New video: Is acetylcholine toxicity the cause of CFS?

Emootje

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http://www.youtube.com/watch?v=n8j3BWeMOuo

Acetylcholine toxicity stimulates the sympathetic nervous system (fight or flight response) and the parasympathetic nervous system (rest and digest response)
The dysautonomia caused by this acetylcholine toxicity could explain the symptoms of CFS.

Symptoms of Parasympathetic Activation
Decreased heart rate
Pupil constriction
Blurred vision
Excess salivation
Lacrimation
Rhinorrhea
Bronchorrhea
Bronchospasm
Abdominal cramps
Nausea
Urinary retention

Symptoms of Sympathetic Activation
Immunosuppression (resulting in secondary infections)
Increased heart rate
Decreased digestive function
Nausea
Gastroparesis
Pupil dilatation
Paleness
Excessive sweating
Anxiety
Irritability

WhatIncreasesAcetylcholine
Organophosphate pesticides (cholinesterase inhibitors)
Carbamate pesticides (cholinesterase inhibitors)
Neonicotinoid pesticides (nicotinic agonists)
Nightshade foods (cholinesterase inhibitors)
Huperzine A (cholinesterase inhibitor)
Nicotine (nicotinic agonists)
Choline, Citicholine, L-Alpha Glycerylphosphorylcholine
Fluoride
Electromagnetic radiation
Alzheimer medication (galantamine, rivastigmine, donepezil)
Myasthenia gravis medication (pyridostigmine, neostigmine)
Nerve agents (e.g. sarin, VX, soman)
 

lucy

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Great video, summarizes so much info in an efficient way. I was reading about AcH too a few weeks ago, and got lost in all the chemistry. I concluded, that it is important to be aware of it and hoped to digest the info over a longer period of time.

Also I decided to observe reactions to related foods. Related foods are the sources of choline, which is the precursor to AcH. And for example I feel great if I eat lots of broccoli and meat which are the sources of choline too. But then it is never clear, vegs are full of many other minerals/vitamins, so only pure Ach injection would show - according to the hypothesis, the reaction would be the same as cfs flare.

For me Ach is also interesting due to my readings about vagus nerve. Personally, I have concluded my vagus nerve is dysfunctional as I am getting palpitations just after eating, and vagus nerve endings are full of receptors for AcH. I think for some people with cfs, AcH could be an important player, while for others some similar competing chemicals, as it is probable that there are multiple paths of dysfunction, I imagine it like a tree, where the result is cfs.
In any case awareness is plausible.
 

richvank

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http://www.youtube.com/watch?v=n8j3BWeMOuo

Acetylcholine toxicity stimulates the sympathetic nervous system (fight or flight response) and the parasympathetic nervous system (rest and digest response)
The dysautonomia caused by this acetylcholine toxicity could explain the symptoms of CFS.

Symptoms of Parasympathetic Activation
Decreased heart rate
Pupil constriction
Blurred vision
Excess salivation
Lacrimation
Rhinorrhea
Bronchorrhea
Bronchospasm
Abdominal cramps
Nausea
Urinary retention

Symptoms of Sympathetic Activation
Immunosuppression (resulting in secondary infections)
Increased heart rate
Decreased digestive function
Nausea
Gastroparesis
Pupil dilatation
Paleness
Excessive sweating
Anxiety
Irritability

WhatIncreasesAcetylcholine
Organophosphate pesticides (cholinesterase inhibitors)
Carbamate pesticides (cholinesterase inhibitors)
Neonicotinoid pesticides (nicotinic agonists)
Nightshade foods (cholinesterase inhibitors)
Huperzine A (cholinesterase inhibitor)
Nicotine (nicotinic agonists)
Choline, Citicholine, L-Alpha Glycerylphosphorylcholine
Fluoride
Electromagnetic radiation
Alzheimer medication (galantamine, rivastigmine, donepezil)
Myasthenia gravis medication (pyridostigmine, neostigmine)
Nerve agents (e.g. sarin, VX, soman)
Hi, emootje.

