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    NMDA antagonists for anxiety? 
    #1
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    Okay I know we have an addiction and tolerance thread here but I wanted to ask this question. Since NMDA blockade seems to prevent a lot of the anxiety and seizures of withdrawal, would NMDA antagonists (memantine and dextromethorphan polisterex, due to their long action) be feasible replacements for GABAergic medications like alprazolam, clonazepam, and diazepam?

    I know that AMPA is involved as well but I don't really see why stand alone NMDA blockade wouldn't help a lot of people without the intense side effects of SSRIs and similiar drugs. Obviously in the case of DXM caution is needed with certain drugs (serotonin releasers) but memantine doesn't pose that issue and the side effects between the two are much more manageable than medications that make specific targets for serotonin and/or norepinephrine.

    The reason that I ask about this is because I just started an NMDA antagonism job to kick Clonazepam once and for all. Well I was up all night and my dose was due at noon and I forgot to take it before I passed out. Obviously I woke up about 4 1/2 hours later with rebound clonazepam anxiety. I was in almost full-blown panic but took my clonazepam and Delsym together. 1mg clonazepam, 15mL Delsym. About 20 minutes later the panic turned to a very stern calming effect and now I feel fine even though I know that for me, clonazepam takes at least an hour and a half to take full effect and usually about around an hour and twenty minutes I would start calming down.

    I have been wondering about the GABA - NMDA model for awhile now and it stands to reason (in my mind) that long-term NMDA antagonists could be quite beneficial for anxiety and would be far safer than GABA agonists. Comments? Theories? I never really thought about it but whenever I was using DXM in high doses daily I never had ANY anxiety, even with the tachycardia and other signs of distress in the body. I would think that this would also give the body a break on cortisol release and maybe replenish its own adrenaline stores again. That last one is just a guess though as I'm thinking that may be a possible downside - the body may stop making adrenaline since the brain would be tricked by the excess GABA to think that everything is okay even when it is not. At the same time though I'd rather have that over panic attacks.
     

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    55 views and nobody has any comment on this? I definitely noticed a distinct (much colder than a benzo though, there was no euphoria involved, just a slam back to being calm - less dependency issues in my opinion) and direct anxiolytic effect from Delsym today. I've been on benzos since 2004 and THEY don't even, and never did, slam me down like that. And its lasted most of the day. Its wearing off right about now but I think once I fully saturate myself with the drug and can maintain plasma levels it will easily go on hours on end... Seriously why hasn't NMDA antagonism been looked at even in animal models for anxiety? It is the most obvious choice in my mind. Yes I know that NMDA plays a crucial role in the functions of the human brain but we eat so much glutamate in our diets anyway that we get a natural spike (or unnatural, depending on the food) in glutamate receptor activity but a lot of people have noticed that cutting glutamate receptor trigger foods from their diet in all sources eliminates their anxiety so why is this not plausible that NMDA antagonism could do the same thing? And if it HAS been studied in animal models I would like to see articles if you have them.
     

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    #3
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    In response to why you felt anxiolysis effects 15 minutes in although clonazepam normally takes longer to kick in... sometimes, when you psychologically know a drug is going to set in, anxiety is relieved.

    An example of this; when I used to get heroin, and I'd be waiting in the car for at least a half hour, the second I saw the dealer walk up, the worst withdrawal symptoms stopped. I'd still not feel totally better till the drug kicked in but, it's such a relief to see the stuff in sight.

    That's just some insight, I can't really say if that's the case for you or not.
     

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    Bluelighter Psychedelic Jay's Avatar
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    You think you know what being slammed with NMDA antagonism really feels like...


    ...One word...

    ...Phencyclidine...

    For harm reduction... BLAH BLAH

    Nitrous oxide.
     

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    #5
    Bluelighter laCster's Avatar
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    NMDA-antagonists definitely help, but they are definitely NOT a long-term solution.
     

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    #6
    Bluelighter Psychedelic Jay's Avatar
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    It in essence depends on which one.
     

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    #7
    Bluelighter /navarone/'s Avatar
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    NMDA tollerance builds up fucking quickly...no wonder that after a week of daily 100mg MXE I went up to 250mg without feeling much of the initial effect.

    Betta leave NMDA receptors to do their job alone if you're simply looking for an anxiety relief......trust me.
    They are feasable in preventing seizures and convulsions but very not as a long range therapy for anxiety...
     

