1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
Hyperparathyroidism: An Often Overlooked Differential Diagnosis to ME/CFS
Andrew Gladman puts hyperparathyroidism under the microscope, exploring what the disease is, how it can mimic ME/CFS in presentation and how it is treated.
Discuss the article on the Forums.

Could autoantibodies to muscarinic acetylcholine receptors underpin ME/CFS?

Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by Hip, Apr 14, 2012.

  1. satoshikasumi

    satoshikasumi Senior Member

    Messages:
    113
    Likes:
    122
    Also, the cholinergic hypothesis of CFS was popular back around 2003-2004, but a randomized controlled trial of the reversible cholinesterase inhibitor galantamine failed, and then researchers lost interest in this hypothesis. As usual, there are so few resources in CFS research that researchers are quick to abandon a paradigm before it is thoroughly investigated- it might be the case that some other approach would have worked. We of course had the same situation with herpesviruses. Researchers lost interest after valtrex failed a placebo controlled trial and it took 10 years before doctors began to study more powerful drugs such as valcyte.

    The problem with treating autonomic dysfunction with drugs is that this is trying to replace a dynamic system with a relatively static system. In a healthy person, the parasympathetic and sympathetic nervous systems are in a balance that can change within seconds when the body is exposed to stress from standing up, exercise, eating, etc. In CFS, we see several things indicating that this *flexibility* in the system is lost. When lying down or resting, CFS patients have higher resting heart rate and supine blood pressure than healthy people- so they don't get the relaxation response. This indicates parasympathetic/cholinergic deficit. When standing, some patients show more of this with a POTS type pattern of rapid heart rate, while others show low blood pressure (lack of sympathetic tone). When exercising, a subgroup of patients fails to increase their heart rate/blood pressure in response to exercise (sympathetic deficit). So, patients' systems are inflexible. You can see why this would be hard to treat with drugs that activate one system or another. This doesn't really make up for the lack of ability to change the system in response to physical stress. But, if it is caused by autoantibodies, approaches to remove the autoantibodies may work.
  2. Hip

    Hip Senior Member

    Messages:
    2,753
    Likes:
    2,495
    Very true, you are never going to recreate the dynamic flexibility of the autonomic nervous system with a drug.

    The thing about galantamine is that it boosts acetylcholine, and acetylcholine is a neurotransmitter that activates an extremely broad set of nerve receptors, including both the preganglionic (nicotinic) and postganglionic (muscarinic) parasympathetic nerve receptors, as well as the preganglionic (nicotinic) sympathetic nerve receptors. So acetylcholine affects most of the autonomic nervous system. Plus acetylcholine activates ALL the somatic nervous system too!

    So boosting acetylcholine has very, very broad effects on these nervous systems.

    My thought was that it might be better to precision target the right area of the autonomic nervous system, by selectively targeting the right subset of nerve receptors — namely the nerve receptor subsets that are known to be perturbed in ME/CFS.

    In 50% of ME/CFS patients, there are autoantibodies that attack the muscarinic class of receptors — and specifically, they attack just the M1 subclass of muscarinic receptor.

    So to try to combat any problem caused by this, we would want to boost (or inhibit) only these M1 class of muscarinic receptors. Thus drugs that selectively target this M1 muscarinic receptor subset are more likely going to provide benefits in ME/CFS.

    Similarly, in orthostatic hypotension, you have autoantibodies that target and activate both the M1 and M2 subtypes of muscarinic receptors, so you would want to find a drug that also just targets just these muscarinic receptor subtypes only.

    Yes, stopping the autoantibodies is definitely the ideal approach. I have high hopes for the rituximab research being the magic bullet for ME/CFS, for this reason.
  3. Emootje

    Emootje Senior Member

    Messages:
    280
    Likes:
    95
    The Netherlands
    "Muscarinic receptor numbers are decreased by oxidative stress.
    Muscarinic receptors are sensitive to NO toxicity, and
    relative to other receptor subtypes, muscarinics are preferentially
    sensitive to inhibition by ONOO and other oxidants. As
    discussed earlier, excess NO in autism may depress CoA.
    Besides its importance in energy production. CoA is a necessary
    precursor for the cholinergic neurotransmitter, acetylcholine.
    (See Figure 2.)
    Insufficient CoA renders cholinergic neurons more vulnerable
    to a variety of toxic insults, including excess NO"
    http://69.164.208.4/files/OXIDATIVE STRESS IN AUTISM.pdf

    cbcgfb.JPG
  4. Hip

    Hip Senior Member

    Messages:
    2,753
    Likes:
    2,495
    Very interesting Emootje. I was not aware that oxidative stress could affect the muscarinic receptors of the parasympathetic nervous system.

