Acetylcholine supplements are the foundation of many nootropic stacks.
Why should you care about acetylcholine?
It plays a super important role in memory. Actually, it also regulates everything from salvation to mood, cognition, and digestion.
Acetylcholine acts in both the brain and the peripheral nervous system. It opposes the sympathetic fight-or-flight response, and tonically tends to decrease heart rate and promote rest and digestion.
Boosting acetylcholine with the very potent herbal supplement Huperzine A has been noted to improve cognition in healthy volunteers.
But too much acetylcholine can be depressogenic, i.e., predispose you to depression. There’s actually a cholinergic theory of depression.
Drugs That Affect Acetylcholine
The role of acetylcholine in cognitive function is well-documented. Many drugs used to treat Alzheimer’s disease increase acetylcholine levels at the synapse.
This class of Alzheimer’s drugs are commonly described as *acetylcholinesterase inhibitors* because they inhibit the degradation of acetylcholine which globally increases acetylcholine in the brain. One example of an acetylcholinesterase inhibitor used for the treatment of Alzheimer’s disease is Donepzil.
Which are the best dietary supplements to reliably boost acetylcholine? That depends on your goals and risk tolerance. I personally prefer CDP-choline, since it seems to have the most peer-reviewed evidence supporting its use.
In addition to CDP-choline, I will review:
- choline bitartrate
Huperzine-A and nicotine are heavy-hitters. They have robust effects and behave more like drugs than supplements, but come with some safety concerns.
In general, people tend to underestimate the risks and side effects of huperzine A, and overestimate the risks of nicotine.
Nicotine is viewed unfavorably due to its association with tobacco. Nicotine is probably less harmful than previously thought (See Gwern's article).
Huperzine A works by irreversibly inhibiting acetylcholinesterases, preventing the removal of acetylcholine. Huperzine-A can be problematic because it’s extremely potent. As little as 1/20 of a milligram elicits effects in sensitive individuals. Huperzine-A overdose resembles organophosphate pesticide poisoning, because organophosphates are also acetylcholinesterase inhibitors. Organophosphates were neurotoxins used in Vietnam.
If you're risk averse, you're better off sticking with acetylcholine supplements like choline bitartrate, cdp-choline and alpha-gpc. A different strategy all-together is to simply avoid acetylcholine supplements and eat lots of foods enriched with choline, like eggs. Eggs are brain food that can contain over 500mg of choline!
1. Choline Bitartrate
Choline Bitartrate is the most basic, ubiquitous, and cheapest form of choline. It is sold as a dietary supplement at stores like GNC or online at Amazon.
Supplementation with choline bitartrate was reported to increase steady-state plasma choline from about 7 micrmolar to ~11.5 micromolar in healthy women. Choline is converted into acetylcholine once in the body by the enzyme choline acetyltransferase (ChAT).
CDP-Choline (also known as citicoline or cytidine diphosphate-choline) is a nootropic compound and nutritional supplement.
It's the bread-and-butter of many popular stacks. CDP-Choline is a potent, blood brain barrier-permeable prodrug for uridine and choline. Choline is the substrate used to synthesize acetylcholine.
Studies in humans suggest that:
- CDP-choline moderately improves attention
- promotes memory consolidation
- may aid in the prevention of cognitive decline.
CDP-Choline is a relatively old compound originally developed and produced in Japan. CDP-Choline in converted to uridine and choline (which is acetylated to acetylcholine) in vivo.
CDP-Choline may also enhance the re-myelination of axons.
The myelin sheath surrounds and insulates projections called axons; the net effect is an increased speed of signals in the brain.
CDP-Choline was first used in the treatment of acute cerebrovascular disorders in Japan. After being introduced in Europe, CDP-Choline was used as an adjunct to levodopa in the treatment of Parkinson’s disease. Some studies have also evaluated the use of CDP-Choline in the treatment of neurodegenerative disease and mild cognitive impairment.
Alpha-GPC is a choline containing compound that appears to be pharmacologically active at higher doses. It is naturally present in small amounts in choline-containing foods.
Alpha-GPC attenuates the rate of cognitive decline in the elderly and may be the most efficient prodrug of choline. (A prodrug is just a precursor that is converted to the active agent in the body).
Alpha-GPC is of interest to athletes due to its propensity to increase human growth hormone.
Alpha-GPC is useful for nootropics purposes, although the majority of evidence supporting its use comes from studies in rodents. However, evidence from human studies does suggest that Alpha-GPC may be modestly effective for mild-to-moderate Alzheimer’s disease.
4. Huperzine A
Huperzine-A is derived from the plant families of Huperziaceae. Within 15 minutes of ingestion, Huperzine A appears in the cerebrospinal fluid and is easily able to penetrate the blood brain barrier.
Huperzine-A is most know for its inhibition of acetylcholinesterases, which increases acetylcholine at the synapse. It is a high-affinity inhibitor, with a slow dissociation constant. Huperzine A is also an NMDA-type glutamate receptor blocker (antagonist), like Magnesium and the Alzheimer’s drug Memantine.
Huperzine-A promotes neurogenesis (the creation of new neurons) in adult mice, though it remains unknown whether this effect translates to humans.
Huperzine-A is extremely potent; the typical recommended dose is 50-200 mcg daily. The LD50 (lethal dose required to kill 50% of a population) for Huperzine-A was reported to be 2-4mg/kg. The LD50 for humans is likely lower due to the difference in surface area between rodents and humans.
Nicotine is an parasympathomimetic alkaloid naturally abundant in tobacco.
Nicotine may improve working memory by activating nicotinic acetylcholine receptors in the brain[^1][^2][^3]. Nicotine is not a supplement in the traditional sense. But it is available over-the-counter (OTC), e.g., as nicotine gum.
Nicotine is an agonist at nicotinic acetylcholine receptors. One researcher claimed that nicotine is the only substance that reliably enhances memory in healthy humans[^7]:
“To my knowledge, nicotine is the most reliable cognitive enhancer that we currently have, bizarrely,” said Jennifer Rusted, professor of experimental psychology at Sussex University in Britain when we spoke. “The cognitive-enhancing effects of nicotine in a normal population are more robust than you get with any other agent. With Provigil, for instance, the evidence for cognitive benefits is nowhere near as strong as it is for nicotine.”
Whether there are any serious health consequences to using nicotine products like the patch or gum remains controversial.
Further reading: A Powerful Nootropic - But At What Cost?
Other Supplements That Boost Acetylcholine
[^1]: Kleykamp BA, Jennings JM, Blank MD, Eissenberg T. The effects of nicotine on attention and working memory in never-smokers. Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors. 2005; 19(4): 433-8.
[^2]: Rezvani AH, Levin ED. Cognitive effects of nicotine. Biological psychiatry. 2001; 49(3): 258-67.
[^3]: Sweet LH, Mulligan RC, Finnerty CE, et al. Effects of nicotine withdrawal on verbal working memory and associated brain response. Psychiatry research. 2010; 183(1): 69-74.
[^4]: Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. The Cochrane database of systematic reviews. 2005; (2): CD000269.
[^5]: Knott V, de la Salle S, Choueiry J, et al. Neurocognitive effects of acute choline supplementation in low, medium and high performer healthy volunteers. Pharmacology, biochemistry, and behavior. 2015; 131(): 119-29.
[^6]: Tomura S, Chida Y, Ida T, Tanoue K, Motomiya T, Yamazaki H. Platelet adenine nucleotides in patients with primary glomerular disease. The Tohoku journal of experimental medicine. 1988; 156(3): 221-7.