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Mythbusters: Piracetam and cholinergic transmission

piracetam choline

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#1 kassem23

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Posted 28 December 2010 - 11:07 AM


To those of you who know next to nothing about Piracetam, read the Wikipedia page, here.

In short, Piracetam is a cyclic derivative of the neurotransmitter GABA, and has gained its wide recognition through its purported nootropic effects, notably improving memory, attention and hypothetically creativity by elevating cross-hemispheric signal transduction.

As to the myth itself, you see it over and over again, in various threads, starting with: “So, as per recommendation of a large amount of people, I have added choline to my Piracetam regime, and hopefully that’ll take care of my acetylcholine depletion induced headache and brain-fog.” which to be honest, doesn’t make any sense at all.

One can even postulate that most – or all – of people’s regimes effects stem from their choline administration, that has some – at least more – evidence in terms of efficacy for memory improvement in vivo.

I hope that, Ex Dubio, one of the great minds at a forum (M&M) who wrote, as to reason why Piracetam doesn’t exert its effects through cholinergic neurotransmission, will make more people aware of the myth, and not pass it around as some sort of "fact" that choline supplementation is a necessary adjunct to Piracetam treatment, and that we don't know -- at all -- what the exact mechanism of action of Piracetam is.


“You know, I've heard the connection between piracetam and acetylcholine discussed dozens, if not hundreds, of times on this forum and others. And you know how many results come up for "piracetam acetylcholine" on PubMed? 36, 5 of which are in the past decade. I sincerely doubt piracetam has direct cholinergic activity. And let me explain why.

(PMID: 9621180) First, it seems clear that piracetam exerts at least part of its action through antioxidant/neuroimmune modulation. In this study, piracetam (among other nootropics) was found to have a protective effect on brain mitochondria during craniocerebral injury.

(PMID: 1794001) Then we have the issue that a review article from around the time of active research in piracetam (early '90s) still notes that we have essentially no idea how piracetam works, though "it is thought to facilitate central nervous system efficiency of cholinergic neurotransmission". Well gee, that's definitive.

(PMID: 10869513) Then we have the fact that although, like nefiracetam, piracetam facilitates hippocampal neurotransmission (in vitro), unlike nefiracetam, piraceteam's facilitation of neurotransmission is not blocked by a nicotinic acetylcholine receptor antagonist.

(PMID: 10850735) On a related note, it seems that nefiracetam (in vitro) potentiates nicotinic ACh receptor function, but piracetam does not.

(PMID: 1559636) Then we have the issue that piracetam is different in yet more ways from the other 'racetams (whose differences are maddeningly difficult to keep straight). Oxiracetam, but not piracetam (or aniracetam) enhanced choline-acetylctransferase activity in the hippocampus (yet again, in vitro).

(PMID: 8276434) One of the few studies supporting piracetam's pro-acetylcholine effects, researchers found that piracetam prevents electroshock-induced acetylcholine decrease. The authors speculate that this implies that piracetam facilitates cholinergic neurotransmission, but an attenuation of electroshock-induced ACh decrease could simply be a manifestation of an anti-inflammatory effect or something even more subtle.

(PMID: 2904660) Piracetam was applied to neurons in the hippocampus of the rat. Depending on the area studied, it either depressed or facilitated spontaneous firing rate. "It's effect were either additive or counteracting the actions of glutamate, [GABA], and ACh, when administered together on the same neuron, this supporting the assumption that its action is directed toward specific membrane elements, presumably synaptic sites." Well, shit, that's about as nebulous a result as I can conceive of.


(PMID: 2829047) This is probably the best evidence of ACh action of piracetam I've seen, and yet its in the PNS of rats. More precisely, piracetam had no effect on muscle contraction by itself, but it facilitated muscle contraction induced by edrophonium, an AChE inhibitor. The mechanism is speculated to be increased synthesis or release of ACh, but this is pure conjecture.

(PMID: 7301036) In a rat strain predisposed to cognitive impairment in later life, choline and piracetam combined improved memory function. Now choline (by itself) increased choline content in the striatum and cortex, but only slightly increased ACh. On the other hand, piracetam alone nearly doubled hippocampal choline and yet decreased hippocampal acetylcholine. Even weirder, the combination of the two drugs (which dramatically potentiated their effects on memory) did not potentiate the neurochemical effects seem with either drug alone, and in some cases attenuated the effects. Again, no damn idea.

(PMID: 3594455) Another oft-cited study regarding piracetam's pro-acetylcholine effects, this study suggests that piracetam increased ACh utilization in the hippocampus of the rat (after a 300 mg/kg i.p. dose) and also increased high-affinity choline uptake. This is almost promising, except that several other studies contradict this study's results.

(PMID: 3035858) Speaking of which -- oops, piracetam has no effect on high-affinity choline uptake. Darn. However, piracetam increased striatal HVA while leaving striatal DA unchanged. (WTF?)

