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)
Bacopa Nootropics

Bacopa Monnieri: The Most Impressive Natural Nootropic

Bacopa monnieri, commonly referred to as Bacopa, it’s a plant that has been used for thousands of years in Ayurvedic medicine. In India, it is also referred to as Brahmi. In the last two decades, many Ayurvedic plants, like Ashwagandha, Brahmi, and Gotu Kola, have been shown to be effective not only in Ayurveda classic books but also in scientific studies; the extract, in particular, has been shown to be as effective as some prescription medications.

Background and Benefits

Perhaps more than other top nootropics, Bacopa highlights the importance of the individual and the makeup of his biology on any given day. Although it reliably promotes enhanced memory and vivid dreaming, other effects are less consistent, often due to the large variety in potency between the different products on the market. Luckily, in the last few years, a standardized and pharmaceutical grade extract has been developed, named Bacognize®.

Bacopa Ayurvedic Medicine BenefitsIt is known to produce clarity or a slight fog, making you relaxed or slightly moody, with the potentiality of leading to mild physical symptoms (like muscle aches and intestinal bloating). In spite of all this critical talk, Bacopa is one of the most underestimated supplements, and this article will paint it as one with profound healing and nootropic abilities. Confused? Don’t worry; we got you covered!

Some of the benefits of Bacopa (according to both scientific research and anecdotal experiences) are:

  • It is neuroprotective[1] and significantly improves acquisition and retention of memories.[2]
  • It also increases acetylcholine synthesis and promotes neurogenesis by enhancing the activity of BDNF and NGF[3]
  • It has anxiolytic[4], antidepressant[5] and anti-stress effects.[6]
  • It is an antioxidant and increases lifespan in animal studies.[7]
  • It is anti-inflammatory[8] and cardioprotective.[9]
  • Bacopa may also help people with epilepsy[10], as well as children with ADHD.[11]

The sedative effect of Bacopa is almost always in the foreground, though anecdotal reports show that this effect happens most strongly at the beginning and tends to disappear after a month (or two) of consistent use. In fact, studies have shown that Bacopa’s peak nootropic effect is seen after two months[12], and keeps on getting stronger as time passes, while the anxiolytic effects are usually felt right from the first dose.

Anecdotal Reports

Before we get into the specifics of Bacopa, let’s have a look at some of the anecdotal experiences in the nootropics community to get a better understanding of how it works in healthy individuals outside the lab.

From Reddit user Nedzilla55

[…] My first nootropic experience, and it was a good one. I noticed acute effects of lowered anxiety, and over the course of a few months noticed increased memory. This amazing herb is subtle enough that I feel normal, but noticeable enough that I felt less stress and anxiety. I didn’t even realize how great it was until I got off of it, and started experiencing my usual increased anxiety. It wasn’t like an acute “Wow, I feel so calm” feeling, more like a background calm. Like turning down the volume of anxiety a couple of notches. Looking back at it, the 6-7 months I used it I was in a much better place mentally. […]

From Reddit user YoungRedPiller —

So I’ve been taking Bacopa Monnieri for about a month at this point. […] I’ll try to explain my experience with it so far.
I’ve heard that the memory effects take at least 8 weeks to show effect but I’ve been feeling some quite significant changes in my ability to recall events that have happened in the past month. It’s also improved the quality of these memories. This is a very nice effect that is very appreciated because I feel if i stick it out for another month my memory will improve noticeably.
One other effect that it’s had that I didn’t really expect it to have was that it made me completely apathetic. To everything. Studying, reading, music, doing anything at all. I’m completely careless to everything and my motivation to do things is very little. But when I start doing things, I don’t want to stop. It’s had a profound effect on my attention. I don’t know if the attention is because of the apathy or something but attention is another aspect that I like about Bacopa. Also due to the apathy, my anxiety is also very minimal in any situation. I completely have a fuck it attitude. Very appreciated as I used to be quite hyperactive.
It’s made me very calm, serene and genuinely carefree. […]

