibitor of the soluble guanylate cyclase (sGC), in the treatment of refractory cases of vasoplegia. This medical hypothesis rationale is focused on the tripod of burns/vasoplegia catecholamine resistant/methylene blue. This article has 3 main objectives: 1) to study the guanylate cyclase inhibition by MB in burns; 2) to suggest MB as a viable, safe and useful co-adjuvant therapeutic tool of fluid resuscitation, and; 3) to suggest MB as burns hypotensive vasoplegia amine-resistant treatment.<br />


Ill keep editing my posts for more updates out of compassion for the ppl that aint got some speed and cant read as fast


----------



## MeDieViL

It seems like CCK regulates also nitric oxide and glutamate, wich also explains that very succesfull anecdote on proglumide someone posted here a while ago, i wonder what the "ultimate" regular is we need to hit thus we can avoid the downsides of supressing first nmda, then it became clear no plays a bigger role that regulates nmda, and from first glance it seems cck plays a very big role here, lets see what i can dig out.

Some shit MB


> Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue.
> Rojas JC, Bruchey AK, Gonzalez-Lima F.
> Source
> Departments of Psychology, Pharmacology and Toxicology, University of Texas at Austin, 1 University Station A8000, Austin, TX 78712, USA.
> Abstract
> This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have important implications as a new neurobiological approach to improve normal memory and to treat memory impairment and neurodegeneration associated with mitochondrial dysfunction. Methylene blue's action is unique because its neurobiological effects are not determined by regular drug-receptor interactions or drug-response paradigms. Methylene blue shows a hormetic dose-response, with opposite effects at low and high doses. At low doses, methylene blue is an electron cycler in the mitochondrial electron transport chain, with unparalleled antioxidant and cell respiration-enhancing properties that affect the function of the nervous system in a versatile manner. A major role of the respiratory enzyme cytochrome oxidase on the memory-enhancing effects of methylene blue is supported by available data. The memory-enhancing effects have been associated with improvement of memory consolidation in a network-specific and use-dependent fashion. In addition, low doses of methylene blue have also been used for neuroprotection against mitochondrial dysfunction in humans and experimental models of disease. The unique auto-oxidizing property of methylene blue and its pleiotropic effects on a number of tissue oxidases explain its potent neuroprotective effects at low doses. The evidence reviewed supports a mechanistic role of low-dose methylene blue as a promising and safe intervention for improving memory and for the treatment of acute and chronic conditions characterized by increased oxidative stress, neurodegeneration and memory impairment.





> Alternative mitochondrial electron transfer as a novel strategy for neuroprotection.
> Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, Ju X, Liu R, Qian H, Marvin MA, Goldberg MS, She H, Mao Z, Simpkins JW, Yang SH.
> Source
> Department of Pharmacology and Neuroscience, Institute for Alzheimer's Disease and Aging Research, University of North Texas Health Science Center, Fort Worth, Texas 76107-2699, USA.
> Abstract
> Neuroprotective strategies, including free radical scavengers, ion channel modulators, and anti-inflammatory agents, have been extensively explored in the last 2 decades for the treatment of neurological diseases. Unfortunately, none of the neuroprotectants has been proved effective in clinical trails. In the current study, we demonstrated that methylene blue (MB) functions as an alternative electron carrier, which accepts electrons from NADH and transfers them to cytochrome c and bypasses complex I/III blockage. A de novo synthesized MB derivative, with the redox center disabled by N-acetylation, had no effect on mitochondrial complex activities. MB increases cellular oxygen consumption rates and reduces anaerobic glycolysis in cultured neuronal cells. MB is protective against various insults in vitro at low nanomolar concentrations. Our data indicate that MB has a unique mechanism and is fundamentally different from traditional antioxidants. We examined the effects of MB in two animal models of neurological diseases. MB dramatically attenuates behavioral, neurochemical, and neuropathological impairment in a Parkinson disease model. Rotenone caused severe dopamine depletion in the striatum, which was almost completely rescued by MB. MB rescued the effects of rotenone on mitochondrial complex I-III inhibition and free radical overproduction. Rotenone induced a severe loss of nigral dopaminergic neurons, which was dramatically attenuated by MB. In addition, MB significantly reduced cerebral ischemia reperfusion damage in a transient focal cerebral ischemia model. The present study indicates that rerouting mitochondrial electron transfer by MB or similar molecules provides a novel strategy for neuroprotection against both chronic and acute neurological diseases involving mitochondrial dysfunction.



Issue with amp:


> Frontal glucose hypometabolism in abstinent methamphetamine users.
> Kim SJ, Lyoo IK, Hwang J, Sung YH, Lee HY, Lee DS, Jeong DU, Renshaw PF.
> Source
> Department of Psychiatry, Seoul National University College of Medicine and Hospital, Seoul, Korea.
> Abstract
> Changes in relative regional cerebral glucose metabolism (rCMRglc) and their potential gender differences in abstinent methamphetamine (MA) users were explored. Relative rCMRglc, as measured by (18)F-fluorodeoxyglucose positron emission tomography, and frontal executive functions, as assessed by Wisconsin card sorting test (WCST), were compared between 35 abstinent MA users and 21 healthy comparison subjects. In addition, male and female MA users and their gender-matched comparison subjects were compared to investigate potential gender differences. MA users had lower rCMRglc levels in the right superior frontal white matter and more perseveration and nonperseveration errors in the WCST, relative to healthy comparison subjects. Relative rCMRglc in the frontal white matter correlated with number of errors in the WCST in MA users. In the subanalysis for gender differences, lower rCMRglc in the frontal white matter and more errors in the WCST were found only in male MA users, not in female MA users, relative to their gender-matched comparison subjects. The current findings suggest that MA use causes persistent hypometabolism in the frontal white matter and impairment in frontal executive function. Our findings also suggest that the neurotoxic effect of MA on frontal lobes of the brain might be more prominent in men than in women.