(PMID: 2987637) And for good measure, one more study showing piracetam has no effect on high-affinity choline uptake in the hippocampus.

(PMID: 3786350) Then we have this study. Piracetam antagonized amnesia induced by hemicholinium-3, a drug which reduces ACh synthesis. How piracetam accomplished this is unknown, but it did not prevent the depletion of cerebral ACh. Again, no one has a clue what this stuff is doing.

So let's see. First, almost all available data is in vitro and certainly not in humans. And second, the most convincing data that piracetam is pro-cholinergic is a study in peripheral motor neurons. Amazing the shit that gets passed around as "fact". The above, by the way, is pretty much all research available on piracetam and acetylcholine.

Now, to answer your question. If piracetam actually had cholinergic activity, you'd be right. But it doesn't. And more importantly, the data on piracetam's effects on the HPA are pretty much limited to two studies. And here they are.

(PMID: 6650196) Get ready for a nice big "WTF?". Piracetam injected into female rats (at very high doses, admittedly) suppressed serum corticosterone compared to controls. It also prevented low-dose morphine-induced corticosterone release. The researchers haven't a clue why piracetam has this effect, but they note that piracetam has no effect on stress-induced activation of the HPA. Moreover, in vitro piracteam has no effect on pituitary ACTH release. Thus its effects are mediated somehow in the hypothalamus. Why it decreases basal HPA activity, I have no idea.

(PMID: 6650196) While piracetam has no effect by itself on plasma prolactin, it inhibits morphine-induced rises in plasma prolactin. Again, no idea why.



In summary: I don't think anyone has a damn clue what piracetam does to delivery nootropic effects or what it does to alter the HPA. Maybe it reduces HPA cortisol, but the only evidence for that is a single study in rats conducted almost thirty years ago. So, hey, good luck. “

[added quote]

Edited by chrono, 21 November 2011 - 02:47 AM.

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#2 chrono

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Posted 01 February 2011 - 11:59 AM

As to the myth itself, you see it over and over again, in various threads, starting with: "So, as per recommendation of a large amount of people, I have added choline to my Piracetam regime, and hopefully that'll take care of my acetylcholine depletion induced headache and brain-fog." which to be honest, doesn't make any sense at all.


Sorry, but I don't see how that doesn't make sense. Choline can be converted to ACh, which could help make up for an ACh depletion. Did you mean to say that it's unproven whether piracetam actually depletes ACh? We're talking about nootropics; of course it's unproven! Posted Image But seriously, Ex Dubio's bombastic incredulity about the coherence of research aside, I don't think the idea is entirely unfounded:


7231039 (not in ExD's review): Hippocampal acetylcholine levels were significantly depressed 30 min after rats received Piracetam (30–300 mg/kg, intraperitoneally).

3594455: Piracetam (300 mg/kg i.p.) also increased ACh utilization in the hippocampus. [measured as decrease in HIPP ACh]

7301036: However, piracetam alone markedly increased choline content in hippocampus (88%) and tended to decrease acetylcholine levels (19%).[/indent]


The argument against ACh depletion seems to be here:

(PMID: 3594455) Another oft-cited study regarding piracetam's pro-acetylcholine effects, this study suggests that piracetam increased ACh utilization in the hippocampus of the rat (after a 300 mg/kg i.p. dose) and also increased high-affinity choline uptake. This is almost promising, except that several other studies contradict this study's results.

(PMID: 3035858) Speaking of which -- oops, piracetam has no effect on high-affinity choline uptake. Darn. However, piracetam increased striatal HVA while leaving striatal DA unchanged. (WTF?)

(PMID: 2987637) And for good measure, one more study showing piracetam has no effect on high-affinity choline uptake in the hippocampus.


These last two papers only contradict the finding in one of the supporting studies, that piracetam increases HACU. However, ACh utilization or depletion does not necessarily entail increased activity of choline uptake carriers, in all models and timeframes (especially with the added variable of a drug with so many mechanisms, like piracetam). So I fail to see how this disproves the multiple findings of depletion. But I'd agree wholeheartedly that this evidence is not conclusive, and I certainly wouldn't say it's piracetam's primary MOA.

What most compellingly suggests this connection is the huge amount of anecdotal evidence. Seriously huge, stretching back 20 years to the publishing of Smart Drugs & Nutrients. Not everyone started taking piracetam and choline together, misled by some kind of myth we've dreamed up out of nowhere. There are so many reports here about piracetam causing brain fog, and guess what...some kind of choline helps 4 out of 5 times. For myself, taking piracetam without a choline source creates brain fog which is many times more powerful than its positive effects (i.e. incredibly obvious). I have confirmed this dozens of times, as well as the solution which obviously reverses this effect. From in here, the assertion that it's a myth, based on someone's opinion that the research isn't coherent, seems laughable.

We can argue all we want about the incomplete and possibly contradictory data, but at a certain point the task becomes formulating a theory to explain a phenomenon, rather than arguing about whether said phenomenon exists at all. The effect may well not be a compensation for ACh depletion, but I've yet to hear any other cogent ideas about this irrefutable connection.

