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All About Cholinergic Activity + Potential Natural Boosters

Written by Ana Aleksic, MSc (Pharmacy) | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Cholinergic activity arises whenever the neurotransmitter acetylcholine is used in the body. Acetylcholine acts on the whole nervous system, from enhancing learning and memory to promoting relaxation, digestion, muscle activity, and even sexual arousal. Read on to learn all about it and factors that may boost its levels naturally.

What is Cholinergic Transmission?

The Rest-and-Digest Response

While the fight-or-flight response uses mostly norepinephrine to bring the body into a state of action, acetylcholine is what balances and reduces this response. Cholinergic activity uses acetylcholine to make the body ready to “feed and breed” and “rest and digest.”

Acetylcholine is part of the so-called “parasympathetic nervous system,” boosting all activities that should happen at rest. And with rest also comes a higher state of consciousness: selective attention, perception, and memory [1].

This may seem counterintuitive at first: how can the same molecule help digestion, sexual activity, and cognition? But imagine pondering deep thoughts or digesting food while being attacked by a lion.

Scientists explain that the sympathetic – fight-or-flight – nervous system helps the body survive when under threat, while the parasympathetic takes care of all the rest [2].

In normal situations, the fight-or-flight and rest-and-digest systems work together. Research suggests that a healthy amount of norepinephrine increases motivation, while acetylcholine boosts cognition. Acetylcholine then syncs dopamine neurons to control the brain’s reward system and whether it’s worth it to act on motivation [3, 4, 5, 6, 7].

To have motivation, actually start learning something new, and to use your memory and focus to retain this knowledge – science says you need a balance of neurotransmitters.

Where Does Cholinergic Activity Occur?

Acetylcholine is made in cholinergic neurons from choline and acetyl-CoA, which comes from burning sugars and fats. Choline cannot be made by the body, so it has to be taken in through diet [8, 9, 10].

After it achieves its effects, acetylcholine is broken down by an enzyme called acetylcholinesterase. If a lot of acetylcholine is broken down, its levels decrease too much. Drugs that block this enzyme boost cognition and are used in Alzheimer’s disease (such as galantamine) [11].

Cholinergic activity of the rest-and-digestion system occurs in [12]:

  • The brain, where it enhances cognition, learning, and memory
  • Nerves that spread to the eyes, face, and mouth, where it controls vision, taste, and salivation
  • The vagus nerve that lands on muscles, the heart, lungs, and digestive organs to slow heart rhythm, affect breathing, and aid digestion
  • Nerves that go to the sexual organs, which influences arousal

According to one experimental theory, acetylcholine may directly reduce inflammation in the brain. The vagus nerve also uses acetylcholine to reduce inflammation in the body [13].

Some studies suggest that, with aging, cholinergic activity slowly becomes less and less efficient. Less acetylcholine is released from brain cells, and cells become less sensitive to the acetylcholine that’s there. This is hypothesized to be one of the causes of a failing memory in older people [14].

But aside from aging, scientists suspect that this system goes awry in many other diseases, such as in Alzheimer’s disease, Parkinson’s disease, schizophrenia, and epilepsy. What they all might have in common is low acetylcholine, poor cognition, and brain inflammation [10].

However, complex disorders like Alzheimer’s or Parkinson’s disease always involve multiple possible factors – including brain chemistry, environment, health status, and genetics – that may vary from one person to another.

Types of Cholinergic Receptors

Acetylcholine can act on the two different types of receptors in the body: nicotinic and muscarinic.

  • Nicotinic receptors got their name because nicotine activates them. They help transmit signals in the brain and activate skeletal muscles. The famous poison curare blocks them and causes paralysis [15]
  • Muscarinic receptors are in all other parts of the body: in the heart, gut, glands, and brain. Muscarine is a mushroom poison that overactivates them. Abnormal activity of these receptors is thought to contribute to addiction, schizophrenia, and Huntington’s disease [16, 17, 18, 19].

Associated Diseases

When we talk about low-cholinergic-activity-associated disorders, it‘s important to know that these disorders are not necessarily due to acetylcholine levels or production as such. They can stem from issues with acetylcholine breakdown or the availability of certain acetylcholine receptors. Many types of nicotinic and muscarinic cholinergic receptors exist.

