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“Acetylcholine Deficiency” & Factors that Increase Levels

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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Does "acetylcholine deficiency" exist and can it cause symptoms like forgetfulness?

The “vagus nerve” uses acetylcholine. Our “rest-and-digest” response requires it. Acetylcholine also plays an important role in learning, memory, and sleep quality. So what happens when acetylcholine runs low? In this post, we’ll explore the science to see if there such as thing as “acetylcholine deficiency” and whether certain lifestyle changes and nutrients can increase acetylcholine levels.

Does “Acetylcholine Deficiency” Exist?

Research Limitations

Due to its wide range of roles throughout the body and brain, low acetylcholine levels or activity in certain brain areas have been implicated in the development, progression, or symptoms of a variety of health conditions.

However, most of the studies dealt with associations only, which means that a cause-and-effect relationship hasn’t been established.

For example, just because dementia has been linked with low acetylcholine activity in certain brain areas doesn’t mean that cognitive dysfunction is always caused by “acetylcholine deficiency.” Data are lacking to make such claims. 

Also, even if a study did find that low acetylcholine contributes to cognitive dysfunction, acetylcholine levels are highly unlikely to be the only cause. Complex disorders like dementia always involve multiple possible factors – including brain chemistry, environment, health status, and genetics – that may vary from one person to another.

Acetylcholine is undoubtedly an important neurotransmitter, but whether low acetylcholine levels in specific brain areas can cause health problems is still uncertain.

Associated Conditions:

There are no symptoms associated with “acetylcholine deficiency” or low acetylcholine levels per se.  Instead, people may only show symptoms of mental health or neurocognitive disorders. Your doctor will discuss your symptoms with you and run tests to pinpoint the underlying cause.

Low or high acetylcholine levels don’t necessarily indicate a problem if there are no symptoms or if your doctor tells you not to worry about it.

1) Dementia

Some studies suggest that poor cholinergic activity and low acetylcholine in the brain may cause cognitive decline and poor memory in people with dementia. Drugs used to slow down dementia work precisely by increasing acetylcholine in the brain [1].

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 [2, 3].

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 [4, 5].

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 [4, 5].

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 [6, 7, 8, 9].

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.

Alzheimer’s disease is marked by a loss of neurons that produce acetylcholine. Drugs that increase acetylcholine levels are commonly prescribed to manage the cognitive symptoms of Alzheimer’s.

3) Parkinson’s Disease

According to limited studies, people with Parkinson’s disease may also have low acetylcholine levels in the brain [10].

On the other hand, low acetylcholine levels might be a consequence, not a cause, of these neurodegenerative diseases. More research is needed [10].

4) Myasthenia Gravis

Myasthenia Gravis is an autoimmune disease where acetylcholine nerves that go to the muscles become destroyed, causing severe muscle weakness. People with this disease also have low brain acetylcholine and cognitive impairment, but a causal link hasn’t been established [11].

5) Schizophrenia

Cholinergic dysfunction has been linked to cognitive difficulties in schizophrenia and other psychiatric disorders. Too little acetylcholine in the brain is hypothesized to contribute to the poor cognition and maybe even psychosis in those with schizophrenia. On the other hand, it might be a consequence of these disorders. Future work should clarify this association [12, 13].

6) Glaucoma

Acetylcholine helps maintain healthy vision and eye blood pressure. Anticholinergic drugs often prescribed to treat overactive bladder can trigger glaucoma [14].

7) Autism

According to one controversial theory, children with autism may lack brain acetylcholine, which can contribute to intellectual impairment and epilepsy. Theoretically, acetylcholine can increase the “calming” neurotransmitter GABA, which reduces the chance of seizures [15, 16].

In mice with autism, increasing acetylcholine improved cognitive and social symptoms. However, this link hasn’t been proven in humans [15, 16].

Can “Acetylcholine Deficiency” Be Confirmed?

Although low acetylcholine levels are commonly described as “acetylcholine deficiency,” this can be misleading. Assessing acetylcholine levels in the brain is extremely difficult.

For one, no deficiency parameters have been established in the scientific or medical literature.

Secondly, acetylcholine levels can’t be directly measured. Even with indirect measurements (such as with brain imaging), acetylcholine levels may vary across brain areas and quickly change depending on many factors.

Currently, no direct-to-consumer test can assess acetylcholine levels. Brain imaging can estimate levels in research settings, but no definition of “acetylcholine deficiency” has been widely accepted.

What Influences Acetylcholine Levels?

Acetylcholine Signaling: It’s Not That Simple

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
Acetylcholine balance is complex because it can be influenced by building blocks, other neurotransmitters, feedback loops, different brain areas, and many receptors and enzymes.

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.

When to See a Doctor

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 are 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.

Choline: The Main Building Block

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 [17].

Choline can be acquired naturally through the diet, and is found in a variety of common foods such as eggs and liver [18]. There are also several types of supplements that are based on choline, such as citicoline / CDP-choline and alpha-GPC [19, 20, 21, 22, 23].

Natural AChE Blockers

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 [24, 25, 26, 27, 28].

The Impact of Other Neurotransmitters & Hormones

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 [29].

Full List of Dietary Compounds & Supplements

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!

Takeaway

Acetylcholine is an important neurotransmitter that plays a role in cognition, digestion, and wakefulness. Researchers suspect that when certain parts of the brain or nervous system start losing acetylcholine, health problems may arise. Yet, a causal link remains to be proven.

The strongest evidence we have to date shows that a loss of acetylcholine neurons contributes to memory decline in Alzheimer’s disease. Drugs that increase acetylcholine are used to manage the cognitive symptoms of Alzheimer’s.

Limited research also suggests a link between “acetylcholine deficiency” and Parkinson’s disease, poor cognition in schizophrenia, autism, glaucoma, and other conditions. Further work is needed to verify these associations.

Many natural compounds may support acetylcholine activity, but their impact on acetylcholine levels is unknown. No commercially available test can measure acetylcholine levels–assessments are still limited to brain imaging in research settings.

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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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