# Acetylcholine

Category: Hormones

Also known as: cholinergic

Acetylcholine is the neurotransmitter of the cholinergic nerves, including the parasympathetic system, and its action is terminated by the enzyme cholinesterase. Peat argued that while acetylcholine is essential for learning and intelligent behavior, its role is fundamentally…

10 passages · 3 authors · 2006–2026 · Most-cited: [Ray Peat](https://bioenergeticoracle.com/md/voices/ray-peat/index.md)

Canonical page: https://bioenergeticoracle.com/concepts/acetylcholine

## Synthesis

**Acetylcholine** is the neurotransmitter of the cholinergic nerves, including the parasympathetic system, and its action is terminated by the enzyme **cholinesterase**. [Source 5] Peat argued that while acetylcholine is essential for learning and intelligent behavior, its role is fundamentally tied to the stress response, particularly the state of *inescapable stress* or "learned helplessness." [Source 1, 10] In this state, the body shifts away from sympathetic-adrenal activation and turns on the acetylcholine-dominant cholinergic system, which lowers blood sugar and activates histamine release, a shift Peat described as moving "towards death and away from life." [Source 1] This parasympathetic dominance was historically overlooked in stress research until Richter observed that the hearts of hopeless rats slowed and relaxed due to vagal nerve activity, secreting acetylcholine, rather than accelerating via noradrenaline. [Source 6]

A central mechanism of acetylcholine's action, and a key to its degenerative potential, is its activation of **nitric oxide** synthesis. [Source 2, 4] Acetylcholine relaxes blood vessels by inducing cells to produce nitric oxide, a free radical that can diffuse and inhibit mitochondrial energy production in nerve cells. [Source 2] This vasodilation via nitric oxide is a fundamentally different and more dangerous mechanism than the normal, CO2-driven regulation of blood flow, and Peat noted that nitric oxide is increasingly seen as a factor in nerve degeneration and cell death. [Source 2] The connection between cholinergic stimulation and excitotoxic damage is further reinforced by the fact that organophosphates, which inactivate cholinesterase and prolong acetylcholine's action, increase nitric oxide formation, while protective **anticholinergic drugs** like atropine reduce it. [Source 2]

Peat was highly critical of the "cholinergic theory" of Alzheimer's disease, which led to treatments using cholinesterase inhibitors like Tacrine to increase acetylcholine stimulation. [Source 6, 10] He maintained that this approach failed and was harmful because it forced neurons to work harder without adequate energy, causing cell death, especially when combined with high cortisol or hypoglycemia. [Source 10] Dinkov has extended this critique, stating the cholinergic theory has been "debunked" and that acetylcholine is a *brain excitotoxicant* very similar in effect to estrogen, manifesting its negative effects through the cholinergic and histaminergic systems. [Source 9] Peat pointed out that drugs originally classified as anticholinergic, such as amantadine and memantine, showed actual improvement in degenerative brain diseases, though they were later reclassified as anti-glutamatergic to avoid conflict with the dominant cholinergic drug paradigm. [Source 7, 10]

The relationship between acetylcholine and a healthy brain is nuanced by environmental context. Peat cited research from the 1960s showing that environmental enrichment increased the enzyme **cholinesterase** in rat brains, and that this increase, along with larger brain size, was passed on to subsequent generations. [Source 3, 5] This suggests that a healthy, stimulated brain upregulates the destruction of acetylcholine, rather than its accumulation. [Source 3] Estrogen intensifies the cholinergic system, which Peat connected to its excitatory and destructive features, including premenstrual epilepsy and miscarriage via uterine contractions, while *progesterone* and *pregnenolone* act as anticholinergic, protective agents. [Source 4, 9] Roddy noted a personal experience where a substance that increased acetylcholine made him feel "super high strung," aligning with Peat's association of the cholinergic system with the stress response and nitric oxide. [Source 8]

## People also ask

### How does acetylcholine relate to the stress response?

Peat argued that acetylcholine is tied to inescapable stress or learned helplessness, where the body shifts to a cholinergic-dominant state that lowers blood sugar and activates histamine, a move he described as toward death and away from life.

### Why did Peat oppose using cholinesterase inhibitors for Alzheimer's?

Peat maintained that forcing neurons to work harder with cholinesterase inhibitors caused cell death without adequate energy, and that drugs originally called anticholinergic, like amantadine, actually improved degenerative brain diseases.

