Research studies on histamine intolerance and mast cells

Inflammation, allergies, and histamine issues affect so many people today, irritating us with a variety of seemingly unrelated symptoms.  Histamine intolerance is a term applied to the symptoms that occur due to eating too many histamine-containing foods.

Symptoms of histamine intolerance include the allergy-type symptoms (sinus drainage, itching, watery eyes, hives), gastrointestinal symptoms (diarrhea, stomach pain, heartburn, nausea), and brain-related symptoms (anxiety, insomnia, headaches).

Getting to the bottom of my own histamine related problems prompted me to search for the ‘root causes’ for histamine intolerance. I broke this problem down by looking at how our body produces histamine, the ways that histamine is used, triggers for producing too much, and solutions for blocking the release of histamine.

This is a departure from my usual articles on genetic variants.  If you are interested in some of the genes involved in histamine intolerance, please read my article on the genetic variants involved in histamine intolerance.  While those genetic variants do play a role in histamine-related issues, they exacerbate the problem rather than being a single cause.

Hopefully, something in the studies below will help you to figure out a root cause of your own histamine related issues.

Sources of Histamine:

There are several sources of histamine in our bodies:

  • Mast cells, a type of white blood cell, release histamine when presented with an allergen (IgE )
  • Basophils, another type of white blood cell and a part of our immune system, can also release histamine.
    • “Mast cells and basophils represent the most relevant source of histamine in the immune system. Histamine is stored in cytoplasmic granules along with other amines (e.g., serotonin), proteases, proteoglycans, cytokines/chemokines, and angiogenic factors and rapidly released upon triggering with a variety of stimuli. Moreover, mast cell and basophil histamine release are regulated by several activating and inhibitory receptors.” [study]
    • Neutrophils have also been discovered to store and release histamine [study]
  • Histamine is generated by histamine decarboxylase enzyme (HDC gene) which converts histidine, an amino acid, to histamine.
    • “Histamine is released from subcutaneous mast cells during the anaphylaxis phase via an IgE-mediated mechanism, whereas in the post-anaphylaxis phase, histamine is produced because of an increased HDC activity “ [study]
  • Enterochromaffin-like cells located in the stomach lining also produce histamine, which signals the release of stomach acid through the H2 receptors
  • Gut bacteria produce histamine: Lactobacillus species (in the presence of histidine) [study] [study].  Alternatively,  h. pylori infection may actually inhibit histamine release in the stomach.[study]

Histamine Receptors:

We have four different histamine receptors in the body, giving rise to the huge variety in symptoms of histamine related problems.

  • H1 receptors:  itchy allergy type response, also in wakefulness in the brain, motion sickness (Zyrtec, Benadryl and other antihistamines block this receptor),
  • H2 receptors: initiate acid production in stomach (H2 Blockers like Zantac attach to these receptors, blocking histamine from binding
  • H3 receptors: in the brain, central nervous system – act in opposite direction to H1 (wakefulness) in brain  [study]
  • H4 receptors: involved in immune response.  [study] [study]

Ways and Reasons that Histamine Is Released:

IgE / IgG / IgA:

  • IgE (typical allergy) is the normal way that mast cells are activated. The antigen links to a receptor on the cell surface causing degranulation. There is lots of information and studies on IgE / allergic reactions and histamine.
  • IgA deficiency has recently been linked to chronic urticaria (itching/hives). A 2016 study (small study) linked IgA deficiency, autoimmunity, and chronic urticaria.  Other studies have found a similar link.  [study] [study]
  • IgG can also bind to mast cells and cause anaphylaxis [study]

Commonly found substances/toxins that cause the release of histamine:

