Cholinergics Nootropics

What Is The Best Choline Supplement For Cognitive Enhancement?

Although any aspiring researcher will no doubt have encountered what was once classified as a vitamin, choline, many intriguing questions surround its use, questions which are not always addressed in the literature. The aim of this article is to provide the reader with an introduction to choline and its effects, as well as the different forms of cholinergic supplements and some of the most common combinations with other nootropics.

What is Choline?

Choline is an essential nutrient for intestinal, cognitive, and neuromuscular health. It is a water-soluble vitamin, and it is sometimes grouped with other B-complex vitamins as vitamin J.

An endogenous agent first isolated from ox bile, choline is distributed throughout the body, where it fulfills a variety of functions ranging from the liver to the brain, but it is notable for being the precursor to acetylcholine, an important neurotransmitter which is involved in many functions including memory, muscle control, and mood.


The forms found in the body are often very close (or exactly the same) as the ones you buy at your supplement store: CDP-Choline (also known as Citicoline) and GPC (glycerophosphocholine) both occur naturally in all animal brains.

CDP is actually the last step before phosphatidylcholine (an essential cell membrane component, like cholesterol), while GPC is the very next step after phosphatidylcholine. From there, it becomes plain old choline, then acetylcholine or betaine. The figure below helps paint a picture of what’s going on inside the brain. GPC appears in the center, while CDP is in the upper right corner. Now, you may wonder how GPC and CDP can occur before choline, that is, be precursors, and still be more effective supplements than plain choline? Surely supplementing the final step in the ladder would be better? Not quite. The answer lies in the fact that the precursor enjoys interesting effects of its own, as well as a higher bioavailability and blood-brain-barrier permeability.

Choline synthesis from Citicoline


Across a range of experiments and ethnicities, elderly individuals show the greatest response to choline supplementation. Age-related memory decline is a complicated process, with many contributing factors. It seems likely that a reduction in the availability of choline in the brain is one of them. By addressing this issue, the severity of the mental decline might be lessened. Choline is also somewhat helpful in stroke recovery, with studies supporting citicoline[1] and Alpha-GPC.[2]

However, there may be benefits for healthy subjects too. A study showed that Donepezil, an acetylcholinesterase inhibitor, improves certain measures of learning and memory in young adults.[3]

Interestingly, it plays a role in physical health too, especially with the liver, which is the first organ to show signs of stress in deficiency, but also in certain autoimmune diseases. In cases where the rogue antibody attacks neuromuscular acetylcholine receptors, symptoms usually include impaired motor skills, and increasing the supply of acetylcholine (to compete with the antibodies) is the first line of treatment.

Natural Occurrence

The recommended daily intake ranges from 350 to 600 mg. It is found in reasonable quantities in many foods, with common sources including eggs, peanuts, grains, meats (especially organ meats), spinach and beets.So while athletes who eat a lot of whole foods are unlikely to benefit from supplementation, elderly and more sedentary individuals may. Those who eat more processed than whole foods may also benefit from a choline supplement because processed foods are often lacking in choline.

So while athletes who eat a lot of whole foods are unlikely to benefit from supplementation, vegans, elderly and more sedentary individuals may. Those who eat more processed than whole foods may also benefit from a choline supplement because processed foods are often lacking in choline.

Interactions & “Stacking”

Too little choline results in mental slowness or brain fog, while too much causes a low mood, dysthymia, and muscular stiffness.

Choline should not be combined with pharmaceutical or herbal acetylcholinesterase inhibitors, like Huperzine, Galantamine, and Donepezil, as this can overwhelm the neuromuscular junction with too much acetylcholine. Many snake and spider venoms work by inhibiting or activating the peripheral acetylcholine receptor, inducing death either by asphyxia (low acetylcholine) or convulsion (high acetylcholine).

When taken with Piracetam (or another “-racetam“), some people find that the Choline should be taken about two hours before Piracetam. So, one idea is to take choline with breakfast, and piracetam with lunch. There are reports of fatigue or brain fog, the fatigue moreso with aniracetam than piracetam, but this may be caused by either an excessively high dose, or also the “depressive” characteristic of aniracetam contrasted against a more stimulant characteristic of piracetam. This may explain why some users have opted for aniracetam without choline (after reporting fatigue, brain fog, and low mood when combining the two). But choline has still been reported to act synergistically with Pramiracetam and Noopept.