Additionally, the majority of studies covered in this article deal with associations only, which means that a cause-and-effect relationship hasn’t been established.

For example, just because Alzheimer’s disease has been linked with low acetylcholine in certain brain areas doesn’t mean that Alzheimer’s disease is caused by low cholinergic activity. Data are lacking to make such claims.

Diseases Linked to Low Cholinergic Activity

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 [20].

Alzheimer’s Disease and Parkinson’s Disease

In Alzheimer’s, neurons that make acetylcholine slowly die off. Scientists believe that the loss of acetylcholine in the brain is what causes gradual cognitive impairment and worsens inflammation in the brain. New drugs attempting to treat Alzheimer’s disease increase acetylcholine levels, but their effectiveness hasn’t yet been determined [21].

According to limited studies, people with Parkinson’s disease may also have low acetylcholine levels in the brain [22].

On the other hand, low acetylcholine levels might be a consequence, not a cause, of these neurodegenerative diseases. More research is needed [22].

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 [23].

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 [24, 25].

Glaucoma

Acetylcholine helps maintain healthy vision and eye blood pressure. Anticholinergic drugs often prescribed to treat overactive bladder can trigger glaucoma [26].

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 [27, 28].

In mice with autism, increasing acetylcholine improved cognitive and social symptoms. However, this link hasn’t been proven in humans [27, 28].

Increased Cholinergic Activity

Limitations

Remember, we’re mostly dealing with associations here. A causal link between low cholinergic activity and these disorders hasn’t been established.

Depression

Low mood and depression may be linked to increased cholinergic sensitivity. Drugs that block acetylcholine (such as scopolamine) have antidepressant effects, while those that increase acetylcholine may worsen depression [26].

It appears that people with depression might be “super sensitive” to acetylcholine, which in turn activates the HPA axis. This stance is experimental, though, and it hasn’t been confirmed in large human studies [29].

In small studies of predisposed people, this heightened reaction to acetylcholine was hypothesized to activate the fight-or-flight response, raise stress hormones, and cause mood disturbances [29].

More research is needed.

Hives

Scientists think that high acetylcholine may contribute to hives, as immune cells produce histamine in response to it [30, 31].

According to one unverified hypothesis, people with hives seem to have higher acetylcholine in the skin, but their cells are less sensitive to it. This causes issues with sweating and histamine release. Drugs that block acetylcholine are being investigated for preventing outbreaks, but their effectiveness is still uncertain [30, 31].

Sleep Quality

Acetylcholine increases during the dreaming, REM phase of sleep. Limited data suggest that choline supplements may even induce lucid dreaming by boosting acetylcholine in the brain. Acetylcholine levels are low during restorative, slow-wave sleep, during which memory is consolidated [32, 33].

Too much acetylcholine is not a good thing. People who have problems due to increased cholinergic activity may be prescribed drugs that decrease it. You can read more about other factors that decrease cholinergic activity in this SelfDecode post.

Drugs Used to Increase Cholinergic Activity

The drugs listed below should only be used under medical supervision. Please discuss your medications with your doctor.

Choline-mimetic Drugs

Tacrine was the first choline-mimicking drug developed to treat Alzheimer’s disease. It is intended to re-establish cholinergic balance in the brain by mimicking acetylcholine. Tacrine also likely reduces the breakdown of acetylcholine [34].

Acetylcholinesterase Inhibitors

Acetylcholinesterase is the enzyme that breaks down acetylcholine. Inhibitors of this enzyme prevent acetylcholine from being broken down, boost its levels and prolong its activity. These drugs, often used for Alzheimer’s disease and cognitive impairment, include:

  • Donepezil [35]
  • Rivastigmine [36]
  • Galantamine [37]

Side effects of cholinesterase inhibitors include [38]:

  • Vomiting and nausea
  • Confusion and hallucinations
  • Low blood pressure and heart rate
  • Increased sweating, salivation, and tear production
  • Increased respiratory mucus secretion
  • Trouble breathing
  • Constriction of pupils
  • Muscle damage

This list does not cover all possible side effects. Contact your doctor or pharmacist if you notice any other side effects.

