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Cholinergic Mechanisms of ALCAR

Posted by chrono , in Review, Nootropics, Uncategorized 26 August 2010 · 52,557 views

nootropics choline piracetam cognitive enhancement ALCAR
ALCAR is a quintessential nootropic: an endogenous amino acid already present in the body and brain, it enhances cognition, protects against damage, and prevents or ameliorates many of the undesirable changes to the brain that occur as we age. As such, it is tolerated well by most, and combines nicely with most other nootropics. This review will focus on the effect ALCAR exerts upon the acetylcholine system, as well as more briefly describe other mechanisms of neurological interest.

This research project grew out of a desire to explain an effect I observed in myself: ALCAR fulfilled a very definite requirement for choline supplementation in piracetam usage. Taking even small amounts of ALCAR with alpha GPC resulted in a tension headache (sign of ACh overload), while much larger doses of either did not. This suggested to me that ALCAR had some kind of synergistic (i.e. multiplicative) effect somewhere in the acetylcholine pathway.

This is very much a work in progress; research of this kind generates a torrential cascade of references, and leads into general areas of inquiry in the pursuit of adequate explanation. But enough people have been asking about these mechanisms that I felt it would be helpful to publish a document with the most relevant details, if not a complete explanation. There are several more mechanisms by which ALCAR impacts the acetylcholine system, which are mentioned briefly at the end of the review. These will be fleshed out and referenced as I have time to read more papers, and adjustments will be made to existing explanations as I receive more full texts.

Feel free to post comments here, though I've created a forum thread to announce updates, discuss the research, and collect experience accounts of those who have tried the ALCAR + piracetam combination.

Piracetam and Choline

There is some confusion about the cholinergic potential of ALCAR, that results from the terminology we use on the board. We say that piracetam requires a "choline source," when what we more precisely mean is that we need to increase production and release of acetylcholine (ACh) to compensate for the hippocampal ACh depletion that piracetam causes [1-2].

The most common way to achieve this is by exogenous supplementation of choline, or a precursor which is converted into (or already is) one of the forms of choline useful in the brain [41]. Exogenous choline protects against artificial ACh depletion [3] (like piracetam), and increases the rate of resynthesis [3, 42, 49-50]. Improved choline supply may also provide a "backup" pool which may be mobilized for synthesis later [4-5, 43]; and increases the magnitude of ACh production in response to neural [3] or chemical [6-7, 42] stimulation.

But there are some drawbacks to this route. A certain elevated concentration of extracellular brain choline is required to effect an increase in ACh [6]; this is one of the reasons why many studies show no increase of ACh in response to exogenous choline [49-54]. An increase in plasma choline results in a net Ch increase in the brain [44], though by a lesser factor [48]. Most of this is rapidly taken up into cells or phosphorylated, and the surplus removed to the CSF [45, 47]—resulting in a small level of sustained extracellular choline [45-46]. In the absence of neural or chemical stimulation, increasing the amount of choline in the brain will only provide a very small and short-lived spike in basal ACh release in the hippocampus and cortex [6, 25]. The fact that added choline does not result in increased basal ACh shows that there are many systems of regulation—activity dependence, phosphorylation, plasma-brain-CSF exchange, choline uptake transporters, and recycling system—which make choline supplementation alone an inefficient and possibly ineffective means. This is where ALCAR comes in.

The Acetyl Moieity

This incredibly helpful graphic illustrates the course of the acetyl moieity (group) that ends up in acetyl-choline [8]:

Posted Image

The first enzyme (on the left) is Carnitine Acetyltransferase (CarAT), which transfers the acetyl group from ALCAR to acetyl-Coenzyme A (acetyl-CoA). Then the enzyme Choline Acetyltransferase (ChAT) transfers the acetyl group to choline to yield ACh. (This process has been demonstrated in slices of rat brains [8, 11, 23], and proposed by several others who could not construct the proper experimental system to demonstrate all of the effects [22-23]).

So, how might increasing availability of the acetyl moeity help us? The answer is in the equilibria of the coupled enzyme reaction above. The CarAT reaction has equilibrium near unity [9-10]; this means that it will utilize about half of any added substrates (ALCAR) to synthesize new products (acetyl-CoA). However, the equilibrium of the ChAT reaction is greatly in favor of the products (Keq of 12.3 [26] or 13.3 [27]); the vast majority of an added substrate will be converted into ACh. In other words, provided that CoA and choline are available, ALCAR should have a dose-dependent impact on amount of acetylcholine produced. (see Acetylcholine Release, below)

(It is worth noting that CarAT is able to acetylate choline directly [36], but with a very low affinity. It is speculated that it plays virtually no role in brain ACh biosynthesis [15]. However, it has been shown to account for up to half of ACh production in some muscular models [56-59], so a possible role in the brain cannot be discounted.)