### What role does nitric oxide play in acetylcholine's effects?

Acetylcholine relaxes blood vessels by inducing cells to produce nitric oxide, a free radical that can inhibit mitochondrial energy production in nerve cells, a mechanism Peat considered more dangerous than normal CO2-driven blood flow regulation.

## Related concepts

- [Learned Helplessness](https://bioenergeticoracle.com/md/concepts/learned-helplessness/index.md)
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- [Alkalosis](https://bioenergeticoracle.com/md/concepts/alkalosis/index.md)
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## Cited passages

Passage numbers match the `[Source N]` markers in the synthesis above.

### Source 1 — Environmental Enrichment & The Brain – 2013

Ray Peat · Interview · 2013

> **Andrew Murray:** Wow, do you know these two compounds that you mentioned...
>
> **Ray Peat:** Tacrine and Galantamine?
>
> **Andrew Murray:** Amantadine and Memantine. Are they still prescribable drugs?
>
> **Ray Peat:** Oh yeah, Memantine I think is now a standard Alzheimer’s treatment along with whatever toxins of the cholinesterase inhibiting...
>
> **Andrew Murray:** In terms of my physiology, studying herbal medicine, I was always taught that acetylcholine was a very important neurotransmitter, and it was mopped up in the synaptic cleft by acetycholinesterase and that prevented any over-­‐stimulation firing. So from what you have just been discussing right now, you’re talking about a kind of excess situation, where there’s an excess?
>
> **Ray Peat:** Yeah, in escapable stress, the stress hormones, rather than pushing higher and higher on the cortisol and adrenalin direction to excite things, run the heart at a faster rate, the body shifts when it sees futility, inability to escape, it can simply switch gears and turn off that system and turn on the acetylcholine cholinergic system. And the confinement, inescapable stress, which is the extreme of isolation, the extreme opposite from an enriched environment, this turns on the cholinergic dominant system, which lowers blood sugar, and in consequence of lowering the blood sugar, activates histamine release. Some of the acetylcholine nerves, such as the vagus nerve, amplify their influence by releasing histamines. It is very similar to its effect to acetylcholine, so you can think of this kind of inescapable stress as turning on the histamine type of cholinergic reaction.

### Source 2 — Dark Side Of Stress Learned Helplessness

Ray Peat · Article · 2016 · https://raypeat.com/articles/articles/dark-side-of-stress-learned-helplessness.shtml

> In 1997, a group (Pike, et al.) created brain injuries in rats to test the idea that a cholinesterase inhibitor would improve their recovery and ability to move through a maze. They found instead that it reduced the cognitive ability of both the injured and normal rats.
>
> An anticholinergic drug, selegeline (deprenyl) that is used to treat Parkinson's disease and, informally, as a mood altering antiaging drug, was found by a different group (Zhu, et al., 2000) to improve cognitive recovery from brain injuries.
>
> One of acetylcholine's important functions, in the brain as elsewhere, is the relaxation of blood vessels, and this is done by activating the synthesis of NO, nitric oxide. (Without NO, acetylcholine constricts blood vessels; Librizzi, et al., 2000.)
>
> The basic control of blood flow in the brain is the result of the relaxation of the wall of blood vessels in the presence of carbon dioxide, which is produced in proportion to the rate at which oxygen and glucose are being metabolically combined by active cells. In the inability of cells to produce CO2 at a normal rate, nitric oxide synthesis in blood vessels can cause them to dilate. The mechanism of relaxation by NO is very different, however, involving the inhibition of mitochondrial energy production (Barron, et al., 2001).
>
> Situations that favor the production and retention of a larger amount of carbon dioxide in the tissues are likely to reduce the basic "tone" of the parasympathetic nervous system, as there is less need for additional vasodilation.
>
> Nitric oxide can diffuse away from the blood vessels, affecting the energy metabolism of nerve cells (Steinert, et al., 2010).
>
> Normally, astrocytes protect nerve cells from nitric oxide (Chen, et al., 2001), but that function can be altered, for example by bacterial endotoxin absorbed from the intestine (Solà, et al., 2002) or by amyloid-beta (Tran, 2001), causing them to produce nitric oxide themselves.
>
> Nitric oxide is increasingly seen as an important factor in nerve degeneration (Doherty, 2011).
>
> Nitric oxide activates processes (Obukuro, et al., 2013) that can lead to cell death.