> Beneficial network effects of methylene blue in an amnestic model.
> Riha PD, Rojas JC, Gonzalez-Lima F.
> Source
> Departments of Psychology, Pharmacology and Toxicology, University of Texas at Austin, Austin, TX 78712, USA.
> Abstract
> Posterior cingulate/retrosplenial cortex (PCC) hypometabolism is a common feature in amnestic mild cognitive impairment and Alzheimer's disease. In rats, PCC hypometabolism induced by mitochondrial dysfunction induces oxidative damage, neurodegeneration and memory deficits. USP methylene blue (MB) is a diaminophenothiazine drug with antioxidant and metabolic-enhancing properties. In rats, MB facilitates memory and prevents neurodegeneration induced by mitochondrial dysfunction. This study tested the memory-enhancing properties of systemic MB in rats that received an infusion of sodium azide, a cytochrome oxidase inhibitor, directly into the PCC. Lesion volumes were estimated with unbiased stereology. MB's network-level mechanism of action was analyzed using graph theory and structural equation modeling based on cytochrome oxidase histochemistry-derived metabolic mapping data. Sodium azide infusions induced PCC hypometabolism and impaired visuospatial memory in a holeboard food-search task. Isolated PCC cytochrome oxidase inhibition disrupted the cingulo-thalamo-hippocampal effective connectivity, decreased the PCC functional networks and created functional redundancy within the thalamus. An intraperitoneal dose of 4 mg/kg MB prevented the memory impairment, reduced the PCC metabolic lesion volume and partially restored the cingulo-thalamo-hippocampal network effects. The effects of MB were dependent upon the local sub-network necessary for memory retrieval. The data support that MB's metabolic-enhancing effects are contingent upon the neural context, and that MB is able to boost coherent and orchestrated adaptations in response to physical alterations to the network involved in visuospatial memory. These results implicate MB as a candidate intervention to improve memory. Because of its neuroprotective properties, MB may have disease-modifying effects in amnestic conditions associated with hypometabolism.





> Neuro- and cardioprotective effects of blockade of nitric oxide action by administration of methylene blue.
> Wiklund L, Basu S, Miclescu A, Wiklund P, Ronquist G, Sharma HS.
> Source
> Department of Surgical Sciences, Uppsala University Hospital, SE-75185 Uppsala, Sweden. lars.wiklund@surgsci.uu.se
> Abstract
> Methylene blue (MB), generic name methylthioninium (C(16)H(18)ClN(3) S . 3H(2)O), is a blue dye synthesized in 1876 by Heinrich Caro for use as a textile dye and used in the laboratory and clinically since the 1890s, with well-known toxicity and pharmacokinetics. It has experimentally proven neuroprotective and cardioprotective effects in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. This effect has been attributed to MB's blocking effect on nitric oxide synthase and guanylyl cyclase, the latter blocking the synthesis of the second messenger of nitric oxide. The physiological effects during reperfusion include stabilization of the systemic circulation without significantly increased total peripheral resistance, moderately increased cerebral cortical blood flow, a decrease of lipid peroxidation and inflammation, and less anoxic tissue injury in the brain and the heart. The last two effects are recorded as less increase in plasma concentrations of astroglial protein S-100beta, as well as troponin I and creatine kinase isoenzyme MB, respectively.
Click to expand...


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## blight12

@campers: Just the type of feedback I was looking for, thank you. I would love to hear anything else you might have on the topic of GSH and/or your interpretations on the functional use of GSH supplementation in context of this thread.

Cheers.


----------



## MeDieViL

I wonder what the negatives of depleting no and glutamate will be with MB? I do have the impression individual receptor functions are potentiated leading to even greater LTP for example from glut is depleted, but this makes me wonder would tolerance still be able to occur to then?


----------



## polarbearsarecool

After various proglumide trials I can conclude various things:

Proglumide seems to be an inhibitory neurotransmitter for not just dopamine but for various excitatory transmitters, glutamate, NO, etc. 

Your comment medievil just sparked a thought finding./...

http://www.jneurosci.org/content/30/15/5136.full.pdf

Cholecystokinin Facilitates Glutamate Release by Increasing the Number of Readily Releasable Vesicles and Releasing Probability

"CCK reduced the coefficient of variation and paired-pulse ratio of AMPA EPSCs suggesting that CCK facilitates presynaptic glutamate release. CCK
increased the release probability and the number of readily releasable vesicles with no effects on the rate of recovery from vesicle
depletion. CCK-mediatedincreasesin glutamate release requiredthefunctions of phospholipase C,intracellular Ca2+
release and protein kinase C. CCK released endogenously from hippocampal interneurons facilitated glutamatergic transmission. Our results provide a
cellular and molecular mechanism to explain the roles of CCK in the brain."