For what it's worth, if my hypothesis about ME/CFS is valid, it is more likely that there will be a deficiency of acetylcholine, rather than too much, producing toxicity. The reason is that the production of phosphatidylcholine in the body, from which choline can be derived to make acetylcholine, is one of the two main users of methylation, and there appears to be a methylation deficit in most cases of ME/CFS, due to a partial block of methionine synthase in the methylation cycle.

I think that a deficiency of acetylcholine is consistent with the high sensitivity to acetylcholine that was observed by Vance Spence's group in Scotland a few years ago. I also think that the MRS experiments that were interpreted as showing elevation of choline in ME/CFS were misinterpreted by assuming that creatine is at normal levels. The problem is that creatine synthesis is the main user of methylation in the body, and creatine is also likely to be low.

Best regards,

Rich

Best regards,

Rich
 

leaves

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Interesting Rich, could you tell more? I find that supplements that increase acetylcholine (eg acetylcarnitine and pregnenelone ) clear brain fog. Phospatidylcholine doesnt. Could you explain? Is it an acetyl defficiency?
 

Emootje

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lucy Palpitations after eating sounds more like increased sympathetic tone. If my hypothesis is right you will improve by eating a diet low in cholinesterase inhibitors (organic foods and no nightshade foods) I agree with your multiple path of dysfunction in CFS. Increased acetylcholine could be humble player. Thanks

@ Rich If the body was low in acetylcholine, PWC would also have low sympathetic tone because the preganglionic sympathetic fibers uses acetylcholine as a neurotransmitter. Many studies found high sympathetic tone or high noradrenalin levels in PWC which supports high levels of acetylcholine in the nervous system. I think the problem lies more in the degradation of acetylcholine then in the synthesis of acetylcholine. Measurement of acetylcholine in the blood is not possible therefore we must navigate on the parasympathetic symptoms to estimate acetylcholine levels.
Thanks you for your comment
P.S. I suspect that improving methylation would stimulate organphophate detoxification. Is that right?
 

richvank

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Interesting Rich, could you tell more? I find that supplements that increase acetylcholine (eg acetylcarnitine and pregnenelone ) clear brain fog. Phospatidylcholine doesnt. Could you explain? Is it an acetyl defficiency?
Hi, leaves.

Thanks for sharing your experience. I think it is certainly possible to have low acetate in ME/CFS. Acetyl CoA is what feeds the Krebs cycle, and I have seen many urine organic acid panel results from PWMEs that are low in citric acid, which is the substance that acetyl CoA is converted into by the first reaction in the cycle. Many PWMEs are not able to convert pyruvate, from the glycolysis pathway, into acetyl CoA very well, judging from their test results. This conversion requires several of the B vitamins, magnesium, and lipoic acid.

So I think difficulty in making acetylcholine could be due either to low choline or low acetyl CoA, or both.

Best regards,

Rich
 

richvank

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@ Rich If the body was low in acetylcholine, PWC would also have low sympathetic tone because the preganglionic sympathetic fibers uses acetylcholine as a neurotransmitter. Many studies found high sympathetic tone or high noradrenalin levels in PWC which supports high levels of acetylcholine in the nervous system. I think the problem lies more in the degradation of acetylcholine then in the synthesis of acetylcholine. Measurement of acetylcholine in the blood is not possible therefore we must navigate on the parasympathetic symptoms to estimate acetylcholine levels.
Thanks you for your comment
P.S. I suspect that improving methylation would stimulate organphophate detoxification. Is that right?
Hi, Emootje.

I think you make a very good point here. It's true that acetylcholine is also involved in the sypathetic nervous system. However, it may be that the sympathetic nervous system is able to access the substrates for synthesizing acetylcholine with a higher priority, built into the biochemistry, so that when there is a scarcity, the parasympathetic system may suffer more.
But I don't know. You might be right.

