New video: Is acetylcholine toxicity the cause of CFS?

[adreno]

One thing worth investigating in the cholinergic activities of ME/CFS patients in the fact that 50% of patients have have auto-antibodies to the acetylcholine muscarinic receptors. Reference: here, and also in this following study:




See also this study of anti-muscarinic autoantibodies in ME/CFS:

Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome


Autoantibodies to muscarinic receptors and beta-adrenergic receptors are also found in orthostatic hypotension:

Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an "autoimmune" orthostatic hypotension


And in Sjgren's syndrome (dry mouth), which a lot of ME/CFS patients suffer from, signal transmission in the parasympathetic nerves is inhibited by these muscarinic receptor autoantibodies, and this is the likely reason the saliva glands do not get fully activated:

Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjgren's syndrome

Antimuscarinic antibodies in primary Sjgren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells

Inhibitory effects of autoantibodies on the muscarinic receptors in Sjgren's syndrome

I believe an underactive parasympathetic can also cause circulation problems: cold hand and feet common symptoms in ME/CFS



So if in Sjgren's syndrome, these anti-muscarinic antibodies inhibit signal transmission in the parasympathetic nerves such that the saliva glands remain under activated, then these anti-muscarinic antibodies in ME/CFS patients will presumably be causing body wide inhibition of the parasympathetic nervous system.

I believe that the sympathetic/parasympathetic balance has an impact on the Th1/Th2 immune system balance, so a parasympathetic nervous system inhibited by these anti-muscarinic antibodies may shift the immune response away from Th1 and towards Th2, thus impeding viral clearance.

I would not be surprised if these anti-muscarinic antibodies were deliberately triggered by invading viruses as a means to stop the immune system from attacking them (ie, as an immune evasion tactic).

So it would seem that for ME/CFS with anti-muscarinic auto-antibodies, it might be a good idea to take supplements that boost the parasympathetic nervous system; or better still, find some medications that can treat this ME/CFS autoimmune condition that targets the muscarinic receptors. Rituximab can treat of autoimmune diseases; perhaps this is the reason rituximab benefits ME/CFS patients: because it helps reduce auto-antibodies to muscarinic receptors.

Actually, this is probably along the right lines, as it seems rituximab can treat Sjgren's, and its anti-muscarinic auto-antibodies:

Rituximab treatment in patients with primary Sjgren's syndrome

I don't agree with your conclusions. The auto-antibodies do not block the receptors - they cause increased activation of them. That's why you get increased vasodilation: "Activating autoantibodies to ?1/2-adrenergic (AA?1/2AR) and M2/3 muscarinic receptors (AAM2/3R) produce vasodilative changes in the vasculature that may contribute to OH". In the PMID 22130180 study, they actually stopped the increased vasodilation by blocking muscarinic and beta adrenoceptors, but patients found the side effects intolerable.

This is also my own personal experience. I also do not have particularly dry mouth or eyes, even though a have severe POTS. And the cold hands and feet is caused by blood pooling, which can result from both excessive vasoconstriction (sympathetic) or vasodilation (parasympathetic). That is also why there are several types of POTS, including high-flow and low-flow. I am pretty sure my case is the high-flow type. Read this:

http://aboutmecfs.org.violet.arvixe.com/Rsrch/OITypes.aspx

But you're right that the solution to the problem is getting rid of the auto-antibodies.

 

[Hip]

I don't agree with your conclusions. The auto-antibodies do not block the receptors - they cause increased activation of them. That's why you get increased vasodilation: "Activating autoantibodies to ?1/2-adrenergic (AA?1/2AR) and M2/3 muscarinic receptors (AAM2/3R) produce vasodilative changes in the vasculature that may contribute to OH".

If that orthostatic hypotension study is correct, then in the case of OH, it seems the auto-antibodies activate the muscarinic receptors. But I have not got access to the full paper, so I am unsure as to how they determined this.

However, in Sjgren's syndrome, the auto-antibodies definitely inhibit the parasympathetic nervous system, as all the studies in my above post say this.