This paper has various interesting approaches; one being that through na+ or ca+ proglumide does not facilitate glutamate transmission- however through k+ channels it does in a manner similar to 4-amino pyridine, suggesting that 4-AP and CCK interact and block K+ channels in a similar manner. thus facilitating glutamate transmission via this indirect means.


the final conclusion being that 



> Our results indicate that CCK augments glutamate release at PP-GC, CA3-CA3 and CA3-CA1 synapses with no effects at MF-CA3 synapses. CCK increases the number of readily releasable vesicles and release probability without effects on the rate of recovery from vesicle depletion. The effects of CCK on glutamate release are mediated by inhibition of a 4-AP-sensitive Kchannel and requirethe functions of CCK-2 receptors, PLC,intracellular Ca2release and PKC. We
> further demonstrate that CCK endogenously released from interneurons increases glutamatergic transmission inthe hippocampus.
> Whereas CCK has been shown to activate a cationic conductance in rat neostriatal neurons (Wu and Wang, 1996) andsupraoptic nucleus neurons (Chakfe andBourque, 2001), our results demonstrate that CCK does not facilitate glutamate release in the hippocampus by activating cationic channels because CCK failed to modulate mEPSCs recorded from dentate granule cells and CCK had no effects on the resting membrane potentials recorded
> from stellate neurons in the entorhinal cortex. Our results also demonstrate that CCK does not increase glutamate release by direct interaction with and facilitation of presynaptic Ca 2 channels because application of the selective P/Q- and N-type Ca 2 channel blockers did not block CCK-induced increases in AMPA EPSCs and application of CCK failed to alter Ca 2 channel currents recorded from stellate neurons, the cell body of the perforant pathway. Actually, CCK slightly inhibits Ca 2
> channels in CA1 pyramidal neurons (Shinohara and Kawasaki, 1997). Our results support the scenario that CCK inhibits IK resulting in increases in presynaptic Ca 2
> influx via voltage-gated Ca 2
> channels to facilitate glutamate release in the hippocampus because application of 4-AP at micromolar concentration blocked CCKinduced increases in AMPA EPSCs and application of CCK inhibited IK recorded from stellate neurons in the entorhinal cortex. In agreement with our results, CCK has been shown to
> inhibit other K channels in a variety of neurons (Branchereau et al., 1993; Cox et al., 1995; Miller et al., 1997; Deng and
> Lei, 2006; Yang et al., 2007; Chung et al., 2009). Furthermore,
> CCK-induced increases in glutamate release gauged by measuring glutamate concentration in the perfusate of hippocampal slices (Migaud et al., 1994) and in purified rat hippocampal
> synaptosomes (Breukel et al., 1997) are Ca 2 -dependent. CCKinduced augmentation of presynaptic Ca2 concentration likely
> contributes to its increased effects on the number of readily releasable vesicles and release probability because both the mobility
> zation of vesicles from the reserve pool to the readily releasable
> pool and the release probability are Ca 2
> -dependent (Zucker
> and Regehr, 2002).
> We have shown that CCK-mediated facilitation of glutamate
> release requires the functions of CCK-2 receptors. This conclusion is consistent with the results obtained by measuring glutamate concentration in the perfusate of hippocampal slices
> (Migaud et al., 1994) and in purified rat hippocampal synaptosomes (Breukel et al., 1997) after application of CCK. The following three lines of evidence indicate that presynaptic CCK-2
> receptors should be responsible for CCK-induced glutamate release in the hippocampus. First, enriched CCK-binding sites have
> been detected in layer II of the entorhinal cortex where the cell
> bodies of the perforant path are located in (Ko¨hler and ChanPalay, 1988). Second, inclusion of GDP--S, a G-protein inhibitor, in the recording pipettes failed to change CCK-induced
> increases in AMPA EPSCs whereas it blocked CCK-induced depression of IK
> recorded from the stellate neurons in layer II of the
> entorhinal cortex. Third, Breukel et al. (1997) have shown that
> CCK increases glutamate release in purified hippocampal synaptosomes because in this preparation the continuity of presynaptic
> and postsynaptic structures should be disconnected. We further
> demonstrate that the down-stream targets of CCK-2 receptors,
> PLC, intracellular Ca
> 2
> and PKC are involved in CCK-induced
> increases in glutamate release. Because our results demonstrate
> that CCK augments glutamate release by inhibiting presynaptic IK, it is reasonable to speculate that the activated PKC phosphorylates IK or IK
> -associated proteins resulting in an inhibition of IK . Consistent with our results, activation of PKC has been shown to inhibit IK in neurons cultured from rat hypothalamus
> and brainstem (Pan et al., 2001) and in cerebrocortical synaptosomes (Barrie et al., 1991) and IK expressed in Xenopus oocytes (Peretz et al., 1996).
> CCK has been shown to transiently increase GABA release in hippocampal CA1 region (Miller et al., 1997; Deng and Lei, 2006;
> Fo¨ldy et al., 2007; Karson et al., 2008). However, these studies did not examine the late effect of CCK on GABAergic transmission.
> We have previously shown that CCK exerts bidirectional modification, with initial transient enhancement followed by a persistent depression, of GABAergic transmission onto the granule
> cells of the dentate gyrus (Deng and Lei, 2006). Here, we further
> assessed the contribution of glutamatergic and GABAergic transmission to CCK-mediated modification of the excitability of
> granule cells. Our results demonstrate that CCK-mediated initial
> transient enhancement of GABA release does not lead to a perceptible inhibition of the excitability of granule cells when both
> GABAergic and glutamatergic transmissions are functional. The
> possible reason is that the inhibition derived from CCK-induced
> transient augmentation of GABA release is inundated by its action on glutamate release because the initial inhibitory effect of
> CCK on neuronal excitability was unfolded when glutamatergic
> transmission was inhibited. However, these results do not deny a
> potential function for CCK-induced initial increase in GABAergic transmission because it is possible that this kind of modification may exert a fine-tuning on neuronal network activity.
> Nonetheless, CCK-induced late phase inhibition on GABAergic
> transmission is in line with its effect on glutamatergic transmission. The concerted actions of CCK on GABAergic and glutamatergic transmissions likely lead to an increase in neuronal
> excitability. CCK has long been known to exert anxiogenic
> effects in both animal models and humans (Rehfeld, 2000) and
> the generation of anxiety can be due to a reduction in GABAergic
> (Rupprecht et al., 2006; Whiting, 2006) and/or an increase of
> glutamatergic (Bergink et al., 2004) function. Our results are
> agreeable with this scenario and may serve as the cellular and
> molecular mechanisms to explain the anxiogenic effects of CCK.
> In addition, CCK has also been implicated in modulating other important brain functions including satiety, analgesia, learning and
> memory processes (Sebret et al., 1999; Rehfeld, 2000; Beinfeld,
> 2001), which are closely related to both glutamate and GABA. Our
> results therefore provide a basis to explain the roles of CCK in these
> physiological functions as well.