It is possible to measure acetylcholine in the platelets. Health Diagnostics and Research Institute (and its parent lab, the European Laboratory of Nutrients there in the Netherlands) does offer this test.

Yes, I would expect that improving methylation would indeed help the detox of organophosphates, since glutathione participates in that, and lifting the partial block in the methylation cycle causes glutathione to come up to normal, as we found in our clinical study using the methylation pathways panel from this same lab.

Best regards,

Rich
 

leaves

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Yes!! Lipoic acid does it too!! Awesome .. Making sense..
:D thanks!

Eta: citrates don't do anything for me I don't think tho. Is that possible?
Hi, leaves.

Thanks for sharing your experience. I think it is certainly possible to have low acetate in ME/CFS. Acetyl CoA is what feeds the Krebs cycle, and I have seen many urine organic acid panel results from PWMEs that are low in citric acid, which is the substance that acetyl CoA is converted into by the first reaction in the cycle. Many PWMEs are not able to convert pyruvate, from the glycolysis pathway, into acetyl CoA very well, judging from their test results. This conversion requires several of the B vitamins, magnesium, and lipoic acid.

So I think difficulty in making acetylcholine could be due either to low choline or low acetyl CoA, or both.

Best regards,

Rich
 

richvank

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Yes!! Lipoic acid does it too!! Awesome .. Making sense..
:D thanks!

Eta: citrates don't do anything for me I don't think tho. Is that possible?
Hi, leaves.

Citrate is downstream of acetyl CoA in the Krebs cycle, so supplementing citrate would probably not boost acetyl CoA. So if a deficit in acetyl CoA is actually the issue for you, this would still be consistent with that.

Best regards,

Rich
 

Emootje

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Anybody ever thought of the possibility the acetylcholine receptors might be deformed?
Hi Lansbergen,
From the Vance Spence's study, mentioned earlier in my film and by Rich:
The response to acetylcholine was significantly higher in patients with CFS than in controls
(Acetylcholine is degraded by cholinesterase)
There were no significant differences from control in the methacholine response for the CFS (P=0.132), GWS (P=0.484) or OPE (P=0.069) groups
(Methacholine is resistant to breakdown by cholinesterase)

Proving that high sensitivity to acetylcholine in the vascular endothelium is caused by low cholinesterase levels and not by acetylcholine receptors abnormalities.
Emootje

http://www.clinsci.org/cs/106/0183/1060183.pdf
 

Emootje

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Hi, Emootje.

I think you make a very good point here. It's true that acetylcholine is also involved in the sypathetic nervous system. However, it may be that the sympathetic nervous system is able to access the substrates for synthesizing acetylcholine with a higher priority, built into the biochemistry, so that when there is a scarcity, the parasympathetic system may suffer more.
But I don't know. You might be right.

It is possible to measure acetylcholine in the platelets. Health Diagnostics and Research Institute (and its parent lab, the European Laboratory of Nutrients there in the Netherlands) does offer this test.

Yes, I would expect that improving methylation would indeed help the detox of organophosphates, since glutathione participates in that, and lifting the partial block in the methylation cycle causes glutathione to come up to normal, as we found in our clinical study using the methylation pathways panel from this same lab.

Best regards,

Rich
Hi Rich,

If PWC have a low parasympathetic tone, would it be likely that they have anticholinergic symptoms, like a dry mouth? My sympathetic tone is increased (noradrenaline = 4,44 nmol/l) but I never experienced any anticholinergic symptoms. On the contrary, the amount of mucus in my mouth and nose indicates a high parasympathetic tone. I realize that my situation does not apply to the whole CFS group. So you could be right for the dry mouth CFS group and I could be right for the drooling CFS group.