Other enzymes and substrates are also responsible for the synthesis of acetyl-CoA, and are responsible for a greater amount than is contributed by ALCAR [11, 18-21]. The substrate which makes the largest contribution to the acetyl-CoA pool is pyruvate [12-13] (a metabolite of glucose), which is converted to acetyl-CoA by pyruvate dehydrogenase (PDC) in the mitochondrial matrix [11] (though PDC may exist extra-mitochondrially [14]). Glucose is slightly less preferred as a source, presumably because it must first be converted to pyruvate. Citrate and acetate play a role, though much less than pyruvate or glucose. ALCAR is preferred about 66% as much as glucose in this rat brain model [11]:

Posted Image

An important point is that ALCAR does not compete with glucose [8] or pyruvate [23] in relative contribution to final ACh production. This means that, even in abnormally high concentrations, ALCAR and other acetyl-CoA substrates still maintain an individual dose-response relationship. This is because the enzymes CarAT and ChAT have a very large amount of excess capacity at the physiological concentrations of their respective substrates, and so are far from saturation [8, 15].

The CarAT reaction has an equilibrium constant near unity [9-10], but is also reversible [29]; this reversibility means that ALCAR may be produced if acetyl-CoA and L-carnitine are in excess (in a certain area). Some of these other substrates (esp. pyruvate) are converted to acetyl-CoA inside the mitochondrial matrix [11]. CarAT itself is a membrane-bound enzyme, probably active at both inner and outer mitochondrial membrane sites [30-32]. One hypothesis is that, since carnitine is able to "shuttle" acetyl groups through the membrane [16-17, 30-35], ALCAR is used to transfer the acetyl groups from mitochondrial pyruvate-derived acetyl-CoA to the cellular cytoplasm, where it can be utilized by ChAT [8, 15]. (CoA and acetyl-CoA are able to pass the mitochondrial membrane directly in the presence of Ca2+ ions, but the required ion concentration is higher than has been demonstrated as possible in intact nerve cells [15, 37-40]). Thus, in addition to providing the acetyl moieity directly, ALCAR/carnitine may also serve as a carrier molecule to bring acetyl-CoA from other substrates, into the cytoplasm.


ALCAR also increases the utilization of glucose in the brain [22, 60], probably by stimulating non-oxidative pyruvate dehydrogenase activity [66, 68], which effectively increases the amount of ACh synthesized from glucose/pyruvate [66]. Utilization increases to varying extents in different regions, and increases more in the aged (who generally suffer from decreased glucose utilization) [62-63].

ALCAR is also able to increase the utilization of alternative energy sources like ketone bodies and lipid substrates [67, 69]; evidence also suggests that more ALCAR is taken up into the brain when levels of glucose are low [61].

It's also interesting that glucose and exogenous choline combine synergistically to increase ACh release [64], in a model of awake mice, when neither alone had much of an effect. While it isn't necessarily healthy to increase glucose intake, ALCAR's enhancement of glucose utilization (theoretically resulting in the same thing: more acetyl-CoA) may result in something of the same synergy.

CoA Supplementation

In the above reactions, CoA is recycled continuously. It is tempting to attempt to increase the quantitiy of this substrate as well, to drive the CarAT reaction forward from another direction. A potential drawback exists, in that CoA is a potent inhibitor of the forward action of the ChAT enzyme [8, 36]. An elegant feature of the CarAT-ChAT enzyme loop is that, in synthesizing acetyl-CoA, levels of this inhibitory product are decreased, allowing an increase in ChAT activity.

It is unknown whether supplementation of pantothenic acid (B5) or pantethine, precursors of CoA, will increase acetyl-CoA more than they interfere with ChAT. Only one paper exists which demonstrates an increase in ACh due to B5 supplementation [55], but it may only be applicable to correcting ACh deficiency due to B5 deficit (see discussion here). From the anecdotal reports of pantethine use, it sounds like ACh is being increased, if anything. Clearly, more experimentation is required. However, I suggest that moderate doses should be used, as increasing the pool of unacetylated CoA will have a negative impact on ACh production [15]:

Posted Image

In Progress

Choline Uptake
Transport of choline into nerve terminals, where it is converted into acetylcholine by the aforementioned process, is carried out by high- and low-affinity choline transporters (CHT); high-affinity choline uptake (HACU) is responsible for most of this process under normal circumstances. ALCAR has been shown to increase the uptake of choline, though the mechanism is not fully understood; as the release of ACh from the terminal results in an influx of new choline, this alone is no doubt implicated to some degree.

