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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.

Acetylcholine

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

Benefits

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

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.

DMAE

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.

Centrophenoxine

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.

ALCAR

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.

Phosphatidylserine

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)
Categories
Reviews Stacks

Axon Labs’ NEXUS Nootropic Stack, My Experience (Review)

Formulating nootropic stacks can sometimes be a difficult or time-consuming process. While the research that goes into drug combinations and synergy can be rewarding and even enjoyable, sometimes it’s difficult to find the right information on specific nootropics. Even when the right ratios are figured out, making multiple capsules of a certain stack can be even more time-consuming than the research.

Although pre-made nootropic stacks can be more expensive than buying bulk powder, they are sometimes well worth the price. Nootropic blends can be specially formulated by individuals with a deep understanding of neuroscience, giving the best cognitive benefits possible. Axon Labs’ NEXUS Nootropic Stack is an encapsulated blend of aniracetam, CDP-choline, phosphatidylserine, and Pycnogenol. The serving size is two capsules, and each serving contains 1.250 mg of this nootropic blend. Although the amounts of each component are not specifically listed, we can make a plausible assumption based on standard dosages for these compounds.

nexus-facts_large.jpg

The key component to this blend is aniracetam, a well-respected nootropic that is gaining popularity for its unique ability to improve cognition and reduce anxiety at the same time. A more detailed look at aniracetam’s mechanism can be found here on our site. Essentially, aniracetam modulates the action of glutamate (an excitatory neurotransmitter) by reducing glutamate receptor desensitization. [1] This, in theory, would improve memory and strengthen the connections between neurons. Aniracetam is also unique among racetams in the fact that it has the ability to reduce feelings of anxiety and depression. It most likely accomplishes this by means of serotonergic, dopaminergic, and cholinergic mediation. [2]

CDP-choline (also known as citicoline) is a source of choline that also serves as a prodrug to uridine, another nootropic supplement. Choline is essential for the production of the neurotransmitter acetylcholine in the body, which is the neurotransmitter thought to be closely involved with the regulation of cognitive processes. Aniracetam is partially cholinergic in its mechanism of action, as it potentiates the action of nicotinic acetylcholine receptors.[3] When aniracetam is paired with a choline source, the increase in acetylcholine will theoretically potentiate the cholinergic effects of aniracetam.

Phosphatidylserine is a naturally-occurring fatty acid derivative that helps comprise cell membranes. In 2003, the Food and Drug Administration (FDA) authorized sellers of phosphatidylserine to label their products with the claim that “consumption of phosphatidylserine may reduce the risk of dementia and cognitive dysfunction in the elderly.” [4] Various studies have indeed confirmed that supplementation of phosphatidylserine can improve cognition[5], memory[6], and processing speed[7], among other factors. Phosphatidylserine also has the potential to increase levels of acetylcholine in the brain, an effect that would work synergistically with aniracetam’s cholinergic mechanisms. [8]

Pycnogenol is a patented extract of pine bark, containing a number of antioxidant flavonoids known as procyanidins. Pycnogenol’s most notable effects include its ability to increase blood flow[9], while also improving attention and cognition.[10] Pycnogenol’s main mechanism seems to be its ability to increase concentrations of nitric oxide (NO). It does this by preventing NO from oxidizing while also inducing the Nitric Oxide Synthase (NOS) enzyme, which catalyzes the production of NO.[11]

My Experience

Note: When dealing with anecdotal experiences, it is difficult to completely rule out the placebo effect as the cause of certain perceived changes in cognition and mood. This is simply my own experience, and it is likely that every individual’s experience with these nootropics will vary. These are simply the effects I perceived.
Previous to this experience, I had taken aniracetam on a few occasions with modest success, taking it with a choline source.

My dosing regimen of Nexus consisted of taking 2 capsules in the morning after I woke up. I took another dose in the afternoon or evening if I was working on tasks that benefit from boosts in cognition (i.e. writing, analysis). During this time period, I was also taking fish oil, bacopa monnieri, and centrophenoxine, which I have been taking regularly for at least a month. I was thus familiar with their effects and would be able to perceive any changes brought on by adding this stack. I took Nexus regularly for about one month.
One of the most marked improvements I noticed was a modest reduction in anxiety that set in about an hour after taking Nexus. I am typically a fairly anxious person, both in general and in social situations. I felt more able to focus on important tasks, rather than focusing on anxious thoughts I was having. I also felt a noticeable clear-headedness and ability to think straight.

There was also a subtle improvement in being able to pick up on new concepts more easily. During college courses, I felt very engaged in the materials being presented, even in the classes, I do not normally find very interesting. I also found it easier to contribute to the discussion.
Taking another dose before working on writing essays and papers seemed to help a great deal with my cognition. Aniracetam has anecdotally been touted to improve holistic and collective thinking, and that seemed to be the case in my experience. It was much easier to weave different concepts and themes together in a way that presented a coherent bigger picture.

Again, when it comes to nootropics, it can be difficult to differentiate legitimate effects from placebo. However, many of the effects I experienced were extreme enough that I am fairly convinced that they were effects of this stack.

Conclusion

Everyone is likely to react differently to a nootropic like aniracetam. There are some people I know who experience little to no effect from taking it. For others, the effects seem to be almost life-changing. However, I do feel like the additional ingredients in Nexus’s blend contribute a good deal to its effects. It seemed to have greater effects than just aniracetam alone.

This being said I can definitely recommend trying Nexus out. It is a good stack for those who are fairly new to nootropics and aren’t sure how to formulate their own stacks, but for the expert nootropic user, it is definitely overpriced. That said, I would definitely like to use it again in the future.

Axon Labs' NEXUS
7.5
Focus
7
Mood
6
Memory
6
Stimulation
7
Relaxation
9
Safety
Reviewer 7.1
Summary
I would recommend this stack to anyone who is into experimenting with nootropics. It gave me a clear cognitive boost while simultaneously reducing anxiety.

References   [ + ]