So via CCK antagonism we can block CCK's ability to bind to CCKA OR CCKB receptor thus increasing synaptic density but where will this take us? Sometimes proglumide made me feel spacy and even somewhat stupid, i'm not sure what the right dose is...




Also:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154098/

"Cholecystokinin Exerts an Effect via the Endocannabinoid System to Inhibit GABAergic Transmission in Midbrain Periaqueductal Gray"

CCK also appears to inhibit GABA in a manner similar to modafinil/opiates(indirect GABA inhibition is one of the possible explanations to opiate wakefullness besides typical DA activity increase. ) but different- through an endocannabinoid system?


If someone can go through this I think a correct proglumide dose+ pramiracetam or nefiracetam or PDE inhibition may be key with stimulants/many drugs of abuse/reward...


----------



## MeDieViL

Whats the benefit of targetting CCK as we can target glutamate more selectively? eg only the nmda receptors, less activation of ampa and other receptors could have detrimental effects?

I want to try something simular with mb wich depletes glut and no but my concern is negative effects caused by hypoactivation of receptors we would want to see agonized?

What are your results with prog? its good to see someone else doing some experiments instead of saying " its too good to be true, you cant only help tolerance a bit" we know better hehe

Shame all those tolerance techniques are ignored mostly.


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## MeDieViL

Wait a sec, you want to deplete no and glut with cck to later add in a pro no and pro glutamate substance? altough nefi blocks morphine tolerance but thats due the cAMP increase wich clearly does seem to overpower the possible tolerance acceleration of increased nmda activity.
I may be missing a few points tough as my exact knowledge of this isnt up to date.


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## Woundrous

Hey all.  I would like to suggest creatine malate to possibly help fight amphetamine-induced mental fatigue (i.e. long-term usage wearing you down).  I assume that is what is generally meant by "amphetamine neurotoxicity" ?

My current hypothesis is that supplementing creatine replenishes ATP levels in the brain.  Since you are using amphetamine, you are overstimulating your (primarily) dopaminergic neurons.  More specifically, the dopamine is trapped in the synaptic cleft and activates dopamine receptors.  These are class A GPCRs, which are coupled to adenylyl cyclase.  

Adenylyl cyclase is an enzyme that catalyzes lots of ATP to be cAMP.  

Hence, if you use lots of amphetamine... you're going to be using up lots of ATP too.

...

;P

FYI - creatine malate NOT regular creatine because regular is hard to digest and swallow... malate form is much better.  =)


----------



## Tussmann

Woundrous said:


> Hey all.  I would like to suggest creatine malate to possibly help fight amphetamine-induced mental fatigue (i.e. long-term usage wearing you down).  I assume that is what is generally meant by "amphetamine neurotoxicity" ?
> 
> My current hypothesis is that supplementing creatine replenishes ATP levels in the brain.  Since you are using amphetamine, you are overstimulating your (primarily) dopaminergic neurons.  More specifically, the dopamine is trapped in the synaptic cleft and activates dopamine receptors.  These are class A GPCRs, which are coupled to adenylyl cyclase.
> 
> Adenylyl cyclase is an enzyme that catalyzes lots of ATP to be cAMP.
> 
> Hence, if you use lots of amphetamine... you're going to be using up lots of ATP too.
> 
> ...
> 
> ;P
> 
> FYI - creatine malate NOT regular creatine because regular is hard to digest and swallow... malate form is much better.  =)




"Many individuals on this forum likely already take creatine for its ergogenic (or nootropic) effects, so much of this will be old news. However, there have been a number of posts recently asking for advice on nootropic compounds, and creatine, one of the best-proven cognitive enhancing compounds, has often been left out.



I'll keep this short. Creatine is safe, ergogenic, and neuroprotective. It also appears to enhance cognition -- in healthy humans no less -- and may in fact have anti-depressant properties. That creatine is safe and ergogenic is well-proven, so I won't go into that here.



Neuroprotection



Improves DA cell survival in models of PD. (PMID: 16355565, PMID: 15890457)
Improves survival of striatal GABAergic neurons. (PMID: 16045451)




Cognition Enhancement (Nootropic)



Reduces mental fatigue during simple task repetition and increases cerebral oxygen utilization. (PMID: 11985880)
Improvement in cognitive function on almost all tasks studied in elderly individuals. (PMID: 17828627)
Decreases variability in responses to a choice reaction-time task in healthy individuals. Also improves memory in healthy vegetarians, who presumably have lower baseline creatine intake. (PMID: 21118604)
Improves memory in healthy volunteers and reduced fMRI BOLD signal, indicating possible increase in efficiency. (PMID: 20570601)
During sleep deprivation, improves PFC-loaded tasks relative to placebo. (PMID: 16416332)
Improves executive functioning.