There was some controversy regarding the mechanism that these auto-antibodies inhibited the parasympathetic, but this new paper looked at this, and found that the auto-antibodies do indeed block the muscarinic receptor:

Autoantibodies in Sjgrens syndrome patients acutely inhibit muscarinic receptor function

 

[Hip]

In my experience, the best way to boost the parasympathetic nervous system is to breath slow and deep.

The science: http://thevirafoundation.org/images/Trauma_Treatment_Breathwork_Part_I.pdf

Yes, and practices like chi gong may also work for this.

I just now came across a bizarre new device, the Lip Trainer, that involves lip exercises to stimulate the parasympathetic nerves:

http://liptrainerguru.com/para

 

[anne_likes_red]

Thanks for the link to that blog Jenny. I found it a very interesting read!!

Hi Sing

Here is a blog from the person who has been preparing it and taking it. You can email her via the blog. She sent me some - not sure if she has any more though. I tried 2 drops a day so far - not sure if it's doing anything - one day I didn't feel anything, the next I had a very bad spell of tachycardia, sweating and nausea, but that may have been because I had two glasses of wine as well!

I'm a bit scared of taking it actually.....

http://flyagarictincture.blogspot.com/

Jenny

 

[Hip]

Actually, Adreno, it seems that the muscarinic receptor auto-antibodies found in ME/CFS, orthostatic hypotension and Sjgren's syndrome are slightly different in each disease, and in fact target different muscarinic receptor subtypes.

It seems that:

ME/CFS has auto-antibodies that target the M1 subtype of muscarinic receptor, in 50% of patients (the study does not say whether these auto-antibodies activate or block the M1 muscarinic receptor, but it does say that the ME/CFS patients with autoantibodies to M1 had a significantly higher score of 'feeling of muscle weakness' than ME/CFS patients without these autoantibodies).

Orthostatic hypotension has auto-antibodies that target both the M2 and M3 subtypes of muscarinic receptor (and in this case, the auto-antibodies activate these two muscarinic receptors).

Sjgren's syndrome has auto-antibodies that target the M3 subtype of muscarinic receptor (and in this case, the auto-antibodies block this M3 muscarinic receptor: "Autoantibodies that act as antagonists at M3-muscarinic receptors on smooth muscle occur in a subset of patients with primary and secondary SS").


Locations of Muscarinic Receptors M1 to M5

M1 receptors are found in the peripheral nerves, brain.

M2 receptors are found in the peripheral nerves, brain, heart, smooth muscle.

M3 receptors are found in the brain, smooth muscle, endothelium (interior surface of blood and lymph vessels), exocrine glands.

M4 and M5 are only found in the brain.


So in my case, since I have both dry mouth symptoms (Sjgren's) and poor peripheral circulation symptoms (cold hands and feet), perhaps I have auto-antibodies that target the M3 muscarinic receptors which control the exocrine glands (like the saliva gland) and the endothelium (blood vessel dilation).

M3 muscarinic receptors also control another important exocrine gland: the pancreas, and I know my digestion has become a little weak (low stomach acid on my "burp test") since getting ME/CFS (though this study says that both M1 and M3 receptors are involved with the pancreas, and this study says that both M1 and M3 are involved in saliva secretion).

This page on the muscarinic acetylcholine receptor has a good list of muscarinic agonists and antagonists; some of which can precisely target particular muscarinic receptor subtypes; for example, pilocarpine is an agonist (activator) just for M3 receptors.



For a list of drugs and supplements that agonize or antagonize the various muscarinic receptors M1, M2, M3, see this post.

 

[Hip]

Another connection: Autoantibodies to the M3 receptor might be important in interstitial cystitis.

Since interstitial cystitis, or overactive bladder, is a known co-morbidity of ME/CFS, it looks like there is mileage in these considerations on muscarinic receptor auto-antibodies. These auto-antibodies might help explain why ME/CFS, Sjgrens, orthostatic hypotension, and now interstitial cystitis, tend to occur together.

However, in the case of overactive bladder, it would appear that a causal factor in this condition is that the M3 muscarinic receptors are over activated, rather than under activated as they are in Sjgren's (a treatment for overactive bladder is the drug darifenacin, which is a M3 receptor antagonist; ref: here).


