91 replies to this topic

[dirdir207]

Does anyone else find that whilst supplementing with glutamic acid or MSG it feels like 99 percent of it is being converted to GABA. Perhaps i just have a peculiar brain chemistry, phenibut actually made me much MORE anxious and extremely tense with horrible clenching and bruxism, as does alcohol to a lesser degree. Glutamic acid however feels how i imagine benzos and suppose to feel. It always induces a sense of intense relaxation with me, completely annihilates any anxiety i have instantly and for the majority of the day.

[LBGSHI]

The article and this book excerpt seem to suggest that Glutamine is just as easily converted to Glutamate within the brain. Is there really a discrepancy of any practical importance that is worthy of noting here? If you keep your glutamine levels up via supplements (whey has on avg. 3-5gs of added glutamine) then, shouldn't you be just as well off as supplementing negligible amount of glutamate directly? I just don't see how, if having eaten a cob of corn, your body would selectively decide to "fund" either, though not both, the muscles (via glutamine) or the brain (via glutamic acid.) It seems it's more likely to go where it is most needed and., in case of piracetam, it seems it's more likely to go to the brain in form of glutamate. Maybe I am missing something crucial.

I just ordered both (with piracetam) and will update, h/e I was just wondering meanwhile b/c I am relatively new to pir + glu combo although I've done a lot of more "novel" noops in the past.

The article and book you reference, along with every article and study I've come across, seem to imply a tendency toward general stasis between glutamine and glutamate. If you're increasing the body's use of glutamate and intent on increasing excitatory neurotransmission (as with nootropics), there are several reasons why you would want to supplement with glutamate directly rather than indirectly via glutamine:

1. Glutamine doesn't convert directly to glutamate; aside from glutamine directly increasing ammonia concentration in the kidneys and elsewhere (http://en.wikipedia....mine#Functions), there are byproducts of its conversion to glutamate - arginine, citrulline, and urea, for example: http://www.ncbi.nlm....pubmed/16400059. Ingesting large amounts of glutamine in an effort to indirectly increase glutamate levels will result in excess quantities of several substances. Though fairly large doses of glutamine are well-tolerated, this doesn't mean they're ideally suited for nootropic use. Since a relatively large dose of glutamine is required to produce a relatively small amount of glutamate, unless you have a specific desire to dramatically increase the levels of these byproducts in your body, glutamine supplementation doesn't seem reasonable.

2. One of glutamate's positive effects is its ability to remove ammonia from cells by combining with it (to form glutamine, I might add). This is mentioned in the article and book you reference above. For a specific example: http://www.ncbi.nlm....pubmed/20680262. Supplementation of glutamine will not produce this effect, unless you count the process of converting to glutamate, then converting back to glutamine.

3. As a corollary to the previous two, taking excess glutamine and waiting for the body to convert some of it to glutamate results in an elevated level of glutamine, followed by a balanced glutamine/glutamate ratio, along with elevated levels of substances like urea, citrulline, and arginine. Taking glutamate results in an elevated level of glutamate, followed by a balanced glutamine/glutamate ratio, along with a reduced amount of free ammonia. The former means you never reach far above the baseline level of glutamate, and you end up with unwanted byproducts, while the latter means you start with significantly elevated glutamate, exactly what you set out to do in the first place, and you actually decrease the level of a harmful byproduct (ammonia).

Does anyone else find that whilst supplementing with glutamic acid or MSG it feels like 99 percent of it is being converted to GABA. Perhaps i just have a peculiar brain chemistry, phenibut actually made me much MORE anxious and extremely tense with horrible clenching and bruxism, as does alcohol to a lesser degree. Glutamic acid however feels how i imagine benzos and suppose to feel. It always induces a sense of intense relaxation with me, completely annihilates any anxiety i have instantly and for the majority of the day.

I haven't experienced this, nor have I read about anyone else experiencing it. However, if pressed for a strictly hypothetical model for explaining it, and assuming it wasn't psychosomatic, you might consider the possibility that you were low on GABA in the first place. Glutamate is a precursor of GABA. Given the necessary enzyme (glutamate decarboxylase), additional precursors, and a shortage of GABA, your body would make short work of that problem. Still, what you would most likely be perceiving is a "normal" level of GABA, as compared to your previous, "sub-normal" level.

[dirdir207]

Does anyone else find that whilst supplementing with glutamic acid or MSG it feels like 99 percent of it is being converted to GABA. Perhaps i just have a peculiar brain chemistry, phenibut actually made me much MORE anxious and extremely tense with horrible clenching and bruxism, as does alcohol to a lesser degree. Glutamic acid however feels how i imagine benzos and suppose to feel. It always induces a sense of intense relaxation with me, completely annihilates any anxiety i have instantly and for the majority of the day.


I haven't experienced this, nor have I read about anyone else experiencing it. However, if pressed for a strictly hypothetical model for explaining it, and assuming it wasn't psychosomatic, you might consider the possibility that you were low on GABA in the first place. Glutamate is a precursor of GABA. Given the necessary enzyme (glutamate decarboxylase), additional precursors, and a shortage of GABA, your body would make short work of that problem. Still, what you would most likely be perceiving is a "normal" level of GABA, as compared to your previous, "sub-normal" level.

I agree 100 percent, this is exactly what I had surmised as well. I had suspected that I have been operating with a hypoglutamergic system for quite some time now, somewhere along the schizoid to add i scale. Studies have shown schizophrenic individuals have a pronounced deficit in glutamate and under activity at the NMDA receptor, and consequently, without the presence of sufficient amounts of glutamate, a pronounced deficiency of GABA as well. I might theorize however, that what I am experiencing is an amelioration of negative schizophrenic symptoms due to increased glutamergic activity, markedly decreasing anhedonia, alogia, blunted affect, asociality and avolition, giving me a paradoxical calming effect.