Mood Enhancement (Anti-depressant)



Beneficial effects on unipolar depression in a small trial. (PMID: 17988366)
During sleep deprivation, improves mood. (PMID: 16416332)
Shows antidepressant effects in females only in rodents. (PMID: 19829292)




Note this is just a small sampling of studies regarding creatine. But note that while piracetam, choline citrate, and dozens of other "nootropics" have no evidence for efficacy in healthy volunteers, creatine in fact does. 



I should note, in closing, that there is one negative study on creatine enhancing cognitive performance in healthy volunteers (PMID: 18579168), but the dose used was fairly low (0.03/g/kg/day, or 2.2g/day in a 75kg man, about half of the more frequently used dose of 5g/day) and there are a number of other studies (see above) showing positive results."


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## Epsilon Alpha

Woundrous said:


> Hey all.  I would like to suggest creatine malate to possibly help fight amphetamine-induced mental fatigue (i.e. long-term usage wearing you down).  I assume that is what is generally meant by "amphetamine neurotoxicity" ?
> 
> My current hypothesis is that supplementing creatine replenishes ATP levels in the brain.  Since you are using amphetamine, you are overstimulating your (primarily) dopaminergic neurons.  More specifically, the dopamine is trapped in the synaptic cleft and activates dopamine receptors.  These are class A GPCRs, which are coupled to adenylyl cyclase.
> 
> Adenylyl cyclase is an enzyme that catalyzes lots of ATP to be cAMP.
> 
> Hence, if you use lots of amphetamine... you're going to be using up lots of ATP too.
> 
> ...
> 
> ;P
> 
> FYI - creatine malate NOT regular creatine because regular is hard to digest and swallow... malate form is much better.  =)


Dopamine receptors don't all crank out cAMP, a lot of them in fact inhibit its production. Creatine is a good place to look though, as you can throw all the neurotransmitters at a cell you want and have nothing happen unless its metabolically supported.


----------



## Woundrous

Epsilon Alpha said:


> Dopamine receptors don't all crank out cAMP, a lot of them in fact inhibit its production.



Do you have a paper/source on this I can check out?  I've never heard of this happening personally.  I just pulled out my (handy dandy) qiagen pathway map reference guide and see only GPCRs coupled to Galpha-short and Galpha-long directly activate adenylyl cyclase.  It was my understanding that most class A/B GPCRs were coupled to either one though.  I'd be interested to see otherwise.

Anyways yeah the whole "creatine is neuroprotective" idea seems a bit vague to me.  Its not that I disagree with it, just I hate those types of blanket statements about "neuroprotection."  Of course, there could be some general way that having high levels of ATP provide this property to neurons.  But I am more of a rational thinker and try to think my way through the molecular basis as much as possible on something like this.

I've been having great success using creatine malate to prevent me from getting brain zaps from using my precious MXE/6APB combo weekend in-weekend out here recently.  I had to quit for a while in the spring/summer and even before in last winter because they kept getting so bad at night days after letting sobriety hit me following a weekend.

But it was only an inadvertent realization.  I just started using the creatine for my workouts, and started using the drugs again shortly thereafter.  Lo and behold this time I am not getting the zaps... and I've been hitting it just like I was previously.

So I am guessing it might help for people using any type of stimulants that put a lot of stress on GPCRs, or just drugs that cause the user to use up a lot of ATP.  Of course, again, it could be some general "neuroprotective" effect... but I really like the ATP depletion hypothesis.  ATP is pretty important... this all has me wondering just how important it is though, like on a scale of 1 to 10 compared to all the other widely used, general metabolic small molecules.  . . .

Also I had skimmed through the thread, regarding stuff like amphetamine neurotoxicity mechanisms.  Things like free radical damage.  Personally I'd be more weary of the effect of general wear and tear over the long run resulting from simply the face that amphetamine will cause overstimulation in the brain.  I mean that's how it works right; it makes your dopamine receptors work harder than normal.  Over the long-term, this can get grueling.  Well, I'm a bit skeptical this wouldn't be the biggest issue.  Anyways that's it for now.


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## Epsilon Alpha

Woundrous said:


> Do you have a paper/source on this I can check out?  I've never heard of this happening personally.  I just pulled out my (handy dandy) qiagen pathway map reference guide and see only GPCRs coupled to Galpha-short and Galpha-long directly activate adenylyl cyclase.  It was my understanding that most class A/B GPCRs were coupled to either one though.  I'd be interested to see otherwise.
> .



http://en.wikipedia.org/wiki/D2-like_receptor
D2, D3, and D4 all inhibit cAMP formation.


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## arohydro

atrollappears said:


> Amphetamine is pretty benign, honestly. AFAIK well-controlled studies haven't found any negative effects (maybe slight positive ones) of even recreational amphetamine use... and there are a bunch of reasons I could give you for why neurotoxicity found in rodent studies is unlikely to apply to any reasonable human use. Amphetamine has been around a long time, so it's pretty safe to assume that its risks have been documented.



Do you mind sharing those reasons? Or linking me to some studies conducted? I can only find megadoses given to rats.

Being convinced does more for my mind than reassurance. : )


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## MeDieViL

That doesnt mean its not neurotoxic you just wont notice negatives as you need to destroy a shitload of da neurons to start shaking around as a parkinson guy, seems that its hard to get there.