    Seems that the impact of oxidative stress is significant: this study shows that oxidative stress severely damages the muscarinic receptors in the bladder, altering its function.
  5. fairlight

    fairlight

    Messages:
    77
    Likes:
    0
    Has anyone tried fly agaric? I read the blog about it helping the lyme sufferer, but it doesn't seem to be redily available? Anyone else tried it?
  6. Hip

    Hip Senior Member

    Messages:
    2,753
    Likes:
    2,495

    I tried taking fly agaric, but in my case it did not help. I took an ⅛ of a dried mushroom cap (around 100 mg in weight), which was roughly the dose mentioned on Sam Malone's Lyme blog. I felt some very, very mild mental effects, but in my case it did not seem to help with the brain fog or fatigue — unlike Sam who experienced a rapid improvement in her Lyme symptoms within half an hour of taking fly agaric mushroom.

    To quote Sam:

    "The initial dose was a seventh of a cap, eaten with breakfast. Within half an hour I began to feel more alert and aware. I spend most of my time lying around feeling like death, but within an hour I was up and about and feeling very lively. I cycled into town and did some chores. There was no "coming up" rush, no hallucinations or change in perceptions beyond feeling lively and really up for it. It was the best day I've had in an awfully long time. Probably years. At no point did I feel any stomach cramps or nausea, possibly because of the small dose, possibly because the mushroom had been cooked." Ref: here.

    If you Google for "legal highs" or "entheogen supply" you should find some websites selling dried fly agaric.

    I think Jenny on this forum tried taking it too, without much improvements (see this thread). So it could be that fly agaric is more helpful for Lyme than it is for CFS. Though the experiences of just two CFS people is not really enough to conclude that fly agaric is not helpful for CFS.

    Note: the fly agaric dose required to get high is around 5 to 10 grams of dried mushroom (ref: here); but for our therapeutic purposes here you only take a fraction of that, around 100 mg.

    Note: there is a concern with toxic effects on the liver, with immature and fresh fly agaric being more toxic than mature, dried specimens. Though this is more of a concern if you are taking many grams of the mushroom to get high.
  7. Tally

    Tally Senior Member

    Messages:
    154
    Likes:
    115
    As far as I know, myasthenia gravis is one condition that needs to be ruled out before diagnosis of CFS can be made.

    One of the ways to test it is to test for acetylcholine and muscarinic receptors. Others are: MNG test, and Thymus CT. I had all these tests and they all came back negative.
  8. snowathlete

    snowathlete

    Messages:
    2,051
    Likes:
    2,168
    UK
    interesting topic Hip.

    Tally - Do many people with me/cfs get tested for myasthenia gravis? I agree that it is worth rulling it out and im thinking about that myself, but i bet a lot of people dont even know about it.
  9. Tally

    Tally Senior Member

    Messages:
    154
    Likes:
    115
    I'm sorry, I really have no idea. I don't personally know anyone else who has ME or CFS.

    I was a bit unhappy that doctors were insisting for so many tests for myasthenia gravis. I especially didn't want to do the CT. I will try to explain why, but please understand that I just got this from wikipedia and places like that, so I'm in no way an expert.

    Myasthenia gravis is a condition where certain type of antibodies which shouldn't be produced are, and they block the receptors on the muscles, so then muscles can't get proper signals and muscle weakness ensues. These receptors get cleared up while we sleep, so condition should be better in the morning.

    Now, as far as I can tell, this can only explain muscle weakness and fatigue (although I have a sneaking suspicion that their type of fatigue is different than our, but even if it is the same....), it doesn't explain 90% of the symptoms I have, like the delayed onset of PEM, forgetfulness, brain fog, sore throat, chrashing, increased pain while crashed, etc.