I suspect also that after long term use with piracetam, this has in fact exacerbated my symptoms due to further reducing already low levels of glutamate. Also after a life time of stimulant use, rarely ever indulging in depressants, that my GABA receptors are probably upregulated or sensitized to a significant degree. So any increase in GABA production would probably have a fairly notable effect in me.

I also started using the SSRI citalopram roughly three weeks ago, which has been shown to correlate in efficacy to a variation in the GRIK4 glutamate gene. What variation is associated with positive outcomes and what variation is associated with an increase in suicidal ideation I have not been able to pin point. Further more SSRIs have been found to possess dose dependent and long term NMDA antagonist activity reminiscent of memantine.

"NMDA antagonists mimic the effects of clinically effective antidepressants in both preclinical tests predictive of antidepressant action and procedures designed to model aspects of depressive symptomatology. These findings led to experiments demonstrating that chronic administration of NMDA antagonists to rodents results in a downregulation of cortical beta-adrenoceptors, a phenomenon also observed following chronic treatment with many antidepressants. These neurochemical and behavioral similarities between antidepressants and NMDA antagonists prompted us to examine the impact of chronic antidepressant treatment on NMDA receptors. Chronic (14 days) but not acute (1 day) administration of seventeen different antidepressants to mice produced adaptive changes in radioligand binding to NMDA receptors. Detailed studies with three antidepressants (imipramine, citalopram, and electroconvulsive shock) show that these changes develop slowly, persist for some time after cessation of treatment, and (for imipramine and citalopram) are dose dependent. Moreover, following chronic treatment with imipramine, these changes in radioligand binding to NMDA receptors appear restricted to the cerebral cortex. Based on the consistency of these effects across antidepressant treatments, we propose that adaptive changes in NMDA receptors may be the final common pathway for antidepressant action. The recent demonstration (Nowak et al., 1995) that radioligand binding to NMDA receptors is altered in frontal cortex of suicide victims (compared to age and post-mortem interval matched controls) is consistent with the hypothesis (Trullas and Skolnick, 1990) that this family of ligand gated ion channels is involved in the pathophysiology of depression."

Supplementing glutamate or MSG while under the influence of citalopram may very well preferentially increase GABA concentrations due to the antagonistic effects on NMDA receptors. Administration of citalopram has also been shown to increase GABA levels by roughly 35 percent after acute ingestion, perhaps this effect had not been occurring with me due to a deficiency in glutamate and supplementation has lead to increased efficacy with citalopram, perhaps somehow related to the GRIK4 gene.

Ultimately there are a lot of variables and any conclusions I can draw are purely theoretical guess work. I always submit that I possess only a rudimentary laymans understanding of mechanisms, as my only experience is through hours of autodidactic research and self education on the matter and I always welcome constructive criticism and counter argument.

[LBGSHI]

Ultimately there are a lot of variables and any conclusions I can draw are purely theoretical guess work. I always submit that I possess only a rudimentary laymans understanding of mechanisms, as my only experience is through hours of autodidactic research and self education on the matter and I always welcome constructive criticism and counter argument.

Given the information available, your conclusion seems pretty sound.

[alecnevsky]

1. Glutamine doesn't convert directly to glutamate; aside from glutamine directly increasing ammonia concentration in the kidneys and elsewhere (http://en.wikipedia....mine#Functions), there are byproducts of its conversion to glutamate - arginine, citrulline, and urea, for example: http://www.ncbi.nlm....pubmed/16400059.

Arginine is an amino acid and citrulline derives from ornithine which is a product of glutamate. (Glutamate, by same study, contributes to production of ornithine.)

Since a relatively large dose of glutamine is required to produce a relatively small amount of glutamate,

Do we know this conversion rate or is it contingent on the whether the body is depleted of one of them i.e., faster rate if glutamine is abundant (which it normally is in non-athletes and non-piracetam users I suppose) and slower rate if there is a glutamine deficiency associated with muscle stress ? I'm just imagining things...

unless you have a specific desire to dramatically increase the levels of these byproducts in your body, glutamine supplementation doesn't seem reasonable.

Again I do not see how these byproducts, especially arginine, are at all harmful. If glutamate produces ornithine and citrulline is derived from ornithine, then we're really talking about same agent at different degrees of its manifestation. So it is yet not clear to me why it is unreasonable (i'll forgive that it may be unfeasible to this end in particular) to supplement glutamine vis-a-vis glutamate considering the former is pretty crucial in all cellular function.

2. One of glutamate's positive effects is its ability to remove ammonia from cells by combining with it (to form glutamine, I might add). This is mentioned in the article and book you reference above. For a specific example: http://www.ncbi.nlm....pubmed/20680262. Supplementation of glutamine will not produce this effect, unless you count the process of converting to glutamate, then converting back to glutamine.

Is there a daily max dose of glutamine ? Given that it's available in 2lb tubs and that each suggested serving is 4-10g, I am going to go with the alternative that ammonia is not really an issue for doses lower than 20gs.

[LBGSHI]

alecnevsky: Great questions.

1. Glutamine doesn't convert directly to glutamate; aside from glutamine directly increasing ammonia concentration in the kidneys and elsewhere (http://en.wikipedia....mine#Functions), there are byproducts of its conversion to glutamate - arginine, citrulline, and urea, for example: http://www.ncbi.nlm....pubmed/16400059.

Arginine is an amino acid and citrulline derives from ornithine which is a product of glutamate. (Glutamate, by same study, contributes to production of ornithine.)

