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

I thought I would post this article here since @Scarecrow mentioned possible connections to menopause and antihistamines earlier in the thread.

What to know about viral menopause trend, according to a doctor

(CNN medical corespondent) Dr. Wen: There is a theoretical mechanism that some online influencers point to, which involves histamine, a chemical from the body’s immune system that acts through different receptors, including H1 and H2 receptors. Antihistamines block H1 receptors, and famotidine blocks H2 receptors. Histamine can affect blood vessels and may contribute to flushing and itching in some conditions, such as allergic reactions and mast cell activation syndrome, a condition that causes intense episodes of swelling, hives and other symptoms.

However, menopause symptoms are primarily driven by changes in estrogen levels and how those changes affect the brain’s temperature regulation system. This process involves complex interactions in the hypothalamus, not simply histamine pathways. I am not aware of any high-quality scientific evidence in the form of clinical trials showing that antihistamines or famotidine are effective treatments for menopause symptoms.

So, while the idea is biologically interesting, it remains unproven. Anecdotal reports should not be confused with rigorous scientific evidence, and more research is needed to study how effective these treatments are for menopause symptoms.
 
Mij said:
I thought I would post this article here since @Scarecrow mentioned possible connections to menopause and antihistamines earlier in the thread.

What to know about viral menopause trend, according to a doctor

(CNN medical corespondent) Dr. Wen: There is a theoretical mechanism that some online influencers point to, which involves histamine, a chemical from the body’s immune system that acts through different receptors, including H1 and H2 receptors. Antihistamines block H1 receptors, and famotidine blocks H2 receptors. Histamine can affect blood vessels and may contribute to flushing and itching in some conditions, such as allergic reactions and mast cell activation syndrome, a condition that causes intense episodes of swelling, hives and other symptoms.

However, menopause symptoms are primarily driven by changes in estrogen levels and how those changes affect the brain’s temperature regulation system. This process involves complex interactions in the hypothalamus, not simply histamine pathways. I am not aware of any high-quality scientific evidence in the form of clinical trials showing that antihistamines or famotidine are effective treatments for menopause symptoms.

So, while the idea is biologically interesting, it remains unproven. Anecdotal reports should not be confused with rigorous scientific evidence, and more research is needed to study how effective these treatments are for menopause symptoms.
Click to expand...

I’m sounding like a broken record, but my theory I mentioned earlier explains the temperature regulation issues with stellate ganglion irritation.
There is evidence (and my personal experience) that an SGB can reduce hot flashes caused by menopause:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10715304/

I’m a male, so in my case it’s definitely not menopause related. Overheating is a common issue among ME patients. An SGB reduced how my temperature feels by about 3C.
Then a few years ago I managed to tear and adjust something in my neck and the temperature regulation issues are almost completely resolved.

(My theory:
https://www.s4me.info/threads/a-theory-inspired-by-my-atypical-case.49655/ )

But it’s more complicated than that because there is a connection to histamine (and the Vagus nerve that runs right next to the stellate ganglion) as well:

Vagus nerve irritation can cause histamine release.
High mast cell levels can also cause high levels of histamine. All that overproduction results in vertigo, nausea, insomnia and fatigue.
Elevated mast cell levels can be also caused by physical irritation. (My theory is based on physical irritation.)

There are estrogen receptors on mast cells.
Estrogen activates mast cells, promoting histamine release. DAO enzyme breaks down histamine, but you can run out of DAO. Women feeling sick during pregnancy and menstrual cycles are partly explained by reduced levels of DAO, that causes elevated histamine levels.

Mitochondria produces pregnenolon, which is the “base” hormone that every other hormone is produced from. If there is mitochondrial damage in ME, perhaps it can result in hormonal imbalance.

So it appears that there is a connection between mitochondria, histamine-mcas and ME/CFS and this partly explains why women are more sensitive to these effects. Women have to deal with more histamine fluctuation naturally that adds to their symptoms if they get ME/CFS.
 
Some of the genes from DecodeME and other studies showed local expression in the Nucleus Accumbens. I noticed this in the Wikipedia entry on NA:

The nucleus accumbens is one of the few regions that receives a high density of histaminergic projections from the tuberomammillary nucleus (the sole source of histamine neurons in the brain).

https://en.wikipedia.org/wiki/Nucleus_accumbens#cite_note-Histamine_pathways-23" says:

Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience(2nd ed.). New York: McGraw-Hill Medical. pp. 175–176. ISBN 978-0-07-148127-4. Within the brain, histamine is synthesized exclusively by neurons with their cell bodies in the tuberomammillary nucleus (TMN) that lies within the posterior hypothalamus. There are approximately 64000 histaminergic neurons per side in humans. These cells project throughout the brain and spinal cord. Areas that receive especially dense projections include the cerebral cortex, hippocampus, neostriatum, nucleus accumbens, amygdala, and hypothalamus. ... While the best characterized function of the histamine system in the brain is regulation of sleep and arousal, histamine is also involved in learning and memory ... It also appears that histamine is involved in the regulation of feeding and energy balance.


You couldn't make it up, really.
 
I know I'm just one person but I often wonder if histamine in some way caused my ME.

I got put on and took myself off mirtazapine in a short timeframe (2.5 months). I know mirtazapine messes with histamine. So while I think I had post viral fatigue earlier in the year and had basically recovered, the mirtazapine seemed to kickstart my ME.
Obviously it could also have been that something else had been triggered during that time but it's always seemed odd to me. Antihistamines haven't helped me at all.
 
Thought this paper was a good fir for this thread. Gut bacteria are involved in histamine production too.

Gut-specific histamine 3 receptor signaling orchestrates microglia-dependent resolution of peripheral inflammation​


Kerstin Dürholz, et al.

Abstract​


Chronic inflammatory diseases like rheumatoid arthritis (RA) have been described to cause CNS activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such a factor.

We showed that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord, and restore homeostatic microglia, thereby reducing inflammation in the joints.

We found that elective histamine 3 receptor (H3R) signaling in the intestine was critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis.

Moreover, therapeutic supplementation of the short-chain fatty acid propionate revealed one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut/CNS/joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.
 
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