A question commonly asked is how often it should be taken, or at what time of the day. With most supplements, it does not make much difference how the dose is divided, but acetylcholine can interfere with the deeper stages of sleep, so taking it with breakfast is advisable. And, as explained above, piracetam itself is thought to deplete choline, so a common strategy is to take the choline a few hours earlier. This lends itself well to taking piracetam with brunch. Some users may choose to take piracetam twice a day, and choline once or twice a day.

Having given the reader a background on choline, we now turn our attention to the focus of the article, which is explaining differences between common forms of choline.

CDP-Choline (Citicoline)

CDP-CholineCDP-Choline is unique among choline sources for containing Cytidine, a compound related to Uridine, a media spectacle which once made rounds in the nootropic community, it has served as the basis to the “Mr. Happy stack” and inspired many nootropic enthusiasts.

After ingestion of Citicoline, there is a significant increase in choline and uridine plasma levels[4], after which the latter goes on to induce a plethora of beneficial effects, particularly on the dopamine system. Studies indicate it promotes dopamine release[5] and increases the densities of dopamine receptors. While offering the benefits of uridine, CDP makes no sacrifice in delivering choline.

Daily dose varies between 300 and 1000 mg.

Alpha GPC

Alpha GPC is glycerylphosphorylcholine (a metabolite of CDP-Choline) with an added acetyl group that makes it more lipophilic, thus able to cross the blood-brain barrier more easily.  The most bioavailable, pure, and blood-brain barrier permeable of all choline sources considered in our review, it also has interesting properties that other sources do not. It boosts HGH and physical performance[6]. It also improves the functioning of the vesicular choline transporter[7], as well as serotonin, dopamine[8] and GABA synthesis.[9]

Although highly effective in the elderly, this one in high doses carries a risk of hypercholinergic states. Even though it is not harmful, too much brain choline is reported to have a counterintuitive effect of causing brain fog, fatigue, or confusion. Used in moderation, this choline source can be very effective. Although expensive, a little goes a long way.

Daily dose varies between 300 and 800 mg.

Choline Bitartrate & Citrate

Behind lecithin, these are the most inexpensive and widely available forms of Choline and are commonly supplemented by those who suffer from fatty liver, hepatitis, and cirrhosis to enhance their liver detoxification pathways.

Choline bitartrate nootropicAs with any supplement, users have reported differing effects, but researchers are inclined to the view that both bitartrate and citrate are more or less identical in effect, with differing experiences being explained by individual differences. The foods you eat, how well you sleep, the mood you wake up in, and your activity level are all things which vary from day to day and things which might influence your response to choline, but these factors are not always included in the reports.

This would be a decent choice for someone looking for general health benefits, but it may not be the best solution for cognitive enhancement as these forms of choline do not cross the blood-brain-barrier as well as Alpha GPC and Citicoline.

Daily dose varies between 250 and 1000 mg.


Lecithin, the most natural form, commonly derived from soy or sunflower, it supplies a unique form of choline, phosphatidylcholine.

Soy lecithinPhosphatidylcholine is an interesting supplement by itself, it not only helps as choline precursor but also plays a role in cell membrane integrity by donating itself to components of the ”phospholipid bilayer” which was so passionately extolled by our high school biology teachers.

Although the least potent form of choline (the most potent being Alpha GPC and Citicoline), a higher dose can be used to a somewhat similar effect. It contains certain other “less essential” phosphatidyl groups (including phosphatidylinositol), which though not harmful, contribute little to the nootropic effects of lecithin. Because of this, a larger dose is needed than with most choline supplements.

Its bioavailability is as good, and there is no concern over contamination or purity, however, beware of cheap soy lecithin because it is often derived from genetically modified soy, so make sure you’re buying GMO-free soy lecithin. More importantly, it may not be as good as other choline precursors, as far as cognitive enhancement.

Daily dose varies between 500 and 2000 mg.


Capable of improving acetylcholine synthesis[10], DMAE improves physical performance and alertness[11], as well as some measures of mood[12] in healthy volunteers, making it by definition a nootropic. However, even though it may look excellent on paper, it is not very effective as a cognitive enhancer, and it may even act as an anticholinergic according to some research.[13]

Daily dose varies between 100 and 500 mg.


