The high acetylcholine syndrome

Could acetylcholine be the root of your mental or physical symptoms?

Acetylcholine is the primary neurotransmitter of the parasympathetic nervous systems, but is also involved with the sympathetic nervous system, such as assisting with muscle contraction, vasodilation to the skin and sweating.

When acetylcholine levels are too high or unopposed, as during REM sleep, the skeletal muscles are under complete paralysis to prevent sudden movement during dreaming.

Acetylcholine is created by the enzyme choline acetyltransferase from choline and acetyl-CoA.

In the brain it is unlikely that choline acetyltransferase is saturated with either of its substrates, so that choline (and possibly acetyl-CoA) availability determines the rate of acetylcholine synthesis.

Acetylcholine is broken down by the enzyme acetylcholinesterase, which converts acetylcholine into choline and acetate. Choline can then be used for the synthesis of phospholipids, methylation, the recreation of acetylcholine, etc.

Acetylcholine plays an important role in arousal, attention, memory, motivation and muscle function. Lots of issues can occur either when in excess or when too low.

Here are a few mental signs of excess acetylcholine. Keep in mind, the low acetylcholine will sometimes have the opposite effect. For example, acetylcholine is needed for attention, so excess can cause hyperfocused rumination on (usually negative) thoughts, whereas too little could contribute to ADHD.

Acetylcholine in the brain:

  • Is low in dementia and possibly depersonalization as well.
  • Reduces anhedonia by stimulating the release of glutamate and dopamine. In this study, knockdown of choline acetyltransferase in the rat habenula was sufficient to evoke anhedonia-like behavior (R). However, striatal acetylcholine, released during stress-induced CRH release (HPA axis stress response), decreases reward-seeking and contributes to anhedonia (R).
  • Is involved in Alzheimer’s and Parkinson’s disease
  • Is elevated in depression/suicide victims. Lowering acetylcholine, by either blocking its receptors or presynaptically activating M2/M4 mAChRs (which act as inhibitory autoreceptors), reduces glutamate release. Excess glutamate is implicated in depression. Nicotinic receptor antagonists are useful against depression and bipolar (R). Atropine, an anticholinergic, upregulates CRH receptors in the cerebral cortex and shows that excess acetylcholine can contribute to CRH insensitivity and lead to high CRH levels (R). Elevated CRH is also implicated in many neurological and mental disorders, such as depression.
  • Increases symptoms of anxiety and reactivity to stress (R). Stressors that would be ignored over time by someone with lower levels of acetylcholine signaling might be paid more attention to and provoke a physiological response in a depressed individual with elevated acetylcholine levels (R). A decrease in hippocampal acetylcholinesterase activity increases anxiety- and depression-like behaviors and decreases resilience to repeated stress during social defeat (R).
  • (In excess) Enhances aggression (R).
  • Increases CB1 receptors, which are involved in fatigue and getting the munchies (R).
  • Increases the signal-to-noise ratio in a learning environment, which can help with focus and reduce being distracted. But too much can cause someone to become too fixated on something and reduces cognitive flexibility, whereas too little could contribute to ADHD.
  • Is involved in fear learning, so too much can make some people too afraid to retry something or even try something new that’s closely related to a certain fear. When acetylcholine input to the amygdala (the part of the brain that’s involved in emotion) is high at baseline, behavioral responses to negative stimuli are likely to be maximal and negative events may be more efficiently stored as negative memories.
  • Inhibits tonic (baseline) dopamine, but promotes phasic bursts. Meaning, you’ll have lower overall brain dopamine, but get larger bursts of dopamine when doing something fun/exciting. This contributes to addiction. Nicotinic receptor α3, α6 and β3 subunits are enriched in midbrain nuclei associated with behavioral reinforcement. Blocking mAChRs have anti-addictive properties.
  • Contributes to rumination (reduces mental flexibility), with a bias towards negative memories.
  • Improves attention and by extension, learning and memory; however, in the absence of cholinergic neuronal loss, stimulation of acetylcholine signaling can impair memory (R).
  • Promotes REM sleep and vivid dreams. Lucid dream promoting supplements usually contain one or more cholinergic. An excess can also promote excessive dreaming and contribute to insomnia.
  • Causes illusory sensations.
  • Contributes to dysphoria, which is a state of unease or generalized dissatisfaction with life.
  • Contributes to irritability and hostility.
  • Can cause delirium, confusion, headache, or drowsiness.
  • Is involved in OCD. Cholinergic supersensitivity is present in obsessive-compulsive disorder (R). Similarly, glutamatergic hyperactivity is associated with OCD, which may be because nicotinic receptor activation releases glutamate (R).