From Reddit user Tester12311

The first month: Contrary to anecdotal reports, I could definitely feel the bacopa kicking in. It acted almost as a mild downer and a definite anxiolytic. I felt calm, chilled out, and careless. […] Many initial reports include drowsiness and upset stomach. Though Bacopa did make me drowsy at first, I can only think of very specific instances with stomach upset which could easily have been as a result of what I ate that day. Besides these mild effects, there was not much else for Bacopa within the first month.
The second month and now: Throughout this entire period of taking Bacopa, I would constantly test my memory to see if it was improving. […] To be completely honest, it is very difficult to measure how much I can and cannot remember. But I can say that when people ask me if I remember something they said the week previous, I am more likely to respond positively. I am also more lucid with conversation topics as I can tie together the flow of a conversation from one topic to another. One can assume that my immediate working memory has greatly improved. […] Bacopa’s anxiolytics effects have also had a nice influence on my life. I am less nervous about social interactions especially with women or job interviews. It has gotten to the point where I really just do not care what people I don’t know think of me. […]
One of the most gratifying and prominent effects that I feel from Bacopa is the attention boost. I have a have a very strong grip on whatever I am doing. It has made reading and studying easier. I can sit and become enamored by a book. I hated reading before Bacopa. I love it now. […]

Learning and Memory

Bacopa Extract PowderBacopa is perhaps most notable for its ability to enhance memory and cognitive performance in mice.[13] In humans, this translates most clearly to improved consolidation of memories into long-term memory.[14] In these respects, bacopa has received a comparable amount of attention (in academic journals) as more mainstream and publicized herbal cognitive enhancers, such as ginkgo.

Later sections will expound on neurotransmitters, serotonin and acetylcholine in particular, which have, respectively anti-stress and pro-cognitive effects. Like other herbal nootropics, its mechanism also relies on adaptogenic properties or lowering stress (this is touched on below, from the perspective of “cytokines,” the body’s natural inflammatory agents).

While not as pronounced as the effect on long-term memory, Bacopa may also be useful for short-term memory, concentration, focus, motivation, and the likes. Clinical studies have found it effective against ADHD[15]. Another study has drawn the same conclusions[16]. This is especially encouraging for those who want to stay away from Adderall, Ritalin, and other pharmaceutical choices, and into other choices which may be more sustainable and less taxing on the psyche.


Inflammation, like oxidation, is too often presented in the press, and almost never in a light which sheds true insight on its value; gradually the public loses interest in the hype and falls into more conservative waters. Despite any skepticism, bacopa has real and impressive anti-inflammatory properties[17]. These anti-inflammatory properties are closely related to its anti-dementia effects, which are as potent as curcumin, and like curcumin may open the avenues in Alzheimer’s research for more potent semi-synthetic derivatives.

Cytokines are compounds which the body releases in response to stress or infection, and although they help to control certain illness, they can quickly lead to runaway inflammation. Many herbal nootropics work in part by regulating this runaway, negative feedback “loop.” Although it is perhaps not as strong as curcumin, there are a few studies and books summarizing bacopa’s effects on inflammation.


It has been shown in multiple studies to be as effective as common antiepileptic meds. This is likely related to its effect as a modulator of GABA[18], although a direct modulation of glutamate cannot be ruled out as a contributing factor.[19]

Oxidative Stress

The anti-stress effect may be directly related to the antioxidant capacity, as suggested by evidence[20]. Although antioxidants are beaten to death in the media, it is important in the absence of rigorous ORAC testing (free radical savaging capacity) to recognize when a particular food or supplement shows promising activity[21]. Ginkgo, bacopa, turmeric and ginger all show potential here. You can look up the antioxidant and anti-inflammatory ratings for turmeric and ginger to get a rough idea of their potency.

Serotonin and BDNF

Besides its broad antioxidant properties, perhaps the most studied mechanisms of Bacopa have been centered on serotonin[22][23]. It has been shown to upregulate the serotonin transporter (SERT) and to increase brain-derived neurotrophic factor (BDNF) in an animal model of depression[24]. The magnitude of the BDNF effect is supported by studies investigating bacopa’s ability to substantially improve the growth and survival of dendrites and axons: the fragile, spindly structures allowing for communication between neurons.