Choline Acetyltransferase
Many studies demonstrate that ALCAR increases activity of this enzyme; indeed, this is the most obvious cholinergic mechanism mentioned in the relevant abstracts. However, this enzyme functions at the convergence of many cholinergic processes, making it difficult to ascertain the exact mechanisms responsible.

As ChAT is the enzyme necessary for synthesis of acetylcholine, any process increasing ACh production and release should concomitantly increase its activity. However, this doesn't rule out the possibility of a direct action on the enzyme. Nerve growth factor (NGF) has such a stimulatory effect on ChAT activity. To complicate this further, ALCAR interacts with NGF in several ways (see below), which may also increase its effect on ChAT in several ways. However, there is evidence to show that ALCAR increases ChAT activity in the absence of NGF, and that increased NGF levels do not necessarily elevate the enzyme activity.

ALCAR demonstrates the greatest efficacy in ameliorating age-related deficits in ChAT activity.

ALCAR has been shown to increase hippocampal levels of NGF. ALCAR also modulates the action of NGF by increasing the expression of its low-affinity receptor, p75-NGFR, and perhaps by acetylating some of NGF's amino acids. This has the effect of potentiating its action, by which much lower amounts produce the same neurotrophic effect. This effect feeds back into stimulation of ChAT, and greater ACh production.

ALCAR most effectively induces NGF activity in aged animals, who suffer a decrease in NGF activity in parallel with a cholinergic deficit.

ALCAR arginyl amide produces a direct neurotrophic effect on neurite outgrowth and cellular morphology. However, only two studies have been conducted, both by the manufacturer Sigma Tau, and it is unknown whether this putative effect translate to an in vivo efficacy.

Direct Action
ALCAR has a very slight direct agonistic effect on ACh receptors, but it is orders of magnitude smaller than that of the neurotransmitter; there is almost no chance that it plays any practical role.

Acetylcholine Release
Or, "the proof is in the pudding." An actual and significant increase in ACh levels has been shown in several studies, which demonstrates that these mechanisms actually do exert an influence.

Other neurological mechanisms

Dopamine: ALCAR ameliorates age-related decline in D2 receptor density, and induces release of vesicular dopamine in the corpus striatum of rats.

NMDA: Reduces age-related decrease in receptors, but increases receptor density by decreasing amounts in adult and young rats.

GABA: Increased the density of GABA-benzodiazepine (but not GABA-A) receptors in aged rats.

Calcium channel: Ameliorated age-related decrease in L-type voltage-gated Ca2+ channel receptors in the hippocampal membrane.

Glucocorticoid: Prevented age-related decrease in number of binding sites.

Neuroprotection: ALCAR inhibits increases in lipid hydroperoxidation, increases expression of NF-κB and mGlu2/3, inhibits ceramide generation, enhances histone acetylation, attenuates apoptosis, and protects against the neurotoxic effects of NMDA (in large doses), MPPP(+), NGF/BDNF/serum deprivation, and ischemia.

Adverse Effects

Anxiety: One study in rats showed that acute (i.e. single) doses of ALCAR were anxiogenic; this study also showed that in chronic administration, 10 and 100mg/kg had no effect on anxiety, while 50mg/kg was anxiolytic [85]. This is suggestive of a bell-shaped response curve, which is consistent with dose-reponse curve of other effects in the Ames studies.

Ultrastructure: One abstract mentions that ALCAR induced a decrease in axosomatic synapses in young rats, in contrast to ameliorated decreases in axosomatic synapses and giant synapsis vesicles in aged rats [86]. Without the full text, and knowledge of the dosage, ROA, and age of the "young" animals, it is difficult to predict whether this is cause for concern in human; though most studies use "young" as an age category quite separate from "adult."


Due to poor planning on my part, I didn't store the medline URLs in my reference list. I will work on linking these, but in the meantime, typing the title into google scholar is probably the easiest way to retrieve the abstract (clicking All Versions will call up the pubmed link).

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Taglialatela G, Angelucci L, Ramacci MT, Werrbach-Perez K, Jackson GR, Perez-Polo JR.

Int J Neuropsychopharmacol. 2005 Mar;8(1):65-74. Epub 2004 Sep 22.
Effect of intraperitoneal acetyl-L-carnitine (ALCAR) on anxiety-like behaviours in rats.
Levine J, Kaplan Z, Pettegrew JW, McClure RJ, Gershon S, Buriakovsky I, Cohen H.

Drugs Exp Clin Res. 1987;13(3):185-9.
Ultrastructural aspects of ageing rat hippocampus and effects of L-acetyl-carnitine treatment.
Badiali de Giorgi L, Bonvicini F, Bianchi D, Bossoni G, Laschi R.


v1.0 2010-08-26

To do:
Update ChAT, NGF
  • like x 11
  • WellResearched x 2
  • Informative x 1

Wow very comprehensive (much of it way over my head), thank you.