    It also doesn't explain why my muscles were not weak at the beginning of my illness, when I felt the worst, and when nothing yet could be explained with deconditioning. It also doesn't explain why I feel the worst in the morning, and best at night when I've already been awake for many hours.
  10. John H Wolfe

    John H Wolfe Senior Member

    Messages:
    220
    Likes:
    36
    London
    Nice theory, consistent with the sense that (gradual) failure of systems (including autonomic), the healthy functioning of which is associated with normal parasympathetic functioning, often seem to pre-date more salient/severe 'onset' events e.g. viruses that hit us hard and then send us into a neuroimmune 'tail spin', when we go back and retrospectively analyse historic signs of disorder

    I wonder how this relates to Rowe's working hypothesis regarding innate vulnerabilities to neurogenic sensitisation (via things like: [nerve tensioning] anatomic abnormalities vs. hyperinflammatory responsiveness) ~ could such autoimmunity be, in itself, "vamped up" by this background of growth/injury/posture/inertia linked peripheral-central sensitisation..
  11. Enid

    Enid Senior Member

    Messages:
    3,309
    Likes:
    840
    UK
    Very interesting - though as a non scientist. What tips the immune system into an auto-immune state - unresolved infection, genetic weakness ( my brother - a Doc) is now diagnosed with autoimmunity - liver). But we are both in our 70s so why now. And it appears ME is as much to do with youth as of age. Personally I'm certain the immune system is initially overwhelmed but by what ?. The expression of latent viruses occurred for us both.
  12. Hip

    Hip Senior Member

    Messages:
    2,753
    Likes:
    2,495
    Not sure; though usually autoimmunity gets ramped up by infections in the body, so if you have one or more chronic viral infections, this tends to increase autoimmunity and autoantibodies (though sometimes infections can do the reverse, and actually lower autoimmunity, so the infection–autoimmunity connection is a complex situation).

    A key player in preventing or ameliorating autoimmunity are tolerogenic dendritic cells, which actually fight against autoimmunity in the body. The hormone estriol increases the production of tolerogenic dendritic cells, and since there is a massive boost of estriol levels during pregnancy, this might explain why ME/CFS often improves in pregnancy.

    The Th17 immune response increases autoimmunity. I do well on the supplement N-acetylglucosamine 750 mg which reduces the Th17 response.
    Valentijn and merylg like this.
  13. John H Wolfe

    John H Wolfe Senior Member

    Messages:
    220
    Likes:
    36
    London
    Interesting link; I wonder whether their production differs between the sexes more generally?

    I ordered some NAG as per your advice, arrived today, so hopefully I'll find it similarly helpful! :)
  14. Hip

    Hip Senior Member

    Messages:
    2,753
    Likes:
    2,495
    That's a good question. If there were, it might help explain the sex differences in the incidence of ME/CFS and autoimmune diseases in general (4 times more women get ME/CFS than men).

    Please let us know whether N-acetylglucosamine is helpful or whether you get no benefits. I haven't got accurate figures, but I think about half the people I got feedback from found NAG pretty helpful for their anxiety and/or ME/CFS symptom, and the other half found no noticeable benefits. The most glowing report I read about NAG was this one from Cath ("To be honest - its helped me so much, its changed my life," she wrote), which does indicate that NAG is certainly a very beneficial supplement for at least some people.
  15. perovyscus

    perovyscus

    Messages:
    61
    Likes:
    7
    Autoreactive ACh antibodies wouldn't antagonize interneuron receptors (I know this term was used loosely), they'd be subject to ROS degradation. Cholinergic potentiation would prove difficult in that case. The point is, we're about 10 years away from anything that resembles a CFS drug that would target this pathway. You'd have to tighten the BBB with simultaneous neurogenesis. What does interest me however, is if these abnormalities are EBV-mediated. .

    In short, ACh antibodies would be cholinomimetic, barring something paradoxical with CFS patients.
  16. Hip

    Hip Senior Member

    Messages:
    2,753
    Likes:
    2,495
    @perovyscus
    Why do you say that autoantibodies would not antagonize the muscarinic acetylcholine receptors due to ROS degradation?

    The Sjögren's study I cited said that autoantibodies antagonize muscarinic acetylcholine receptors, and the orthostatic hypotension study said that autoantibodies agonize muscarinic acetylcholine receptors. So these studies found that autoantibodies can both agonize or antagonize muscarinic acetylcholine receptors, depending on what disease we are referring to.
    Last edited: Jul 18, 2014

See more popular forum discussions.

Share This Page