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All About Acetylcholine: Functions, Mechanisms, Potential Uses & More

Written by Puya Yazdi, MD | Last updated:
Jonathan Ritter
Matt Carland
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Matt Carland, PhD (Neuroscience) | Written by Puya Yazdi, MD | Last updated:

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Acetylcholine is a hot topic within the realm of memory enhancement. It is a neurotransmitter that is critical for the everyday functioning of the brain: particularly in the areas of movement, learning & memory, and sleep quality. Check out this post to learn how to promote balanced acetylcholine in your body and function at your very best!

What Is Acetylcholine?

Acetylcholine was first discovered in 1914, and was in fact the first of the brain’s major neurotransmitters to be identified [1, 2].

Acetylcholine was first studied for its role in regulating wakefulness and sleep. However, since its initial discovery it has been associated with a wide variety of different important functions and roles throughout the brain and the rest of the body [1, 2].

It is believed that choline — the chemical and metabolic precursor to acetylcholine — was originally used by single-celled organisms billions of years ago to create their protective outer cell layers (membranes). Since this earliest biological function, its role has since been expanded over the course of evolution to become involved in a wide range of important functions including muscular control, sleep regulation, and even higher cognitive functions, such as learning and memory [3, 4].

Acetylcholine is synthesized from acetyl-coenzyme A (which comes from glucose) and choline, with the help of an enzyme called choline acetyltransferase [5]. However, unlike many other neurotransmitters, acetylcholine is created (synthesized) within the connections between neurons (the neural synapses), rather than inside neurons themselves [3].

One of the central functions of acetylcholine is to trigger muscle movements, which it does by stimulating the synapses where the nervous system connects to the muscular system (neuromuscular junctions, or “NMJs”) [3].

However, this role is not just limited to controlling the muscles that move the body around: for example, acetylcholine and histamine interact together to contract muscles in the lungs, which enables breathing (respiration) [6, 7].

While it plays a large and complex variety of roles throughout the brain, acetylcholine is most commonly associated with certain cognitive functions, such as memory and attention. It is also believed to play a role in promoting the phase of sleep associated with dreaming (REM sleep) [8, 9, 10].

Roles and Effects of Acetylcholine

1) Learning and Memory

Several different lines of scientific evidence suggest that acetylcholine plays a crucial role in learning and memory.

For example, acetylcholine is believed to be critically involved in the development and progression of several common neurodegenerative diseases that involve memory impairments, such as dementia and Alzheimer’s disease. In fact, some of the memory-related symptoms of these disorders appear to correlate with reduced levels and activity of acetylcholine — especially in certain brain regions known to play a key role in memory, such as the hippocampus [8].

For this reason, drugs that increase acetylcholine are commonly used by medical practitioners to treat patients with Alzheimer’s [11, 12].

Scopolamine — a drug that is known to block acetylcholine activity — has been reported to impair the acquisition of new information and memories, according to several studies in both humans and animals [13, 14].

In monkeys, disruption of the brain’s supply of acetylcholine — especially in the cerebral cortex and hippocampus — has been reported to impair the acquisition of factual information (during a discrimination learning task), and also reportedly produces memory impairments comparable to human amnesia [15, 16].

Although the precise mechanisms involved in acetylcholine’s effects on memory are complex and not yet fully-understood, some researchers believe that it plays a central role in synaptic plasticity, the biological mechanism which allows neurons to store new information and memories by modifying the way they connect to each other [17].

Due to its potential role in stimulating learning and memory, some researchers have investigated whether using dietary supplements or other compounds to increase acetylcholine levels might influence cognitive functioning.

Although this research is in a relatively early stage, some studies have reported some interesting preliminary findings. For example, according to one observational study in almost 1,400 people, higher dietary intake of choline was associated with slightly better cognitive performance (especially verbal and visual memory) [18].

Relatedly, one small-scale trial in 24 healthy male volunteers reported that supplementation with 500-1,000mg of CDP-choline may have improved a variety of cognitive processes (including working memory and verbal memory). However, this effect was only observed in people whose normal (“baseline”) cognitive performance was already relatively below-average. By contrast, people with “average” levels of cognitive performance showed no effects from choline supplementation, while high-performing subjects actually got worse [19]!