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## Tussmann

arohydro said:


> Do you mind sharing those reasons? Or linking me to some studies conducted? I can only find megadoses given to rats.
> 
> Being convinced does more for my mind than reassurance. : )



If we are including all amphetamines here -- meth in particular -- megadosing addicts barely harness smiles and laughs even with 10 years of cession. Literal DA destruction in the reward pathway.

Call it extreme and chronic receptor downregulation if you want but honestly its still doing permanent debilitating effects.


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## arohydro

Tussmann said:


> If we are including all amphetamines here -- meth in particular -- megadosing addicts barely harness smiles and laughs even with 10 years of cession. Literal DA destruction in the reward pathway.
> 
> Call it extreme and chronic receptor downregulation if you want but honestly its still doing permanent debilitating effects.



Precisely my point; I'd like to AVOID that, even in very, very small doses of anhedonia. I have a history of depression and attentive issues, no reason to exacerbate them. I am afraid that should I utilize adderall, later on in life I might be far worse off than I am now as it's more of a band-aid. Right now, my goal is to be completely medication free. If I use medication to get me halfway there, then it's much easier to finish.

We don't know how long we'll be living in the future, I'd like to save all of my dopamine for later in life if possible. Maybe you say, as a consequence, 'just don't fool with amphetamines.' Fine with me, but it's cool to see proof, see studies, see interpretations. Understand why, for instance, rat studies might not be applicable to humans. Where the 'threshold', if any, for neurotoxicity exists, and how to avoid crossing it. If that's finnicky, then how you can protect against damage assuming that the threshold will sometimes be crossed in order to mitigate long-term risk.


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## Woundrous

Epsilon Alpha said:


> http://en.wikipedia.org/wiki/D2-like_receptor
> D2, D3, and D4 all inhibit cAMP formation.



This is nonsense.  You do not know what you are posting about.


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## MeDieViL

He does, its just a bit complicated pal:


> Two intracellular signaling pathways for the dopamine D3 receptor: opposite and synergistic interactions with cyclic AMP.
> Griffon N, Pilon C, Sautel F, Schwartz JC, Sokoloff P.
> Source
> Unité de Neurobiologie et Pharmacologie, Centre Paul Broca de l'INSERM, Paris, France.
> Abstract
> As cerebral neurons express the dopamine D1 receptor positively coupled with adenylyl cyclase, together with the D3 receptor, we have investigated in a heterologous cell expression system the relationships of cyclic AMP with D3 receptor signaling pathways. In NG108-15 cells transfected with the human D3 receptor cDNA, dopamine, quinpirole, and other dopamine receptor agonists inhibited cyclic AMP accumulation induced by forskolin. Quinpirole also increased mitogenesis, assessed by measuring [3H]thymidine incorporation. This effect was blocked partially by genistein, a tyrosine kinase inhibitor. Forskolin enhanced by 50-75% the quinpirole-induced [3H]thymidine incorporation. This effect was maximal with 100 nM forskolin, occurred after 6-16 h, was reproduced by cyclic AMP-permeable analogues, and was blocked by a protein kinase A inhibitor. Forskolin increased D3 receptor expression up to 135%, but only after 16 h and at concentrations of > 1 microM. Thus, in this cell line, the D3 receptor uses two distinct signaling pathways: it efficiently inhibits adenylyl cyclase and induces mitogenesis, an effect possibly involving tyrosine phosphorylation. Activation of the cyclic AMP cascade potentiates the D3 receptor-mediated mitogenic response, through phosphorylation by a cyclic AMP-dependent kinase of a yet unidentified component. Hence, transduction of the D3 receptor can involve both opposite and synergistic interactions with cyclic AMP.


----------



## Cloudy

I'm pretty sure that D2 like receptors [D2, D3 ( though it can be weaker at this as to not be very detectable), and D4 receptors] inhibit AC via g-protien coupled receptors which leads to a negatively regulate production of cAMP which result in a decrease in activity of PKA, and a decrease in DARPP-32 phosphorylation.  Through other mechanisms involving an increase of intercellular Ca+ by D2 like receptors, there is an increase of dephospho-DARPP-32 leading to a decrease in DARPP-32 phosphorylation as well.  So from what I understand, he's not really completely wrong.  If you have critique why don't you post something of more substance to enlighten us to help use better understand why he may be wrong.


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## Epsilon Alpha

Woundrous said:


> This is nonsense.  You do not know what you are posting about.



Do you have evidence to the contrary? Excitatory vs inhibitory neurotransmission goes a lot further than increasing/decreasing [cAMP].


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## MeDieViL

What is your opinion on MB epsilon alpha? as it depletes glut and no it should theoretically do what we want here but it seems some receptors take over the job such as LTP, so tolerance may still occur due to a diff mechanism but thats a gues.


----------



## Woundrous

Ok sorry my bad, I did not click the links.  I just opened the first page and it didn't say much.  I need to refresh my class A GPCR signal transduction knowledgebank.  =(

Anyways, my underlying point is that I've had huge personal success adding creatine malate into my regimen to prevent brain zaps from using MXE/6APB too much.  I don't know exactly why it is working so well, just that it is helping a damn lot (enough to get me to rejoin the forum to post about it!), but you'd think ATP has to be the reason.  So I was thinking it could possibly be of use for long-term amphetamine users too.

But of course, people would have to try it out first...


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## MeDieViL

Creatine and atp are anticonvulsant, sero is implicated in epileptic activity thats why after abusing serotogenics you get mild seizure activity mainly by 5HT2C downregulation.


