What is the evidence for histamine as a possible cause of ME/CFS symptoms?

[Scarecrow]

If you have seen my (re)introductory thread you will know that the last five years has been a period of significant improvement for me. I have been cribbing treatment approaches from the histamine intolerance community. Histamine intolerance, narrowly defined, is a failure to degrade histamine in food due to an insufficiency of the enzyme diamine oxidase but mast cell degranulation by foods that are deemed histamine liberators is also considered to be part of the condition. I don't actually believe I have histamine intolerance but I do think I have excess endogenous histamine. I'm pretty certain there is no mast cell involvement because that would presumably mimic symptoms of allergy. I suspect an alternative cell type is involved and that the histamine is being released due to another unknown endogenous substance but that's not important right now.

My initial treatment strategy was the tried and trusted shotgun approach: chuck everything at it in the hope that some of it finds the target. And it did. I very quickly gained relative mental clarity. I stopped and restarted the treatment a couple of times to check the improvement wasn't coincidental and every six months or so I stop all treatment for a while to review where I am without it and how long it takes for symptoms to return. At the same time, I have identified which supplements are most effective and I now rely on only one to keep symptoms at bay. Gradually, my physical and cognitive capacity improved. Cognitively, I took a GET approach, always pushing for more and retraining my brain to work again. Physically, I was much more careful, other than a coup!e of whoopsie incidents, and I have slowly taken up the space as my boundaries expanded.

Initially, I viewed histamine as exacerbating the symptoms of ME/CFS but I have come to view it as the driving factor. Until very recently, I would have said I was about 95% confident about that but four weeks ago I had major abdominal surgery and I'm now so certain I would bet my house on it. I was expecting a certain amount of histamine from the operation but I was completely unprepared for the onslaught and the resulting disturbed sleep, headaches and brain fog. I crashed for several days shortly after getting out of hospital and less severely a couple of times since. That hasn't happened for two years at least. In particular what I am noticing is an increased sensitivity to standing. I'm fine if I go for a walk but if I prune the bushes and the brambles, there's hell to pay. If I go into the kitchen and lose myself in thought, I find myself pacing to and fro. At about three weeks post surgery, I noticed the histamine starting to tail off more quickly, so it will be interesting to see when the orthostatic intolerance improves. Meanwhile I have temporarily added a couple of my original supplements back in for extra support.

If you're still with me, I have a challenge. If you are anything like me when I first noticed someone mentioning histamine in the context of ME/CFS, which would have been about 15 years ago, you are probably very skeptical. I dismissed it for 10 years because histamine meant something to do with allergies, and I didn't have allergies. I completely missed the multiple biological roles that histamine has, as a vasodilator, a neurotransmitter and an immune modulator. When I review the symptoms in the NICE guidelines, all I see now is histamine, which is probably a bit over zealous of me without stopping to consider the evidence in detail.

So my challenge is to help compile evidence for the possible role histamine may have in causing the symptoms of ME/CFS. 'Possible' because although histamine in its role as a vasodilator, for example, could be causing low blood pressure, there are other substances that cause vasodilation or that inhibit vasoconstriction. My hope is that by documenting how histamine could be responsible for many of the symptoms of ME/CFS we could solve part of the puzzle and perhaps consider if there are any other candidates that could be responsible for multiple symptoms.

Can any of the DecodeME experts comment on any possible links between the genes identified in that study and histamine? Perhaps as a signal for histamine release?

Does anyone have ideas as to the best way to proceed with this? If we all post at random of the same thread, things are going to get messy pretty quickly. Would it be possible to start a thread for each of the NICE symptom categories in the various subfora of the Symptoms and signs discussions?

 

[Trish]

I look forward to hearing more. Do you have any particular sources we could read for information on histamine intolerance and what led you along this path of connecting histamine to ME/CFS without invoking either allergies or mast cells.

And I'm sure I'll not be the only one who notices you have carefully avoided mentioning which supplements you tried, and which one you have settled on as sufficient for your case. Are you willing to share?

And which specific symptoms other than brain fog do you think are particularly impacted by histamine problems in ME/CFS?

 

[poetinsf]

When I review the symptoms in the NICE guidelines, all I see now is histamine, which is probably a bit over zealous of me without stopping to consider the evidence in detail.

Welcome to the club! People who improved/recovered through a particular regimen tend to do that. I myself light up when I see "dopamine" because its effect on *my* me/cfs is 100% provable, lol.

Histamine is potent inflammatory mediator. So, it still could be exacerbating the symptoms if not driving, more so on some than others. I myself go under the weather during the pollen season. I'm no longer sure if pollen/histamine is the cause though. We had very wet Spring last year and the pollen count went way down, but I struggled the same.

