Inflammation and histamine issues seem to be rampant today, and getting to the bottom of my own histamine related problems has been a quest for a while. Things that work to partially relieve my histamine related symptoms (heartburn, migraines, chronic stuffy nose, periodic hives, sinus drainage, voice issues) are Benadryl and a low histamine diet, neither of which are good long term solutions for me.
There is a lot of information on the internet about histamine intolerance and mast cells. I’m not always sure of the accuracy of some of the information, so below is a collection of studies about histamine release and mast cell degranulation. Possible root causes of histamine increase include lingering viral and bacterial infections, a combo of things in the environment such as fluoride in the water and preservatives in foods, PFOA’s from using Teflon pans and stain-resistant coatings on carpeting for many years, toxins released from molds, and, I’m sure, many more.
This is a departure from my usual articles on genetic variants. If you are interested in some of the genes involved in histamine intolerance, I do have an article on the gene that produces DAO (breaks down histamine in intestines) and HMNT (breaks down histamine in the rest of the body). While those genetic variants do play a role in histamine-related issues, I think for me they exacerbate an underlying problem.
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 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 H4 receptors
- Gut bacteria produce histamine. Lactobacillus species (in the presence of histidine) [study] [study], h. pylori,
- 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:
- 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]
- Histamine released from mast cells at an acupoint plays a role in acupuncture. [study]
- Histamine is released in response to exercise [study] [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. I wonder if H1 receptor antagonist will raise body temp.
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:
- 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. https://en.wikipedia.org/wiki/Rosa_multiflora
- 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:z
- 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]
- Interesting study on retinoic acid (vitamin A) and mast cells— inhibits proliferation of mast cells but not histamine release.
- Vitamin E, in some studies, has been found to decrease mast cell degranulation. [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.