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## Woundrous

Thanks that's an interesting idea.  If we can actually nail that down as a mechanism, this type of information should be added to something regarding harm reduction.  So probably it would only work for stuff like 6APB and MDMA then... also probably serotonergic antidepressants (which I have seen people mention getting brain zaps from).  I'm not sure about LSD or any 2C-whatever.  I never got zaps from those, just MDMA and the 6APB/MXE combo (I always combine them) but I have never really used LSD/2C-X on consecutive nights for consecutive weekends either.

I'm actually a bit surprised there is not a general harm reduction guide for this site on the front page or something.  I mean, that is supposed to be a primary point of this place anyways; general harm reduction strategies for drug classes.  A quick and easy "what to do" type guide on the front page that is easily noticeable would be sweet for people to have easy access to I think.  

I'd probably volunteer to get it started... but I am clueless about stuff like heroin/opiate harm reduction, if there even is anything besides having a healthy lifestyle and not getting yourself addicted.


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## amanitadine

I think a better approach to harm reduction is not take 6-apb and methoxetamine "weekend in and weekend out" rather than some virtually baseless conjecture and subjective reasoning that creatine ameliorates the damage caused by such. Two very unstudied drugs that are obviously hard on the body when taken once, let alone repeatedly.


----------



## MeDieViL

Woundrous said:


> Thanks that's an interesting idea.  If we can actually nail that down as a mechanism, this type of information should be added to something regarding harm reduction.  So probably it would only work for stuff like 6APB and MDMA then... also probably serotonergic antidepressants (which I have seen people mention getting brain zaps from).  I'm not sure about LSD or any 2C-whatever.  I never got zaps from those, just MDMA and the 6APB/MXE combo (I always combine them) but I have never really used LSD/2C-X on consecutive nights for consecutive weekends either.
> 
> I'm actually a bit surprised there is not a general harm reduction guide for this site on the front page or something.  I mean, that is supposed to be a primary point of this place anyways; general harm reduction strategies for drug classes.  A quick and easy "what to do" type guide on the front page that is easily noticeable would be sweet for people to have easy access to I think.
> 
> I'd probably volunteer to get it started... but I am clueless about stuff like heroin/opiate harm reduction, if there even is anything besides having a healthy lifestyle and not getting yourself addicted.


lol, its a complete failure at that, the advice of using memantine for tolerance issues should be all over the place, the use of neuroprotection, dont really see the point of brainzaps tough they are just extremely anoying, especially when you add g to it as that is a bit convulsive inducing.

I posted a complete list of meds somewhere once that reduce addiction, also its stupid ppl dont even have a clue that ordering a couple of xanax theyd never have to worry about accidently running out of g. That said the g neurotoxiticy data should be spread out more i had to post it here after reading it on drugs forum, everyone tought it was harmless.


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## MeDieViL

amanitadine said:


> I think a better approach to harm reduction is not take 6-apb and methoxetamine "weekend in and weekend out" rather than some virtually baseless conjecture and subjective reasoning that creatine ameliorates the damage caused by such. Two very unstudied drugs that are obviously hard on the body when taken once, let alone repeatedly.



Where talking about harm reduction not harm avoidance, then you might as well say never take drugs, eat healthy and go to bed early.

PPl allways go very far, so saying something like "dont do that" if its extremely bad wont help, but some things that limit the damage can.


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## Epsilon Alpha

MeDieViL said:


> What is your opinion on MB epsilon alpha? as it depletes glut and no it should theoretically do what we want here but it seems some receptors take over the job such as LTP, so tolerance may still occur due to a diff mechanism but thats a gues.



I don't really have much time between my job, medschool applications, classes, and my charity work; mind posting relevant links towards its pharmacology? It looks decent at first glance, as do PQQ and lithium, but we really need trials to be done before we can say anything but "looks promising".


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## campers

Mean to post this up a while ago.  A couple have already been posted but here's a nice list of studies I found, focused on glutathione, but also some on Vit C, Selenium (required for glutathione enzymes) and Nrf2 (a whole topic in itself).

NAC = N-Acetyl-Cystine
(fyi there is a better cysteine pro-drug than NAC available now, and also an acylated form of glutathione)

http://www.ncbi.nlm.nih.gov/pubmed/3992009

Pretreatment with 100.0 mg/kg of ascorbic acid 30 minutes before each methamphetamine injection significantly (but not completely) attenuated this neurotoxic action of methamphetamine.

http://www.ncbi.nlm.nih.gov/pubmed/15199373

These results suggest that NAC could attenuate the reduction of DAT (dopamine transporter ) in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/?tool=pubmed

The idea that oxygen-based free radicals are involved in METH neurotoxicity is further strengthened by reports that the drug can reduce the levels of glutathione

http://www.ncbi.nlm.nih.gov/pubmed/9839724

Our observations provide further evidence in support of the oxidative stress hypothesis of MA neurotoxicity and indirectly suggest that drugs designed to increase glutathione might protect against such damage.

http://www.ncbi.nlm.nih.gov/pubmed/10642830

 We have shown that dietary Selenium attenuated methamphetamine neurotoxicity and that this protection involves Glutathione Peroxidase-mediated antioxidant mechanisms

http://www.ncbi.nlm.nih.gov/pubmed/10650149

These data suggest that METH-induced neurotoxicity is mediated by the production of peroxynitrite, and selenium plays a protective role in METH-induced neurotoxicity.

http://www.ncbi.nlm.nih.gov/pubmed/10913590

These findings indicate selectivity of methamphetamine for the glutathione system and a role for methamphetamine in inducing oxidative stress.