Certainly, but if someone takes glutamine, with the intention of indirectly increasing glutamate, much larger quantities of glutamine will be required to elicit a significant increase in glutamate than if glutamate were taken directly. Thus, while there will always be byproducts left by supplementing either amino acid, the byproducts will be much more significant when taking glutamine, because glutamine constitutes a longer, more convoluted path. Moreover, dramatically increasing glutamine levels is non-trivial in relation to ammonia toxicity: http://www.ncbi.nlm....ubmed/17127302/ ("Excessive accumulation of Gln in brain cells may be deleterious to brain function. In hyperammonemia associated with acute liver failure, excess Gln leads to cerebral edema, which largely results from its interference with mitochondrial function and partly from its osmotic action."). In any case, there doesn't appear to be a benefit to taking something that will become glutamate, rather than taking glutamate itself.

Since a relatively large dose of glutamine is required to produce a relatively small amount of glutamate,

Do we know this conversion rate or is it contingent on the whether the body is depleted of one of them i.e., faster rate if glutamine is abundant (which it normally is in non-athletes and non-piracetam users I suppose) and slower rate if there is a glutamine deficiency associated with muscle stress ? I'm just imagining things...

Yes, studies have been performed relative to the conversion rate. For example:

http://www.ncbi.nlm..../pubmed/6140648 - Rat brain converted 29% of glutamine to glutamate


More specific to this discussion:

http://www.ncbi.nlm....pubmed/17715355 - "Although raising glutamine augments synaptic transmission by increasing vesicular glutamate, access to this synthetic pathway by exogenously applied glutamine to neurons is delayed and slow, challenging mechanisms linking the rapid effects of pharmacological inhibitors to decreased vesicular glutamate."

The above study involved increasing glutamine levels and observing the resulting effect on glutamate. In the study, researchers increased glutamine levels by between 4 and 20 times the norm (from 200-900μM to 4 mM), and maintained these levels for 4 hours, with no change in glutamate levels. Finally, after the 4 hour mark, a moderate increase in glutamate was observed.

unless you have a specific desire to dramatically increase the levels of these byproducts in your body, glutamine supplementation doesn't seem reasonable.

Again I do not see how these byproducts, especially arginine, are at all harmful. If glutamate produces ornithine and citrulline is derived from ornithine, then we're really talking about same agent at different degrees of its manifestation. So it is yet not clear to me why it is unreasonable (i'll forgive that it may be unfeasible to this end in particular) to supplement glutamine vis-a-vis glutamate considering the former is pretty crucial in all cellular function.

Though this probably goes without saying now, I'll refer you to the above studies, relating that glutamine converts only weakly and in delayed fashion to glutamate, and that increased levels of ammonia due to excess glutamine can indeed impair mental function. I certainly don't think this is a true hazard to health, but it's yet another reason why involving glutamine at such high levels as required to dramatically increase glutamate is probably not called for.

2. One of glutamate's positive effects is its ability to remove ammonia from cells by combining with it (to form glutamine, I might add). This is mentioned in the article and book you reference above. For a specific example: http://www.ncbi.nlm....pubmed/20680262. Supplementation of glutamine will not produce this effect, unless you count the process of converting to glutamate, then converting back to glutamine.

Is there a daily max dose of glutamine ? Given that it's available in 2lb tubs and that each suggested serving is 4-10g, I am going to go with the alternative that ammonia is not really an issue for doses lower than 20gs.

As mentioned above, I doubt a minor overdose of glutamine will put anyone in the hospital. Still, there are plenty of things that average people consume every day that cause negative effects, yet they're still up and about in spite of this. In all, it would seem ill-advised to supplement glutamine in an effort to increase glutamate, given the increased efficacy and decreased side-effects of direct glutamate supplementation. After all, if we're interested in increasing glutamate, why would we add steps to the process in the first place?

Edited by LBGSHI, 23 January 2013 - 06:47 PM.

[alecnevsky]

Very good stud(ies) LBGSHI. I got to paste some findings h/e.

"We show that pharmacological inhibition of the glutamate–glutamine cycle fails to abolish synaptic transmission, even during intense synaptic activation. Our findings indicate that even in the absence of glial support, neurons can maintain a releasable pool of vesicular glutamate for long periods of time."

"Based on our results, the neuronal TCA cycle seems capable of maintaining the neurotransmitter pool of glutamate, as well as meeting basic energetic demands for several hours in the absence of known exogenous sources. Rather than an exclusive flow of carbons from vesicle to astrocyte and back, we support a model in which neurons are also capable of de novo synthesis of glutamate from TCA cycle intermediates, which can then be replenished from glutamine, glucose, or any other source of carbons that can be transported into the cell. Multiple biosynthetic pathways ensure a robust supply of vesicular glutamate to support synaptic transmission in neurons."

"Although glutamine synthetase may not generate the glutamine that serves as the biosynthetic precursor of vesicular glutamate, neurons may still import glutamine from other sources through neutral amino acid transporters."

"We hypothesized that, with spontaneous glutamate release ongoing while the slices are in the incubating chamber, blocking the glutamate–glutamine cycle for an extended period of time would eventually deplete vesicular glutamate; however, basal synaptic transmission was unaffected by the prolonged incubation, similar to MSO-incubated slices"

Could this suggest some kind of temporary independence of glutamate levels in the brain? It looks like there is a 2hr window following a complete inhibition of the glutamate-glutamine cycle where the brain produces glutamate out of some kind of intermediaries?

I may just try piracetam with [grossly] equivalent amounts of each. Since the Glu/Gln conversion rate is ~ .29 I am going to take 4.8 pir (for the first time ever) with ~1725mg of glutamine and then take 4.8g pir with 500mg of Solgar glutamic acid. I doubt that's an equivalent dose, considering Glu metabolizes like 70% within 7 min and Gln only 50% so maybe I will take 2500mg Gln to get the equivalent 500mg Glu dose given the bioavailability rate to gauge immediate effect.

