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Conclusive evidence that aniracetam is an AMPA modulator


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#1 LabRat84

Posted 18 April 2010 - 06:03 PM


I know there are several racetam threads (some of which have been bumped), but there's been a new development in the past month:

The structure (and implied mechanism) of how piracetam and aniracetam bind to a certain subtype of AMPA glutamate receptors has been discovered. "Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors."

Aniracetam binds in one specific place and is a moderately potent AMPA modulator. In fact, it's been used as a "lead compound" in developing more potent AMPA modulators (whereby different side groups and modifications are tried, first via computer simulation, then by biochemical screening).

Piracetam binds to AMPA receptors in several locations, but does not seem to have much effect on them. If you're interested, you can see the structure of aniracetam or piracetam bound to the AMPA receptor. In addition to the online viewers, you can download Swiss PDB Viewer for more power.

I couldn't find any data on pramiracetam. It's not well-studied; there are few Russian articles on it. Does anyone have access to this paper? I only have access to this journal up to six months ago.

As a comparison, oxiracetam seems to protect certain types of memory and is involved in NMDA pathways: http://www.ncbi.nlm....pubmed/15922047 http://www.ncbi.nlm....pubmed/12110475 http://www.ncbi.nlm....pubmed/11099768
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#2 sugarstack Re: Conclusive evidence that aniracetam is an AMPA modulator

Posted 18 April 2010 - 09:48 PM

I know there are several racetam threads (some of which have been bumped), but there's been a new development in the past month:

The structure (and implied mechanism) of how piracetam and aniracetam bind to a certain subtype of AMPA glutamate receptors has been discovered. "Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors."

Aniracetam binds in one specific place and is a moderately potent AMPA modulator. In fact, it's been used as a "lead compound" in developing more potent AMPA modulators (whereby different side groups and modifications are tried, first via computer simulation, then by biochemical screening).

Piracetam binds to AMPA receptors in several locations, but does not seem to have much effect on them. If you're interested, you can see the structure of aniracetam or piracetam bound to the AMPA receptor. In addition to the online viewers, you can download Swiss PDB Viewer for more power.

I couldn't find any data on pramiracetam. It's not well-studied; there are few Russian articles on it. Does anyone have access to this paper? I only have access to this journal up to six months ago.

As a comparison, oxiracetam seems to protect certain types of memory and is involved in NMDA pathways: http://www.ncbi.nlm....pubmed/15922047 http://www.ncbi.nlm....pubmed/12110475 http://www.ncbi.nlm....pubmed/11099768


wow, thank you for that post very helpfull.
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#3 chrono Re: Conclusive evidence that aniracetam is an AMPA modulator

  • Location:New England

Posted 19 April 2010 - 02:29 PM

Very nice find, Labrat. I should be able to grab that paper within a week, or maybe two.

I've only read anecdotal reports about ampakines so far. Could you explain anything about the pk/cognitive implications of activity at this receptor?
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#4 LabRat84 Re: Conclusive evidence that aniracetam is an AMPA modulator

Posted 19 April 2010 - 07:35 PM

http://www.ncbi.nlm....pubmed/17119538 : Test of a drug in development; significant improvements in short-term memory, but actually reduced performance in long-term memory (delayed recall). Subjects experiencing side effects had worse performance compared to those who did not.

http://www.ncbi.nlm....pubmed/20350557: Mice with a subtype of AMPA receptors knocked out have a deficit in short-term memory.

The Wikipedia page on ampakines says pramiracetam is also an ampakine, but it's not cited and I couldn't find any information on it.

This class of substances looks interesting.
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#5 LabRat84 Re: Conclusive evidence that aniracetam is an AMPA modulator

Posted 21 April 2010 - 01:54 PM

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Very nice find, Labrat. I should be able to grab that paper within a week, or maybe two.

I've only read anecdotal reports about ampakines so far. Could you explain anything about the pk/cognitive implications of activity at this receptor?


I just learned about glutamate receptors in a lecture yesterday. (Specifically, ionotropic - meaning the receptors themselves are ion channels). There are two kinds of ionotropic glutamate receptors: AMPA and NMDA. They're named that because of exogenous chemicals that are agonists for them; you can look them up, but they're actually not important).