Dopamine and glutamate

Although bacopa is known to restore dopamine function[25], and as mentioned above, glutamate function as well, it is still not clear the extent to which these factors play into its nootropic qualities. The acetylcholine, serotonin, antioxidant and (as we will touch on later) the cardiovascular properties all likely outshine dopamine and glutamate in this respect.

Physical Health

Bacopa Monnieri has been implicated in increasing specifically cerebral blood flow independent of overall blood pressure[26] it can also decrease blood pressure (both systolic and diastolic) independent of heart rate[27] by releasing nitric oxide — a molecule that helps cells communicate with each other — from the endothelium.

Bacopa is also cardioprotective, and in research has been showed to protect from several cardiotoxic substances, such as isoprotenerol.[28] and may likely have a protective effect for everyday cardiotoxic activities like smoking. drinking, and taking stimulants.

Although it has primarily been studied on opiate (morphine) related kidney damage (where it was found to be effective[29]), it may serve in the otherwise healthy as a general tonifying agent in the kidneys.


Due to its cholinergic activity, those with a known mood disorder should approach bacopa extremely cautiously. High acetylcholine levels have even been used in lab mice to simulate bipolar and borderline features[30].

Bacopa has a potent stimulatory effect on the thyroids. Persons with known thyroid conditions are accordingly advised to consult a healthcare professional before considering bacopa.
As said before, it is known to accumulate heavy metals. Nowadays, most nootropic suppliers have certificates of analysis, and this is not raised as a concern.

Closing Remarks

Buy Bacognize capsulesAlthough bacopa’s initial sedative effect may be partially balanced out by natural energizers, such as ginseng, cocoa or royal jelly, we are recommending you consult a healthcare professional before beginning such an aggressive regimen. It is instead more strongly recommended to simply lower the dose, particularly when using the 50% extract which some people may find too intense.

By the way, you can buy Bacognize capsules and powder at Nootropics Depot. Or, if you’re on a tight budget, check out Powder City’s bulk 50% extract and 20% extract capsules. I personally recommend the capsules as the powder has an unpleasant taste. The dosage depends on the type of extract you have, typically a 50% extract like Bacognize is taken 300 mg once or twice a daily, while a 20% extract is taken at 500-650 mg two to three times a day. It is typically taken with food.

The good news is that much of bacopa’s nootropic effect is cumulative. Although it does take up to four to six months to see full effects, modest effects can still be observed from switching to the lower dose after a mere two months. This is especially true when it is paired off in the long-term with other highly effective and synergistic supplements. You could even take it just one summer, completely remove it from your stack after that point, and still theoretically retain some of its nootropic qualities.

Bacopa Monnieri
Reviewer 8

References   [ + ]