Edited by alecnevsky, 23 January 2013 - 10:18 PM.

[LBGSHI]

Could this suggest some kind of temporary independence of glutamate levels in the brain? It looks like there is a 2hr window following a complete inhibition of the glutamate-glutamine cycle where the brain produces glutamate out of some kind of intermediaries?

I may just try piracetam with [grossly] equivalent amounts of each. Since the Glu/Gln conversion rate is ~ .29 I am going to take 4.8 pir (for the first time ever) with ~1725mg of glutamine and then take 4.8g pir with 500mg of Solgar glutamic acid. I doubt that's an equivalent dose, considering Glu metabolizes like 70% within 7 min and Gln only 50% so maybe I will take 2500mg Gln to get the equivalent 500mg Glu dose given the bioavailability rate to gauge immediate effect.

Yes, the brain does appear to have both alternate methods of producing glutamate and emergency stores to be released if necessary.

The chief problem here is that ingesting large amounts of glutamine will require a long lead-time (4 hours, if the above study is any indication), after which less than a third of the glutamine will end up converting to glutamate. It's certainly interesting to attempt both in the spirit of science, but I don't think there's any gain to taking the indirect route of glutamine. Is there something I'm missing, or are you just interested in substitutes in case of lack of access to glutamic acid/simplification of a stack if you're already taking glutamine?

[alecnevsky]

I do a lot of HII strength+cardio every day thereby expanding a lot of my glutamine and creatine. So, given that I supplement whey that has 3.06g of "Glutamine + Glutamic Acid" I was wondering whether I could kill two birds with one stone by keeping my glutamine blood level high enough so as to afford both, expansion of glutamine due to muscle stress and expansion of glutamate due to Piracetam. So yes, it's one less pill to digest, which is really negligible relative to how many i take daily anyway (upwards of 20.)

[LBGSHI]

I do a lot of HII strength+cardio every day thereby expanding a lot of my glutamine and creatine. So, given that I supplement whey that has 3.06g of "Glutamine + Glutamic Acid" I was wondering whether I could kill two birds with one stone by keeping my glutamine blood level high enough so as to afford both, expansion of glutamine due to muscle stress and expansion of glutamate due to Piracetam. So yes, it's one less pill to digest, which is really negligible relative to how many i take daily anyway (upwards of 20.)

Ah, now that makes sense. Still, that seems to leave a lot of free ammonia in your system without enough glutamate to bind to it and form glutamine. And my question is, although glutamine can, to a limited extent and over a considerable amount of time, convert to glutamate, will it be able to do so in times of dramatically increased glutamate requirements? In other words, will there be sufficient glutaminase present to handle enough conversion to be adequate, or will glutaminase be depleted too rapidly, leading to optimal levels of glutamate for racetam supplementation never being reached by glutamine supplementation alone?

[Heh]

Taking more than 125mg of L-Glutamic Acid seems like a really bad idea.

[alecnevsky]

I do a lot of HII strength+cardio every day thereby expanding a lot of my glutamine and creatine. So, given that I supplement whey that has 3.06g of "Glutamine + Glutamic Acid" I was wondering whether I could kill two birds with one stone by keeping my glutamine blood level high enough so as to afford both, expansion of glutamine due to muscle stress and expansion of glutamate due to Piracetam. So yes, it's one less pill to digest, which is really negligible relative to how many i take daily anyway (upwards of 20.)

Ah, now that makes sense. Still, that seems to leave a lot of free ammonia in your system without enough glutamate to bind to it and form glutamine. And my question is, although glutamine can, to a limited extent and over a considerable amount of time, convert to glutamate, will it be able to do so in times of dramatically increased glutamate requirements? In other words, will there be sufficient glutaminase present to handle enough conversion to be adequate, or will glutaminase be depleted too rapidly, leading to optimal levels of glutamate for racetam supplementation never being reached by glutamine supplementation alone?

I am not sure how or why one would have depleted levels of glutaminase. It would be some kind of genetic disease, no ?

And,

"Taking more than 125mg of L-Glutamic Acid seems like a really bad idea."

Why?

[Heh]

Because 125mg is all that's needed, and anything more is just increasing the odds of excitotoxicity.

[LBGSHI]

I am not sure how or why one would have depleted levels of glutaminase. It would be some kind of genetic disease, no ?

What I was considering was that, given a larger amount of glutaminase activity required to convert large quantities of glutamine to glutamate, glutaminase may be depleted or temporarily bound in such a way as to require more glutaminase to convert glutamine to glutamate at a sufficient rate. It's just a hypothesis, but it seems to me that if you require a certain amount of glutaminase to convert a certain amount of glutamine to glutamate, if you increased the level of glutamine dramatically and expected a dramatic increase in the level of glutamate by conversion from glutamine, you'd require an increase in glutaminase to support that.

Taking more than 125mg of L-Glutamic Acid seems like a really bad idea.

Have you read the contents of this thread? I've specifically targeted that claim, found a slew of studies to debunk the idea that a dose as small as 500mg of glutamic acid is harmful, and found zero studies to support the idea of such small doses of glutamic acid being harmful. I'm very interested in any scientific studies asserting either safety or danger of such doses of glutamic acid, so please do reference any you find. Otherwise, it's not helpful to say things like "It's bad" or "It's fine".

Because 125mg is all that's needed, and anything more is just increasing the odds of excitotoxicity.