  • “Calcium triggers the secretion of histamine from mast cells after previous exposure to sodium fluoride.” [study]  And we put sodium fluoride in our water — since 1960 in the US.  
  • PFOA’s (Perfluorooctanoic acid) have been found to release histamine and cause mast cell degranulation. “Also, PFOA exacerbated allergic symptoms via hypothermia, and an increase of serum histamine, TNF-α, IgE and IgG1 in the ovalbumin-induced systemic anaphylaxis. The present data indicate that PFOA aggravated FcɛRI-mediated mast cell degranulation and allergic symptoms.” [study] PFOA’s are found in Teflon, stain-resistant carpeting, microwave popcorn bags and other food wrappers, etc.  They bioaccumulate – never breaking down in the environment. More on PFOA’s…
  • Carpeting is suspected for mast cell release in this case of sick building syndrome
  • Sodium benzoate (very common preservative) causes histamine release in people with allergies and asthma. [study]
  • For some people, aspirin and other salicylates can cause histamine problems – possibly through basophil activation [study]
  • The food additive Polysorbate 80 may cause histamine release [study]

Virus and bacteria:

  • Lyme disease (Borrelia burgdorferi) causes mast cells to release histamine.[study]
  • Influenza A virus was found to increase histamine released by e. Coli, salmonella, and staph. [study] And other studies show the virus (as well as other viruses) can trigger mast cell degranulation [study]
  • Here is a proposal to use cimetidine(Tagamet), which is an H2 blocker used for heartburn, in conjunction with other treatments for Lyme disease.
  • h. Pylori can cause activate mast cells and cause chronic urticaria (hives) [study] [study]
  • Lipopolysaccharide, aka endotoxin, from bacteria exacerbates mast cell activation [study]
  • An antihistamine (chlorcyclizine ) inhibits hepatitis C. [study]

Fungi / mold:

  • Inhaled mold spores cause histamine release – Trichoderma viride
  • Another role that mast cells play in the immune response is to react to fungi, specifically, this 2016 study used Malassezia sympodialis which binds to the Decklin-1 (aka CLEC7A) receptor on the mast cell and causes degranulation.  Curdlan was also used in the study and shown to bind to the Decklin-1 receptor on mast cells.  So what is curdlan? It is a beta-glucan produced by certain bacteria used as a food additive (gum) allowed in the US but not in the EU.
  • Sweat allergy and atopic dermatitis can be due to Malassezia globosa, a fungus commonly found on the skin [study]

Physical stimulation:

  • Histamine released from mast cells at an acupoint plays a role in acupuncture. [study]
  • Histamine is released in response to exercise [study] [study]  specifically aerobic exercise [study]
  • Taking OTC histamine blockers (Allegra + Zantac) decreased muscle pain and strength loss but increase muscle damage through creatine release after exercise. [study]
  • Vibratory urticaria (hives due to vibrations) can be caused by a mutation in the ADGRE2 gene [study]


  • Histamine regulates sleep phases [study]
  • Ambien, a prescription sleep medicine, works by increasing the action of GABA on histaminergic neurons in the brain.  [study]

Regulation of Body Temperature:

  • In a mouse study using histamine knockout mice, it was found that histamine lowered body temperature only in mice with a functioning HDC (histamine decarboxylase) gene.
  • Another study from the 1950’s looked at the effect of histamine on body temperature in several mammals and found that adding histamine lowered body temperature.  Another 2016 study found that histamine was involved in low body temperature set point using the H1 receptor.

Other conditions that are tied to histamine dysregulation:

  • Histamine plays a role ADHD – antihistamines help [study] [study] H3 receptors [study] [study]
  • Oral Lichen Planus is linked to histamine derangement and H4 receptors [study]
  • Rheumatoid arthritis is linked to histamine [article] [study] [study]
  • Cardiovascular disease “Mast cells have also been detected in the arterial wall and are implicated in the onset and progression of numerous cardiovascular diseases.” [study]
  • Atherosclerosis – “The results of this work indicate that the co-activation of macrophages and mast cells by oxLDL is an important mechanism for the endothelial dysfunction and atherogenesis. The observed synergistic effect suggests that both macrophages and mast cells play a significant role in early stages of atherosclerosis. Allergic patients with a lipid-rich diet may be at high risk for cardiovascular events due to high concentrations of low-density lipoprotein and histamine in arterial vessel walls.” [study] [study] interaction with nicotine [study]
  • IBS and intestinal permeability [study] [study]
  • Interstitial cystitis (bladder) is caused by mast cell dysfunction [study] [study]
  • Benign prostate problems can include mast cell degranulation / inflammation [study] [study] [study]
  • Role of mast cells in diabetes [study]
  • Mast cell involvement in endometriosis [study]
  • Histamine and mast cell degranulation both have a role in migraines [study] The role in migraines may also be influenced by estrogen levels including BPA (xenoestrogen) [study]
  • Mast cells and histamine are involved in post-surgery mental confusion and inflammation. Cromolyn (mast cell stabilizer) decreases the mental confusion. [study]
  • Interesting links to autism spectrum disorders with mast cell degranulation and brain inflammation. [study] [study] [study] [study]
  • “histamine plays a pivotal role in the pathogenesis of atherosclerosis” and “although its etiology is complicated and multifactorial, histamine/HRs signaling has a close relationship with the development of metabolic syndrome” [study]
  • BMI and skin reactivity in people with nasal allergies are all linked.

Foods, herbs, and probiotics to reduce histamine:

Switching gears here to focus on some of the things we can do to reduce histamine related problems.  The first line of defense is to lower histamine levels from food through eating a low histamine diet. You can use this list of histamine-containing foods as a starting point for customizing your low-histamine diet.

  • A low FODMAP diet reduces histamine [study]  8x reduction in histamine [study]
  • Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin. [study] Luteolin is used as a natural antihistamine. Another study looked at the synergistic effect of PEA and luteolin. [study]
  • Rosae multiflora fructus extract stops mast cell release of histamine (rat study) [study] This is used in Korean medicine as a tea – same plant as the wild rose that is an invasive species in my backyard.
  • Quercetin blocks histamine release due to chemotherapy drug [study] and generally works for allergies [study]
  • Cannabinoid receptor agonists suppress mast cell release of histamine [study]
  • Chicoric acid (from chicory and Echinacea) inhibit mast cell degranulation [study]
  • Curcumin also acts as an antihistamine [study] [study]
  • Manuka honey, when used topically for atopic dermatitis, was found to inhibit mast cell degranulation [study]
  • Nigella sativa (black cumin seed) blocks mast cell degranulation [study]
  • Probiotics that help:
    • Clostridium butyricum C/GMC/C0313-1 inhibits mast cell degranulation [study]
    • Lactobacillus G/G [study]
  • The way that a food is processed can change how much of an IgE reaction a person has to it. Here is a study discussing the different effects of processing on hazelnuts [study].  I’m throwing this in here to explain (at least to myself) one reason why food that is fine sometimes, at other times will cause a histamine reaction.
  • Luteolin protects against histamine release from mast cells [study]
  • Citrus peels contain flavonoids that inhibit mast cell release [study]
  • Arsenic inhibits mast cell degranulation [study] Still not a good reason to eat arsenic in rice.
  • Geranium essential oil was found to inhibit mast cell degranulation [study]
  • Omega 3 fats may suppress allergy activation of mast cells [study] [study]
  • Omega-6 fats may promote inflammatory activation of mast cells [study]


Stopping histamine production with OTC drugs:

  • Antihistamines that block the H1 receptor can downregulate the production of histamine by histamine decarboxylase (HDC gene). Specifically, diphenhydramine (Benadryl) suppressed the production the most with effects continuing for 9 hours or more.  Other antihistamines suppressed histamine production at least somewhat, with the exception of chlorphenamine (Allarest, Tylenol Cold). [study]

You do need mast cells:

  • While I’ve focused here on mast cells misbehaving, they do play an important role in immune function and shouldn’t be suppressed too much. For example, a study of diabetic wound healing found that reduced mast cell function was what caused the extended wound healing time.  This increased wound healing from mast cells may also play a role in how low-level laser therapy works in wound healing.