 

[Creekside]

I think your thread title should be: "what-is-the-evidence-for-histamine-as-a-possible-cause-of-some people's-me-cfs-symptoms". I think it's reasonable for some people to have ME symptoms affected by histamine levels, but it doesn't mean that it's the root cause for all PWME. I do have some airborne allergies, but they don't affect my ME symptoms. Other factors that affect my ME symptoms don't seem to relate to histamine. The fact that many PWME have their histamine levels rapidly increase due to allergies, seems a valid test of the theory, and the results don't support it.

At about three weeks post surgery, I noticed the histamine starting to tail off more quickly,

Are you measuring your histamine levels, or just inferring them from symptoms you are theorizing are caused by them? Healing from major surgery would result in changes in a lot of factors that could affect symptoms.

 

[Scarecrow]

I look forward to hearing more. Do you have any particular sources we could read for information on histamine intolerance

The problem with the whole histamine intolerance thing is that it is still very much on the margins. Much of the information is put up by people who are self-diagnosed and however well meaning they are, the quality of the information is subject to personal bias. Information provided by therapists is often no better. One of my particular peeves was trying to sort out which foods are high in histamine and which are commonly considered to be histamine liberators because if a person reacts to a particular food, they may incorrectly label it as high in histamine. In essence, foods that's are high in histamine tend to be aged, preserved or fermented such as mature hard cheese and tinned fish, in fact a lot of seafood and fish is pretty high in histamine unless it's very fresh.

I fairly quickly came to the conclusion that histamine in food was not a particular issue for me unless I was eating a lot of high histamine food. If I consider a meal to be high in histamine I'll often take diamine oxidase (DAO) 15 minutes before eating for a bit of insurance. I haven't found I react to any foods that are commonly considered histamine liberators except for coffee. But I really like one cup of freshly ground coffee in the morning and the reaction is so subtle, just the merest cognitive blunting, and it soon passes.

A fairly comprehensive list of low and high histamine foods can be found at mastcell360.com. For a primer on histamine intolerance, I would recommend the ZOE podcast on YouTube: The surprising truth about histamine intolerance.

Ultimately, histamine intolerance was useful to me as a way in to deal with what I came to realise was mostly endogenous rather than ingested histamine.

and what led you along this path.

It was late 2020/early 2021. About ten years previous!y I had read someone's account on Health Rising of limiting histamine in their diet. For some reason it stuck with me even though it seemed irrelevant to me personally.

Some years later it occurred to me that histamine was related to migraine. I noticed the stuffy nose and stinging eyes. When I did a bit of researching I learned that in Spain, DAO is often prescribed for new migraine sufferers and it can reduce frequency and severity. I didn't act on that, just filed the information away. I now also attribute the brain fog of a migraine and the hangover to histamine.

In 2020, the year of COVID, I started to follow the long haulers on Reddit to see how they were doing. I noticed the discussions on histamine and I recalled the post on Health Rising.

Finally, I had a persistent cough at the time and slight pain low in my throat and high in my chest slightly off centre to the right. My GP suspected the cause was acid reflux but he sent me off for an X-ray to rule out anything more sinister. That came back clear, so he prescribed omeprazole and a steroid. I was grateful for the diagnosis and the prescription but I prefer to fix lifestyle and diet before turning to medicine. I found a diet plan for acid reflux, which successfully treated the pain and the reflux and I noticed that the diet plan was low in histamine. Histamine stimulates production of stomach acid.

At that stage, I still didn't particularly connect histamine to the symptoms of ME/CFS but while I was on the acid reflux diet I felt better, definitely clearer headed. That led me to histamine intolerance which uses a low histamine diet on a temporary basis as confirmation of the condition if symptoms improve.

And of I'm sure I'll not be the only one who notices you have carefully avoided mentioning which supplements you tried, and which one you have settled on as sufficient for your case. Are you willing to share?

Of course. I just didn't want to encourage anyone to try a whole lot of supplements, most of which are probably not going to be useful, particularly since I haven't proven my case!

In no particular order

• DAO
• supplements to support synthesis of DAO
• Supplements to support synthesis of histamine N-methyltransferase (HNMT) the other enzyme that degrades histamine. It works intracellularly and cannot be directly supplemented.
• supplements to inhibit histamine release from mast cells and possibly also from basophils
• natural antihistamines
• histamine degrading probiotics (B. longum, L. planetarium)

I don't have the list of actual supplements properly categorised but they are SAM-e, vitamin B6, quercitin, brome!ain, stinging nettles, NAC, omega 3, zinc, iron, vitamin B12. Some of these would in more than one of the categories above.

Of those, I already use omega 3 and, from to time, B12 as needed for sleep. I decided that iron and vitamin C wouldn't be necessary. Instead of the recommended probiotics, I found one off the shelf product that was suitable: Bioglan Biotic Balance doesn't have L. planetarium but it contains another histamine degrader but also one low or moderate histamine producer.