Dr. Shattock has confirmed your suspicion in a article about organophophates (OP) and autism:

"Since it is not possible to avoid intake of OP pesticides through food and through drinking and bathing water without taking extreme precautions, we must assume that we all eat, drink and absorb such compounds. However, not everyone develops Autistic Spectrum Disorders, ADHD, Dyslexia, Asthma, Parkinsons disease, Gulf War Syndrome or other conditions for which OPs are sometimes blamed. Most of us have the genetic ability to break down OP pesticides using a number of genetically controlled systems. The enzymes paraoxanase 1 and 2 are known to be involved but sulphation and methylation are also involved. Deficiencies in any of these systems could result in elevated levels of OPs remaining in the body. It has been well documented that people with ASDs have inefficient systems for sulphation 19,20,21 and methylation and glutathione-based systems 22. There is also preliminary evidence that at least one of the genes controlling paraoxanase production (PON1)23 is aberrant in some subjects with ASDs and we are currently attempting to replicate this, using PCR techniques, on subjects from various parts of the world"
http://www.espa-research.org.uk/linked/iagandtryptophan.pdf

Thanks for the information.
Emootje
 

richvank

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Hi Lansbergen,
From the Vance Spence's study, mentioned earlier in my film and by Rich:
The response to acetylcholine was significantly higher in patients with CFS than in controls
(Acetylcholine is degraded by cholinesterase)
There were no significant differences from control in the methacholine response for the CFS (P=0.132), GWS (P=0.484) or OPE (P=0.069) groups
(Methacholine is resistant to breakdown by cholinesterase)

Proving that high sensitivity to acetylcholine in the vascular endothelium is caused by low cholinesterase levels and not by acetylcholine receptors abnormalities.
Emootje

http://www.clinsci.org/cs/106/0183/1060183.pdf
Hi, emootje.

I suggest that Vance Spence's group was led astray in their interpretation of their results by a previous misinterpretation of the results of MRS measurements in CFS. These MRS measurements were of the ratio of choline to creatine. The researchers ASSUMED that creatine was at normal levels, and because the ratio was high, they concluded that choline was high in CFS. Vance Spence's group accepted this, and that's why they didn't consider that the elevated sensitivity they observed to acetylcholine could be due to low acetylcholine in CFS, which causes higher expression of acetylcholine receptors as a compensation.

The problem with this, in my opinion, is that both creatine and choline require methylation for their synthesis in the body, and in fact, these two syntheses are the largest users of methylaion. Thus, both creatine and choline production are low in CFS. Creatine is affected more by the methylation deficit, and that causes the ratio of choline to creatine to be higher than normal. but I expect that both creatine and choline are low. It is possible to make absolute measurements by the use of phantoms in MRS research, and I'm hopeful that this will be done, so that we can see whether the absolute level of choline is indeed low in CFS.

There was one MRS study that normalized to the water peak rather than the creatine peak, and also found a higher than normal choline to water ratio in CFS. However, people with CFS often have what is interpreted as "mild" diabetes insipidus (not the same as diabetes mellitus) and as a result are low in water, too. So I think these conclusions are based on "shifting sands." Absolute level measurements need to be done. Dr. Dikoma Shungu at Cornell may be able to do this.

I don't think that the methacholine comparison proves that the problem is with the cholinesterase. Methacholine is a synthetic analog of acetylcholine, that is not normally found in the body. Vance Spence's group found that the PWCs responded similarly to both. If they had a high expression of acetylcholine receptors, as I am suggesting, I think that would be consistent with their results.

Best regards,

Rich
 

richvank

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Hi Rich,

If PWC have a low parasympathetic tone, would it be likely that they have anticholinergic symptoms, like a dry mouth? My sympathetic tone is increased (noradrenaline = 4,44 nmol/l) but I never experienced any anticholinergic symptoms. On the contrary, the amount of mucus in my mouth and nose indicates a high parasympathetic tone. I realize that my situation does not apply to the whole CFS group. So you could be right for the dry mouth CFS group and I could be right for the drooling CFS group.

