Preprint Hypothesis: Myalgic Encephalomyelitis (ME) as a Mast Cell Activation Disorder (MCAD), 2026, Carroll

[Jonathan Edwards]

I guess the hypothesis is that scar tissue of mast cells may be the source of a propagating chronic inflammatory signal. Not all patients with scar tissue have this so it's not like it creates it on its own. But if you have a proclivity to experience ME or MCAS, then perhaps this is the initiating chronic stressor that perpetuates the condition. Which then shuts down the symptom experience when removed.

Isn't this just the ME physician witch-doctor theorising about mast cell activation? There are 101 reasons why somebody might feel better after having a scar removed. Mast cells would be the last thing anyone would think of if it wasn't for the folklore. Sadly the vast majority of private physicians who specialise in seeing ME/CFS seem to go in for this.

 

[MelbME]

Isn't this just the ME physician witch-doctor theorising about mast cell activation? There are 101 reasons why somebody might feel better after having a scar removed. Mast cells would be the last thing anyone would think of if it wasn't for the folklore. Sadly the vast majority of private physicians who specialise in seeing ME/CFS seem to go in for this.

Well these aren't ME/CFS clinicians. These are typically surgeons that have been told of symptoms relief of MCAS by their patients. Then they've had some interest in MCAS because of that.

I've spoken to them and asked about symptom improvements, they describe PEM without knowing the word.

I do think it's interesting to think of scar tissue as a chronic trigger, the same way leftover viral proteins might be or a dysfunctional set of immune cells.

 

[Jonathan Edwards]

Well these aren't ME/CFS clinicians. These are typically surgeons that have been told of symptoms relief of MCAS by their patients. Then they've had some interest in MCAS because of that.

Yeah, and the patients will have been told they have "MCAS", which as far as I know is a meaningless term, by a "MCAS-literate" physician not too easily distinguished from an "ME-literate" one. I cannot see any possible way that anyone can know reliably that any of this makes sense in mast cell terms. We see exactly the same sort of thing with EDS and "tethered cord" surgery. If the magic is predicted the magic may well occur. Goodness knows why.

 

[MelbME]

Yeah, and the patients will have been told they have "MCAS", which as far as I know is a meaningless term, by a "MCAS-literate" physician not too easily distinguished from an "ME-literate" one. I cannot see any possible way that anyone can know reliably that any of this makes sense in mast cell terms. We see exactly the same sort of thing with EDS and "tethered cord" surgery. If the magic is predicted the magic may well occur. Goodness knows why.

Yes this is probable. It's still an worthwhile area to understand more. I think it's interesting that removing a chronic stressor by surgery can be transformative for some people with EDS or ME/CFS or MCAS. Not saying it's the cause but it could be part of it for a subset. Or it could be placebo. I think further investigation is needed.

 

[OrganicChilli]

So patients started reporting ME/CFS symptoms after the scar had formed? So probably after surgery or after an accident? This must be an implausibly small sub group. How does this help 99% of the patients who don't have scars? Or those without "MCAS"/allergy symptoms. I would really prefer if research wasn't focused on unlikely subgroups especially now that we have other leads.

 

[MelbME]

So patients started reporting ME/CFS symptoms after the scar had formed? So probably after surgery or after an accident? This must be an implausibly small sub group. How does this help 99% of the patients who don't have scars? Or those without "MCAS"/allergy symptoms. I would really prefer if research wasn't focused on unlikely subgroups especially now that we have other leads.

There are a few disease mechanisms that were understood because of research on a specific subset.

It can actually help because it's unlikely. You have people with a different and specific biological phenomena that share the same symptoms. Perhaps there is a shared downstream pathway this subset links to.

 

[hotblack]

Found it. They're not neurons, ME5 was one of several hypotheses about ME (as in myalgic encephalomyelitis): https://forums.phoenixrising.me/threads/do-mes-cause-cfs.31930/

It’s interesting reading that post by @Jonathan Edwards to see how parts of his thinking have changed and evolved over the years. I think it’s possibly a useful counter to some of the accusations he and the forum more widely sometimes receive of not being open to or considering certain ideas. Heterogeneity is there, auto immunity is there and so on.

 

[Jonathan Edwards]

Looking back at that 2014 post I realise how some thoughts have not changed much, but others have.

This was an attempt to classify causes of a rather broad category of unexplained chronic fatigue. I think even Fukuda's CFS was tighter than that, so I would change the framing now.

After talking to people with ME/CFS for 12 years and seeing the DecodeME data, I think I can be sure that ME1, ME2 and ME4 make no more than a trivial contribution to the population carrying an ME/CFS diagnosis. These were the cases I had met in my clinic. Interestingly, I don't think anyone with genuine ME/CFS was ever referred to me over a period of 35 years.

Similarly, I don't think ME6 is a real subgroup. If there were people with mitochondrial abnormalities sufficient to account for moderate to severe ME/CFS symptoms we would have identified them by now. Mitochondrial abnormalities, at least metabolic abnormalities, do not explain PEM (or anything else much).

That leaves ME3 and ME5.

I re-invented ME5 a year or so ago, having forgotten it. I am intrigued by a post suggesting that I discussed it with Hugh Perry in 2014, who seemed to agree with the logic. Perry was at that time head of the MRC neurosciences panel. But the MRC did not fund any meaningful research into ME/CFS until DecodeME. I still think ME5 is vaguely plausible, but only just. I think there is a T cell equivalent that has some resemblance to ME2 but I think it would involve innate populations and invariant receptors if it existed.

The hypothalamic approach is a form of ME3. The more I hear of the unique clinical pattern of ME/CFS the more I think a hypothalamic ME3 is the most likely explanation. But being hypothalamic it would be explicitly closed to any psychological interpretation or psychotherapeutic approach.

 

[hotblack]

Looking back at that 2014 post I realise how some thoughts have not changed much, but others have.

Really interesting to hear how you see it, thanks for sharing and reflecting. I thought it showed a similar (if not characteristic) approach or framework to thinking about the problem, but with differences in specifics no doubt influenced by changing evidence. Which is why it was such a good counter to some of the accusations.