AMPA receptors
are permeable to sodium and potassium. They respond very quickly to glutamate.
NMDA receptors are permeable to calcium. Glutamate has a higher affinity for NMDA, but the actions of glutamate are delayed by a voltage-dependent magnesium block. Also, glycine or an analogue is required to open the NMDA channel.

Both channels "densensitize" - they close automatically after being exposed to glutamate and won't reopen until glutamate is taken away and re-introduced. This is probably to prevent overstimulation and excitotoxicity in case of glutamate excess. I won't go into the mechanism of denensitization, but one has been proposed.

In a normal dendrite (neuron input branch) where both AMPA and NMDA receptors are found:

1) Glutamate is released from a pre-synaptic neuron and binds to both AMPA and NMDA receptors
2) In the post-synaptic neuron, AMPA receptors allow sodium and potassium cross the cell membrane, which depolarizes it (drives the resting voltage from negative up toward 0). The NMDA channel stays closed.
3) The depolarization triggers the release of magnesium from the NMDA receptor, and the NMDA opens.
4) Calcium enters the cell through the NMDA channel
5) Glutamate is taken up by the presynaptic neuron and glia, which causes glutamate to dissociate from the receptors (or other things can happen, like glycine uptake)
6) The AMPA and NMDA channels close
(If glutamate is in excess, the receptors will close anyway)

This all happens in under 10 ms. It has to be fast, and the affinity of glutamate for the recepors is tuned so that small changes in concentration can happen rapidly.
The glutamergic signaling system is the fastest in the nervous system; in needs to be sensitive to high-frequency stimuli. The example our professor gave us was that a trained musician can tell the difference between a note at 350Hz and 351Hz - auditory processing requires sensory input and signal transduction that's extremely fast.

Calcium then triggers other functions in the post-synaptic cell. Under normal conditions, the concentration of calcium is nowhere near enough to be cytotoxic. But if the NMDA channel is kept open (with a toxin), then enough calcium enters and the cell dies.

Ampakines (positive allosteric modulators of the AMPA receptor) can A) increase glutamate affinity for AMPA B) prevent the AMPA channel from desensitizing and/or C) make the channel more permeable to ions Case (A) is actually not that interesting: the channel will just desensitize anyway, and it might activate at low physiological levels of glutamate, without pre-synaptic firing (too much "noise"). Case (B), reducing desensitization, and ©, increasing permeability, are much more interesting: the AMPA channel lets through more ions, which increases the strength of glutamergic transmission - and it can be switched on and off more rapidly (if all the other glutamate machinery is in place). Instead of having a refractory period, it becomes "multi-orgasmic." These are the kinds of ampakines that researchers are looking at; aniracetam and its derivatives seem to do (B): prevent desensitization of the AMPA channel. Piracetam does not; its effects must be mediated through some other system.

The NMDA channel is a "fire when ready" receptor - it's sensitive to voltage changes (often caused by the AMPA receptor). For the NMDA channel, reducing desensitization can lead to too much calcium and excitotoxicity. But increasing its permeability to calcium is not so bad, as long as it still closes properly (which requires the presence of magnesium). Increased permeability to calcium means stronger response. (For calcium to reach toxic levels, the channel has to be open a long time -- too long to do any good.) It's likely that piracetam is a positive allosteric modulator of the NMDA receptor.

There are other factors that determine sensitivity of these channels, like additional membrane proteins, which are modified by more ligands.

Memantine is a voltage-dependent blocker of NMDA. It prevents calcium from entering the cell until a certain threshold is reached. Whether this is responsible for the cognitive effects is unclear. Dextromethorphan, ketamine and PCP are full NMDA blockers - not voltage-dependent.

There's an old thread about amphetamine tolerance being caused by too much intracellular calcium. I believe this to be false. Instead, I believe it's caused, at least in part, by the desensitization of glutamate receptors. (Downregulation of dopamine and NE receptors probably contributes too).