### Source 3 — Herb Doctors: Environmental Enrichment-Bad Science

Ray Peat · Interview · Aug 16, 2013 · http://l-i-g-h-t.com/files/herb-doctors-environmental-enrichment -bad-science.mp4

> **Ray Peat:** And animal studies starting in the 1960s at University of California Berkeley, they first found that animals given stimulation - a big playground to roam in during when they weren’t eating and sleeping - they found that they learned better, could solve problems better - and so they examined their brains to see what was happening and they found that the enzyme cholinesterase was increased in proportion to how much they were stimulated and how well they learned, and they kept that study going on generation after generation and found that it not only increased this enzyme that destroys acetylcholine, it involved enlargement of the whole brain especially the cortex, and each generation both the enzyme increased and the brain got larger but....

### Source 4 — Learned Helplessness KMUD 2013

Ray Peat · Interview · 2013 · http://www.l-i-g-h-t.com/files/herb-doctors-learned-helplessness-nervous-system-and-thyroid-questionaire.mp4

> **Andrew Murray:** How do you look at estrogen, at it’s destructive features? Why is it so bad for you?
>
> **Ray Peat:** A lot of people by now have heard that there is a premenstrual related epilepsy, that revolves from an excess of estrogen in relation to progesterone (because estrogen is excitatory, while progesterone is calming). And it happens that estrogen intensifies the parasympathetic part of the autonomic nervous system, while progesterone tends to relax it. You can see that parasympathetic function of estrogen in the uterus. If there is too much estrogen in pregnancy, it will cause strong contractions of the uterus, and can cause miscarriage. If you give the drug they give to treat Alzheimer's, which is a pro-cholinergic drug, it will cause spasms of the uterus, just like estrogen. So, estrogen is acting with, or through that part of the nervous system. For about 50 years there was a puzzle about how acetylcholine for the cholinergic nerves could inhibit the heart and the sphincters, while causing contractions of the various ducts (intestines, and so on). It's been proposed that something was being released in the cells that combined with acetylcholine to determine whether it was excitatory or inhibitory. But the main thing that happens; it’s that acetylcholine causes cells to produce nitric oxide, the chemical that became famous with Viagra and Rogaine, which causes vasodilatation.

### Source 5 — Dark Side Of Stress Learned Helplessness

Ray Peat · Article · 2016 · https://raypeat.com/articles/articles/dark-side-of-stress-learned-helplessness.shtml

> # The dark side of stress (learned helplessness)
>
> Acetylcholine is the "neurotransmitter" of cholinergic nerves, including the parasympathetic system. Cholinesterase (or acetylcholinesterase) is an enzyme that destroys acetylcholine, limiting the action of the cholinergic nerves. Attaching a phosphate group to the cholinesterase enzyme inactivates it, prolonging and intensifying the action of cholinergic stimulation.
>
> The autonomic nervous system has traditionally been divided into the sympathetic-adrenergic system, and the parasympathetic-cholinergic system, with approximately opposing functions, intensifying energy expenditure and limiting energy expenditure, respectively. The hormonal system and the behavioral system interact with these systems, and each is capable of disrupting the others. Disruptive factors in the environment have increased in recent decades.
>
> Living is development; the choices we make create our individuality. If genetically identical mice grow up in a large and varied environment, small differences in their experience will affect cell growth in their brains, leading to large differences in their exploratory behavior as they age (Freund, et al., 2013). Geneticists used to say that "genes determine our limits," but this experiment shows that an environment can provide both limitations and opportunities for expanding the inherited potential. If our environment restricts our choices, our becoming human is thwarted, the way rats' potentials weren't discovered when they were kept in the standard little laboratory boxes. An opportunity to be complexly involved in a complex environment lets us become more of what we are, more humanly differentiated.
>
> A series of experiments that started at the University of California in 1960 found that rats that lived in larger spaces with various things to explore were better at learning and solving problems than rats that were raised in the standard little laboratory cages (Krech, et al., 1960). Studying their brains, they found that the enzyme cholinesterase, which destroys the neurotransmitter, acetylcholine, was increased. They later found that the offspring of these rats were better learners than their parents, and their brains contained more cholinesterase. Their brains were also larger, with a considerable thickening of the cortex, which is considered to be the part mainly responsible for complex behavior, learning and intelligence.
>
> These processes aren't limited to childhood.

