Cholinesterase Inhibitors


Cholinesterase inhibitors (CIs) are neurotoxins which inhibit the action of cholinesterase enzymes.  The body uses cholinesterase to break down the neurotransmitter acetylcholine.  Inhibition of cholinesterase interferes with the propogation of signals from the brain and central nervous system (CNS) to command various systems in the body controlled by use of acetycholine. 

CIs are naturally produced by certain plants, benefitting the plant by killing or disabling pests which try to eat it.  People also produce them for use as pesticides and nerve gasses.  The dangers of acute cholinesterase inhibitor poisoning are well documented (see refs [1], [11], and [14]).  However, the effects of chronic low level exposure to CIs are less well documented or understood. 

We are constantly exposed to low levels of CIs through the food we eat -- both from the residue of CI pesticides and from the naturally occurring CIs present in the tissues of many vegetables and fruits.  In susceptible individuals, normal levels of exposure in the diet can cause health and quality of life problems, though others eating the same diet notice no untoward effects. 

I will use the term "Cholinesterase Inhibitor Sensitivity", or CIS for short, to designate those who suffer negative effects when exposed to CIs at levels found in their normal diet, but who would experience a relief of such symptoms if they were to follow a diet which sufficiently reduces their exposure.  Information on avoiding foods containing CIs can be found here.  This term is inclusive of Nightshade Sensitivity since nightshade foods (potato, tomato, eggplant, peppers, and a few others) are the primary source of dietary CI exposure for most people.  However, there are other sources of CI exposure which are not nightshade related, and I wanted to use a more inclusive term to reflect this.

The effects of CIS which can directly be linked to the effects of cholinesterase inhibition include intermittent and recurrent dysfunctions of muscles (spasms, cramps, twitches, muscle pain, etc.), gastrointestinal system (diarrhea, abdominal pain, etc.), poor sleep, exaggerated stress response, and anxiety (see below for more details).  Sources which address Nightshade Sensitivity mainly focus on arthritis, pain, and inflammation.  See the "Cholinesterase inhibitor effects" section below for more details.

Unfortunately, the general public is unaware of this issue, and doctors are not trained to recognize or diagnose it.  The effects are widespread across multiple systems, each of which is handled by a different medical specialty.  A sufferer is not likely to see or investigate the overall pattern, but rather focus on whatever one issue is most disruptive at a given point in time and discuss only that issue with an appropriate medical practitioner.  Tests come up negative, since neither the commands from the CNS nor the systems being controlled are at fault, and doctors don't know to suspect that the messaging between the two may be interfered with.  The likely result is that it will either be treated as a psychiatric problem (such as somatoform disorder), or one of a set of chronic functional syndromes which are consistent with the reported symptoms but which have no known cause (such as IBS or dysautonomia). 

I am not claiming that everyone suffering from these sorts of symptoms and diagnoses suffers from CIS, but I bet some do.  I want to find ways to help them.  If CIS is what's causing or exacerbating such symptoms for a given individual, then the symptoms can be improved by methods which decrease the effective ACh/DA ratio (see below). 

There are no tests to detect CIS, though that's a dream I'm working on.  The only way to know if it's CIS or not is to try the diet modification and see what happens.  Note that it may take a few weeks to notice the effects, and months before all the effects go away.  This is because at least some of the cholinesterase inhibiting substances, particularly the solanaceous glycoalkaloids (SGA) present in nightshade foods, build up in your tissues and are re-released slowly over time (see ref [9]). 

People can't discover whether or not this would help them if they don't know about it.  That is why I'm trying to collect together here what I've learned so far so that others may benefit.  I hope it helps. 

Please comment here if you have relevant experiences to share, or if there are points which require further clarification.

How do cholinesterase and cholinesterase inhibitors work?

We tend to think of nervous system signalling as electrical in nature.  However, this mostly applies to the propagation of the signal within a given nerve cell and its associated fibers.  The body uses chemical messengers (neurotransmitters) to bridge the gap (synapse) between the end of a nerve fiber sending a message (presynaptic cell) and receptors on the membrane of the cell which the nerve impulse is meant to activate (postsynaptic cell).  The body uses a variety of different types of synapses and neurotransmitters for various purposes.  The most notable uses of cholinergic synapses (that is, ones using acetylcholine for transmission) are in controlling muscle contraction and the autonomic nervous system

When an action potential arrives at the presynaptic side of a cholinergic synapse, acetylcholine is released into the synaptic cleft, and drifts over to bind to receptors on the postsynaptic side causing the desired action, such as muscle contraction.  Cholinesterase breaks down the acetylcholine, clearing the receptors, allowing the postsynaptic side to relax, and resetting the synapse in preparation for the next signal. 

