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All About Cholinergic Activity + Natural Boosters

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 how to boost your levels naturally.

What is Cholinergic Transmission?

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. The sympathetic – fight-or-flight – nervous system helps the body survive when under threat, while the parasympathetic takes care of all the rest.

In normal situations, the fight-or-flight and rest-and-digest systems work together. 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 [2, 3, 4, 5, 6].

To have motivation, actually start learning something new, and to use your memory and focus to retain this knowledge – 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 [7, 8, 9].

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) [10].

Cholinergic activity of the rest-and-digestion system occurs in [11]:

  • 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
  • Vagus nerves that land on muscles, the heart, lungs, and digestive organs, which slows heart rhythm, affects breathing, and aids digestion
  • Nerves that go to the sexual organs, which influences arousal

Acetylcholine can directly reduce inflammation in the brain. The vagus nerve also uses acetylcholine to reduce inflammation in the body [12].

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 what causes a failing memory in older people [13].

But aside from aging, this system goes awry in many other diseases, such as in Alzheimer’s disease, Parkinson’s disease, schizophrenia, and epilepsy. What they all have in common is low acetylcholine, poor cognition, and brain inflammation [9].

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 [14]
  • 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 can contribute to addiction, schizophrenia, and Huntington’s disease [15, 16, 17, 18].

Diseases Linked to Low Cholinergic Activity


Poor cholinergic activity and low acetylcholine in the brain is the main cause of cognitive decline and poor memory in people with dementia. Drugs used to slow down dementia work precisely by increasing acetylcholine in the brain [19].

Alzheimer’s Disease and Parkinson’s Disease

In Alzheimer’s, neurons that make acetylcholine slowly die off. The loss in 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 [20].

People with Parkinson’s disease also have low acetylcholine levels in the brain [21].

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 [22].


Cholinergic dysfunction is linked to cognitive difficulties in schizophrenia and other psychiatric disorders. Too little acetylcholine in the brain contributes to the poor cognition and maybe even psychosis in those with schizophrenia [23, 24].


Acetylcholine helps maintain healthy vision and eye blood pressure. Anticholinergic drugs often prescribed to treat overactive bladder can trigger glaucoma [25].


Children with autism may lack brain acetylcholine, which can contribute to intellectual impairment and epilepsy. Acetylcholine can increase the calming neurotransmitter GABA, which reduces the chance of seizures. In mice with autism, increasing acetylcholine improved cognitive and social symptoms [2627].

Increased Cholinergic Activity


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 [25].

It appears that people with depression may be “super sensitive” to acetylcholine, which in turn activates the HPA axis. In predisposed people, this heightened reaction to acetylcholine may activate the fight-or-flight response, raise stress hormones, and cause mood disturbances [28].


High acetylcholine can cause hives, as immune cells produce histamine in response to it. 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 may be able to prevent the outbreaks [29, 30].

Sleep Quality

Acetylcholine increases during the dreaming, REM phase of sleep. 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 [31, 32].

Too much of acetylcholine is not a good thing. People who have problems due to increased cholinergic activity should look to decrease it. You can read more about ways to do that in this SelfHacked post.

Genetics of Cholinergic Transmission

A type of epilepsy is linked to mutations in nicotinic acetylcholine receptors, CHRNA2 and CHRNA4 [33].

SNPs in the muscarinic acetylcholine receptors (CHRM2) that increase their sensitivity are linked to depression [28].

Drugs Used to Increase Cholinergic Activity

Choline-mimetic Drugs

Tacrine was the first choline-mimicking drug developed to treat Alzheimer’s disease. It was used to re-establish the cholinergic balance in the brain by mimicking acetylcholine. Tacrine also 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 prolongs 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

We don’t recommend taking cholinergic drugs. Only people with a prescription for neurodegenerative diseases should use these drugs with guidance from their doctor.

There are many natural ways to boost your cholinergic system – from lifestyle changes to various supplements.

Lifestyle to Boost Cholinergic Activity

1) Fasting

Fasting reduced acetylcholine breakdown in the brain in mice [39].

Dietary restriction or fasting may boost acetylcholine in the brain.

2) Cold

Studies show that when your body adjusts to cold, your fight-or-flight (sympathetic) system declines and your rest-and-digest (parasympathetic) system increases, which boosts cholinergic activity [40].

Any kind of acute cold exposure will increase acetylcholine in the body [41].

3) Yoga

Yoga increases vagus nerve, acetylcholine and parasympathetic system activity in general [42, 43].

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 [42].

4) Meditation

Several types of meditation can boost the rest-and-digest system, increase acetylcholine, and cognition.

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

Also, Om chanting stimulates the vagus nerve, which boosts acetylcholine [44].

5) Breathing Exercises

Deep and slow breathing stimulates the vagus nerve and acetylcholine activity.

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).

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.

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 [45].

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

Tip: 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.

Supplements To Boost Cholinergic Activity

1) Choline

In order to increase your body’s levels of acetylcholine, you should increase your choline intake. Choline can be found in a variety of sources [46]:

The other supplements listed below 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 blocks acetylcholine breakdown and increases the activity of the enzyme that produces acetylcholine, based on cellular and animal studies [47].

3) Huperzine A

Huperzine A is found in the Chinese herb firmoss (Huperzia serrata). It is a potent acetylcholinesterase inhibitor and is approved for the treatment of Alzheimer’s disease in China [48].

4) Epimedium

Epimedium, also known as icariin, is an acetylcholinesterase inhibitor. It prevented cognitive impairment in rats with stroke [49, 50].