Based on these initial findings, it is likely that acetylcholine has an important role to play in cognition, learning and memory — although the conflicting evidence suggests that its role is complex, and is not as simple as “more acetylcholine = better”!

2) Controlling the Sleep-Wake Cycle

When acetylcholine was first discovered, it was being studied primarily for its role in the regulation of the sleep-wake cycle [1, 2]. Today, acetylcholine is still one of the main neurotransmitters believed to be responsible for stimulating wakefulness (along with other important neurotransmitters and hormones, such as orexin, histamine, norepinephrine, and dopamine) [1, 10].

For example, some studies have reported that the activity of acetylcholine neurons is significantly increased during waking, whereas the activity of these same neurons is suppressed during certain stages of sleep (such as slow-wave sleep, or SWS) [10].

Some researchers have proposed that the wakefulness-promoting effects of acetylcholine may be involved in the “stimulating” effects of certain drugs that increase the activity this neurotransmitter, such as amphetamines and other stimulant drugs like modafinil and cocaine. Conversely, the effects of sleep-promoting (“sedative/hypnotic”) drugs, such as zolpidem (Ambien) and various antihistamines, may partially come from their ability to reduce acetylcholine activity [10].

Relatedly, animal studies in rats have reported that the sedative/hypnotic drugs zolpidem (Ambien), diazepam, and eszopiclone may induce their effects by stimulating GABA receptors that (in turn) suppress acetylcholine release by the brainstem [1].

Acetylcholine’s role in sleep- and wakefulness-related behaviors may also tie into its role in learning and memory. For example, while acetylcholine activity is generally suppressed during many stages of sleep, acetylcholine levels have been reported to increase during REM sleep — one of the most important stages of sleep for storing (“consolidating”) new memories [20, 21, 22, 23].

3) Attention and Alertness

Historically, acetylcholine has been thought to be mainly important in learning and short-term memory functions. However, more recent studies have provided support for acetylcholine’s role in attention and alertness [24].

For example, one animal study reported that acetylcholine levels in the brain increased significantly when rats were placed into an environment that required high degrees of sustained attention (high attentional effort). Furthermore, increasing the difficulty of the attention task (by adding distracting stimuli) further increased acetylcholine levels. Based on these findings, the authors of this study concluded that acetylcholine may play a direct role in stimulating attention and focus [9].

Relatedly, one study of 60 healthy adult women aged 40-60 reported improvements in attention after 28 days of supplementation with CDP-choline, a compound that is believed to increase acetylcholine levels throughout the brain [25].

While these early results are promising, much more research will be needed to confirm whether acetylcholine supplementation can consistently influence memory abilities in healthy human users.

4) Inflammation

Acetylcholine is also believed to be involved in inflammation. In fact, its influence on inflammation is so significant that it even has a biological pathway named after it, called the cholinergic anti-inflammatory pathway [26].

Pro-inflammatory cytokines are produced by cells of the immune system in response to injury or infection. These cytokines, in turn, initiate a chain of effects that recruit a variety of inflammatory cells to the site of infection in order to contain it.

The cholinergic anti-inflammatory pathway is currently believed to provide a sort of “braking” effect on this immune response. This may protect the body against the tissue damage that can occur if an acute inflammatory response spreads beyond the local tissues to affect the kidney, liver, lungs, or other major organs [27].

For example, according to one animal study, increased acetylcholine levels were associated with reduced inflammation in the intestinal gut mucosa — possibly due to the activation of alpha-7 nicotinic acetylcholine receptors (α7nAChRs), which inhibit the release of pro-inflammatory cytokines [26].

Relatedly, according to studies of inflammation-related health conditions (such as IBD), acetylcholine has also been reported to reduce the levels of other pro-inflammatory cytokines, such as IL-6, IL1B, and TNF-a [26].

Additionally, specific sub-types of acetylcholine receptors — such as alpha-7 nicotinic acetylcholine receptors, or “α7nAChRs” for short — have been reportedly found on a number of different immune system cell types, including macrophages, monocytes, and mast cells. Some researchers have proposed that acetylcholine may reduce inflammation by inhibiting these immune cells [26].

Other systems involved in anti-inflammatory mechanisms, such as vagus nerve stimulation, are also believed to be activated by acetylcholine [26]. Decreased vagus nerve activity has been reported in studies of inflammatory bowel disease (IBD), and may in part result from reduced anti-inflammatory stimulation from acetylcholine [26].