At least, that's the way it's supposed to work.  If the cholinesterase is inhibited then the release step may not work right, causing the receptors to be occupied for longer than they should be, and the postsynaptic side to get stuck in the activated state.  This can cause problems. 

Imagine the presynaptic side of a cholinergic synapse as a morse code operator.  When he wants to send a message (a dot or a dash), he presses the code key down to complete a circuit and send a pulse.  After the right amount of time (short for a dot, long for a dash) he lets go of the key.   He trusts the spring in the code key to break the circuit in a timely fashion. 

The operator holding down the code key corresponds to acetylcholine being released into the synapse.  Receptor activation happens while the key is down and completing the circuit.  Cholinesterase breaking down the acetylcholine is the spring that breaks the circuit.  Cholinesterase inhibitors, when present, interfere with the proper functioning of the spring and may cause the key to get stuck down for longer than it should.

In the absence of cholinesterase inhibitors everything works fine, and what the recipient receives is the same as what the operator intended to send.  However, in the presence of cholinesterase inhibitors, the spring becomes unreliable: the code key randomly sticks, and the messages get munged. The length of the activated parts (dots and dashes) get lengthened, the intervening spaces get shortened or left out, and what the recipient receives doesn't match what the sender intended. 

Also, just as gravity pulls down on the code key even when the operator is not intentionally pressing it down, presynaptic membranes leak small amounts of acetylcholine even in the absence of intentional action potentials.  Normally the spring can be relied on to prevent this from being an issue.  However, in the presence of cholinesterase inhibitors it may make contact and send a blip by itself. 

Whether or not the key actually gets stuck or blips at any given time is probabilistic.  As the concentration of cholinesterase inhibitor increases, the probability of the key sticking or blipping also increases.   In cholinergic synaptic transmission, the key getting stuck corresponds to the action triggered on the postsynaptic side to continue for too long.  For example, in muscle signalling the "key sticking" results in muscles being contracted for longer than they should, and "blipping" result in random involuntary muscle twitches

Cholinesterase inhibitor effects

We mostly aren't able to perceive the effects of CIs on individual cholinergic nerve activations.  It is the overall increase in cholinergic tone that causes problems.  This means that the systems which use acetylcholine to signal activation become more active than they should -- more active than the central nervous system is really trying to command them to be.  It's like turning up the gain on an amplifier: for the same amount of input signal you get a bigger effect.  The higher the level of CIs in your system, the higher the gain gets.  The diagram here shows which systems are affected (the diagram is from a set of environmental course materials here).

A major repercussion of this is that it increases the effective acetylcholine/dopamine (ACh/DA) ratio.  When this ratio is too high, either by increased acetylcholine (ACh) tone, or decreased dopamine (DA) tone, it can cause problems.  Factors which increase acetylcholine tone, such as CI levels and stress, make these problems worse.  Factors which increase dopamine tone, such as exercise and positive/empowering life events make these problems better.  See the "Improving Ach/DA ratio" section below for more details.

The following is a list of symptoms which I have found to be caused or exacerbated by these effects:
  • Voluntary muscle problems: can cause a range of problems including excess muscle tension, decreased agility, muscle cramps, tremors, spasms, muscle weakness, and increased formation of trigger points (positive feedback loops where muscles continue to stay contracted until released by an outside force, such as massage). 
  • Involuntary muscle problems: disrupts proper peristalsis in the GI tract leading to motility problems (such as diarrhea), intestinal spasms, and abdominal pain.  This can also lead to problems with nutrient absorption and proper maintenance of gut flora due to food not spending the appropriate amount of time at each stage of the GI tract.  This may be diagnosed as "irritable bowel syndrome" (IBS), a functional syndrome which covers these types of GI symptoms without reference to the cause.  Interestingly, medications prescribed for treating the intestinal spasms and abdominal pain of IBS, such as dicyclomine, work by decreasing the sensitivity of muscarinic acetylcholine receptors.  
  • Excessive stress response: increases release of stress chemicals (epinephrine/adrenaline, etc.) and sympathetic nervous system (fight or flight) activation in respose to a given stimulus (see ref [2]).  This makes life events seem more threatening and harder to cope with.  It may also exacerbate problems of addiction: drugs of addiction mostly increase dopamine, which provides short-term relief from these effects.
  • Sleep problems: increases awareness during sleep and vividness of dreams; decreases soundness of sleep.  This means that you're more likely to know if anything happens while you're asleep, but less likely to wake up refreshed in the morning.  There is even a product containing the CI galanthamine which aims to exploit this effect to cause more vivid dreams.  Their claims about the neurochemical mechanisms seem correct.  However, they don't mention the down side: less refreshing sleep.
  • Mood/psychiatric problems: increases anxiety (see Excessive stress response above and ref [15]).  I believe that sufficiently high ACh/DA ratio can cause many of the same physiological effects seen in depression (irritability, tension, loss of energy, changes in appetite, changes in sleep pattern, etc.).  I speculate that the combination of those effects with negative beliefs about their meaning and impact on personal worth can indeed lead to depression.  (It's a question of semantics whether those physiological effects in the absence of such beliefs and low mood should be called depression or not.  I would say not.  I'm not sure anyone else would agree.)
  • Inflammation/arthritis: Sources which address Nightshade Sensitivity mainly focus on arthritis, pain, and inflammation.  It is not clear to me the extent to which those effects are directly caused by cholinesterase inhibition versus other properties of nightshade toxicity.  However, many people have found that these effects go away when nightshades are eliminated from their diet, and recur if they are reintroduced.  Dr. Norman Childers in particular includes many letters describing such experiences in his book, Arthritis-- Childer's Diet That Stops itGloria Gilbère and Michael Fowler have also written books describing similar experiences.  This indicates to me that arthritis, pain, and inflammation should also be considered as potential effects of CIS even if the mechanisms are less clear. 
  • Metabolic instability?: I have found that a sufficiently high ACh/DA ratio can cause effects consistent with low metabolism: slow movement, feeling cold, not feeling hungry, not losing weight despite decreased food consumption.  At intermediate levels, it causes the opposite effect: fast movement, feeling warm, increased appetite, not gaining weight despite increased food consumption.  These changes seem to happen randomly.  I call the former "slow mode" and the latter "fast mode."  They look like either moving in and out of depression, bipolar disorder, or changes in thyroid function (depending on the proclivities of the viewer). 