Can you point us to any studies or other evidence that, given chronic nootropic supplementation, 150mg of glutamic acid is "all that's needed"? As referenced in the very first post of this thread, multiple studies have established that brain glutamate levels are indeed depleted by chronic racetam use. Can you point us to any studies which indicate that low doses of glutamic acid are unsafe, or increase in any significant manner the risks of excitotoxicity?

Edited by LBGSHI, 25 January 2013 - 04:57 PM.

[Heh]

I am not sure how or why one would have depleted levels of glutaminase. It would be some kind of genetic disease, no ?

What I was considering was that, given a larger amount of glutaminase activity required to convert large quantities of glutamine to glutamate, glutaminase may be depleted or temporarily bound in such a way as to require more glutaminase to convert glutamine to glutamate at a sufficient rate. It's just a hypothesis, but it seems to me that if you require a certain amount of glutaminase to convert a certain amount of glutamine to glutamate, if you increased the level of glutamine dramatically and expected a dramatic increase in the level of glutamate by conversion from glutamine, you'd require an increase in glutaminase to support that.

Taking more than 125mg of L-Glutamic Acid seems like a really bad idea.

Have you read the contents of this thread? I've specifically targeted that claim, found a slew of studies to debunk the idea that a dose as small as 500mg of glutamic acid is harmful, and found zero studies to support the idea of such small doses of glutamic acid being harmful. I'm very interested in any scientific studies asserting either safety or danger of such doses of glutamic acid, so please do reference any you find. Otherwise, it's not helpful to say things like "It's bad" or "It's fine".

Because 125mg is all that's needed, and anything more is just increasing the odds of excitotoxicity.

Can you point us to any studies or other evidence that, given chronic nootropic supplementation, 150mg of glutamic acid is "all that's needed"? As referenced in the very first post of this thread, multiple studies have established that brain glutamate levels are indeed depleted by chronic racetam use. Can you point us to any studies which indicate that low doses of glutamic acid are unsafe, or increase in any significant manner the risks of excitotoxicity?

Are you saying 125mg of L-Glutamic Acid isn't enough, and if so, then why? I don't see the point in taking more of anything than needed, especially if taking more increases the risk of inducing negative side effects.

Edited by Joel, 25 January 2013 - 06:29 PM.

[LBGSHI]

125mg may indeed be enough, and yet it may not. I would love to see something quantifying that. I have observed that 500mg is quite effective, with no negative side effects (and a host of studies, which I've referenced in this thread, have corroborated this). After some time longer, I may try a smaller dose to see if I receive the same positive effects, but unfortunately, with any tablets I've found so far, that would require me breaking the tablet into two or more pieces, which would inherently be inaccurate in measurement and a hassle to perform on a regular basis. The fact that these tablets are all sold in 500mg form is another hint that 500mg may be a standard dose.

In any case, you didn't really answer any of the questions that alecnevsky and I asked you.

[Heh]

I think I answered your questions by saying, "I don't see the point in taking more of anything than needed, especially if taking more increases the risk of inducing negative side effects."

As far as identifying the specific dosage at which L-Glutamic Acid by itself (rather than as part of, say, whey protein) becomes excitotoxic, I wouldn't know. But given the risk of excitotoxicity at higher dosages, I just don't see the point in taking more than is necessary.

I also could be biased, because I tried taking 500mg-1g of L-Glutamic Acid and after 3 days I experienced the symptoms of MSG poisoning (yes, I know L-Glutamic Acid isn't MSG) and the racetams still didn't work.

Edited by Joel, 25 January 2013 - 07:28 PM.

[LBGSHI]

I think I answered your questions by saying, "I don't see the point in taking more of anything than needed, especially if taking more increases the risk of inducing negative side effects."

As far as identifying the specific dosage at which L-Glutamic Acid by itself (rather than as part of, say, whey protein) becomes excitotoxic, I wouldn't know. But given the risk of excitotoxicity at higher dosages, I just don't see the point in taking more than is necessary.

I agree; that's the point of determining "how much is necessary". Huge doses have been found to be quite safe, with no ill effects reported by multiple human subjects after prolonged supplementation. However, if you were to take many grams in one sitting, you could certainly hurt yourself. If a small dose is sufficient for you, that's great. Otherwise, increasing the dose seems quite unlikely to harm you, especially given the low doses we're talking about.

I also could be biased, because I tried taking 500mg-1g of L-Glutamic Acid and after 3 days I experienced the symptoms of MSG poisoning (yes, I know L-Glutamic Acid isn't MSG) and the racetams still didn't work.

What exactly do you mean by "MSG poisoning"? My guess is, you experienced symptoms unrelated to your glutamic acid supplementation. It's quite unlikely that you "poisoned" yourself with only a gram of glutamic acid. Otherwise, you'd get really sick every time you had a subway sandwich, or some corn, or ate basically anything in Asia.

[dirdir207]

On a semi-related note, does anyone have any experience supplementing sarcosine with piracetam? It seems to me the pairing would be highly complimentary, however I unfortunately do not have the funds to test it out myself.

[LBGSHI]

On a semi-related note, does anyone have any experience supplementing sarcosine with piracetam? It seems to me the pairing would be highly complimentary, however I unfortunately do not have the funds to test it out myself.

So, boost glycine levels by inhibiting glycine transport, thereby activating more NMDA receptors than usual? After looking around at sarcosine, it does seem to be an interesting supplement. I want to spend some more time testing and establishing my current stack, but I could certainly be persuaded to try sarcosine out sometime in the future. Price aside, have you found any good places to get it from? I see that SmartPowders carries it, but is currently out of stock.