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    #8
    Bluelighter Psychedelic Jay's Avatar
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    This is not all the way put together.

    I think this will be rather safer than running with benzodiazepines or ethanol... And actually work unlike bat shit conventional antidepressants SSRIs/SNRIs....

    I think that tolerance isn't going to be as fast or an issue if you have lower dosing longer acting compounds.
     

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    #9
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    Its not like I am talking about large doses of NMDA antagonists... like 30mL of Delsym a day max (15mL every 12 hours). Or 20-40mg of memantine a day.

    Why not in the long term? You don't ever really build a tolerance to DXM in doses that low and there's pretty much zero in terms of withdrawal... I would know since I used to do 2nd-3rd plateau doses daily for the better part of a year and a half and I just quit one day.

    As for the placebo effect... I've been on benzos so long that I know my brain doesn't calm down until I take them or I can speed up the process with alcohol (obviously a bad combo).

    EDIT: Psychedelic Jay, I had left this post open all day... you said what I wanted to say lol.

    And yes, MXE and ketamine and PCP all build tolerance rapidly but DXM and memantine do not from what I've seen.
     

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    #10
    Ive thought about this for quite sometime. Don't have any real information to add though except that from my experience dxm is not very addicting mentally or physically especially compared to benzos.
    Seems to make so much sense that a dissociative would help with anxiety... maybe in kinda a fuck-it/nihilistic way
     

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    #11
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    Well in low doses DXM has virtually no effects on the mind... but the DXO conversion from the polisterex formulation antagonizes NMDA sufficiently well and for a long enough period that it would only require a twice daily dosage.

    Memantine works but has a crazy long half life... And with it retaining, in higher doses, the respiratory depression that PCP does I am a bit worried about its use for this purpose.

    The only problem I see is people using the wrong form of DXM (HBr obviously metabolizes too rapidly to DXO and DXO has a pretty short halflife itself) or people that are CYP2D6 deficient.

    There is one thing that scares me about DXM though. Apparently even using recommended doses in combination with trazodone can cause permanent liver damage. I take trazodone for sleep once in awhile and I could have really used it yesterday but I was too concerned about the liver damage possibility. I have Remeron around here too but after taking Remeron to try to come off of 2C-E and the resulting psychedelic potentiation, I am leery to use that with DXM as well.

    Memantine, overall, would be the best for this purpose in my belief. The respiratory depression that I experienced what during a taper from Valium... obviously it might be significantly less of a problem for someone who is taking memantine INSTEAD of Valium.
     

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    #12
    Bluelighter Psychedelic Jay's Avatar
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    DXM is too dirty of a drug for this purpose and it inhibits the re-uptake of norepinephrine.

    This in turn might be very bad depending on how sensitive you are to anxiety.

    You need a cleaner acting molecule.

    PCP is the perfect canidate. You would only need one dose per day. Doesn't have to be a mind-fucking dose either. (I'm not talking about smoking Dust either. That would be almost impossible to gage batch to batch.)

    The dopamine effects in low doses has very potent antidepressant effects.

    I think PCP in it's right form is very useful. It just needs to be evaluated in further studies.
     

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    #13
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    Long term usgae of dopaminergic/dissociative drugs like PCP, MXE etc is asking for trouble. PCP especially - the dose will accumulate and eventually you'll be full blown insane.
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    #14
    Bluelighter CrackAndScrabble's Avatar
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    I read some shit about that Memantine drug and damn it sounds interesting.

    I could see someone maybe taking that drug for a month max or so to give the NMDA antagonists sometime to "repair" your brain. I don't know but it has some interesting disorders that are under "Investigational use" on wikipedia. This would be cool if it had similar ketamine induced repairing of the brain that was postulated.

    Why are you using DXM as well though? Why 2 NMDA affecting drugs?
     

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    #15
    Bluelighter Nagelfar's Avatar
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    I am interested in 'toll-like receptor 4' antagonism from dissociatives. Seeing as many dissociatives are dextro-isomers of morphinan opioids, and it seems many levo-morphinans are TLR 4 antagonists when reversed.

    Might other common dissociatives besides DXM (ketamine, PCP) also be TLR 4 antagonists I wonder? If not, well DXM may have an extra benefit for anxiety other those:

    Modified reduced gene expression of TLR 4 in rats "bred and trained to drink (alcohol) excessively" showed to have a "profound reduction" in drinking behaviours. Seeing as alcoholism is reinforced partly through the anxiogenic qualities of increased activity GABAergic mechanisms. (and so in turn the sought sedation from it at discontinuation of ethanol administration) TLR 4 antagonism may reset overactive GABAergic-induced anxiety to some degree.
    Last edited by Nagelfar; 06-11-2011 at 02:27.
     