1. Neuroprotective role of Bacopa monniera extract against aluminium-induced oxidative stress in the hippocampus of rat brain (2006)
2, 14. Chronic Effects of Brahmi (Bacopa monnieri) on Human Memory (2002)
3. Bacopa monnieri and L-deprenyl differentially enhance the activities of antioxidant enzymes and the expression of tyrosine hydroxylase and nerve growth factor via ERK 1/2 and NF-κB pathways in the spleen of female wistar rats. (2013)
4. Anxiolytic activity of a standardized extract of Bacopa monniera: An experimental study. (1998)
5. Antidepressant-like effects of methanolic extract of Bacopa monniera in mice (2015)
6. Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain. (2002)
7. Bacopa monnieri promotes longevity in Caenorhabditis elegans under stress conditions (2015)
8. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. (2016)
9, 28. Cardioprotective Effect of Bacopa monneira Against Isoproterenol-Induced Myocardial Necrosis in Rats (1997)
10, 19. Decreased glutamate receptor binding and NMDA R1 gene expression in hippocampus of pilocarpine-induced epileptic rats: neuroprotective role of Bacopa monnieri extract. (2008)
11, 15. An open-label study to elucidate the effects of standardized Bacopa monnieri extract in the management of symptoms of attention-deficit hyperactivity disorder in children. (2014)
12. Effects of a Standardized Bacopa monnieri Extract on Cognitive Performance, Anxiety, and Depression in the Elderly: A Randomized, Double-Blind, Placebo-Controlled Trial (2008)
13. Effect of bacosides, alcoholic extract of Bacopa monniera Linn. (brahmi), on experimental amnesia in mice (2004)
16. A Randomized Controlled Trial Investigating the Effects of a Special Extract of Bacopa monnieri (CDRI 08) on Hyperactivity and Inattention in Male Children and Adolescents: BACHI Study Protocol. (2015)
17. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. (2016)
18. Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A. (2012)
20. Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain. (2002)
21. Bacopa monnieri as an Antioxidant Therapy to Reduce Oxidative Stress in the Aging Brain. (2015)
22, 23. Bacopa monniera leaf extract up-regulates tryptophan hydroxylase (TPH2) and serotonin transporter (SERT) expression: implications in memory formation. (2011)
24. Chronic Administration of Bacopa Monniera Increases BDNF Protein and mRNA Expressions: A Study in Chronic Unpredictable Stress Induced Animal Model of Depression (2014)
25. Neuroprotective potential of Bacopa monnieri and Bacoside A against dopamine receptor dysfunction in the cerebral cortex of neonatal hypoglycaemic rats. (2013)
26. Bacopa monnieri increases cerebral blood flow in rat independent of blood pressure. (2013)
27. Bacopa monnieri and its constituents is hypotensive in anaesthetized rats and vasodilator in various artery types. (2011)
29. Beneficial effects of Bacopa monnieri extract on opioid induced toxicity (2016)
30. Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features. (2015)

The Neurological Benefits of Sarcosine and D-Serine

Sarcosine and D-Serine are two endogenous substances that are currently being researched for a number of conditions. Although these substances have many interesting properties and may be effective add-on treatments to disorders such as depression and schizophrenia, they are too nonspecific to work effectively as a standalone, and should never be used in place of a doctor’s recommendation. That being said, there is some promising evidence for a nootropic, antidepressant and antipsychotic effect.

D-serine vs L-serine

This article includes references from studies using both enantiomers of serine. The two may have somewhat similar effects since L-serine is converted to D-serine by serine racemase, an enzyme that requires vitamin B6 to function. It is thus important to supplement vitamin B6 when supplementing L-serine.

Studies involving both forms of serine clearly demonstrate its interesting scope of effect. That being said, L-serine may be less effective since it requires an extra step before it can be used by the body.

L- and D-Serine

Mood and Depression

D-serine produces both acute[1] and chronic[2] antidepressant effects in animal models. Chronic use was also reported to lower markers of anxiety. Studies have also shown that it may prevent cognitive impairment in subjects exposed to stressful situations[3] (like a job interview) but not in normal day-to-day situations. D-serine, therefore, does not strictly meet the definition of a nootropic. It is, however, ubiquitous in the body, and with many interesting effects in promoting cerebral health, certainly a worthy supplement.

Sarcosine was the star of a landmark 2013 study, which underpinned a role of the Glycine transporter 1 (GlyT1) in depression[4]. The antidepressant effect of sarcosine and other GlyT1 inhibitors may be related to the increased levels of glycine, an inhibitory neurotransmitter that seems to have an anti-stress effect. The study found sarcosine monotherapy to be superior to the SSRI citalopram (Celexa) in remitting depression, with rapid onset of action and few side-effects.[5] The role of glycine in mental disorder may be much larger than originally thought.

As expected, users have reported varying levels of effectiveness from sarcosine as an antidepressant, with some drawing a comparison between ketamine or citalopram, while others have not noticed a significant effect. The research has suggested a strong general effect, which may still nevertheless depend on the individual.