Only people with a prescription for neurodegenerative diseases should use these drugs with guidance from their doctor.

Lifestyle Factors that May Boost Cholinergic Activity

When to see a doctor

If your goal is to increase acetylcholine to improve your memory-related issues – including those of dementia or cognitive dysfunction – it’s important to talk to your doctor, especially your symptoms are significantly impacting your daily life.

Notable memory decline, such as excessive forgetfulness, confusion, and mood or personality changes, are all reasons to see a doctor.

Your doctor should diagnose and treat the condition causing your symptoms.

Remember that the existing evidence does not suggest that low cholinergic activity causes neurodegenerative disorders.

Additionally, changes in brain chemistry are not something that people can change on their own with the approaches listed below. Instead, the factors listed here are meant to reduce daily stress and support overall mental health and well-being.

Therefore, you may try the additional strategies listed below if you and your doctor determine that they could be appropriate. Read through the approaches listed here and discuss them with your doctor before trying them out. None of these strategies should ever be done in place of what your doctor recommends or prescribes.

1) Yoga

Studies suggest that yoga increases vagus nerve, acetylcholine, and parasympathetic system activity in general [39, 40].

A 12-week yoga intervention was associated with greater improvements in mood and anxiety than a control group who did walking exercises. The study found increased thalamic GABA levels, which are associated with improved mood and decreased anxiety [39].

2) Meditation

Several types of meditation may boost the rest-and-digest system, increase acetylcholine, and cognition [41].

Loving-kindness meditation increases vagal tone, as measured by heart rate variability [41].

Also, Om chanting stimulates the vagus nerve, which possibly boosts acetylcholine [41].

3) Breathing Exercises

Deep and slow breathing likely stimulates the vagus nerve and acetylcholine activity [42].

Specialized neurons in the heart and neck can detect your blood pressure and transmit the signal to your brain, which goes on to activate your vagus nerve that connects to your heart to lower blood pressure and heart rate by releasing acetylcholine. The result is a lower fight-or-flight activation (sympathetic) and more rest-and-digest (parasympathetic) [42].

Scientists believe that the more sensitive these receptors are, the more likely they are going to fire and tell your brain that the blood pressure is too high and it’s time to activate cholinergic activity to lower it [42].

Slow breathing, with a roughly equal amount of time breathing in and out, increases the sensitivity of baroreceptors and vagal activation, which lowers blood pressure, boosts acetylcholine, and reduces anxiety by increasing your parasympathetic system [43].

For an average adult, breathing around 5 – 6 breaths per minute can be very helpful [43].

Tip: Yoga practitioners explain that you need to breathe from your belly and slowly. That means when you breathe in, your belly should expand or go out. When you breathe out your belly should cave in. The more your belly expands and the more it caves in, the deeper you’re breathing.

4) Cold Exposure

Limited human studies reveal that when the body adjusts to cold, the fight-or-flight (sympathetic) system declines and the rest-and-digest (parasympathetic) system increases, which boosts cholinergic activity. In this study, temperatures of 50°F (10°C) were considered cold [44].

Sudden cold exposure (39°F/4°C) also increases vagus nerve activation through cholinergic receptors in rats [45].

Although the effects of cold showers on cholinergic activity haven’t been studied, many people advocate for this traditional cooling method.

When we think about it, all the showers were cold showers before the advent of water-heating techniques. Anecdotally, cold tubs are popular in Japan, while many Northern nations partake in dips in the ocean for special occasions during the winter or early spring.

It usually takes a while to get accustomed to fully cold showers, though. Some people say it’s good to dip your face in cold water for starts.

Remember to consult your healthcare provider first, though. Most doctors recommend against cold showers in people with heart disease or in those at risk. That’s because sudden cold exposure can restrict blood vessels, which may raise heart rate and blood pressure.

5) Fasting

Fasting reduced acetylcholine breakdown in the brain in mice. Although dietary restriction or fasting may hypothetically boost acetylcholine in the brain, this hasn’t been confirmed in humans [46].

Supplements that May Boost Cholinergic Activity

Limitations

Remember to speak with your doctor before taking any supplements. Make sure to let them know about any prescription or over-the-counter medication you may be taking, including vitamins and herbal supplements.