Although not strictly a “choline source,” Centrophenoxine (also known as Meclofenoxate) is a potently and selectively cholinergic supplement often used in dementia patients. It is an improved version of DMAE, and it has been found to improve memory, attention, and general cognition in young and aged rats.[14]

One of its remarkable properties is to increase acetylcholine release[15] while slowing down lipofuscin accumulation[16] [17], which is thought to cause Alzheimer’s disease.[18]

Daily dose varies between 200 and 800 mg.


Acetyl-L-carnitine has more rich and interesting effects on brain health than plain L-carnitine, suggesting the acetyl group plays a pivotal role, helping acetylcholine pathways.

It is known to significantly boost NGF[19], mitochondrial function, and alertness in both healthy and elderly subjects. Supplementation increases serotonin and noradrenaline synthesis in the cortex and hippocampus[20].

Daily dose varies between 400 and 2000 mg.


Although not strictly cholinergic, this supplement often taken alongside ALCAR, an acetyl donor, and both supplements can indirectly help in methylation as well as acetylcholine pathways.

Taken on its own, it is able to partially restore acetylcholine levels of aged rats. It has cortisol and stress-lowering properties, particularly after chronic administration.[21] Studies on spatial memory in healthy volunteers have been mixed, but against ADHD they have been more conclusive[22] [23], with a noteworthy effectiveness. Phosphatidylserine makes up an important part of the nerve membrane, its ratio to phosphatidylethanolamine and phosphatidylcholine determines the overall strength of the membrane.

Daily dose varies between 100 and 300 mg.

References   [ + ]

1. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). (2012)
2. alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial. (1994)
3. Acute cognitive effects of donepezil in young, healthy volunteers. (2009)
4. Effect of oral CDP-choline on plasma choline and uridine levels in humans. (2000)
5. Dietary uridine-5′-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. (2005)
6. Acute supplementation with alpha-glycerylphosphorylcholine augments growth hormone response to, and peak force production during, resistance exercise (2008)
7. Effect of L-alpha-glyceryl-phosphorylcholine on amnesia caused by scopolamine. (1991)
8. Modulation of monoaminergic transporters by choline-containing phospholipids in rat brain. (2013)
9. Evidence for an in vivo and in vitro modulation of endogenous cortical GABA release by alpha-glycerylphosphorylcholine. (1996)
10. Dimethylaminoethanol (deanol) metabolism in rat brain and its effect on acetylcholine synthesis. (1979)
11. The influence of 2-dimethylaminoethanol (DMAE) on the mental and physical efficiency in man. (1967)
12. Mood alterations during deanol therapy. (1979)
13. Deanol and methylphenidate in minimal brain dysfunction. (1975)
14. Age-related differences in memory and in the memory effects of nootropic drugs. (1990)
15. Effect of centrophenoxine on acetylcholine release in perfused cerebral ventricles of cats under dynamic electrophysiological control. (1979)
16. Neuronal lipofuscin in centrophenoxine treated rats. (1977)
17. Lipofuscinogenesis in mice early treated with centrophenoxine. (1978)
18. Lipofuscin hypothesis of Alzheimer’s disease. (2011)
19. Acetyl-L-carnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats. (1994)
20. Chronic acetyl-L-carnitine alters brain energy metabolism and increases noradrenaline and serotonin content in healthy mice. (2012)
21. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men. (1992)
22. The effect of phosphatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children: a double-blind placebo-controlled trial, followed by an open-label extension. (2012)
23. The effect of phosphatidylserine administration on memory and symptoms of attention-deficit hyperactivity disorder: a randomised, double-blind, placebo-controlled clinical trial. (2014)
Coluracetam Nootropics Racetams Reviews

Coluracetam Review: A Nootropic With Antidepressant Properties

The drug piracetam is often regarded as the first truly nootropic drug, due to its ability to promote healthy brain function and cognition without potentially debilitating side effects. The family of nootropics that are structurally related to piracetam, known as racetams, have also been held in high esteem by the nootropics community. Coluracetam is one of the many members of this nootropic drug class, but it has some unique properties that set it apart from the rest.