I just found another chart of the: Muscarinic receptor subtypes, locations, and potential effects of antagonism

 

[Emootje]

I just now came across a bizarre new device, the Lip Trainer, that involves lip exercises to stimulate the parasympathetic nerves:

http://liptrainerguru.com/para

Thank you Hip!
It is always good to know there are weird options to stimulate the parasympathetic nerves

I am currently investigating if Transcutaneous Vagus Nerve Stimulation (t-VNS) would work.

http://www.cerbomed.com/
"Transcutaneous Vagus Nerve Stimulation (t-VNS) uses the fact that a branch of the vagus nerve is located directly under the skin in areas of the outer ear. Such nerve fibres can be stimulated through the skin (transcutaneously) with electrical impulses"

http://www.acupuncture-australia.com.au/aa-acuslim.html
"AcuSlim also stimulates the auricular branch of the vagal nerve"

http://www.clinsci.org/cs/118/0537/1180537.pdf
"The results underline the potential role of auricular electrical stimulation to induce an increase in vagal activity, and it therefore might be used as preventive or adjuvant therapeutic intervention promoting health."

 

[Hip]

That looks interesting. Another vagus nerve stimulator, a surgically implantable medical device, has been tested for severely depressed people:

http://www.mayoclinic.com/health/vagus-nerve-stimulation/MY00183

 

[Emootje]

Some fibromyalgia patients have also been successfully treated with vagus nerve stimulation:

"CONCLUSIONS: Side effects and tolerability were similar to those found in disorders currently treated with VNS. Preliminary outcome measures suggested that VNS may be a useful adjunct treatment for FM patients resistant to conventional therapeutic management, but further research is required to better understand its actual role in the treatment of FM"
http://www.ncbi.nlm.nih.gov/pubmed/21812908

Other indications transcutaneous Vagus Nerve Stimulation:
Epilepsies
Migraine
Pain
Tinnitus
Schizophrenia
Depression
Mild cognitive impairment
Dementia
Inflammatory diseases
http://www.cerbomed.com/index.php?lang=en#indications

 

[adreno]

I have just learned that I am homozygeous for the PON1 gene, discussed earlier in this thread, which means I have a very hard time detoxing pesticides. As you already know, pesticides inhibit cholinesterase.

Before developing fullblown ME, I was living in SE Asia. I have since learned that the pesticides levels there are exceeded more than 100x the EU safe limits.

I wonder if I now, 4 years later, could still have high pesticid levels? I also wonder whether I should still avoid cholinergics? Could the pesticides have caused permanent damage?

I seem to have a good reaction to ALCAR, so maybe at this point, the benefits outweigh the negatives? Maybe if the nervous system was damaged, ALCAR is actually helping at this point. Not quite sure about this.

 

[adreno]

The effects of N-acetylcysteine on oxidative stress in organophosphate poisoning model.
http://www.ncbi.nlm.nih.gov/m/pubmed/16020401/

 

[adreno]

Evaluation of protective effects of sulforaphane on DNA damage caused by exposure to low levels of pesticide mixture using comet assay.
http://www.ncbi.nlm.nih.gov/m/pubmed/20183075/

 

[Emootje]

PON-1 simulators:

1. Pomegranate
2. Resveratrol
3. Quercetin
4. Flavone
5. Naringenin

http://www.life-enhancement.com/article_template.asp?id=2205

 

[adreno]

PON-1 simulators:

1. Pomegranate
2. Resveratrol
3. Quercetin
4. Flavone
5. Naringenin

http://www.life-enhancement.com/article_template.asp?id=2205

Nice, thanks

 

[Hip]

I had significant chronic exposure to organophosphates due to an accident. At that time, all my lymph nodes in my armpit and chest area (in the breast muscles) became swollen and hard, and they have never returned to normal. I experienced other effects also from this organophosphate poisoning, like a very disconcerting cessation of semen production for around two or three months (God knows what would happen if I ever had kids).

Long-term exposure to the popular organophosphate malathion may cause mutations in human blood cells, including white blood cells and lymph cells, though it does not cause cancer.1

So I wonder whether there might be some genetic alterations to my white blood cells and lymph cells which predispose to ME/CFS? The lymph nodes are where B cells go when they are mature, and since we know from the rituximab study that B cells are involved in ME/CFS, I wonder if organophosphate exposure may have permanently altered the genetic makeup of these cells.