Excess acetylcholine in the body:

  • Decreases heart rate. Usually, people that are very fit or do keto have reduced heart rate and this is due to excess acetylcholine activity. Eating carbs, which increases the release of insulin, normalizes heart rate again. Too much acetylcholine can cause paralysis of the heart which stops it from beating.
  • Increases body temperature and is involved with flushing and excessive sweating.
  • Increases blood pressure due to increasing aldosterone and vasopressin. Although in smaller amounts it can contribute to vasodilation by releasing nitric oxide, possibly by increasing the aromatase (R).
  • Could contribute to cold hands and feet, since it increases adrenaline secretion through nicotinic receptor activation.
  • Contributes to pancreatitis (R).
  • Causes cramps.
  • Promotes mucus/liquid secretion from the mouth (excess saliva), nose, throat, eyes (lacrimation), skin (sweating) and infected/inflamed areas.
  • Contributes to constriction/contraction of the throat, which is involved in asthma / COPD / sleep apnea (R, R).
  • Releases too much gastric acid and can contribute to stomach ulcers.
  • Contracts the bladder, giving the sensation of “small bladder syndrome” and increases the urge to urinate. Too little acetylcholine can lead to urine buildup and reduced the urge to urinate, which can actually contribute to bladder inflammation.
  • Contracts the smooth muscle in the gastrointestinal tract and can lead to diarrhea if in excess. Too little can contribute to constipation.
  • Contributes to muscular fasciculation (twitching) (is also involved in the dopamine induced dyskinesias (R)), muscular weakness, paralysis and the disease called Myasthenia gravis (through nicotinic receptor activation).
  • Constricts pupils and can contribute to blurry vision. If you ever wondered why some people have such very small pupils, it’s because of elevated acetylcholine and serotonin. As a side note, acetylcholine eye drops can be used for glaucoma.
  • Reduces thirst. Inhibiting acetylcholine can cause loss of parasympathetic activity (and increase thirst and cause constipation). This is why insulin can make people thirsty, because insulin opposes acetylcholine.
  • Increases cortisol. The nAChR antagonist, mecamylamine, has been found to block the physostigmine (a highly toxic parasympathomimetic alkaloid)-induced rise in plasma corticosterone levels in rats. In addition, acetylcholine-induced CRH release from the hypothalamus is inhibited by nAChR blockade (R).
  • Stimulates prolactin release (R).
  • Can make you feel nauseous and cause vomiting through the mAChR activation.
  • Contribute to epileptic episodes.

Now that you got a pretty good idea what high/low acetylcholine looks like, let’s discuss what can lower excess acetylcholine and provide relief from these symptoms.

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Anticholinergics:

  • Procaine
  • Quinidine
  • Magnesium ( it antagonizes P-type calcium channels)
  • Atropine 
  • Jimson weed
  • Adamantane/amantadine/memantine
  • Quinine in tonic water
  • Compounds found in foods part of the deadly nightshade (Atropa belladonna) such as tomatoes, potatoes, and eggplant
  • Hyoscyamine (which has 98% of the anticholinergic power of atropine) found in Solanaceae, including henbane, mandrake, angel’s trumpets, jimsonweed, tomato and the sorcerers’ tree. It can also be anti-serotoninergic.
  • Hyoscine found in the corkwood tree, which has been previously used to treat nausea and seasickness amongst other things.
  • Progesterone inhibits rat neuronal nAChRs (R).
  • Dehydroepiandrosterone sulfate (DHEA-S) inhibits rat neuronal nAChRs (R). DHEA-S also activates the sigma receptor which promotes the release of dopamine and acetylcholine. So it can lead to more acetylcholine and less nAChRs activation, which could be how it contributes to depersonalization/anhedonia.
  • Hydrocortisone inhibit rat neuronal nAChRs (R)
  • 3α,5α,17β-3-hydroxyandrostane-17-carbonitrile (ACN) inhibit rat neuronal nAChRs (R).
  • Pregnenolone-sulfate inhibits nAChR-regulated release of catecholamines from the adrenal medulla (R).
  • T3 inhibits nAChR (R).
  • Lower doses (2.5–5 mg b.i.d.), mecamylamine (anti-hypertensive drug) functions as a potent centrally acting nAChR antagonist that may be useful for treating tobacco, cocaine and alcohol dependency (R).
  • Bupropion (Zyban®) is relatively selective at inhibiting α3β2-nAChRs.
  • Organic mercurial compounds, such as methylmercury, can cause dysfunction of the enzyme choline acetyltransferase. This inhibition may lead to acetylcholine deficiency and can have consequences on motor function.
  • Botulinum toxin (Botox) suppresses the release of acetylcholine.
  • Cysteine inhibits choline acetyltransferase (R).
  • Angiotensin inhibits acetylcholine release and can lead to cognitive defects (R).
  • Dopamine receptor D2 agonist (R)
  • Hyperventilation (low CO2) lowers acetylcholine, whereas high CO2 and ATP increases the release of acetylcholine (R, R).
  • Vitamin A and K decreased the synthesis of acetylcholine in low and increasing concentrations (R).
  • Vitamin D only decreases acetylcholine synthesis in higher doses(R).
  • Vitamin B1 slightly increases the synthesis of acetylcholine in low concentrations and decreases it in higher ones (R).
  • Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against organophosphate (a pesticide that inhibits acetylcholinesterase) exposure (R).