However, the precise role of acetylcholine in overall inflammation is not fully clear, and is probably more complex than some of the above findings may suggest. For example, some studies have reported that acetylcholine (again acting via nAChRs) also suppresses the production of antiinflammatory cytokines, such as IL-10. Therefore, more research will still be needed to understand exactly how acetylcholine either increases or decreases the inflammatory response in different contexts.

5) Protecting Against Infections

In addition to its role in inflammation, some preliminary evidence from animal research suggests that acetylcholine may have important interactions with the immune system, and may play a role in how it responds to infections.

For example, one animal study has reported that acetylcholine may inhibit the formation of “biofilms” during certain kinds of infections (such as fungal infections caused by Candida albicans) [28].

6) Helping Gut Movement

Another important function of acetylcholine is to facilitate the movement of food through the gastrointestinal tract (a process called peristalsis).

More specifically, this function is associated with acetylcholine activity within the “parasympathetic” nervous system — the part of the nervous system that is associated with the “rest-and-digest” functions (which are the counterpart to the “fight-or-flight” responses caused by the sympathetic nervous system) [29].

Specific types of acetylcholine receptor, called nicotinic acetylcholine receptors (nAChRs), are believed to be particularly involved in this process. These receptors get their name from the fact that they are stimulated by nicotine: and the involvement of nicotine in stimulating these receptors is believed to be why up to 1 in 6 people who quit smoking report (temporary) gastrointestinal symptoms, such as constipation. The idea behind this is that because a chronic smoker’s gastrointestinal acetylcholine system is “used” to getting more nicotine-based stimulation from tobacco, it may become less able to function properly once this extra source of stimulation is removed, thereby resulting in impaired digestive processes (such as constipation symptoms) [30].

Additionally, some antidepressant drugs (monoamine reuptake inhibitors) that are able to inhibit these nicotinic acetylcholine receptors have been commonly reported to cause constipation as a potential side-effect. Some such antidepressant medications include [31]:

  • Desipramine (Norpramin)
  • Fluoxetine (Prozac)
  • Citalopram (Celexa)
  • Sertraline (Zoloft)
  • Reboxetine (Edronax)
  • Venlafaxine (Effexor)
  • Paroxetine (Paxil)
  • Imipramine (Tofranil)
  • Clomipramine (Anafranil)
  • Amitriptyline

7) Reducing Pain

Some evidence also suggests that acetylcholine may also be involved in mediating the perception of pain, and that targeting this system may potentially help treat pain.

For example, some research has reported that the Alzheimer’s disease medication donepezil — which primarily acts by increasing acetylcholine levels — produces a dose-dependent pain-relieving effect in human patients, and may also have some efficacy as a preventative treatment for the symptoms of migraines [32].

Relatedly, a systematic review of multiple cell- and animal-based studies concluded that higher levels of acetylcholine in the spinal cord are generally associated with pain relief, whereas reducing acetylcholine activity (such as by blocking its receptors) often results in increased sensitivity to pain [33].

Although the exact mechanisms behind these potential effects are not fully understood yet, early evidence from various studies in both humans and animals suggests that nicotinic and muscarinic types of acetylcholine receptors are each likely involved in these potential pain-related effects [34, 33].

8) Improving Blood Flow

According to some early cell-based studies, acetylcholine may play a role in regulating blood circulation — specifically, by stimulating the production of nitric oxide, a compound that controls blood pressure by relaxing the blood vessels (vasodilation) throughout the cardiovascular system [35].

Some preliminary findings also suggest that muscarinic acetylcholine receptors, in particular, may be especially relevant to the potential cardiovascular functions of acetylcholine [35].

9) Hormone Balance

Finally, some research also suggests that acetylcholine activity has an influence on the production or secretion of various hormones throughout the body and brain.

For example, some studies have reported that acetylcholine levels are correlated with the secretion of hormones such as prolactin and growth hormone from the pituitary gland. Although the full mechanisms are not known yet, some researchers believe that a significant amount of acetylcholine’s effects on hormones may come from its ability to influence neural activity in the hypothalamus, a brain region that is widely believed to be heavily involved in hormone regulation [36, 37].