I certainly try to dispel the idea the choline supplementation is a necessity, in advance of negative side effects, which is what I would describe as the myth. But as far as ameliorating those side effects when they do occur, it's worked for so many people that calling this connection a "myth" is fairly absurd, I think, even if we don't have a perfect explanation for it.

Edited by chrono, 21 November 2011 - 03:06 AM.

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#3 Ichoose2live

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Posted 01 February 2011 - 08:00 PM

I certainly try to dispel the idea the choline supplementation is a necessity in advance of negative side effects, which is what I would describe as the myth. But as far as ameliorating those side effects, it's worked for so many people that calling this effect a "myth" is fairly absurd, I think, even if we don't have a perfect explanation.


I agree with you. It's hard to make a conclusion based on 20 years old studies and in animals.

I take 4g/day of Piracetam without any choline and I get very positive effects. One thing I find intriguing is that recently I've tried 460mg of Alpha-GPC, it gave me a headache and I felt depressed, some kind of strange mood-depressed. This is an obvious cause of too high much Acetylcholine, then two days after I've tried 250mg of CDP-choline, I felt a slight headache-tension. This is a sign of too much Acetylcholine again. But that intriguing part is that 250mg of CDP-Choline alone should NOT gives you headache because of over levels of Acetylcholine. Right?

I have come up with a subjective theory:

Piracetam significantly stimulate the Cholinergics effects of CDP-Choline and gave me too much Acetylcholine. Possible, because if we consider that Piracetam actually does not act directly on any neurotransmitters or cortex, it could just stimulate the release of many mechanisms, e.g. Corpus Callosum, Acetylcholine, Glutamate, ATP, etc... That could explain why we find opposing results in the studies??? Or maybe the headache-tension came from another mechanism interacting between CDP-Choline and Piracetam, like ATP? It's almost impossible that it came from another supplements I only take High-dose of fish oil and Vitamin D-3.
I would like to have your thoughts about that, please.

Edited by chrono, 21 November 2011 - 02:45 AM.


#4 onetimevisit

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Posted 02 February 2011 - 06:01 AM

Ever considered that a cholinergnic effect is really an alteration of NMDA Glutamate to facilitate long range communication? Think phosphorated NR1a,That a substance increases activity in a neuron that shows cholinergnic markers doesnt not mean that the substance works through ACh receptors. Anyway Pir definitly increase Long Term Potentiation, as does nicotineR agonism.
I would speculate it has both a GABA,sigma-1 agonist effect.

Im making no call for/against choline supplementation, apart from the advice that choline supplementation should be less than 2grams a day.
Just a hypothesis

#5 Sobriquet

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Posted 08 July 2012 - 09:41 AM

taking choline does not necessarily equate to more ACh. It is a precursor, yes, but neurons will synthesize ACh via choline acetyltransferase from the compounds choline and acetyl-CoA relative to their capacities--- which are to be determined by the intra/extracellular environment at that given moment. look at the structure of a neuron, consider each step in the complex process of ACh sythesis. Can you see how 1 + 1≠ 2. We're oversimplifying!
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#6 Galantamine

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Posted 08 July 2012 - 07:45 PM

taking choline does not necessarily equate to more ACh. It is a precursor, yes, but neurons will synthesize ACh via choline acetyltransferase from the compounds choline and acetyl-CoA relative to their capacities--- which are to be determined by the intra/extracellular environment at that given moment. look at the structure of a neuron, consider each step in the complex process of ACh sythesis. Can you see how 1 + 1≠ 2. We're oversimplifying!


Interesting bump.

Pharmacology of Piracetam: http://hightowerphar...s-volume-1.html
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#7 Sobriquet

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Posted 09 July 2012 - 12:17 AM

thanks :)
too often we overlook the big picture.

Edited by Sobriquet, 09 July 2012 - 12:19 AM.


#8 Teerayoot

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Posted 19 October 2012 - 12:38 AM

Mean we should not take with choline at all ,in every choline source ?

#9 megatron

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Posted 19 October 2012 - 11:42 AM

Waste of money if you ask me.

#10 Teerayoot

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Posted 19 October 2012 - 12:45 PM

Choline and Piracetam individual give good benefit on each own ,but when combine the two seem negative effect will more produced.

#11 Sobriquet

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Posted 23 October 2012 - 03:21 PM

you don't need to take choline..
if you're eating adequate protein you'll be getting plenty of it
invest in other supps (ginko, fish oil, 5HTP, sam-e) I've had good results with all of these.
Brain Elevate by Now Foods makes my brain zippy too. It's a nice combo of serine, huperzine, ginko, and a few others. You can find it online pretty cheap: http://www.supplemen...CFQ45nAod7BEAdg

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#12 Teerayoot

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Posted 06 December 2012 - 07:19 PM

Choline is so much potent than anything else that Piracetam synergistic with .
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