Dr. Shattock has confirmed your suspicion in a article about organophophates (OP) and autism:

"Since it is not possible to avoid intake of OP pesticides through food and through drinking and bathing water without taking extreme precautions, we must assume that we all eat, drink and absorb such compounds. However, not everyone develops Autistic Spectrum Disorders, ADHD, Dyslexia, Asthma, Parkinsons disease, Gulf War Syndrome or other conditions for which OPs are sometimes blamed. Most of us have the genetic ability to break down OP pesticides using a number of genetically controlled systems. The enzymes paraoxanase 1 and 2 are known to be involved but sulphation and methylation are also involved. Deficiencies in any of these systems could result in elevated levels of OPs remaining in the body. It has been well documented that people with ASDs have inefficient systems for sulphation 19,20,21 and methylation and glutathione-based systems 22. There is also preliminary evidence that at least one of the genes controlling paraoxanase production (PON1)23 is aberrant in some subjects with ASDs and we are currently attempting to replicate this, using PCR techniques, on subjects from various parts of the world"
http://www.espa-research.org.uk/linked/iagandtryptophan.pdf

Thanks for the information.
Emootje
Hi, Emootje.

Sorry, I don't know whether a dry mouth would be expected with low parasympathetic activity. There may be other factors involved. I do find that a dry mouth is reported by quite a few PWCs. I have suspected that it is associated with low water content in the blood (low total blood volume) which I think is also common as a result of the diabetes insipidus (low secretion of antidiuretic hormone or arginine vasopressin).

Thanks for the reference from Dr. Shattock. Their group was one of the first to note the similarity in biochemistry between autism and ME/CFS.

Best regards,

Rich
 

leaves

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Wouldn't the low vasopressin explain everything? It reduces ACTH, blocks conversion of ribo into it's active form and therefore also the transformation from pryviate into coa, as well as b5 into p5p and the transformation to succinate (at least explains my test results )
 

lansbergen

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Hi Lansbergen,
From the Vance Spence's study, mentioned earlier in my film and by Rich:
The response to acetylcholine was significantly higher in patients with CFS than in controls
(Acetylcholine is degraded by cholinesterase)
There were no significant differences from control in the methacholine response for the CFS (P=0.132), GWS (P=0.484) or OPE (P=0.069) groups
(Methacholine is resistant to breakdown by cholinesterase)

Proving that high sensitivity to acetylcholine in the vascular endothelium is aused by low cholinesterase levels and not by acetylcholine receptors abnormalities.
Emootje

http://www.clinsci.org/cs/106/0183/1060183.pdf
Thanks

Now I am confused

I use an immunomodulator that also binds to postsynaptic achetylcholine receptors at a slighty different spot than acethylcholine.

I works for me but my explanation of why it works might be wrong.

It passes the BBB. It is in the brain within 10 minutes.

The first thing I noticed was that it very fast eased the horrible neuropathic pain for a few hours. I was very happy with that and it made me keep taking it.

It seems to do its job as an immunomodulator well. I gradual improved.

I still need it. When I forget to take it I am worse the next day.

I am happy it works for me but I want to know the how and why.

Can it be that the achetylcholine excess is irrelevant when an agonist binds to a slighty different spot at the receptor?
 

Emootje

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Hi, emootje.

I suggest that Vance Spence's group was led astray in their interpretation of their results by a previous misinterpretation of the results of MRS measurements in CFS. These MRS measurements were of the ratio of choline to creatine. The researchers ASSUMED that creatine was at normal levels, and because the ratio was high, they concluded that choline was high in CFS. Vance Spence's group accepted this, and that's why they didn't consider that the elevated sensitivity they observed to acetylcholine could be due to low acetylcholine in CFS, which causes higher expression of acetylcholine receptors as a compensation.

The problem with this, in my opinion, is that both creatine and choline require methylation for their synthesis in the body, and in fact, these two syntheses are the largest users of methylaion. Thus, both creatine and choline production are low in CFS. Creatine is affected more by the methylation deficit, and that causes the ratio of choline to creatine to be higher than normal. but I expect that both creatine and choline are low. It is possible to make absolute measurements by the use of phantoms in MRS research, and I'm hopeful that this will be done, so that we can see whether the absolute level of choline is indeed low in CFS.