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13 Comments on “Research studies on histamine intolerance and mast cells

  1. Great Article! What about the connection of Epstein Barr Virus possibly being a mast-cell trigger?

    • Hi Esther,
      Thanks for reading the article! I haven’t really looked into EBV as a mast-cell trigger. I’m putting it on my list of things to read about! Seems like EBV can play a role in a lot of different chronic issues… Maybe I need to do a blog post on the link between genes and susceptibility to EBV. I had looked into it a few years ago when mono was going around with my kids and found that there are several different genes that play a role in a person’s response to the Epstein Barr virus.

      • I used to be healthy, hitting the gym almost everyday and eating almost anything I wanted, that is until I contracted EBV 5 years ago. After that I was constantly getting sick with colds at times of the year other than winter, having allergies, other symptoms, including no longer able to tolerate caffeine, and getting sick or feeling ill after exercising, and bad reactions after certain foods. However, I noticed I could get some relief with Zyrtec. Took 4 years until I read about Histamine Intolerance on the web and realized what my problem now is. So there is most definitely a connection between EBV and mast cell activation disorder/histamine intolerance.

        • Hi Kevin,
          I’m glad you are figuring out your histamine problems. I’ve heard the same thing from other about Epstein Barr triggering longer-term problems. There is a genetic component to the likelihood of getting mono from EBV, so I wouldn’t be surprised to find that there are gene variants tied to long-term problems with the virus.

  2. My 5 year old Grandson has EOE. ANY of this could be causing his illness? Doctors cannot decide which branch he is in. He also has a problem with his muscles not supporting his body. Any information would be greatly appreciated.

    • Hi-
      I don’t know much about eosinophilic esophagitis, but it makes sense that mast cells would be involved.
      A quick pubmed search turned up quite a few studies looking into the link between EoE and mast cells. Here is one from a few years ago: The introduction to the study has some good background information, and there are quite a few other studies that cite this study that may be good to read.
      Also, there is probably a genetic component to EoE. This study may be a good starting point for you: as well as looking into rs2302009 (CC genotype has 4x the risk for EoE):
      Hope this helps you in your search for more information to help out your grandson.

    • Hi, Dana, You might consider Ehlers Danlos as to the muscular issues. EDS causes faulty connective tissue and can manifest in many different ways–and many have EOE and mast cell issues. I hope you find some answers soon!

  3. How do we find out what genes are associated with the histamine sensitivity following the EBV. Any ideas of what to do if you believe this could be associated with my sons inability to gain weight and ADD?

  4. Bob Miller at NutriGenetic Research is looking into genetic variants in relation to mast cells and inflammation.
    He teaches an incredibly well-organized and insightful class, MethylGenetic Nutrition and his organization will soon be offering its own genetic testing, far more robust and extensive than 23andMe.

  5. Should add this research. After eating food for years that was often “old” food (rich meal with vegetables, but kept in the fridge for too long and eaten) and a possible infection of bedbugs/other insects (or a chronic reaction to their pooping) caused me for years to experience joint pains. I thought it was all about old age. I am a serious tennis player and am generally fit, but I saw my general condition fall over the last 4 or 5 years. Whatever was the real cause before (old food,…), one day, I considered checking my mattress (from a 2 year old rental). No sign. It looked new on the surface, but then when I lifted it, under, on the boards that were holding it, I found what could be described as yellow stains (possible bedbug or something else (other insect). I cleaned with paper towel without any protection (just some water) and within a few hours both of my hands swelled. After, I noticed that my joint pains were getting stronger and more intense than before. Then, good luck, I read this: I have eaten low-histamine foods for 4 weeks now and ALL my joint pains have vanished. The itchy hives have vanished too.

  6. Pingback: The effect of high or low histamines. – Lee's Stuff

  7. TPSAB1 rs138390396 is related to mast cells, and could be an answer for a lot of people with symptoms like hypermobility. I can’t find any information on which variants are risk variants…

    • Hi Robin,
      Thanks for reading and posting your comment. I’m not finding a lot of information on the TPSAB1 variant — do you know of good studies on it?

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