Acetylcholine supplements are the foundation of many nootropic stacks. Acetylcholine is a neurotransmitter that regulates everything from salivation to mood, memory, and cognition. Acetylcholine acts in both the brain and the peripheral nervous system. Specifically, acetylcholine opposes the sympathetic fight-or-flight response, and tonically tends to decrease heart rate and promote rest and digestion.
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. (Synpases are gaps between dendrites and neurons that neurotransmitters must diffuse across to transmit a signal). 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 Donepezil.
Which are the best dietary supplements to reliably boost acetylcholine? That depends on what you’re going for. I personally recommend CDP-choline, since it seems to have the most peer-reviewed evidence supporting its use.
In addition, to CDP-choline, I review choline bitartrate, alpha-gpc, Huperzine-A, and nicotine. Huperzine-A and nicotine are heavy-hitters. They have the most robust effects and are more like drugs than supplements, but come with serious safety concerns. In general, people tend to underestimate the risks and side effects of Huperzine A, and overestimate the risks of nicotine.
The health effects of nicotine should not be conflated with tobacco. However, nicotine can stress the cardiovascular system by raising blood pressure and temporarily narrowing blood vessels (though it remains controversial whether this effect is really harmful for healthy individuals). Huperzine-A, on the other hand, can be problematic because it’s extremely potent- as little as 1/20 of a milligram may elicit effects in sensitive individuals. Huperzine-A overdose resembles organophosphate pesticide poisoning.
If you’re risk averse, you’re better off sticking with acetylcholine supplements like choline bitartrate, cdp-choline and alpha-gpc. Another strategy all-together is to simply avoid acetylcholine supplements and eat lots of foods enriched with choline, like eggs. Eggs can contain over 500mg of choline!
1. Choline Bitartrate
Choline Bitartrate is the most basic 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 choline acetyltransferase (ChAT)
CDP-Choline (also known as citicoline or cytidine diphosphate-choline) is a nootropic compound and nutritional supplement that is the bread-and-butter of many popular stacks. CDP-Choline is a potent, blood brain barrier-permeable prodrug for uridine and choline, the latter of which is the substrate used to synthesize acetylcholine.
Studies in humans suggest that CDP-choline moderately improves attention, promotes memory consolidation and 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. Alpha-GPC attenuates the rate of cognitive decline in the elderly and may be the most efficient prodrug of choline.
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. Evidence suggests that nicotine may improve working memory by activating nicotinic acetylcholine receptors in the brain. Nicotine is not a supplement in the traditional sense, but it is available over-the-counter (OTC).
Nicotine is an agonist at nicotinic acetylcholine receptors. One researcher claimed that nicotine is the only substance that reliably enhances memory in healthy humans. Whether there are any serious health consequences to using nicotine products like the patch or gum remains controversial.