Acetylcholine-Related Health Conditions

Due to its wide range of roles throughout the body and brain, acetylcholine has been implicated in the development, progression, or symptoms of a variety of health conditions.

1) Depression

Although serotonin is the neurotransmitter most commonly associated with depression and other mood disorders, other major neurotransmitters — including acetylcholine — may also play important roles in these psychiatric conditions.

Although the exact role of acetylcholine in depression is not yet fully-understood, a handful of preliminary animal studies have reported that drugs which block nicotinic acetylcholine receptors (nAChRs) — such as mecamylamine — appear to have “antidepressant-like” effects in rodents [38, 39].

Building on this, according to two early phase-II clinical trials in humans with treatment-resistant depression (TRD), mecamylamine was reported to alleviate some depression symptoms when used in combination with more traditional antidepressants (such as selective serotonin reuptake inhibitors, or SSRIs) [40].

Nonetheless, while acetylcholine may play some role in depression, it is likely to be only one piece of a much larger and more complex puzzle. In the meantime, most scientific research on the development and treatment of depression will likely continue to focus primarily on the role of other neurotransmitters, such as serotonin, which have relatively much more research behind their role in depression and mood disorders.

Smoking And Depression

Interestingly, some of the preliminary findings described above may account for some of the widespread associations that many studies have reported between smoking and depression [41, 42, 43].

Specifically, some researchers have proposed that short-term (acute) nicotine exposure can result in a reduction (“down-regulation”) of acetylcholine receptors [44]. This may initially produce an “antidepressant” or “anti-anxiety” effect in relatively new smokers, which could in turn contribute to the development of an addiction to (or dependence on) nicotine.

However, chronic exposure to nicotine may eventually cause nicotinic acetylcholine receptors to actually increase in number, which would reverse these initial effects. Therefore, smoking may actually lead to increased negative moods and anxiety in the long term [45, 46].

These adverse long-term effects, then, could potentially explain why rates of depression and other mood disorders tend to be higher in people who smoke [41].

2) Alzheimer’s Disease

Acetylcholine has also been proposed to play a potentially-significant role in the development or symptoms of certain common neurodegenerative diseases, including Alzheimer’s disease and various other forms of dementia [11, 12].

In Alzheimer’s disease, the so-called “cholinergic” neurons — the brain cells that primarily use acetylcholine — gradually become damaged and destroyed. Additionally, important molecules called acetylcholine transporters may also become impaired as the disease progresses. These molecules are responsible for transporting acetylcholine into neurons: and impairing them can therefore make it more difficult for acetylcholine to fulfill its normal functions throughout the brain. Together, then, these two important acetylcholine-related mechanisms are likely to contribute significantly to some of the hallmark cognitive symptoms of these disorders [47, 48].

Many (though not all) drugs that are currently used to treat Alzheimer’s disease are acetylcholinesterase inhibitors. As their name suggests, these drugs inhibit the enzyme acetylcholinesterase, which is responsible for breaking down the neurotransmitter acetylcholine throughout the brain. Therefore, inhibiting these enzymes can result in an overall increase of acetylcholine levels and activity, which may potentially compensate for the loss of cholinergic neurons that typically occurs in Alzheimer’s disease [47, 48].

For example, two common Alzheimer’s medications, galantamine and donepezil, are each acetylcholinesterase inhibitors — and their therapeutic effects in relieving some of the cognitive symptoms of Alzheimer’s are believed to stem primarily from to their ability to stimulate acetylcholine activity throughout the brain [49, 50, 51, 52].

However, not all Alzheimer’s medications target acetylcholine. For example, the widely-used Alzheimer’s drug memantine targets other mechanisms entirely (specifically, NMDA receptors).

Therefore, acetylcholine is probably only one piece of a much more complex puzzle. Nonetheless, it does appear to play an important role in at least some of the main mechanisms and symptoms of Alzheimer’s disease — and more research will be needed to explore these mechanisms more fully, as well as to potentially develop future medical treatments for these neurodegenerative disorders.

Factors That May Influence Acetylcholine Levels

Many biological processes and pathways are involved in determining the total amount of acetylcholine in the body and brain, as well as its overall degree of activity.

