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

Jonathan Edwards said:
There is no reason to suspect anyone with Long Covid of 'mast cell involvement' or having an 'MCAS phenotype" which is whatever complaints the patient brings along to Dr Afrin. This is all folklore @Dude. It is not biology. We aren't particularly sceptical here in comparison to the rest of the biomedical clinical and research community who are totally sceptical of this stuff. It belongs to a sort of religious sect supported by the failing wallets of vulnerable people. We need to dig everyone out of this cloud-cuckoo land.
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I have to admit that I'm not particularly knowledgeable about MCAS, so I'm certainly not claiming to understand all the underlying mechanisms or the current evidence.

However, I'm curious: do you actually question the existence of MCAS itself, or do you mainly disagree with the way it is diagnosed and its proposed role in Long COVID and ME/CFS?

I agree that we shouldn't assume that every Long COVID patient has mast cell involvement. But dismissing the possibility of a role in certain subgroups without proper investigation also seems premature to me.

I'm genuinely interested in understanding where you draw that distinction.
 
jnmaciuch said:
They reported one tiny statistically significant outcome on their fatigue scale, which was less than 2 point improvement on a 50 point scale beyond control arm (where the average improvement across all groups was 4 points)
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Was that reported with trumpets and fireworks, and followed by lots of citations in various health magazines?
 
Dude said:
I'm not trying to defend these medications, but Dr Stingl doesn't strike me as someone trying to make money off desperate patients. He seems genuinely interested in helping them. That's why I'd be interested to hear about his clinical experience with these medications and the patients he has treated.
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In recognition of the fact you’re already receiving pushback from several people in this thread, I just want to say that my intention isn’t to further pile on here and that I appreciate the way you’re handling (sometimes blunt) criticism without being defensive.

I wanted to talk about these few sentences because I think they’re interesting and I myself have said similar in defense of doctors whom I felt were being unfairly criticized.

I think it’s uncommon for doctors in this space to be trying to make money off desperate patients, and I think the vast majority are genuinely trying to help us. But if the result of their practice is profiting off prescribing us ineffective treatments, how much does the purity of their intentions really matter?
 
Dude said:
However, I'm curious: do you actually question the existence of MCAS itself, or do you mainly disagree with the way it is diagnosed and its proposed role in Long COVID and ME/CFS?
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Pretty much everyone in medicine beyond a few zealots questions the existence of MCAS. In fact even the people who say they believe in it question it. There are two groups of people who call themselves consensus 1 and consensus 2 who think it is something different from the other lot. Nobody knows what it is. It is about as imaginary as you can get in medicine. Mast cells exist. They are activated in all sorts of situations, but nobody knows what MCAS means.

Dude said:
But dismissing the possibility of a role in certain subgroups without proper investigation also seems premature to me.
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But why, if we have no initial reason to think it is of any relevance at all? "ME physicians" talk about it because there was a myth that people with ME had allergies. Almost certainly what they had were intolerances - which people with ME/CFS have in spades. For forty years nobody has found any evidence for anything to do with mast cells but that does not stop the zealots from passing the mantra down to the next generation.

Honestly, I understand you puzzlement but we all need to be aware that this is an area swimming in bullshit. Medicine started off as quackery and in some quarters that never changed.
And if a trial the size of STIMULATE ICP produces no meaningful signal you can be pretty sure there are no subsets that benefit in a big way. Everything is consistent with all of this being a mirage.
 
jonathan_h said:
I think it’s uncommon for doctors in this space to be trying to make money off desperate patients, and I think the vast majority are genuinely trying to help us. But if the result of their practice is profiting off prescribing us ineffective treatments, how much does the purity of their intentions really matter?
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I think this is an important point. In my view 'having good intentions' is no excuse in medicine. Doctors have responsibility to ensure what they are doing is in the interests of the patient. Believing you are doing good is not an excuse. Our one time prime minister believed it was doing good to drop bombs on children in Iraq. Someone else has been doing the same recently in Iran. Good intentions do not matter when other people's lives are at stake.
 
I wanted to post this somewhere for weeks now, looking for the right thread, and looking at this discussion that hows on here it might isn't the worst place.

In this year I have seen more and more patients , and sometimes also Drs., calling their various intolerances and sensitivites to foods/drugs/supplements, with an onset after they got ME/CFS, MCAS or "mast-cell-issues", while having not much proof that this is actually the case and the cause of their newly onset sensibilities and intolerances.

I wonder why that is, because mostly this term neither helps them to get more recognition nor treatments who do improve their level of functioning nor anything else that would make this term feel valuable for me. I wanted to ask the forum what you make of this and how you feel about the usefulness of the concept of MCAS for people with ME/CFS.

Also I wanted to share my own story, because my views about mast-cell issues and MCAS and ME are deeply shaped by this.