Pro-acetylcholine

  • Huperzine increases both acetylcholine & dopamine and can protect against Alzheimers by decreasing iron content in the brain (R).
  • Betaine, folate and B12 can spare choline, through the methylation cycle.
  • Jaborandi
  • CRP and other markers of systemic inflammation decrease the expression of AChE, resulting in a reduced breakdown of acetylcholine.
  • Loss of cholinergic neurons can lead to low acetylcholine release. Anti-oxidant enzymes containing, zinc, copper, iron, manganese and selenium can help protect cholinergic neurons against oxidative stress. Other neuroprotective factors include progesterone, pregnenolone, taurine, agmatine, methylene blue, magnesium, etc.
  • Vitamin B5is essential for the production of acetyl-CoA, which can then be used to create acetylcholine (R).
  • The active form of vitamin D, 1,25-(OH)2D3, increases acetylcholine synthesis. A low calcium diet can lead to an excess of acetylcholine, by increasing the amount of active vitamin D (R).
  • A vitamin B1 deficiency results in reduced activity of choline acetyltransferase (ChAT), in the cortex and hippocampus and can lead to memory impairment (R). In this study, 200mg intravenous significantly reduced symptoms of delirium (R). Benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely by suppressing glycogen synthase kinase-3 (GSK-3) activities (R). Combining citicoline combined with benfotiamine offers greater benefits for memory impairment in mice than either one alone (R).
  • Pesticides (organophosphates and the carbamates) inhibit acetylcholinesterase, which is implicated in depression.
  • Estrogen (R)
  • Dopamine D1 receptor agonist (R).
  • Activation of the serotonin receptor, 5-HT2A boosts the release of acetylcholine after stimulation of dopamine D1 receptors (R). Serotonin, by binding to the 5-HT1A receptor can also activate the parasympathetic nervous system via the release of acetylcholine (R).
  • The venom from a black widow spider (alpha-latrotoxin) stimulates acetylcholine release. When bitten by a black widow spider, one experiences the wastage of acetylcholine supplies and the muscles begin to contract. If and when the supply is depleted, paralysis occurs.
  • Muscarine, a poisonous molecule found in mushrooms (Amanita muscaria), induces a strong activation of the peripheral parasympathetic nervous system (muscarinic syndrome) (R).
  • Carpolobia lutea (cholinesterase inhibitor) (R)
  • Catuaba bark (R).
  • Activation of the sigma receptor releases acetylcholine. Progesterone and testosterone are antagonistic and can lower excess acetylcholine release, whereas choline, DHEA-S and pregnenolone-S are agonistic (R, R).
  • Morphine, by acting on the kappa opioid receptor (R).
  • Galantamine inhibits acetylcholinesterase and also acting as a positive allosteric modulator of α7 nAChR.
  • Memantine increases acetylcholine in the nucleus accumbens & ventral tegmental area (R).
  • Bitters, such as coffee, gentian, etc. (R).
  • Sage (R)
  • Saffron (30mg) (R)
  • Vitamin B2, B3 (niacin and nicotinamide), B5, B6, and vitamin C increase acetylcholine synthesis in high doses (R).
  • Vitamin E increases the synthesis of acetylcholine (R).

As always, thanks so much for reading my article. Let me know in the comments below if you have any questions. And if you found this article to be insightful and helpful please like and share so this information can help others as well.

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One Reply to “The high acetylcholine syndrome”

  1. This article interested members of a nightshade and cholinesterase inhibitor Facebook page. If you know of any studies that stimulate acetylcholinestase, they would be of interest as well.

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