Glutamergic transmission is important:

Simplified, dopamine, norepinephrine, and serotonin are responsible for mood and cognitive states - alertness, reward, fear, attention, well-being. All the neurotransmitter systems are connected, but ultimately glutamate and GABA do the information processing; they're the ones that encode sensory inputs and thoughts (GABA directly modulates the effect of glutamate). Acetylcholine probably does both: sustains certain states (e.g. REM sleep) and directly influences information encoding. But basically, the other systems affect how glutamate and GABA are going to behave. (This is the complicated part and basically the point of neuroscience: how chemical and electrical signals are encoded into thoughts and sustain consciousness).

A rational approach to "cognitive enhancement" requires knowing what cognition involves. What are we after: Increased short-term memory? Faster information processing? Faster recall? Enhanced long-term potentiation? Each one involves different circuits that involve multiple neurotransmitter systems.

Our professor mentioned cognitive enhancers, and I had a brief discussion with him about them (he noted that I seemed to know more about the field than him). Glutamate receptors are found throughout the CNS, so effects can be systemic. Furthermore, pharmaceutical companies have a very low success rate using them as drug targets. My professor was also skeptical about cognitive enhancers because the glutamate system is so fine-tuned: both fast and sensitive to changes in concentration. He also mentioned ethical concerns, but that was more of an aside. He's probably like a cognitive enhancer as much as anyone.

The lack of cognitive enhancers that modulate glutamate receptors (the ones that would really make a difference in cognition--not just attention, alertness, mood, etc) is based on a cost-benefit analysis.

Here's a good illustration of glutamergic synapse:
Posted Image
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#6 Novotropic Re: Conclusive evidence that aniracetam is an AMPA modulator

Posted 21 April 2010 - 05:05 PM

The NMDA channel is a "fire when ready" receptor - it's sensitive to voltage changes (often caused by the AMPA receptor). For the NMDA channel, reducing desensitization can lead to too much calcium and excitotoxicity. But increasing its permeability to calcium is not so bad, as long as it still closes properly (which requires the presence of magnesium). Increased permeability to calcium means stronger response. (For calcium to reach toxic levels, the channel has to be open a long time -- too long to do any good.) It's likely that piracetam is a positive allosteric modulator of the NMDA receptor.


Great post, LabRat. Good to see this forum becoming more scientific again..

I have a question about the above quote. I know this is all very speculative, but is there any reason to believe magnesium supplementation could potentially prevent the supposed excitotoxicity caused by piracetam?
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#7 Thorsten Re: Conclusive evidence that aniracetam is an AMPA modulator

Posted 21 April 2010 - 07:31 PM

The NMDA channel is a "fire when ready" receptor - it's sensitive to voltage changes (often caused by the AMPA receptor). For the NMDA channel, reducing desensitization can lead to too much calcium and excitotoxicity. But increasing its permeability to calcium is not so bad, as long as it still closes properly (which requires the presence of magnesium). Increased permeability to calcium means stronger response. (For calcium to reach toxic levels, the channel has to be open a long time -- too long to do any good.) It's likely that piracetam is a positive allosteric modulator of the NMDA receptor.


Great post, LabRat. Good to see this forum becoming more scientific again..

I have a question about the above quote. I know this is all very speculative, but is there any reason to believe magnesium supplementation could potentially prevent the supposed excitotoxicity caused by piracetam?


Where has it been said that piracetam is excitoxic? I'm aware of some people specualating it could be but are there any solid methods of thinking wherby you could come to such a conclusion? I've heard piracetam potentiating the NMDA receptor also the quote above says it modulates the NDMA receptor in a positve way....So from these 2 quotes I would say it essentially improves the functioning of the NMDA receptor. It would only be excitotoxic if it was causing abnormalities at the NMDA receptor I would presume, as explained by labrat above. So what I'm asking is if anyone knows why it is speculated that piracetam could be excitotoxic?