### Source 6 — Dark Side Of Stress Learned Helplessness

Ray Peat · Article · 2016 · https://raypeat.com/articles/articles/dark-side-of-stress-learned-helplessness.shtml

> Richter made the important discovery that the hearts of the hopeless rats slowed down before they died, remaining relaxed and filled with blood, revealing the dominant activity of the vagal nerve, secreting acetylcholine. The sympathetic nervous system (secreting noradrenaline) accelerates the heart, and is usually activated in stress, in the "fight or flight" reaction, but this radically different (parasympathetic) nervous activity hadn't previously been seen to occur in stressful situations.
>
> The parasympathetic, cholinergic, nervous system had been thought of as inactive during stress, and activated to regulate processes of digestion, sleep, and repair.
>
> Besides the cholinergic nerves of the parasympathetic system, many nerves of the central nervous system also secrete acetylcholine, which activates smooth muscles, skeletal muscles, glands, and other nerves, and also has some inhibitory effects. The parasympathetic nerves also secrete the enzyme, cholinesterase, which destroys acetylcholine. However, many other types of cell (red blood cells, fibroblasts, sympathetic nerves, marrow cells), maybe all cells, can secrete cholinesterase.
>
> Because cholinergic nerves have been opposed to the sympathetic, adrenergic, nerves, there has been a tendency to neglect their nerve exciting roles, when looking at causes of excitotoxicity, or the stress-induced loss of brain cells. Excessive cholinergic stimulation, however, can contribute to excitotoxic cell death, for example when it's combined with high cortisol and/or hypoglycemia.
>
> Drugs that block the stimulating effects of acetylcholine (the anticholinergics) as well as chemicals that mimic the effects of acetylcholine, such as the organophosphate insecticides, can impair the ability to think and learn. This suggested to some people that age-related dementia was the result of the deterioration of the cholinergic nerves in the brain. Drugs to increase the stimulating effects of acetylcholine in the brain (by inactivating cholinesterase) were promoted as treatment for Alzheimer's disease. Although herbal inhibitors were well known, profitable new drugs, starting with Tacrine, were put into use. It was soon evident that Tacrine was causing serious liver damage, but wasn't slowing the rate of mental deterioration.

### Source 7 — Autonomic systems

Ray Peat · Article · 2006 · https://raypeat.com/articles/other/autonomic-systems.shtml

> Although mast cells have been known to be a common component of tumors for many years, it is only recently that antihistamines and other antiinflammatory drugs have been recognized as valuable therapies in cancer. The whole issue of the role of nerves in tumor development and physiology has been submerged by the mystique of the “intrinsically bad cancer cell.”
>
> In Alzheimer’s disease, there has been a great investment in the doctrine that drugs to promote the function of cholinergic (acetylcholine forming) nerves will restore lost mental function, or at least retard the progression of the disease. The success of anti cholinergic drugs in treating several degenerative brain diseases is probably embarrassing to the companies whose cholinergic-intensifying drugs aren’t very successful. Conveniently for them, these formerly “anticholinergic” drugs are now being called anti-excitotoxic or anti-glutamatergic drugs. There is no serious conflict in the terminology, since the cholinergic processes (like the serotonergic processes) are closely associated with excitotoxic nerve damage. The cholinergic drugs will probably be sold as long as their patents are effective, and then will be quietly forgotten.
>
> The modern conception of pharmacology, with receptors and transmitters turning functions on or off, has turned into an unproductive and dangerous scholasticism. No one will ever successfully count the number of transmitter angels dancing on the variable sites of the variable receptor molecules.
>
> The functional “meaning” of a receptor or transmitter changes according to circumstances, and the effect of activating a particular nerve depends on surrounding conditions, and on preceding conditions. Each cell integrates stimuli adaptively.
>
> If no reflex is simply mechanical and innate, then all reflexes are conditional. (M. Merleau-Ponty argued against the validity of the reflex concept itself, because of this conditionality.)
>
> P. K. Anokhin’s concept of the “Acceptor of Action” (described in my book, Mind and Tissue ) provides an image in which we can see the “set-points” for the relatively “autonomic” reflexes as reflections of the general needs of the organism. The local tissue reflexes, the organ reflexes, the spinal reflexes, etc., are variable, according to their energetic resources, and according to the way in which they are organized under the influence of the cerebral cortex and the environment.