So, I myself have various allergies to pollen and hazel/walnuts, always elevated values for ECP and elevated values for histamine; and I had all of these before I got housebound with ME/CFS. Also I was always sensitive to drugs that impact the central nervous system. Then after getting ME/CFS all of this got worse and I got problems with digesting milk-protein and gluten.

But I still have "healthy" values for other mast cell related things like leukotriene or tryptase which afaik are often seen as signs for mast-cell related problems.

Furthermore treating my allergies also doesn't makes my ME/CFS any better, no matter if I take antihistamines or even Xolair, they both lessen the allergies but did 0 on my ME/CFS symptoms and the intolerance of milk/gluten.

However, interestingly, when my overall condition – that is, the typical ME/CFS symptoms such as PEM, brain fog, autonomic dysfunction, etc., etc. – improves a bit, my allergies and other sensitivities also become less severe again.

In my case that's also true for the minor seborrheic dermatitis problems I had before ME/CFS, with ME/CFS they got worse and they also seem to fluctuate with my general condition. In this case of course it could also simply be due to the fact that I can't go outside in the sun anymore, something that apparently would help with this kind of skin problems.

So if I had to guess I would speculate that whatever is the reason for my new intolerances and the worsening of the old ones isn't what people would call MCAS, but something different that comes along with ME/CFS, like some signaling issues in the immune system, in the autonomic nervous system, in parts of the brain or wherever.

I would be interested what others on the forum think about this and even more interested in how people insisting that mast-cell and histamine issues are at the core of this disease would think of my case.
 
Jonathan Edwards said:
Pretty much everyone in medicine beyond a few zealots questions the existence of MCAS. In fact even the people who say they believe in it question it. There are two groups of people who call themselves consensus 1 and consensus 2 who think it is something different from the other lot. Nobody knows what it is. It is about as imaginary as you can get in medicine. Mast cells exist. They are activated in all sorts of situations, but nobody knows what MCAS means.


But why, if we have no initial reason to think it is of any relevance at all? "ME physicians" talk about it because there was a myth that people with ME had allergies. Almost certainly what they had were intolerances - which people with ME/CFS have in spades. For forty years nobody has found any evidence for anything to do with mast cells but that does not stop the zealots from passing the mantra down to the next generation.

Honestly, I understand you puzzlement but we all need to be aware that this is an area swimming in bullshit. Medicine started off as quackery and in some quarters that never changed.
And if a trial the size of STIMULATE ICP produces no meaningful signal you can be pretty sure there are no subsets that benefit in a big way. Everything is consistent with all of this being a mirage.
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Oh, I wasn't aware that MCAS was so controversial, to the point where some people question whether it is an established medical condition at all. I knew there were disagreements about the diagnostic criteria, particularly the differences between Consensus-1 and Consensus-2, and the risk of overdiagnosis.

I always thought the main issue was that MCAS is a recognised clinical entity, but that its diagnostic boundaries and prevalence remain controversial. I also agree that we should be careful about extrapolating mast cell involvement to ME/CFS or Long COVID without stronger evidence.

Interesting perspective.
 
jonathan_h said:
In recognition of the fact you’re already receiving pushback from several people in this thread, I just want to say that my intention isn’t to further pile on here and that I appreciate the way you’re handling (sometimes blunt) criticism without being defensive.

I wanted to talk about these few sentences because I think they’re interesting and I myself have said similar in defense of doctors whom I felt were being unfairly criticized.

I think it’s uncommon for doctors in this space to be trying to make money off desperate patients, and I think the vast majority are genuinely trying to help us. But if the result of their practice is profiting off prescribing us ineffective treatments, how much does the purity of their intentions really matter?
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I actually agree with your point, and I think there is an important distinction between a doctor's intentions and the actual effectiveness of the treatments they prescribe.

At the same time, I think we have to be careful not to dismiss clinical experience entirely. Take Abilify, for example. There are anecdotal reports of some ME/CFS patients experiencing significant improvements, in some cases even going from being bedridden to being able to function again. Yet we still lack good clinical trials providing robust evidence of its effectiveness.

If we applied the strictest possible standard, wouldn't that mean that ME/CFS doctors should essentially stop prescribing almost everything, simply because we don't have sufficient evidence for most treatments?

But is that really what we want, knowing that some patients appear to benefit from certain medications, even if it's only a small subset?

I understand your argument, and I agree that good intentions alone are not enough to justify prescribing treatments without evidence. But I also understand patients who seek out doctors because they are desperate to try something that might help, even when the evidence is still limited.

Personally, I think there is room for both: being transparent about the lack of evidence and the uncertainty involved, while still being open to carefully monitored treatment trials when there is a reasonable rationale and some indication that certain patients might benefit.
 
Silip said:
So, I myself have various allergies to pollen and hazel/walnuts, always elevated values for ECP and elevated values for histamine; and I had all of these before I got housebound with ME/CFS. Also I was always sensitive to drugs that impact the central nervous system. Then after getting ME/CFS all of this got worse and I got problems with digesting milk-protein and gluten.
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I've been taking H1 and H2 antihistamines for a year and a half, prescribed by my ME/CFS specialist in France. As far as I know, he's the only French doctor treating ME/CFS patients who systematically prescribes them to all his patients. Personally, I haven't noticed much benefit, and I'm thinking of stopping them soon.