Also magnesium is a very weak NMDA antagonist. If you were looking to guard against the effects of excitoxcity from glutamte you may as well go the full hog and take Ketamine (just an example, there are other powerful and more sensible NMDA antagonists). Again I don't think piracetam causes excitotoxic effects through over stimulation of glutmate (hence my question above) but hey there may be someone here who corrects me and says that I am wrong.
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#8 LabRat84 Re: Conclusive evidence that aniracetam is an AMPA modulator

Posted 21 April 2010 - 08:32 PM

The NMDA channel is a "fire when ready" receptor - it's sensitive to voltage changes (often caused by the AMPA receptor). For the NMDA channel, reducing desensitization can lead to too much calcium and excitotoxicity. But increasing its permeability to calcium is not so bad, as long as it still closes properly (which requires the presence of magnesium). Increased permeability to calcium means stronger response. (For calcium to reach toxic levels, the channel has to be open a long time -- too long to do any good.) It's likely that piracetam is a positive allosteric modulator of the NMDA receptor.


Great post, LabRat. Good to see this forum becoming more scientific again..

I have a question about the above quote. I know this is all very speculative, but is there any reason to believe magnesium supplementation could potentially prevent the supposed excitotoxicity caused by piracetam?


Where has it been said that piracetam is excitoxic? I'm aware of some people specualating it could be but are there any solid methods of thinking wherby you could come to such a conclusion? I've heard piracetam potentiating the NMDA receptor also the quote above says it modulates the NDMA receptor in a positve way....So from these 2 quotes I would say it essentially improves the functioning of the NMDA receptor. It would only be excitotoxic if it was causing abnormalities at the NMDA receptor I would presume, as explained by labrat above. So what I'm asking is if anyone knows why it is speculated that piracetam could be excitotoxic?

Also magnesium is a very weak NMDA antagonist. If you were looking to guard against the effects of excitoxcity from glutamte you may as well go the full hog and take Ketamine (just an example, there are other powerful and more sensible NMDA antagonists). Again I don't think piracetam causes excitotoxic effects through over stimulation of glutmate (hence my question above) but hey there may be someone here who corrects me and says that I am wrong.



There are different sites on the NMDA receptor that modulate it in different ways.

The famous list of "NMDA antagonists" is misleading. Magnesium is a voltage-dependent antagonist and has its own binding site outside the channel. Ketamine is a channel blocker that binds inside the channel (I believe). The two are actually synergistic: http://www.anesthesi...5/1173.abstract

Just like there are different kinds of antagonists, there are different kinds of agonists. For example, glycine (or a similar molecule, like D-serine or D-cycloserine) is required for NMDA activation, but it doesn't activate the receptor by itself. See the wikipedia page on NMDA for a useful (but limited) illustration.

Excitotoxicity usually results from excess calcium entering the cell, although there are other causes. What's clear is that glutamate can induce excitotoxicity. What's not clear is if that happens when AMPA and NMDA receptors desensitize normally.

Here are non-scientific categories of what are called "positive allosteric modulators" (compounds that enhance the activity of a channel without binding at the same place as the agonist):

"Sensitizer": increases affinity of normal agonist for the receptor, allowing it to activate at lower concentrations of agonist. This type of modification is common. Benzodiazapines work this way for GABA receptors (although not with ion channels).
"Permeability enhancer": allows more calcium "per shot." In theory, this should not cause excitotoxicity. Even increasing the amount of calcium per channel opening by an order of magnitude doesn't involve much calcium.
"Resensitizer": prevents the receptor from desensitizing, allowing it to open and close repeatedly. This kind of modulator might cause excitotoxicity if stimulated excessively. It doesn't have to be "all-or-nothing" - you could have a "partial resensitizer" or a "sensitivity delayer."
"Open channel stabilizer": keeps the channel open even when the agonist is not present, either for a longer period of time than normal (slows closing) or all the time (usually a toxin). Some drugs work this way (for example, valproic acid and other mood stabilizers keep sodium channels open). This is an extraordinarily BAD idea for calcium channels.

The concern with piracetam, I guess, is that it might lead to too much calcium. But it binds to glutamate receptors rather weakly and has subtle effects. Some new structures that have been released show piracetam binding at multiple sites of the "ligand binding domain" of glutamate receptors, so it's possible that it has more than one mechanism.