Wow very comprehensive (much of it way over my head), thank you.

Well, you're certainly welcome! :-D

I realize it's somewhat advanced; in this first draft, I've concentrated most on reviewing what can be said based on the current literature. There is a huge gap in effort required between reading the abstracts and getting a vague idea of what's probably going on, and delving into the actual papers and being able to explain it in this way. But after reading so many papers about these complicated mechanisms, it's somewhat difficult to step back and see it from the perspective of someone who hasn't read all these papers ;)

I've tried to make it relevant to basic usage, and to explain a bit of why piracetam requires a choline source. As I revise, I'll probably try to add in some more explanations for those who aren't as familiar with the neurochemistry. If you (or anyone) would like to comment on where there are gaps in what you're able to understand of this (in the thread I linked to), it would probably help in future revisions.
Sep 05 2010 06:07 PM
beautiful, absolute masterpiece. I wouldn't be surprised if this became a standard advanced alcar tutorial on the net.
Sep 08 2010 04:19 PM
There's only one thing that worries me a bit: PMID: 15591013

There's only one thing that worries me a bit: PMID: 15591013

That's an interesting question. There are several other papers showing effectiveness in reducing hyperthyroidism, but there don't seem to be any showing the induction of hypothyroidism in normal people. But it certainly bears more researching.
Sep 15 2010 07:12 PM
Yep, I saw them too. But from what I've read, carnitine reduces the availability (sorry, i really don't know the terminology) of the thyroid hormones, but not their levels in the blood. So I imagine there would be no easy way do determine if carnitine does something in that regard to you - you could only watch out for symptoms of hypothyroidism (which are rather nonspecific from what I gather).

Sorry, I don't mean to goof on alcar, it's imho a promising supplement, but I'm just a bit paranoid (also my thyroid levels are in the low-normal range, so I'll pass for now)
(Also, you did a good job on writing the summary on alcar, I appreciate it)

I believe you already found them, but a few more studies:

Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake.

Usefulness of L-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism

Really lovely paper. Thanks for putting in the effort. Hugely appreciated.
Your work is superbly written, and pitched correctly. you may have underestimated the importance of the Carnitine group in the nootropic effect observed.
Thanks for the elaborate article, Chrono. I'm curious: Would you recommend ALCAR-arginate or -hydrochloride?
Great work, Chrono. I wonder though: all of this hinges on the assumption that more ACh is "better" for cognition. Do you know of any evidence for this, other than user reports? Do we know that the positive effects of piracetam are not due to its depletion of hippocampal ACh? (Doesn't seem plausible when everyone is busy increasing ACh, but is there evidence?)
just read this recently
so much to research
thankyou for your ability to do this for us.
much appreciated

It is unknown whether supplementation of pantothenic acid (B5) or pantethine, precursors of CoA, will increase acetyl-CoA more than they interfere with ChAT. Only one paper exists which demonstrates an increase in ACh due to B5 supplementation [55], but it may only be applicable to correcting ACh deficiency due to B5 deficit (see discussion here). From the anecdotal reports of pantethine use, it sounds like ACh is being increased, if anything. Clearly, more experimentation is required. However, I suggest that moderate doses should be used, as increasing the pool of unacetylated CoA will have a negative impact on ACh production [15]

I take 1g x2 of B5 (from calcium pantothenate), 500mg ALCAR, and 500mg citicoline. Am I doing something wrong? Thanks.
Thanks for this. I've been planning to experiment with a topical dmso + noot stack and was considering whether ALCAR and R-ALA should be in there or not. Sounds like maybe so.
ALCAR recently got screwed because L-carnitine is known to be metabolized to TMA by gut bacteria, leading to TMAO production in the body, leading to heart disease. One may be inclined to complain that L-carnitine is known to be good for the heart, but this doesn't mean that it can't effectively be both good and bad at the same time.


I'm curious whether, given that ALCAR increases acetycholine uptake, like Piracetem, and it increases NGF, like Noopept, if anyone has experimented with using ALCAR not just as a choline source but as a racetam substitute as well. I'm trying to build as minimal a stack as possible, and I'm curious whether ALCAR could help cut racetams out. I'll give it a try myself, of course, but thought I'd ask whether anyone else had any experience with this.

Climactic: There was a thread about carnitine supplementation elsewhere on the forum that has some good information: http://www.longecity...-heart-disease/ Obviously everyone will need to make their own decision about whether they think it's safe (I don't eat meat so I'm not worried about it).
Good one ! Do Alcar has any use for young people ?

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