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Evidence BasedThis post has 105 references
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All About Cholinergic Activity + Potential Natural
Boosters
Medically reviewed by Puya Yazdi, MD | Written by Ana Aleksic, MSc (Pharmacy) | Last updated: February 12,
2020
CONTENTS
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.
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What is Cholinergic Transmission?
The Rest-and-Digest Response
While the ght-or- ight 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 rst: 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 – ght-or- ight – nervous system helps the body
survive when under threat, while the parasympathetic takes care of all the rest [2].
In normal situations, the ght-or- ight 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 e ects, 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]:
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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, a ect breathing, and aid digestion
Nerves that go to the sexual organs, which in uences arousal
According to one experimental theory, acetylcholine may directly reduce in ammation in
the brain. The vagus nerve also uses acetylcholine to reduce in ammation in the body [13].
Some studies suggest that, with aging, cholinergic activity slowly becomes less and less
e cient. 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 in ammation [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 di erent 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
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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-e ect 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].
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Alzheimer’s Disease and Parkinson’s Disease
In Alzheimer’s, neurons that make acetylcholine slowly die o . Scientists believe that the
loss of acetylcholine in the brain is what causes gradual cognitive impairment and
worsens in ammation in the brain. New drugs attempting to treat Alzheimer’s disease
increase acetylcholine levels, but their e ectiveness 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 di culties 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
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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 e ects, 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
con rmed in large human studies [29].
In small studies of predisposed people, this heightened reaction to acetylcholine was
hypothesized to activate the ght-or- ight response, raise stress hormones, and cause
mood disturbances [29].
More research is needed.
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Hives
Scientists think that high acetylcholine may contribute to hives, as immune cells produce
histamine in response to it [30, 31].
According to one unveri ed 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 e ectiveness 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 rst 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]
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Galantamine [37]
Side e ects 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 e ects. Contact your doctor or pharmacist if you
notice any other side e ects.
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 signi cantly 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.
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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 ght-or- ight 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 re 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
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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 ght-or- ight
(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 e ects 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 waterheating 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 rst, 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 con rmed
in humans [46].
Supplements that May Boost Cholinergic Activity
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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 cholinemimetic 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 e ective.
Many of the studies listed below were done on animals. Animal ndings 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 a ect 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].
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3) Huperzine A
Huperzine A is found in the Chinese herb rmoss (Huperzia serrata), described as a strong
acetylcholinesterase inhibitor. In China, it’s used for Alzheimer’s disease [49].
A systematic review of di erent 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 aws, and potential bias [50].
Due to a lack of proper e ectiveness 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, ca eine 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 con rmed 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,
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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 in ammation. However, it has poor bioavailability. Clinical trials are
needed [70, 71].
16) DHA/Fish Oil
DHA and sh oil increased acetylcholine in the brain and digestive system in rats [72, 73].
17) Luteolin
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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
avonoids, 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
Sa ron blocked acetylcholine breakdown in test tubes [79].
Crocetin, a carotenoid in sa ron, 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].
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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 e ects [66].
32) Fenugreek Trigonella foenum graecum)
Similarly, fenugreek extracts reduced acetylcholine breakdown in test tubes [95].
32) Melatonin
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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 di culties [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
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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].
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About the Author
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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 su er from various mental health issues and chronic health problems. She is a strong
advocate of integrating scienti c knowledge and holistic medicine.
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