This means that there are many different mechanisms and pathways that can influence acetylcholine, such as:

  • Increasing or decreasing the levels of its “ingredients” (metabolic precursors), such as choline
  • Activating or inhibiting the enzymes that produce (synthesize) active acetylcholine from its precursors, such as choline acetyltransferase or acetyl-coenzyme A
  • Stimulating or suppressing the release of acetylcholine by nervous system cells
  • Directly activating acetylcholine receptors, such as by “imitating” natural (“endogenous”) acetylcholine
  • Blocking acetylcholine receptors, thereby preventing them from being activated by natural acetylcholine
  • Increasing or decreasing the number of acetylcholine receptors

Why Target The Acetylcholine System?

Because acetylcholine is believed to be involved in the development of a variety of diseases and other health conditions, there are many potential uses that have been proposed for substances that can target the acetylcholine system.

Additionally, many people in the “nootropics” community believe that certain compounds and supplements that target this system may have certain “cognitive benefits.” While the evidence for these compounds having significant effects on cognition in healthy human users is currently relatively weak, this is another common reason that people are sometimes interested in finding out more about substances and compounds that can affect this important neurotransmitter system.

In any case, If you believe you have a health condition or other reason to try to influence your acetylcholine levels, it is extremely important to always talk to your doctor about any new supplements or dietary changes you make. This is because these approaches could have negative interactions with any other drugs you are taking, other pre-existing health conditions, and other health-related factors. None of the information in this post should ever be used to replace conventional medical treatment.

It is also important to keep in mind that many of the compounds and substances discussed below have only been tested in animal- or cell-based studies. This means that their effects and overall safety in healthy human users is not known.

Therefore, these compounds should be considered as currently having “insufficient evidence” for any specific use — and much more research will be needed to verify what effects they may have in humans, as well as how safe they may be.

Factors That May Increase Acetylcholine

A large number of different supplements, dietary compounds, and other factors have been proposed to play a role in increasing acetylcholine levels and activity throughout the brain. Once again, because the acetylcholine system is highly complex, there are several different mechanisms and pathways that can be targeted to achieve these effects.

For example, one relatively common approach to increasing acetylcholine levels is to supplement with choline, one of the most important “ingredients” that the nervous system requires in order to produce the active neurotransmitter acetylcholine [5].

Choline can be acquired naturally through the diet, and is found in a variety of common foods such as eggs and liver [53]. There are also several types of supplements that are based on choline, such as citicoline / CDP-choline and alpha-GPC [54, 55, 56, 57, 58].

Alternatively, another common way to increase acetylcholine levels is to inhibit acetylcholine esterase (AChE), the enzyme responsible for breaking this neurotransmitter down throughout the brain. Many herbs and other natural plant compounds fall into this category of mechanisms, such as rosemary, huperzine A, bacopa monnieri, and ginkgo biloba [59, 60, 61, 62, 63].

Other factors, such as hormone levels, may have a less direct — but still potentially significant — effect on acetylcholine activity. For example, some serotonin neurons are believed to be involved in stimulating the release of acetylcholine. According to one animal study, rats whose levels of estrogen were experimentally increased were reported to show a significantly greater release of acetylcholine in response to serotonin activity, suggesting that estrogen might be playing an indirect role in “setting” the sensitivity of the acetylcholine system to other forms of stimulation [64].

All in all, a large variety of dietary compounds and supplements have been reported to potentially increase the levels of and activity of acetylcholine throughout the brain, and each one may act through one or more of the above mechanisms and pathways. A more comprehensive list of such potential compounds includes:

Once again, it is important to keep in mind that many of the above compounds have only been tested in animal- or cell-based studies, and their effects and overall safety in healthy human users is not fully known. Therefore, we don’t recommend casually experimenting with any of these compounds — especially not without talking to your doctor first!

Factors That May Decrease Acetylcholine

There are also many compounds and drugs that may decrease acetylcholine levels, or reduce its activity.

In general, drugs or other compounds that reduce acetylcholine levels — or otherwise inhibit its activity — are commonly known as “anticholinergics.” (To learn more about these substances and how they work, we recommend checking out our detailed SelfDecode posts on anticholinergics, which you can find here and here.)

Once again, these drugs may exert this effect by targeting one or more of the multiple different potential mechanisms and pathways related to the creation or release of acetylcholine.

Some of the supplements, dietary compounds, and drugs that have been proposed to have some potential anticholinergic effects and mechanisms include:

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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