[blueenigma]

I've seen a few threads here and elsewhere promoting supplementation of glutamate in conjunction with nootropics, and I've also seen a few condemning it. However, I haven't seen a clear consensus, nor have I seen much evidence to back up either side of the debate. Perhaps we can get to the bottom of this.

First, a little introduction and specificity:

Glutamic acid is one of 20 directly encoded proteinogenic amino acids (the other two proteinogenic amino acids, selenocysteine and pyrrolysine, are incorporated into proteins by distinctive biosynthetic mechanisms). In the body, glutamic acid loses one hydrogen atom and becomes glutamate...although in general, this technicality is ignored and people (even scientists) use the terms "glutamate" and "glutamic acid" interchangeably. Nevertheless, it bears reminding that glutamate is not the same thing as glutamine. Incidentally, glutamate can be converted by the body to glutamine, and likewise glutamine can be converted to glutamate, but this does not imply that sufficient levels of one will guarantee sufficient levels of the other.

A quick look on Wikipedia will inform the reader that "Glutamate is an important neurotransmitter that plays a key role in long-term potentiation and is important for learning and memory." Couple that with the fact that several nootropics, including and perhaps most notably the racetams, increase the brain's use of glutamate, and thereby decrease brain glutamate levels. For example:

Piracetam decreases the glutamate content of the brains of mice - http://www.ncbi.nlm..../pubmed/1685614

Aniracetam increases cortical glutamate release - http://www.ncbi.nlm....d?term=11852174

Oxiracetam selectively increases the release of glutamate in the hippocampus - http://www.ncbi.nlm..../pubmed/1361044


It would seem that glutamate reserves are depleted by racetam use (and likely the use of other nootropics with similar mechanisms of action), and that glutamate supplementation may be desired in this case.

However, there have been concerns over glutamate excitotoxicity, which could cause neuronal damage and cell death, resulting in everything from stroke to epileptic seizures. This is the real crux of the matter, and what must be addressed.

Glutamate, as mentioned above, is essential to the body, and is present in sufficient levels in normal humans. A diet low in natural sources of glutamate results in symptoms such as insomnia, problems concentrating, and mental exhaustion. Total deficiency of glutamate would cause death, but it would be almost impossible to deplete this amino acid completely, as the body produces it from glutamine when it cannot acquire it dietarily.

The question becomes: If glutamate is important for nootropic users, how might one determine if he or she is deficient, and how might one supplement it without running the risk of excitotoxicity?

Although nothing comes to mind for determining deficiency other than trial and error (suggestions?), we can take a quick look at dietary sources of glutamate to see how much humans safely ingest every day.

If, for example, we drop by USDA's FNS web site, we see that the average serving of corn is about 90 grams: http://www.fns.usda...._F210_Final.pdf

If we take a look at USDA's NAL web site, we see that corn contains 0.636 grams of glutamate per 100 grams: http://ndb.nal.usda....ormat=Full&new=

Given the average 90 gram serving noted above, this means that humans regularly consume 0.5724 grams (or 572.4 milligrams) of glutamate via corn.

If you think that's significant, the next example blows it out of the water. The USDA recommends that at a bare minimum, adults consume at least 6 ounces of grains per day, 3 of which should be whole grains: http://www.ers.usda....48/err50_1_.pdf

However, the average healthy, active human far exceeds this recommendation. Per the USDA's NAL web site, the average slice of whole wheat bread weighs 28 grams, and is composed of 1.894 grams per 100 grams glutamate: http://ndb.nal.usda....ormat=Full&new=

This means that every time you eat a slice of whole wheat bread, you're ingesting 0.530 grams (or 530 milligrams) of glutamate. In general, people use two slices per sandwich, which amounts to 1.06 grams per sandwich, aside from any additional items containing glutamate.

Cracked wheat weighs about 25 grams per slice, and contains 2.770 grams per 100 grams glutamate: http://ndb.nal.usda....ormat=Full&new=

This means that for every cracked wheat sandwich you eat, you're ingesting 1.385 grams of glutamate.

Considering the fact that many very healthy people consume multiple sandwiches per day, and adding to that the fact that, for example, 12-inch subway sandwiches contain at least three times as much bread as normal sandwiches, people ingest many grams of glutamate per day via wheat bread alone.

Other natural dietary sources of glutamate include:

Eggs (for example, fried eggs, weighing on average 46 grams, contain 1.87 grams per 100 grams glutamate, or 860.2 milligrams glutamate per fried egg) - http://ndb.nal.usda....ormat=Full&new=

Peas (peas contains 0.741 grams per 100 grams glutamate - the average serving of peas, one cup or 145 grams, thus contains 1.07 grams of glutamate) - http://ndb.nal.usda....ormat=Full&new=

Parmesan Cheese (contains a whopping 8.696 grams per 100 grams glutamate - the average serving of one ounce or 28.35 grams thus contains 2.465 grams of glutamate) - http://ndb.nal.usda....ormat=Full&new=

...and the list goes on. Google the other twenty or so common dietary sources, and run them through the USDA NAL foods list here: http://ndb.nal.usda....ndb/search/list


All this points to the fact that, if one can easily skew glutamate ingestion by several grams just eating a subway sandwich, supplementing a gram or two isn't going to cause any significant harm. Moreover, if it's been conclusively established that the racetams deplete glutamate, taking a glutamate supplement while taking a racetam supplement would seem to be a very good idea. Alternately, you could just increase your dietary intake of glutamate, by eating more of the foods mentioned above (and others that contain significant amounts of glutamate).

Input?