http://www.ncbi.nlm.nih.gov/pubmed/12018843

METH toxicity seems to be produced by oxidative stress, as it was attenuated by the antioxidant glutathione

http://www.ncbi.nlm.nih.gov/pubmed/21882243

We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons

http://www.ncbi.nlm.nih.gov/pubmed/11746378

 A dose-dependent depletion of total glutathione levels was detected in human brain microvascular endothelial cells exposed to METH

http://www.ncbi.nlm.nih.gov/pubmed/12230306

These results suggest that METH-induced disturbances in cellular redox status and that activation of AP-1 can play a critical role in signaling pathways leading to upregulation of inflammatory genes in vivo

http://www.ncbi.nlm.nih.gov/pubmed/15234256

These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

http://www.ncbi.nlm.nih.gov/pubmed/15111252

 It was found that acute administration of methamphetamine (5 and 15 mg kg(-1)) resulted in production of oxidative stress as demonstrated by decreased glutathione and increased oxidized glutathione levels

http://www.ncbi.nlm.nih.gov/pubmed/16038959

Enantiomers of trans-phenylpropylene oxide (Pyrolytic products of smoked methamphetamine) were stereoselectively and regioselectively conjugated in a Phase II drug metabolism reaction catalyzed by human liver cytosolic enzymes consisting of conjugation with glutathione

http://www.ncbi.nlm.nih.gov/pubmed/16760923

The levels of the reduced form of glutathione (GSH) in striatum, amygdala, hippocampus and frontal cortex were significantly lower in METH-treated mice compared to control during the period of conditioned place preference training. Acute and repeated administration of NAC to METH-treated mice restored the decreased brain GSH but had no effect on controls.

http://www.ncbi.nlm.nih.gov/pubmed/22354084

This suggests that METH induces oxidative stress in various organs and that a combination of N-acetylcysteine amide as a neuro- or tissue-protective agent, in conjunction with current treatment, might effectively treat METH abusers.



http://www.ncbi.nlm.nih.gov/pubmed/17481858 Glutathione prevented dopamine-induced apoptosis of melanocytes and its signaling. 

"Among various antioxidants used in this study, only thiol-containing antioxidants such as NAC or GSH inhibited both JNK and p38 MAPK activation and apoptosis, indicating the unique protective capacity of thiol compounds."


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## polarbearsarecool

My latest stack-which I've found the greatest results with has been

1/3 nuvigil 250 before wakeup
1/3 nuvigil 250 at wakeup-----> directly at wakeup take 1 source naturals activated quercetin, 250mg uridine monophosphate sublingual, 30 minutes later with food take 200-400mg nefiracetam/idebenone 500mg-1g/ Omega 3 EPA/DHA 2200mg..
1/3 nuvigil 250 4/5 hours later 

and continue nefiracetam 2x more times in the day, as well as 1x omega 3, and another uridine dose..

Idebenone is a powerful antioxidant that also has NGF releasing capabilities... 

But for amph tolerance quercetin/uridine.... HUGE CHANGE. 

PQQ though, is not that good. I used it and went through 2 bottles, eventually my thoughts became slurried, and I realized my memory was taking a hit because I was combining it with 4+ other PDE inhibitors, now with just quercetin/nuvigil, it still has a slurry effect.. 

PQQ is a quinone just like quercetin, just hugely overpriced.


----------



## Epsilon Alpha

Wow, I really need to get back to this thread.
Work. So. Busy. Med. School. Apps. 

For what its worth my personal experience over the last year with 10-20mg Adderall 3-5 times a week scripted for a sleep disorder:

CoQ10: preserves wake promoting effects, as well as anorexic effects
Magnesium: preserves a bit of the mood lift, biggest effect for me was on neck tension
Multivitamin: I feel much more groggy if I skip 2 days of multivitamin
Vitamin D: Increases wakefulness, not too significant but for someone like me it's a noticeable difference.
Curcumin (for 2 weeks): My GIT did not like this... I used it during a tolerance break and upon using my perscription found it significantly reduced the tolerance to the motivational effects, mood lift was moderately increased over what I would expect for a 2 week break, no real difference with wakefulness over what I would expect, significant increase in anorexic effects.

Been doing some digging through some obscure NOS/transcriptional changes lately, and I'm slowly finding why several studies have identified continued cell death for up to 2 weeks in rat models. What are possible implications of that? Well it would suggest that longer post loading for recreational users might be a good idea.


----------



## Tussmann

Epsilon Alpha said:


> Well it would suggest that longer post loading for recreational users might be a good idea.



Could you expand on this a bit? I have no idea what this means.


----------



## campers

Epsilon Alpha said:


> Been doing some digging through some obscure NOS/transcriptional changes lately, and I'm slowly finding why several studies have identified continued cell death for up to 2 weeks in rat models. What are possible implications of that? Well it would suggest that longer post loading for recreational users might be a good idea.



Could you post some links to the papers? I'd be interested to have a read.

I just noticed a couple of papers about modafinil protecting against meth toxicity, interesting.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464292/
http://www.ncbi.nlm.nih.gov/pubmed/21590747/
http://www.ncbi.nlm.nih.gov/pubmed/1347270 (this one is MPTP induced DA neurotoxicity, not meth)


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## Epsilon Alpha

Tussmann said:


> Could you expand on this a bit? I have no idea what this means.



As cell death seems to happen over a longer period than one would expect in animal studies there is reason to try and maintain levels of antioxidants post usage, and possibly let them build up in your system prior to dosing.

Gonna close this at 300 replies, see you in Part III!


----------