### Source 8 — Bioenergetic Helpline #14: Heroic Medicine, Progesterone Cycling, Eggnog, Hypertension, Cancer

Danny Roddy · Interview · May 26, 2026 · https://www.youtube.com/watch?v=rbWSdTQARy4

> **Danny Roddy:** Acetylcholine and the cholinergic system are some of the things I probably know the least about. But a long time ago, I used to take paracetam before going to work. And I think paracetam's big future was to increase acetylcholine. And I remember it making me feel like, hell, you feel super high strung from it. And so when Ray was saying that it was associated with nitric oxide and it's part of the stress system, I was not surprised. I bet that flushing is some mixture of histamine and nitric oxide. And besides trying an antihistamine, I think aspirin in different doses might be valuable for something like that. Yeah, without knowing too much about it, I'm sure it's just some mast cell activation, release of histamine, nitric oxide, et cetera.
>
> **Caller:** Yeah, no, I've been taking a ciproabdidine, and I honestly can't tell because I started taking it when the temperature outside started to really get hot, so I can't really tell if it's helping. But do you know what they mean by serum factor?
>
> **Danny Roddy:** That sounds like maybe they don't know what's going on.

### Source 9 — Maintain Your Brain w/Georgi Dinkov & Constantine Kanargelidis

Georgi Dinkov · Interview · Dec 31, 2022

> **Georgi Dinkov:** So the cholinergic theory of Alzheimer's has already been debunked. I mean, they tried so many drugs that increase, they tried supplementing people with choline, right? Acetylcholine. They tried giving people drugs that inhibit the enzyme cholinesterase, which breaks down acetylcholine, right? None of these things work. In fact, made the situation worse. And I think this flawed reasoning stands on the fact that back in the day they saw that choline is actually a brain excitant. So if you have somebody who is like in an extremely sluggish state, like an animal that has been hibernating, you give them a little bit of acetylcholine, they kind of perked up, right? And they thought, wow, must have a cognitive enhancing effect. It doesn't. In fact, acetylcholine is a brain excitotoxicant, very similar in effect to estrogen. And in fact, now we know that estrogen manifests all of its negative effects through only two systems, by activating the cholinergic system and by activating the histaminergic system. Conversely, antihistamine drugs act like partial anti-estrogens, and anticholinergic drugs act as partial anti-estrogens. If estrogen is one of the causes of Alzheimer's, as you said, the incidence of Alzheimer's is like 4 to 1 or even 5 to 1. in favor of females, right? We know that estrogen is involved. Then giving things that can block estrogen should be beneficial. It's already been shown that progesterone, which is also anticholinergic, has very good pro-mnesic effects in animal models. Prenanolone, which is also anticholinergic, not very well known, but you can find it in Google if you type, also very strong pro-cognitive, pro-mnesic effect, anti-dementia. So really, I think the argument for the anticholinergic drugs stems from the old hypothesis, which now has been dropped. There are no new cholinergic drugs on the market. It stems from the old hypothesis that giving acetylcholine will actually perk up the brain. it will excite it, right?

### Source 10 — Learned Helplessness KMUD 2013

Ray Peat · Interview · 2013 · http://www.l-i-g-h-t.com/files/herb-doctors-learned-helplessness-nervous-system-and-thyroid-questionaire.mp4

> **Ray Peat:** The brain processes that allow learning and intelligent behavior, the cholinergic nerves of the brain are very important in that, as well as the serotonin, adrenaline (several other types of nerves have to be functioning). But several types of evidence made doctors concentrate on the loss of the cholinergic system. If you stimulate the cholinergic nerves, you can improve learning and behavior; but if you aren't increasing energy to keep up with that increased stimulation, you put the cell in a stress between having to work harder, but not having the fuel to do it. So if your cortisol is high, for example, interfering with your ability to use sugar, or if your blood sugar is simply low and you are being stimulated, then the cell tends to die. The reasoning that the Alzheimer's disease was simply a wasting away of the cholinergic nerves led to treating it for the first 10 or 15 years just with chemicals to increase excitation of the cholinergic nerves; and that wasn't working at all (people were dying at a higher rate than liver disease, and such). But from the 1950’s, people were already suggesting treating dementia and other brain degenerative diseases with atropine and other chemicals that block the cholinergic nerves. And amantadine, which is now used for treating Parkinson's disease, was one of the chemicals considered anti-cholinergic in the 50’s, 60’s and 70’s. Since people were seeing actual improvement with the anti-cholinergic chemicals, someone said: “Why not try adding that to the treatment?”(- Instead of stopping the excitatory cholinergic drugs, “Why not add one of these?”-). So, they reclassified them as acting against another excitatory nervous system, the system that causes glutamate (MSG) nerve toxicity. So they now call it an anti-NMDA chemical, “memantine”, which is similar to amantadine. So, it's a very similar chemical, which used to be called anticholinergic, that’s being used for both Parkinson's and Alzheimer's disease.

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