This is particularly important if you are already taking medications, such as choline-mimetic drugs or acetylcholinesterase inhibitors. Supplement-drug interactions can be dangerous and, in rare cases, even life-threatening.

If you and your doctor agree that supplementing is a good idea, choose products made by a trusted and reliable manufacturer.

Remember that dietary supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.

Many of the studies listed below were done on animals. Animal findings can’t be translated to humans. No valid clinical evidence supports their use for increasing cholinergic activity.

Some research suggests these supplements may help increase acetylcholine and support cognitive health:

1) Choline

The body uses choline to make acetylcholine. That’s why increasing choline intake might raise levels of acetylcholine. Choline can be found in a variety of sources [47]:

  • Foods high in choline include eggs and liver

The other supplements listed below are hypothesized to increase acetylcholine mostly by blocking the enzyme that breaks acetylcholine down. Some of them affect other neurotransmitters or pathways that may indirectly boost cholinergic activity. But only choline provides the building blocks for making acetylcholine in the body.

2) Bacopa monnieri

Bacopa may block acetylcholine breakdown and increase the activity of the enzyme that produces acetylcholine, based on cellular and animal studies [48].

3) Huperzine A

Huperzine A is found in the Chinese herb firmoss (Huperzia serrata), described as a strong acetylcholinesterase inhibitor. In China, it’s used for Alzheimer’s disease [49].

A systematic review of different interventions concluded that huperzine A may reduce cognitive decline in Alzheimer‘s disease. However, the studies included in this analysis had several limitations, including low quality, design flaws, and potential bias [50].

Due to a lack of proper effectiveness and safety data, huperzine A is not approved for medical use in the US by the FDA [49].

4) Epimedium

Epimedium, also known as icariin, is hypothesized to be an acetylcholinesterase inhibitor. It prevented cognitive impairment in rats with stroke [51, 52].

5) Caffeine

Based on animal data, caffeine might increase acetylcholine in the brain, especially in the “memory hub” – the hippocampus [53, 54]

6) Blueberries

Some polyphenolic bioactive compounds found in blueberry extract may act as acetylcholinesterase inhibitors, but this hasn’t been confirmed in humans. These compounds increased cognitive function in mice [55, 56]

7) Zinc

Zinc is hypothesized to inhibit acetylcholinesterase [57].

Scientists think it can both activate and block nicotinic acetylcholine receptors, but it likely has an overall positive impact on cognition in adequate doses [58, 59, 57].

8) Copper

Copper is required for acetylcholine to relax blood vessels in rats [60, 57].

9) Grape Seed Extract

Grape seed extract contains proanthocyanidin, which has been suggested to increase the activity of the acetylcholine-making enzyme and decrease its breakdown in animals [60, 61]

10) Rosemary

Scientists are investigating whether rosemary extract has antidepressant potential by boosting cholinergic activity in brain cells [62].

11) Cinnamon

Studies are examining if cinnamon can increase acetylcholine by inhibiting acetylcholinesterase in test tubes [63, 64].

12) Tulsi (Ocimum sactum)

Tulsi blocked acetylcholinesterase and improved cognitive ability in rats dementia [65].

13) Gotu Kola

Gotu Kola increased acetylcholine levels and decreased acetylcholinesterase in rats with seizures [66].

Gotu Kola also enhanced learning and memory in mice [67].

But, as with most other natural compounds, human data are lacking.

14) EGCG

EGCG improved cholinergic signaling and protected the brain in animal studies [68].

15) Curcumin (Curcuminoids)

Curcuminoids are hypothesized to be strong inhibitors of acetylcholinesterase [69].

Curcumin enhanced the activity of acetylcholine in mice and in cell studies, while also reducing pain and inflammation. However, it has poor bioavailability. Clinical trials are needed [70, 71].

16) DHA/Fish Oil

DHA and fish oil increased acetylcholine in the brain and digestive system in rats [72, 73].

17) Luteolin

Scientists are determining if luteolin enhances cholinergic signaling and acetylcholine levels in brain cells [74].

18) Quercetin

Quercetin increased acetylcholine in rats [75].

In mice, it seemed to enhance memory and reduce anxiety. But like curcumin and many flavonoids, quercetin has bioavailability issues. Clinical trials are required [76].