Each of the above has its corollary. All could be considered "antagonists" but they're actually not. An antagonist binds at the same site as the agonist, either competitively (some agonist binds, some antagonist binds) or non-competitively (prevents agonist binding completely). To mirror the above, you would have a "desensitizer," "Permeability reducer", "desensitization accelerator," and a "closed channel stabilizer."

Finally, there are channel blockers, as above - some are voltage dependent, some are not. (They're often called "uncompetitive antagonists" even though they're different from "real" antagonists, because the kinetics will look the same as an antagonist.) The terminology in biochemistry is confusing, but if you think about it structurally/descriptively it makes more sense (at least for me).

"Improves the functioning" doesn't mean "makes it safe." You could boost "improve the functioning" of your car's engine so that it outputs 300hp, but then drive your car into a wall at 120mph (193kph).
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#9 Thorsten Re: Conclusive evidence that aniracetam is an AMPA modulator

Posted 22 April 2010 - 06:52 AM

There are different sites on the NMDA receptor that modulate it in different ways.

The famous list of "NMDA antagonists" is misleading. Magnesium is a voltage-dependent antagonist and has its own binding site outside the channel. Ketamine is a channel blocker that binds inside the channel (I believe). The two are actually synergistic: http://www.anesthesi...5/1173.abstract

Just like there are different kinds of antagonists, there are different kinds of agonists. For example, glycine (or a similar molecule, like D-serine or D-cycloserine) is required for NMDA activation, but it doesn't activate the receptor by itself. See the wikipedia page on NMDA for a useful (but limited) illustration.

Excitotoxicity usually results from excess calcium entering the cell, although there are other causes. What's clear is that glutamate can induce excitotoxicity. What's not clear is if that happens when AMPA and NMDA receptors desensitize normally.

Here are non-scientific categories of what are called "positive allosteric modulators" (compounds that enhance the activity of a channel without binding at the same place as the agonist):

"Sensitizer": increases affinity of normal agonist for the receptor, allowing it to activate at lower concentrations of agonist. This type of modification is common. Benzodiazapines work this way for GABA receptors (although not with ion channels).
"Permeability enhancer": allows more calcium "per shot." In theory, this should not cause excitotoxicity. Even increasing the amount of calcium per channel opening by an order of magnitude doesn't involve much calcium.
"Resensitizer": prevents the receptor from desensitizing, allowing it to open and close repeatedly. This kind of modulator might cause excitotoxicity if stimulated excessively. It doesn't have to be "all-or-nothing" - you could have a "partial resensitizer" or a "sensitivity delayer."
"Open channel stabilizer": keeps the channel open even when the agonist is not present, either for a longer period of time than normal (slows closing) or all the time (usually a toxin). Some drugs work this way (for example, valproic acid and other mood stabilizers keep sodium channels open). This is an extraordinarily BAD idea for calcium channels.

The concern with piracetam, I guess, is that it might lead to too much calcium. But it binds to glutamate receptors rather weakly and has subtle effects. Some new structures that have been released show piracetam binding at multiple sites of the "ligand binding domain" of glutamate receptors, so it's possible that it has more than one mechanism.

Each of the above has its corollary. All could be considered "antagonists" but they're actually not. An antagonist binds at the same site as the agonist, either competitively (some agonist binds, some antagonist binds) or non-competitively (prevents agonist binding completely). To mirror the above, you would have a "desensitizer," "Permeability reducer", "desensitization accelerator," and a "closed channel stabilizer."

Finally, there are channel blockers, as above - some are voltage dependent, some are not. (They're often called "uncompetitive antagonists" even though they're different from "real" antagonists, because the kinetics will look the same as an antagonist.) The terminology in biochemistry is confusing, but if you think about it structurally/descriptively it makes more sense (at least for me).

"Improves the functioning" doesn't mean "makes it safe." You could boost "improve the functioning" of your car's engine so that it outputs 300hp, but then drive your car into a wall at 120mph (193kph).


Interesting, thanks for that labrat.
Nice info.
Would you consider memantine and piracetam to be a good combo? I've never had the guts to take both as they sound as if their mechanisms would clash. I only take memantine right now so piracetam has kind of been pushed to one side although I miss the benefits I get from piracetam. Although I'm a lot happier on memantine i'm nowhere near as fast as I was on piracetam.