Around 2 years after this organophosphate exposure incident, I then caught a nasty virus, and slowly descended into ME/CFS in the years afterwards. The virus I know was bad, because some of my friends that caught it began suffering from very mild chronic fatigue, as well as some depression and anhedonia. So think the virus played a major role in my ME/CFS.

However, I always wonder if the organophosphate exposure may also have played a pivotal role in precipitating my ME/CFS?

Farmers who apply the pesticide formulation "sheep dip" to their sheep to protect from infestation are 4 times more likely to develop ME/CFS. These farmers also have more neuro-behavioral abnormalities.


Note that organophosphate residues in food are considered far too small to be of concern, at least in developed countries. The vast majority people's daily exposure to pesticides comes from domestic garden use, even in the gardens adjacent to you, or from municipal spraying.


One important factor in pesticide poisoning is whether the pesticide is water or fat soluble: the latter means it can bioaccumulate in the body.

 

[Gavman]

For me i think a major player is serotonin in regulating acetylcholine. If you are anxious alot while low on serotonin, its like consistent shocks to the system. HELP HELP I'm afraid but i don't have the stress hormones to deal with it. Could be the other way where its the release of serotonin that isnt working so well.

 

[Marlène]

Serotonin is influenced by the methylation cycle : B12 -> SAM -> SAH -> Homocysteine
It is between SAM and SAH phosphatitidyl ... is generated that has a connection with acetylcholine.
Serotonin has a link with the folate cycle that is driven by the methylation cycle.

 

[Gavman]

Thats dissecting the specific cycles, Marlene. SAM-e helps to create acetylcholine. So looking at the SAM-e cycle to fix adrenaline is like looking at SSRIs to lower neurochemicals. If the SAM-e cycle runs twenty times while the B6/Zinc cycle runs four, then an imbalance in utilising the neurochemicals will occur. Don't SSRIs generally inhibit adrenaline? All three cycles are interconnected.


I'm not sure the methylation cycle will fix those with a tendency towards utilising adrenaline over those who don't really utilise it at all. Once methylation is balanced, the next step may be to look at dealing with the bodies constant push for adrenaline. (not everyone gets CFS from overutilising adrenaline but i think plenty do)

 

[being]

I noticed something a while back that potentially deals with acetylcholine- I noticed that whenever I ate potatos I would get really tired the next day, even on top of how tired/sick I am already, with the skin especially making me ill. It turns out potatos are a big source of solanine, which is an acetylcholinesterase inhibitor, as are other nightshade vegetables such as tomatos, eggplant and bell peppers, as well as artichokes, blueberries and blackberries. Whenever I eat any of these I feel like I'm going to drop out the next day. I would even notice it after I ate shredded cheese and after the longest time of this I finally looked at the label. Guess what it said? Potato starch was an ingredient, I guess to keep the cheese from sticking together. I wonder if there are things such as acetylcholinesterase promotors, ie the opposite of acetylcholinesterase inhibitor?

 

[Jenny]

I noticed something a while back that potentially deals with acetylcholine- I noticed that whenever I ate potatos I would get really tired the next day, even on top of how tired/sick I am already, with the skin especially making me ill. It turns out potatos are a big source of solanine, which is an acetylcholinesterase inhibitor, as are other nightshade vegetables such as tomatos, eggplant and bell peppers, as well as artichokes, blueberries and blackberries. Whenever I eat any of these I feel like I'm going to drop out the next day. I would even notice it after I ate shredded cheese and after the longest time of this I finally looked at the label. Guess what it said? Potato starch was an ingredient, I guess to keep the cheese from sticking together. I wonder if there are things such as acetylcholinesterase promotors, ie the opposite of acetylcholinesterase inhibitor?

I have a problem with nightshades too. After years of testing for food allergies and intolerances, it's clear these are the only group of foods that affect me. My pain gets much worse after eating potatoes, tomatoes etc.

Like you, I think this may be significant!

Jenny