[blueenigma]

I'm somewhat mystified by your apparent understanding of the studies you cite. In particular, the study involving aniracetam speaks to the extracellular levels of glutamate in the prefrontal cortex and the basolateral amygdala regions of the brain. The study showed that Aniracetam significantly increased glutamate levels in the pre frontal cortex of the stroke-prone rats, but not in the amygdala region. Ultimately, the findings suggest that aniracetam enhances glutamatergic release, which may be the mechanism by which it exerts an ameliorating effect on neuronal dysfunctions. Nothing in this study suggests a depletion of glutamate, but rather demonstrates increased extra cellular levels of glutamine in the prefrontal region. Further, the glutamatergic increase is thought to have an ameliorative effect on neuronal function, so I don't comprehend the initial concern on this front. I do get that your original concern was glutamate depletion yet I do not see that this study would evoke such a concern. Glutamate levels were increased extracellularly, not diminished. Unless your thinking is that there is a set bucket of glutamate and aniracetam's enhancement of glutamatergic release used up these stores I'm uncertain about your position. It appears that aniracetam significantly increases conductance on glutamate, not facilitate depletion.

The study you cited for oxiraceram seems equally inapposite. The study you cited for piracetam makes more of an argument for your concern, however.

Edited by blueenigma, 22 January 2014 - 09:03 AM.

[blueenigma]

@LBGSHI: The above is directed to you. I'm
typing on my iPhone and do not know how to navigate this forum from this handset yet. I meant to quote and reply in the same box. Sorry for the double posts.

[LBGSHI]

I'm somewhat mystified by your apparent understanding of the studies you cite.

Don't be. I've been quite transparent about the fact that this thread is an open inquiry to sate my curiosity. The first paragraph of the first post ends with "Perhaps we can get to the bottom of this.", then the post ends with "Input?". If you disagree with my reasoning, I'm all ears (or eyes, as it were).

In particular, the study involving aniracetam speaks to the extracellular levels of glutamate in the prefrontal cortex and the basolateral amygdala regions of the brain. The study showed that Aniracetam significantly increased glutamate levels in the pre frontal cortex of the stroke-prone rats, but not in the amygdala region. Ultimately, the findings suggest that aniracetam enhances glutamatergic release, which may be the mechanism by which it exerts an ameliorating effect on neuronal dysfunctions. Nothing in this study suggests a depletion of glutamate, but rather demonstrates increased extra cellular levels of glutamine in the prefrontal region.

It's probably just a typo on your part (otherwise, you should read up on the difference between the two), but your last sentence above refers incorrectly to glutamine; glutamate is the topic of discussion (glutamine was not mentioned in the article in question, either). That aside, the point you're making, that this study doesn't support nor refute the idea that aniracetam depletes glutamate, is correct. Since there are very few studies that focus on depletion (I could only find one referring to piracetam at the time I wrote that post), I added as supplementary food for thought two studies focusing on glutamate release in the brain. Whether or not release implies depletion is also a topic of discussion, and I'm open to input as stated above. I would tend to think that release coupled with the glutamate-glutamine cycle would mean at least short-term reduction in glutamate levels, even if glutamine could later be broken down into sufficient glutamate to support requirements (see the later discussion of this cycle). However, since glutamate depletion has been established in at least one study with piracetam, one begins to wonder how exactly glutamate would be depleted other than being released and undergoing the standard cycle to glutamine, and if it's reasonable to assume it would occur differently with the other racetams.

Further, the glutamatergic increase is thought to have an ameliorative effect on neuronal function,

You're misquoting. "Our findings suggest that aniracetam enhances cortical glutamatergic release, which may be the mechanism involved in the ameliorating effects of aniracetam on various neuronal dysfunctions." This does not mean it improves all neuronal function; it means it improves the condition of people with various neuronal dysfunctions. In other words, if someone is not releasing normal amounts of glutamate, increasing glutamate release may be an ameliorating factor in aniracetam supplementation for that person. And once again, glutamate reserves are finite, and release would seem to imply depletion, so if a higher glutamate level is a good thing (as in, if you're not borderline overdosing on glutamate when more is suddenly released, and/or you're not releasing enough glutamate), then in order to keep up with a desired level of glutamate once the finite supply has been released, it would seem that supplementation is required (unless you prefer to wait several hours for glutamine to be converted to glutamate).

Glutamate levels were increased extracellularly, not diminished. Unless your thinking is that there is a set bucket of glutamate and aniracetam's enhancement of glutamatergic release used up these stores I'm uncertain about your position.

That is my thought, yes. Is your thought that glutamate reserves are infinite? If glutamate was increased extracellularly, what happened intracellularly, where the glutamate came from?

The study you cited for oxiraceram seems equally inapposite.

As before, glutamate is being released, which to me implies depletion.

Your thoughts are certainly desired; that's the reason I created this thread.

[blueenigma]

@LBGSHI: Indeed there is a typo in that I transplanted 'gluatamine' for 'glutamate'. I did mean 'glutamate' at each turn.

That aside, I suppose that when the study talks about increased extra cellular glutamate, your thinking is that this release into the extracellular matrix implies an eventual depletion. This presupposes that the body does not simultaneously continue to make more. Indeed you could be right. I'll look into this further. Interesting thing.

[noos]

EGCG facilitates glutamate release
http://www.ncbi.nlm....pubmed/17663453
and is neuroprotective, nevertheless.

Good find. Maybe this could explain why I find some types of green tea simulating, different from caffeine, or maybe it is the theanine?

[jadamgo]

EGCG facilitates glutamate release
http://www.ncbi.nlm....pubmed/17663453
and is neuroprotective, nevertheless.

Good find. Maybe this could explain why I find some types of green tea simulating, different from caffeine, or maybe it is the theanine?

This is probably just the fact that caffeine + theanine feels pretty different from caffeine alone. Interestingly enough, theanine's primary mechanism appears to be anti-glutamatergic. This is why it's so sedating.