ColuracetamColuracetam is a fairly new addition to the racetam category of nootropics, being developed and initially researched in the mid-1990s.[1] Coluracetam, known also by its research names of MKC-231 and BCI-540, was initially developed and researched by the Mitsubishi Tanabe Pharma Corporation in Japan as a potential treatment for Alzheimer’s disease. Coluracetam has also seen some limited research concerning its potential use for treating Major Depressive Disorder and Generalized Anxiety Disorder.[2]

Mechanism of Action

When ingested, coluracetam becomes present in nerve tissue within 30 minutes of administration. The concentration in the body begins to decrease about 3 hours after ingestion.[3]
The most definitive mechanism through which coluracetam works is high-affinity choline uptake (HACU). HACU is a crucial step in the process of the body’s converting of choline into acetylcholine, a vital neurotransmitter for cognition processes. [4] In essence, this means that an increase in HACU (caused by coluracetam) will also increase the activity level of acetylcholine in the nervous system. This is the basis for coluracetam’s ability to enhance cognition

My Experience with Coluracetam

My trial run for NootropicsDepot’s coluracetam lasted for one week, due to the fact that coluracetam’s effects seem to all take place rather quickly. In other words, the effects do not appear to be cumulative like some other nootropics. Typically, I took 30 mg orally in the morning, along with another 30 mg in the afternoon. If necessary, I took another dose later on in the day. Dosage recommendations for coluracetam range anywhere from 3 mg up to 100 mg or more, but this dose seemed to work just fine. Having experimented with coluracetam briefly a few months ago, I had a general feel for what dose might work.

Coluracetam powder nootropicDuring the time of this trial, I was not taking any prescription medications. In the morning, I was taking Vitamin B12, Vitamin D, potassium gluconate, fish oil, and turmeric. The effects I experienced from taking coluracetam have been very positive. However, bear in mind that this is only a subjective experience. The placebo effects cannot be ruled out (although I am convinced it was the coluracetam I felt), and experiences will vary between individuals. That being said, I will now go into what I felt are the major benefits of coluracetam:

  1. Motivation enhancement
    Right off the bat, coluracetam seems to provide a decent increase in motivation to engage in productive work. I felt a stronger desire to work on school work that I don’t find very interesting. It made it much easier to push through to get things done, leaving a very satisfactory feeling when things were accomplished.
  2. Stimulation
    This effect goes somewhat hand-in-hand with motivation enhancement. Coluracetam has the effect of making me feel more awake and alert. It seems to help me feel more ready and able to get work done. It didn’t make me feel “jittery” either – I felt quite relaxed the whole time.
  3. Reduction in fatigue
    Coluracetam appears to help alleviate both physical and mental fatigue. There were a few instances when taking it where I went from being exhausted and drained to energized and ready to go.
  4. Enhanced cognition
    This effect is very important for any nootropic compound. After all, it is the main thing that nootropics are purported to influence. Within half an hour of taking coluracetam, I felt much more able to formulate thoughts and translate them into writing. I also felt more able to connect ideas in my mind and get a better idea of the “bigger picture.” I also felt more naturally able to hold conversations with others, feeling much more engaged and fluent.
  5. Music enhancement
    While this is mostly unrelated to the topic of cognitive enhancement, listening to music while on coluracetam was very pleasant. The music itself felt more full, interwoven, and immersive than usual. Individual pieces of melody and minor details became more distinguishable than usual.
  6. Mood Boost
    After taking coluracetam, I can understand why it is being researched as a treatment for depression. It helped me remain more positive and upbeat throughout the day. I also seemed to make things more enjoyable in general.


Coluracetam seems to be a very promising nootropic in terms of its multiple benefits and few side-effects. I did not experience any apparent increase in tolerance during the week I was taking it, even with multiple doses in one day. Experiments in which rats were given coluracetam for 14 days at a time seems to reinforce this.[5] The only possible side-effect I experience was mild to moderate headaches, which occurred throughout the week. This should be taken with a grain of salt because I am normally fairly prone to headaches in the first place. I’ve also heard that taking choline can alleviate headaches that come with racetam supplementation, so that could be a potential remedy.


All things considered, I was very pleased with the effects of coluracetam. I will certainly be implementing it into my nootropic stacks, as it is one of the most noticeable and useful nootropics I have personally taken. It seemed to have a real impact on my motivation, energy, and cognition. Everyone is bound to react differently to coluracetam, but I strongly encourage nootropics users to give it a try.

You can buy Coluracetam powder and capsules at NootropicsDepot.

Reviewer 8.4
I highly recommend coluracetam for anyone who needs to spend extended periods of time working on demanding mental tasks. The cognitive boost and mental stimulation was extremely useful.

References   [ + ]