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    #16
    Why not just use magnesium or zinc instead? They're both NMDA antagonists.
     

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    #17
    Bluelighter Biovail's Avatar
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    Quote Originally Posted by ProducedRaw View Post
    Why not just use magnesium or zinc instead? They're both NMDA antagonists.
    Well, ignoring the fact that this is a 7 month old thread, you simply can't (safely) regularly ingest enough magnesium/zinc for the same effects you would get from drugs such as Memantine or DXM. You'd be popping 20+ pills a day. Not to mention both these supplements have effects other than calcium ion channel blockade. With a Mg dosage high enough for therapeutic effects, you'd probably end up doing more long term damage than you would attempting to treat yourself with PCP or DXM.
     

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    Bluelighter Nagelfar's Avatar
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    Quote Originally Posted by Biovail View Post
    Well, ignoring the fact that this is a 7 month old thread,
    The dating system is European my friend.
     

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    #19
    I can only speak to anecdotal reports and my personal experience, but the NMDA antagonism of racemic Methadone, when prescribed in high daily doses as part of ORT, does not decrease anxiety typical of other full mu agonist opioids for a lot of GAD/SAD/PD diagnosed MMT patients. Many Methadone patients describe continued anxiety problems (or those that had anxiety disorders before becoming addicted to opioids would begin showing symptoms following Methadone stabilization). It appears to be a fairly effective NMDA antagonist as well. On the flip side of this there are anecdotal reports of emotional blunting on a level beyond that of other opioids; being unable to 'feel' the spectrum of human emotions normally (similar to what happens during DXM use, or following trips/'Afterglow'). Though this emotional numbing does not always equate anxiolysis. But other than subjective and anecdotal reports, I don't know how you'd judge this beyond speculation.
     

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    #20
    Quote Originally Posted by Biovail View Post
    With a Mg dosage high enough for therapeutic effects, you'd probably end up doing more long term damage than you would attempting to treat yourself with PCP or DXM.
    Never heard of long term damage with magnésium supplementation. I saw that the worst side effect is a great diarrhoea, isn't it?
     

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    #21
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    So the answer is rather that one simply could not achieve sufficient concentration of Mg ions in the CNS to yield the desired effect.

    ebola

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    #22
    Bluelighter Psychedelic Jay's Avatar
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    Why are some stuck on DXM?

    DXM is a terrible drug to use in this manner.

    Understand that DXM is not doing what most of you think... I have some issues with this drug:

    -Barely binds to NMDA receptors in low to low-medium recreational doses. (What this whole thread was talking about. Heavier doses would be impossible to roam on.)

    -Antagonizes the nicotinic receptors incredibly strongly. (I would find very mood un-stabilizing.)

    -Binds heavily to sigma type 1 receptor. (May be a good thing in depressed individuals. Might be the reason for "mind fucking" in larger doses. Might be the main reason for the "moment of clarity" it gives in light doses.)

    -It blocks the re-uptake of serotonin very strongly. (Would mean watching what else you might intake during the day. Becoming necessary to prevent serotonin overload.)

    -It blocks the re-uptake of norepinephrine strongly. (Again, would mean watching what else you might intake during the day. Becoming necessary to prevent hypertensive crisis.)

    DXO is the real answer...
     

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    #23
    This is like using opioids for anxiety

    Oh, by the way

    Never underestimate the power of the placebo effect, and the mind in general.
     

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    #24
    I heard IV Mg used for anxiety but i wouldn't want to ingest a laxative everyday for anxiety. I heard of sigma agonists being used for anxiety tho... I can say from personal experience that PCP in sub "P-Hole" doses is by far the most powerful anxiolytic i ever had and it can last quite long so there is something to be said for that however PCP is also a strong sigma agonist and DARI and I personally believe it has effects on hormone levels to some degree, makes me feel more masculine. Brain damage is definately a concern for long term daily use but not sure if small doses are that damaging?
     

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    #25
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    Quote Originally Posted by Steps View Post
    This is like using opioids for anxiety
    Effective? Or did you mean effective but not a long term solution, in which case it's pretty similar to using benzos for anxiety..
     

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