Schizophrenia and Psychosis

The glutamate system is the largest excitatory system in the brain and it commands functions across every region, so one would expect sarcosine to be useful in depression, memory loss, or interestingly, psychotic disorders. The glycine transporter’s influence over NMDA receptors (which are essential for memory and learning) may also explain why sarcosine makes a useful adjunctive therapy to antipsychotics. It’s all to do with the involvement of NMDA and glutamate in schizophrenia:

… the hypofunction hypothesis of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of schizophrenia suggests that increasing NMDA receptor function via pharmacological manipulation could provide a new therapeutic strategy for schizophrenia. The glycine modulatory site on NMDA receptor complex is the one of the most attractive therapeutic targets for schizophrenia. […] Some clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methylglycine) shows antipsychotic activity in patients with schizophrenia. Currently, a number of pharmaceutical companies have been developing novel and selective GlyT-1 inhibitors for the treatment of schizophrenia..

Because of the diverse actions of the glycine transporter and its involvement in other neurotransmitter systems, sarcosine has also been found to modulate striatal dopamine release. This may help further explain its antipsychotic properties.

SchizophreniaWhile it may not be terribly effective on its own, used in conjunction with pharmaceuticals, sarcosine can deliver a real knockout blow[6], conveniently complimenting pharmaceuticals in treating both negative and positive symptoms. This is particularly remarkable because most pharmaceuticals were developed to address only positive symptoms; there has been a race to find more effective treatments for the negative symptoms, which have often come in the form of over-the-counter supplements, exercise programs, and specific diets.

Sarcosine and N-acetylcysteine were both found to restore glutamate activity in mGluR5 knockout mice[7] Low activity of this receptor may be related to schizophrenia. Interestingly, positive allosteric modulators of mGluR5 may have nootropic properties. [8]

Sarcosine is known to have potential in Parkinson’s[9] and other dopamine dysfunction disorders, such as ADHD.[10] Sarcosine and its metabolite glycine modulate dopamine in the striatum[11], which includes the hippocampus.

Another study[12] has confirmed as helpful the addition of sarcosine to antipsychotic therapy, concluding it increases survival of neurons and glial cells in the dorsolateral prefrontal cortex (a key structure damaged by aging and drug abuse, it is involved in executive functions, such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning). Sarcosine may soon become a popular supplement in the psychiatric industry.


Even though they are far from being popular nootropic supplements, D-Serine and Sarcosine are two fascinating compounds.

If you are being medicated for schizophrenia or depression, you should definitely consider supplementing one of these two compounds to augment your psychiatric medication. Sarcosine, in particular, is very inexpensive and has a lot of evidence backing up its use. [13] [14]

Nootropic users who have tried Sarcosine report improvements in focus, motivation[15] and visual acuity[16], and there is some evidence that it may help those living with ADHD.[17]

References   [ + ]

1. Acute D-serine treatment produces antidepressant-like effects in rodents. (2012)
2. Effects of Chronic D-Serine Elevation on Animal Models of Depression and Anxiety-Related Behavior. (2013)
3. D-serine prevents cognitive deficits induced by acute stress. (2014)
4. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. (2013)
5. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. (2013)
6. Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex. (2015)
7. The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice. (2010)
8. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning (2009)
9. Activation of N-methyl-D-aspartate receptor glycine site temporally ameliorates neuropsychiatric symptoms of Parkinson’s disease with dementia. (2014)
10, 17. Sarcosine treatment for oppositional defiant disorder symptoms of attention deficit hyperactivity disorder children. (2016)
11. Modulation of striatal dopamine release by glycine transport inhibitors. (2005)
12. Glycine transporter inhibitor sarcosine changes neuronal and glial parameters in the left dorsolateral prefrontal cortex and glutamatergic parameters in the left hippocampus in stable schizophrenia (2016)
13. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. (2005)
14. A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. (2010)
15. Sarcosine – The Model NMDA-Receptor Co-Agonist – Brain Health – LONGECITY
16. Sarcosine – The Model NMDA-Receptor Co-Agonist – Brain Health – LONGECITY