5) Caffeine

Caffeine increases acetylcholine in the brain, especially in the memory hub – the hippocampus [51, 52]

6) Blueberries

Some polyphenolic bioactive compounds found in blueberry extract may act as acetylcholinesterase inhibitors. They increased cognitive function in mice [5354]

7) Zinc

Zinc inhibits acetylcholinesterase [55].

Zinc can both activate and block nicotinic acetylcholine receptors, but overall has a positive impact on cognition [56, 57, 55].

8) Copper

Copper is required for acetylcholine to relax blood vessels in rats [58, 55].

9) Grape Seed Extract

Grape seed extract contains proanthocyanidin, which has been shown to increase the activity of the acetylcholine-making enzyme and decrease its breakdown [58, 59]

10) Rosemary

Rosemary extract had an antidepressant effect by boosting cholinergic activity in brain cells [60].

11) Cinnamon

Cinnamon increased acetylcholine by inhibiting acetylcholinesterase in text tubes [61, 62, 61].

12) Tulsi (Ocimum sactum)

Tulsi blocked acetylcholinesterase and improved cognitive ability in rats dementia [63].

13) Gotu Kola

Gotu Kola increased acetylcholine levels and decreased acetylcholinesterase in rats with seizures [64].

Gotu Kola also enhanced learning and memory in mice [65].

14) EGCG

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

15) Curcumin (Curcuminoids)

Curcuminoids are strong inhibitors of acetylcholinesterase [66].

Curcumin enhanced the activity of acetylcholine in mice and in cell studies, while also reducing pain and inflammation [67, 68].

16) DHA/Fish Oils

DHA and fish oil increased acetylcholine in the brain and digestive system in rats [69, 70].

17) Luteolin

Luteolin enhanced cholinergic signaling and acetylcholine levels in brain cells [71].

18) Quercetin

Quercetin increased acetylcholine in rats [R].

Quercetin enhanced memory and reduced anxiety in mice [72].

19) Fo-ti

Radix Polygonum (Fo-ti) is a Chinese herb that blocked acetylcholine breakdown in test tubes [73].

20) Ashwagandha

Ashwagandha protected the brain in mice with by acting on the cholinergic system [74].

21) Saffron

Saffron blocked acetylcholine breakdown in test tubes [75].

Crocetin, a carotenoid in Saffron, increased cholinergic blood vessel relaxation in rats with high blood pressure [76].

22) Reishi (Ganoderma lucidum)

Reishi mushrooms increased acetylcholine in animal studies [77].

Fermented reishi extract enhanced learning, memory and cognitive function in rats [78].

23) Carvacrol

Carvacrol, a bioactive compound in wild oregano, blocked acetylcholine breakdown in animal studies [79, 80].

24) Rhodiola

Rhodiola extracts increased acetylcholine in test tubes [81].

Rhodiola improved learning and memory in mice and rats with cognitive decline [82, 83].

25) Catalpol

Catalpol, a bioactive compound in Rehmannia, increased levels of acetylcholine and its activity in mice [84].

26) Noni (Morinda citrifolia)

Noni prevented memory impairment and cognitive dysfunction in mice by boosting acetylcholine [85].

27) Ginkgo

Ginkgo extract increased acetylcholine in the brain of rats [86].

It also increased acetylcholine in the blood, reducing blood pressure in rats with high blood pressure [86, 87].

It could increase acetylcholine in the brain’s memory region (the hippocampus) in mice with Alzheimer’s disease [88].

28) Schisandra

Schisandra extract increases acetylcholine in test tubes [R].

30) Magnesium

Magnesium indirectly increases acetylcholine by increasing the activity of cognition-boosting drugs, galanthamine and physostigmine [89].

31) Andrographis

Andrographis weakly blocked acetylcholine breakdown in test tubes [64].

32) Fenugreek Trigonella foenum graecum)

Fenugreek extracts reduced acetylcholine breakdown in test tubes [90].

32) Melatonin

Melatonin has increased cholinergic activity and improved memory in mice with dementia [91].

33) Ginger

Both white and red ginger extracts could boost acetylcholine in brain cells [92].

34) Danshen (Salvia miltiorrhiza)

Danshen extracts reduced acetylcholine breakdown in cells [93].

35) Licorice (Glycyrrhiza glabra)

Licorice reduced acetylcholine breakdown in the brain in mice [94].

36) Sulforaphane

Sulforaphane increased acetylcholine production and reduced its breakdown. It could boost cognitive function in mice with dementia [95].

37) Ginseng

White, red and black ginseng reduced acetylcholine breakdown in mice [96].

38) Propolis

Propolis contains many bioactive compounds, many of which could block acetylcholine breakdown and enhance cholinergic signaling in cells [97].

It could also boost learning and memory in mice with cognitive difficulties [98].

39) Muira puama (Ptychopetalum olacoides)

Muira could prevent acetylcholine breakdown in mice [99].

40) Boost Insulin

Insulin increased cholinergic function and improved memory in mice with dementia [91].

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

Want More Targeted Ways to Enhance Brain Function?

If you’re interested in improving your cognitive function, we recommend checking out SelfDecode’s Limitless Mind DNA Protocol. It gives genetic-based diet, lifestyle and supplement tips that can help improve your cognitive function. The recommendations are personalized based on your genes.

SelfDecode is a sister company of SelfHacked. The proceeds from your purchase of this product are reinvested into our research and development, in order to serve you better. Thanks for your support!

About the Author

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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