Populations at risk of CIS

The following factors likely increase the risk of experiencing negative effects from dietary and/or environmental CI intake:
  • People who have a decreased ability to detoxify CIs.  This may be caused by genetic polymorphisms, such as those affecting the ACHE, BCHE, and PON1 genes.  It may also include those whose AChE (acetylcholinesterase), BuChE (butyrylcholinesterase), and/or PON (paraoxonase) enzymes are less prevalent or less efficient for other reasons.  Possible reasons could include age (levels are lower in small children and the elderly), poor nutritional status, or impaired liver function.
  • People chronically under high stress.  In this case high ACh leads to a decreased margin before ACh/DA ratio becomes a problem.
  • People who have conditions causing low dopamine tone, such as Parkinson's Disease (PD) or dopamine deficiency.  Certain genetic polymorphisms affecting dopamine metabolism, such as those affecting the COMT gene, may also contribute.  In this case low DA increases the ACh/DA ratio.

Improving ACh/DA ratio

If such problems are caused or exacerbated by CI levels, avoiding CIs should reduce these symptoms.  If you experience metabolic instability, this approach may move you from "slow mode," through "fast mode," then into a more balanced state over the course of weeks.  If such problems are caused or exacerbated by low dopamine levels, they may respond to treatments such as dopamine reuptake inhibitors (like bupropion, which is used either for depression (Wellbutrin) or smoking cessation (Zyban)) or PD medication.  Both approaches may be beneficial. 

Exploring the former option can be done at home on your own by modifications to your diet and environmental exposure.  The latter option requires medical assistance from a psychiatric or motion specialist. 

The severity of ACh/DA ratio related issues also vary at a smaller time scale (ups and downs during the course of each day) in response to thoughts and experiences which increase or decrease the ratio.  Those which increase stress and/or decrease dopamine, such as negative interpersonal interactions, perceived failures, received criticism, etc. make these problems worse.  Those which decrease stress and/or increase dopamine, such as meditation, exercise, loving interactions with people or pets, helping people, perceived successes, positive feedback, etc. make these problems better.  See this blog post for further ideas of what factors influence dopamine levels.

ACh/DA ratio and addictive substances

It may be tempting to seek short-term relief of these symptoms through more easily available means for increasing dopamine, such as cigarettes or other non-prescription drugs.  You may already be doing so.  I recommend against this path, as the addictive potential and side effects on long-term quality of life can be severe.  They also desensitize dopamine receptors over time. leading to increasing ACh/DA ratio problems.

Cigarette smoking is of particular concern because tobacco is a nightshade and thus contains SGA (the CI present in all nightshades).  The short term effect of increasing dopamine may provide immediate decrease in the ACh/DA ratio and relieve related problems.  However, in the long term, it can exacerbate build up of SGA in your system and increase your ACh/DA ratio, further fueling the cycle of dependence. 

The good news is that decreasing CIs in your system can potentially make it easier to stop smoking.  Both  Dr. Norman Childers and Michael Fowler comment on this effect in their books on nightshade.  I suspect that changes leading to a decrease in ACh/DA ratio can also help with other problems of addiction/dependency. 


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