19) Fo-ti

Radix Polygonum (Fo-ti) is a Chinese herb that seems to block acetylcholine breakdown in test tubes [77].

20) Ashwagandha

Ashwagandha protected the brains of mice, supposedly by acting on the cholinergic system [78].

21) Saffron

Saffron blocked acetylcholine breakdown in test tubes [79].

Crocetin, a carotenoid in saffron, increased cholinergic blood vessel relaxation in rats with high blood pressure [80].

22) Reishi (Ganoderma lucidum)

Reishi mushrooms increased acetylcholine in animal studies [81].

Fermented reishi extract enhanced learning, memory and cognitive function in rats [82].

23) Carvacrol

Carvacrol, a bioactive compound in wild oregano, blocked acetylcholine breakdown in animal studies [83, 84].

24) Rhodiola

Researchers are exploring if rhodiola extracts increase acetylcholine in test tubes [85].

Rhodiola improved learning and memory in mice and rats with cognitive decline [86, 87].

25) Catalpol

Catalpol, a bioactive compound in Rehmannia, increased levels of acetylcholine and its activity in mice [88].

26) Noni (Morinda citrifolia)

Noni prevented memory impairment and cognitive dysfunction in mice by boosting acetylcholine. But beware, many fraudulent health claims have surrounded Noni products on the market in recent years. If you decide to go with Noni, do your research and buy only from reputable manufacturers [89].

27) Ginkgo

Ginkgo extract increased acetylcholine in the brain of rats [90].

It also increased acetylcholine in rats’ blood, reducing blood pressure in animals with high blood pressure [90, 91].

It could increase acetylcholine in the brain’s memory region (the hippocampus) in mice with Alzheimer’s disease [92].

28) Schisandra

Schisandra extract is being studied for increasing acetylcholine in test tubes [93].

30) Magnesium

Scientists believe that magnesium indirectly increases acetylcholine by increasing the activity of cognition-boosting drugs, galanthamine and physostigmine. This hasn’t been proven in humans [94].

31) Andrographis

Andrographis weakly blocked acetylcholine breakdown in test tubes, so it’s hard to draw any conclusions about its effects [66].

32) Fenugreek Trigonella foenum graecum)

Similarly, fenugreek extracts reduced acetylcholine breakdown in test tubes [95].

32) Melatonin

Melatonin increased cholinergic activity and improved memory in mice with dementia [96].

33) Ginger

Both white and red ginger extracts seemed to boost acetylcholine in brain cells [97].

34) Danshen (Salvia miltiorrhiza)

Researchers are studying if danshen extracts reduce acetylcholine breakdown in cells [98].

35) Licorice (Glycyrrhiza glabra)

Licorice reduced acetylcholine breakdown in the brain in mice [99].

36) Sulforaphane

Sulforaphane increased acetylcholine production and reduced its breakdown in animals. It could boost cognitive function in mice with dementia [100].

37) Ginseng

White, red and black ginseng reduced acetylcholine breakdown in mice [101].

38) Propolis

Propolis contains many bioactive compounds, many of which are hypothesized to block acetylcholine breakdown and enhance cholinergic signaling in cells [102].

It also appeared to boost learning and memory in mice with cognitive difficulties [103].

39) Muira puama (Ptychopetalum olacoides)

Muira could prevent acetylcholine breakdown in mice [104].

Other

Insulin increased cholinergic function and improved memory in mice with dementia [96].

Keeping your insulin levels in check may support healthy cholinergic activity.

Genetics of Cholinergic Transmission

A type of epilepsy has been linked to mutations in nicotinic acetylcholine receptors, CHRNA2 and CHRNA4 [105].

SNPs in the muscarinic acetylcholine receptors (CHRM2) that increase their sensitivity have been linked to depression [29].

About the Author

Ana Aleksic

Ana Aleksic

MSc (Pharmacy)
Ana received her MS in Pharmacy from the University of Belgrade.
Ana has many years of experience in clinical research and health advising. She loves communicating science and empowering people to achieve their optimal health. Ana spent years working with patients who suffer from various mental health issues and chronic health problems. She is a strong advocate of integrating scientific knowledge and holistic medicine.

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