Edited by chrono, 08 September 2010 - 02:44 PM.
trimmed quote

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#10 LabRat84 Re: Conclusive evidence that aniracetam is an AMPA modulator

Posted 22 April 2010 - 08:17 AM

Interesting, thanks for that labrat.
Nice info.
Would you consider memantine and piracetam to be a good combo? I've never had the guts to take both as they sound as if their mechanisms would clash. I only take memantine right now so piracetam has kind of been pushed to one side although I miss the benefits I get from piracetam. Although I'm a lot happier on memantine i'm nowhere near as fast as I was on piracetam.


Today I increased my memantine dose to 20mg. I also took 800mg of aniracetam in the morning and 1.6g of piracetam in the afternoon. I conducted an interview phenomenally with very little preparation.

Memantine and channel modulators like piracetam should be synergistic: memantine blocks NMDA receptors until they're ready to fire and piracetam (probably) allows them to fire stronger. Ampakines cause them to fire with less delay.

Edited by chrono, 08 September 2010 - 02:45 PM.
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#11 Thorsten Re: Conclusive evidence that aniracetam is an AMPA modulator

Posted 22 April 2010 - 10:23 AM

Today I increased my memantine dose to 20mg. I also took 800mg of aniracetam in the morning and 1.6g of piracetam in the afternoon. I conducted an interview phenomenally with very little preparation.

Memantine and channel modulators like piracetam should be synergistic: memantine blocks NMDA receptors until they're ready to fire and piracetam (probably) allows them to fire stronger. Ampakines cause them to fire with less delay.


Cool thanks. You've convinced me to give this a go. I've just taken 1000mg of piracetam to top up my memantine dose of 15mg (taken 4hrs ago). I'll be interested to see how this pans out!! Incidentally I've always wanted to try aniracetam (it's been on my 'to do' list for years now) so I may finally take the plunge with this one too at the end of this month. I'd be pretty apprehensive about it synergizing with piracetam because I had so little success with oxiracetam and piracetam but I'll give it a go anyhow.

Edited by chrono, 08 September 2010 - 02:46 PM.
trimmed quote

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#12 John Barleycorn Re: Conclusive evidence that aniracetam is an AMPA modulator

  • Location:Canberra

Posted 28 May 2010 - 04:43 AM

Excitotoxicity usually results from excess calcium entering the cell, although there are other causes. What's clear is that glutamate can induce excitotoxicity. What's not clear is if that happens when AMPA and NMDA receptors desensitize normally.


From digging around on PubMed, I was surprised to see that ethanol is a strong NMDA antagonist, which can ultimately induce excitotoxicity. The theory goes that the NMDA receptors "upregulate" by an unspecified means during withdrawal, and this raises glutamate levels, also by an unspecified process. So that is a possible example of receptor sensitization actually being the problem. NMDA antagonists during withdrawal are said to not only prevent damage, but also to make people feel better and to reduce cravings. It is not clear how much this applies to anyone who has not chronically downregulated their receptors.

I was actually doing this research out of an interest in the issue of whether or not aniracetam compounds tolerance to other substances, as is occasionally suggested. Here, the terminology gets confusing. Some studies do indeed purport to show that aniracetam increases ethanol tolerance. However, what they actually show is that pre-dosing rats with aniracetam, then giving them a drink, then testing them somehow or other, improves performance. I call that "coping", not tolerance. These studies do not show that rats given aniracetam then escalate their ethanol dose or engage in ethanol-seeking behaviour.

It could be that ethanol is a different category to other abusable substances because of its NMDA antagonism, or it could be that all of these habit-forming substances ultimately share common pathways. Anyone know anything more here?
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#13 golden1 Re: Conclusive evidence that aniracetam is an AMPA modulator

  • Location:US

Posted 29 May 2010 - 08:18 PM

I would think that if piracetam were excitotoxic it would have been mentioned in one of the numerous studies done on it, does anyone have any studies which do mention this?
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