There was one MRS study that normalized to the water peak rather than the creatine peak, and also found a higher than normal choline to water ratio in CFS. However, people with CFS often have what is interpreted as "mild" diabetes insipidus (not the same as diabetes mellitus) and as a result are low in water, too. So I think these conclusions are based on "shifting sands." Absolute level measurements need to be done. Dr. Dikoma Shungu at Cornell may be able to do this.

I don't think that the methacholine comparison proves that the problem is with the cholinesterase. Methacholine is a synthetic analog of acetylcholine, that is not normally found in the body. Vance Spence's group found that the PWCs responded similarly to both. If they had a high expression of acetylcholine receptors, as I am suggesting, I think that would be consistent with their results.

Best regards,

Rich
From another Vance Spence's study:
http://cfids-cab.org/cfs-inform/Coicfs/spence.etal04.pdf

"The results (Table 1) show that resting skin perfusion was normal and the peak responses to the single doses of ACh, BK and NO were also normal" (Peak ACh controls 92.2, Peak ACh CFS 88.3)

"The data demonstrated that the dynamics of the ACh stimulated blood flow response is significantly different in CFS patients compared with control subjects in that the action of ACh is prolonged in the CFS patientsthe blood flow recovery half times (t75 and t50) were 13.7 and 8.8 min and 24.5 and 15.1 min for control subjectsand CFS patients respectively"

If there was a high expression of acetylcholine receptors you would expect a high peak response and no prolonged response. The Vance Spence's group found a normal peak response and a prolonged response in the CFS patients which is consistent with low cholinesterase levels.
 

lansbergen

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In this paper I read:
Recent evidence in a very small group of patients suggested that CFS might be the consequence of a cholinergic dysautonomia and that treatment with cholinesterase inhibiting agents might well be therapeutic [27].Such a hypothesis is in direct contrast with the findings reported here so great caution is needed in treating an illness with such obvious heterogeneity.
The immunomodulator I use inhibits cholinesterase but that is not the reason I started taking it.

I searched for ref nr 27
Y. Kawamura, M. Kihara, K. Nishimoto, M. Taki, Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports, Pathophysiology 9 (2003) 189194.

Abstract

Chronic fatigue syndrome (CFS) is characterized by persistent mental and physical fatigue for at least 6 months. Its pathophysiology is unknown and there is no proven effective treatment. We describe three cases who fulfill the criteria of CFS, in whom a defect of neuromuscular transmission and dysautonomia are present and who respond to acetylcholine-esterase inhibition. Case 1: 18-year-old female with a 3-year history of CFS. Response of compound-muscle-action potential, recorded using surface recording electrode, over left abductor pollicis brevis muscle, to repetitive nerve stimulation (RNS) at a rate of 10 Hz showed a 42% incremental response. Composite autonomic scoring system (CASS) showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2). Serological tests for EpsteinBarr virus (EBV) revealed positive antiviral capsid antigens (anti-VCA) immunoglobulins G (IgG). Oral pyridostigmine therapy (30 mg) resulted in marked improvement in symptoms. Case 2: 28-year-old female with 10-year history of CFS. RNS, using identical protocol, showed a 60% incremental response over the same muscle. CASS showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2) and this patient was also positive for EBV. This patient responded dramatically to 10-mg pyridostigmine. Case 3: 29-year-old female with a history of CFS for longer than 15 years. Repetitive stimulation, using identical paradigm to left abductor pollicis brevis muscle, showed a 42% incremental response. CASS showed mildly cholinergic impairment (cardiovagal score: 2; sudomotor score: 1). EBV antibody titers were positive. Patient responded to 30-mg pyridostigmine with an improvement in her fatigue. These three cases generate the hypothesis that the fatigue in some patients with clinical CFS might be due to a combination of mild neuromuscular transmission defect combined with cholinergic dysautonomia. Support for this thesis derives from the improvement with cholinesterase inhibition.