But getting back to drug intolerance, I'm extremely sensitive to almost every medication. I've long suspected that I have some kind of hypersensitivity involving the central nervous system.

I first started noticing this with tramadol, which I was dependent on for three years, before my ME/CFS symptoms began. I'd call it dependence rather than addiction, because I never increased the dose. I consistently took between 75 and 100 mg a day, which is a relatively modest dose, yet the effects on my nervous system were absolutely extraordinary.

I usually took my tablets around 2 or 3 pm. They allowed me to work much harder, feel more relaxed, and sometimes even slightly euphoric. But in the evening, I had enormous difficulty falling asleep because my brain felt so overstimulated. The level of stimulation seemed completely disproportionate to the dose.

I sometimes wonder whether taking tramadol for so long might have indirectly contributed to the onset of my ME/CFS. Perhaps the drug was already masking certain signs of fatigue, allowing me to push beyond my limits without realising it. Or perhaps it played some role in disrupting my nervous system. I really don't know, and it's probably something worth asking the experts on the forum. Could there have been an effect similar to buspirone?

What I do know is that as my ME/CFS progressed, I became completely unable to tolerate tramadol. It started causing very abnormal reactions, including extremely intense feelings of panic.

The same goes for antidepressants: I simply cannot tolerate them. My heart starts racing, and I immediately experience an overwhelming, almost uncontrollable feeling of fear. Mestinon pushed my heart rate up to 110 bpm, while DXM, a cough suppressant sometimes recommended to help prevent PEM, sent it soaring to 180 bpm.

All of this makes me suspect that, in my particular case, the problem may lie more in the central nervous system than in something involving mast cells, for example.
 
Dude said:
However, I'm curious: do you actually question the existence of MCAS itself, or do you mainly disagree with the way it is diagnosed and its proposed role in Long COVID and ME/CFS?
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I did a bit a of dive into the literature on MCAS recently (particularly the research of it intersecting with ME/CFS). I was honestly shocked not only by how thin the evidence was (thin is putting it mildly, actually almost everything solid I found was negative evidence), but also how it seemed to be an open secret that the claims of a connection to traditional IgE mediated allergy don't hold up (i.e. researchers seem to be aware, maybe from their own unpublished data, that early studies showing higher rates of allergy in ME/CFS patients don't replicate and were probably due to cohort selection effects).

The argument for MCAS in ME/CFS boiled down to:
1. We think 'MCAS-type' ME/CFS is caused by mast cells because the symptoms arguably look like conventional mast cell activation and because patients have higher allergy rates and report anti-histamines help.
2. Actually, the one RCT of antihistamines in ME/CFS was negative, we have found that the early data showing higher allergy rates in ME/CFS doesn't replicate, and we haven't been able to find any evidence of conventional mast cell activation in ME/CFS (i.e. tryptase).
3. We need to research this more to find out how these mast cells are activating in such a sneaky way.

I've been meaning to write this up with proper citations so people don't just have to take my word for it. But in short I came away feeling like patients with these intolerances and reactions (which is many of us, myself included) are just being totally mislead into supporting a research direction with an extremely low likelihood of ever helping us.

Nightsong also has some posts about the history of MCAS more broadly (e.g. here and here).
 
Dude said:
Yes, I completely agree. When you read in the support groups how much people spend on consultations and all these useless supplements and treatments they end up buying, that money would probably be much better invested in donations to ME/CFS research.
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Or just supporting themselves, many patients have very strained financials even before accounting for the money they’ve been robbed of by fraudsters.

It’s the charities and funders that should spend their money elsewhere. The patients should focus on themselves unless they want to donate of course.
 
Jonathan Edwards said:
Nerves are involved in allergic responses and the trigeminal (ophthalmic branch) does the conjectiva if I remember rightly. So it will mediate, but I don't think that tells us anything.
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I was just wondering if there’s a potential CN V role in yet another kind of ME/CFS intolerance
 
Dude said:
If we applied the strictest possible standard, wouldn't that mean that ME/CFS doctors should essentially stop prescribing almost everything, simply because we don't have sufficient evidence for most treatments?
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Yes, exactly.
Dude said:
But is that really what we want, knowing that some patients appear to benefit from certain medications, even if it's only a small subset?
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Yes. The risk of adverse events is far far higher than the risk of benefit for a randomly selected medication, so the expected benefit is negative.

If patients that are currently taking drugs claim they benefit, it might be reasonable to try to taper them off and see what happens.

That’s the case even for drugs we know work. You’re not supposed to just stay on the same dose forever without considering if things have changed. I suspect many will find that they do not miss the drugs at all.
 
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