[civilizedsavage]

I've spent the last four hours trying to figure out why my first attempt at an attack dose of 6 grams piracetam has left me in such a confused state.

My previous regimen included:

Deprenyl Sublingual 5 mg
Piracetam 2 g
Aniracetam 1.2 g
Alpha-GPC at 25% of my total racetam dose (I'm using 99% purity)
Dexedrine 15 mg
Caffeine 200 mg
Multivitamin
Fish Oil
6 hard boiled eggs

Side note. The 1 to 4 ratio of alpha GPC to racetam dosage has worked quite well for me. It should be noted that I take the racetams and the GPC with milk to ensure that each compound is absorbed properly. You might think it strange that I mandate eggs as part of my regimen, but oddly enough, after someone suggested this addition to me, the irritability I experienced from the racetams seemed to lift to a moderate extent. I'm hoping the addition of L-Glutamic Acid will unlock the full potential of the racetams.

I take all of these in the morning, so that by the time I go to sleep, there will be minimal interference with my sleep. After lurking these forums for a few years, I've noticed no one really emphasizes the importance of paying attention to the elimination half-life of all supplements being ingested on a daily basis, and the solubility of said substances. Keep in mind that these are just my preferences, and many people do not even experience the insomnia I experience with improper timing of my medicines.

I've thought about adding 5-HTP, and I did eventually try it out for a few days, but since I was already taking melatonin, this proved to be a BIG no-no for me. I ended up waking up either extremely groggy, or in a manic/frenzied state of mind. I presume the melatonin I take is enough to trigger a REM rebound for me sometime during the night, as it has helped me to maintain a constant sleep schedule. If you take melatonin, try using Time Release version first, instead of the instant release. I don't exactly know why, but whenever I take instant release I seem to wake up midway through the night wide awake and unable to go back to sleep. The time release version resolved this issue for me.

Some other things I've noted is the highly potent synergism between Aniracetam and Piracetam, with most of the energy/focus/creativity/mood-enhancements coming from the Aniracetam. Remember that Aniracetam is 1/8 the potency of Piracetam, so you don't have to take that much, but you do have to take it with some healthy fats as it is fat soluble. The Alpha GPC is also fat soluble, while piracetam is water soluble. Honestly, after I added aniracetam to the mix, I was able to progress through each day with near perfect efficiency. Sadly, I ran out last week, and have been miserable ever since, but I've ordered more, and hope that it reaches me tomorrow as I cannot afford to waste anymore time.

One last point before I get to the main reason for my post: If you haven't yet included some cardio training in your regimen, I highly recommend you do so. If you want to get technical, you can find out your HRmax and your HR target, in order to reap legit cardiovascular benefits. Not only has this helped me manage my heart health, but I've noticed everytime I run, it potentiates everything I'm taking to a very noticeable extent. Another thing I like to do to is sleep extremely early, as in like I start getting ready for bed at 7:00 PM, asleep by 8:00 PM, and wake up at 4 AM every day. Ever since I've started doing this, I will say that my all day energy and productivity levels increased like never before. The important part of maintaining a consistent sleep schedule is eating at the same time every day, and leaving a 4 hour gap between dinner and bed time.

If you need to hack your way into a new sleep cycle, I offer you this little trick that's worked like a charm every single time I've needed to reboot:

http://lifehacker.co...est-you-deserve

Anyways, getting to the point, I came across what may be a better source for L-Glutamic acid.

http://www.nutrabio....duct_Code=24240

So what do you guys think? Should I get Solgin's 500 mg L-Glutamic Acid tabs?
Or should I get NutraBio's powdered form, and just cap them myself?

Edited by civilizedsavage, 30 January 2014 - 10:21 PM.

[LBGSHI]

All interesting stuff. One I'll comment on is:

I presume the melatonin I take is enough to trigger a REM rebound for me sometime during the night, as it has helped me to maintain a constant sleep schedule.

Yes, melatonin will generally induce prolonged or multiple REM cycles. This is good for multiple reasons (most obviously a deeper, more refreshing sleep than you'd otherwise expect), but most importantly because REM affects memory consolidation. The best thing about learning something today is hopefully remembering it tomorrow (and the next day).

If you'd like to measure this, check out Sleep As Android if you have an Android phone, or an iOS/etc equivalent if you don't. I've been using Sleep As Android for over a year now, and it's quite interesting to track my sleep duration, amount and time of movement during sleep, and various other factors.

[civilizedsavage]

So i've just received my L-glutamic acid from NutraBio, and will be trialing it as part of my regimen for the first time today.

Although....

I'm not even quite sure I needed it in the first place. You see, I've discovered something incredibly important recently about my current regimen. I've been taking too much choline! I should have known! The tip off came after weeks of terrible join pain, abdominal cramping, and crippling depression. I thought this might have just been initial symptoms that would eventually subside, but apparently, even a 1:4 ratio for a powerful substance like Alpha GPC is enough to trigger an overload for my particular body chemistry. I tried a dosage of Alpha GPC roughly 1/8 of my racetam dose (or 15%), and I felt the racetams working their magic for the first time.

I will still try out the L-glutamic acid just to see if it would add to the positive effects. If it doesn't, oh well, it was only 7 bucks

Oh yeah, and LBGSHI, will that Sleep as Android app try to wake me up at the right time? Just the statistics would be something i'd be interested in (and thanks for the suggestion by the way!). My sleep patterns have returned to somewhat normal, and i've been able to get 8 hours a night consistently, however I've come to accept there will just be some days where my body won't need the full 8. It would be nice if this app could keep track of those hours for me, since I always forget to update my sleep log~

Edited by civilizedsavage, 08 February 2014 - 11:19 AM.