Of all those, I dropped the probiotics, SAM-e, B6, AND and the zinc quite early on leaving DAO for occasional use, quercitin, bromelain and the nettles (as tea).

Most recently, I dropped down to the occasional DAO and my MVP: Clipper organic nettle tea.

Before my operation I was on one tea bag a day, in a large mug, sipped warm or cold. Immediately after the operation, I needed six tea bags and I've gradually come down to two and am about to try going back to one. The two supplements I have just added back temporarily are the quercitin and bromelain.

In a nutshell, I dropped the supplements that support enzyme synthesis but kept the anti-inflammatories, anti histamines, and histamine release inhibitors.

And which specific symptoms other than brain fog do you think are particularly impacted by histamine problems in ME/CFS?

I suspect most of them when you examine how many functions histamine is already known to influence. Histamine is still very much a focus of recent and current research. Irritable bladder, anyone? And if histamine is causing an irritable bladder through nerve damage (if I recall correctly), what other nerves might it be affecting?

I emphasise headaches and brain fog because they still feature so prominently in my symptoms and they abate very quickly, generally within a few hours of taking the nettle tea. Also bear in mind that most of my physical symptoms had already improved until my operation. Since then, if you accept that histamine from my abdominal surgery is the proximate cause of my re-emerging symptoms, it is responsible for orthostatic intolerance, insomnia, flu-like PEM, sore muscles, diastolic blood pressure of 60 overnight ( which is low enough for me to feel as if my life is slipping away from me!) and thirst associated with the drop in blood pressure overnight.

To quantify the affect of the nettle tea on my cognitive symptoms and headache, between early February (5th or 6th), when I recommenced the tea after a break, and the end of March, I had one migraine lasting two days and had started to get a histamine headache and brain fog on one other day until I realised I hadn't made my tea. In the 14 days prior to the 5th Feb I had only four days without brain fog or headache. From the start of the year to 5th Feb, I had eight migraine days.

Question. How daft do you think I feel insisting that nettle tea has such a significant effect? I may die of embarrassment.

 

[Trish]

Thank you, that's all very interesting.

 

[Scarecrow]

Welcome to the club! People who improved/recovered through a particular regimen tend to do that. I myself light up when I see "dopamine" because its effect on *my* me/cfs is 100% provable, lol.

Do you think that dopamine has an effect on your most prominent symptoms or on all your symptoms? Do you have any idea why dopamine might have that effect?

Histamine is potent inflammatory mediator. So, it still could be exacerbating the symptoms if not driving, more so on some than others. I myself go under the weather during the pollen season. I'm no longer sure if pollen/histamine is the cause though. We had very wet Spring last year and the pollen count went way down, but I struggled the same.

That's fair. Still, if the known actions of histamine can be linked to the symptoms of ME/CFS over several categories, it's potentially persuasive that histamine is a driver. Hence my challenge.

I had wanted to ask people who get seasonal allergies if they experienced worsening of their ME/CFS symptoms in addition to the localised symptoms of allergy. To be clear, are you saying you had no symptoms of allergy at all last year or were they just milder than usual?

 

[Scarecrow]

Thank you, that's all very interesting.

I forgot to say that I have another two potential treatments, one of which is a prescription medication in the UK. Neither has an obvious link to histamine. I would not like to say any more on them at the moment because I think that it would be more useful to focus on symptoms for now.

 

[Scarecrow]

The fact that many PWME have their histamine levels rapidly increase due to allergies, seems a valid test of the theory, and the results don't support it.

I'm not sure if I agree with that statement even though I think that it would be interesting to ask people if specific symptoms of ME/CFS worsened during seasonal allergies. If substance X is causing symptoms, does more of substance X cause worse symptoms? Perhaps yes, perhaps no.

Are you measuring your histamine levels, or just inferring them from symptoms you are theorizing are caused by them? Healing from major surgery would result in changes in a lot of factors that could affect symptoms.

Obviously not direct!y measuring but inferring from the degree of swelling and the amount of nettle tea needed to treat. I know. Nettle tea. I know. I'm mortified.

Could you expand on your assertion? What factors and how might they affect symptoms?

 

[Utsikt]

Obviously not direct!y measuring but inferring from the degree of swelling and the amount of nettle tea needed to treat. I know. Nettle tea. I know. I'm mortified.

I think it might be helpful if you differentiate between what the observations are and your interpretation of those observations. Our interpretations are often wrong for all kinds of reasons, even the ones that seem obvious to us.

Could you expand on your assertion? What factors and how might they affect symptoms?

We have no idea what causes the ME/CFS symptoms so we have no idea how symptoms might be affected and by what.