PMS, Genetics, and Solutions (Patrons Only)

A lot of women know the moodiness and brain fog that comes with premenstrual syndrome (PMS).  It can range from simply feeling irritable and icky to being something that really interferes with our lives.

What role do genes play in PMS?  It has been shown in the past few years that there is a genetic component, especially for a severe form of PMS called premenstrual dysphoric disorder (PMDD). PMS is thought to affect about 30-40% of women, while PMDD is rarer and affects only 3-8%.[ref] One 2011 study of twins estimated that heritability of PMS was around 95%.[ref]

Neurotransmitters cause some of the symptoms of PMS and PMDD. Serotonin is an important neurotransmitter involved in mood stability.

Estrogen is a serotonin agonist, and fluctuations in estrogen levels also affect serotonin levels. GABA, another neurotransmitter, is also involved in PMS symptoms for some.

Genes involved in PMS and PMDD


The rest of this article is available to Patrons via Patreon.  Thank you to all of you who support Genetic Lifehacks on Patreon!


Are you allergic to grass pollen? It may be genetic.

Spring is in full force here, and with it has come the need to dust off the lawnmower.  As the smell of fresh cut grass fills the air, many people also know the feelings of watery eyes, runny noses, and itching everything.

Speaking of smelling the grass… Did you know that some people can’t smell the odor of fresh cut grass?  There is actually a genetic variant (not covered by 23andMe data) that prevents some people from knowing that wonderful summertime smell.

There are several different gene variants that are tied to an increased risk of grass pollen allergies.

A study found that in people with grass pollen allergies there was an upregulation of MC1R in their noses.  If that gene sounds familiar, it is the same gene that codes for the melanin receptor which causes red hair.

HLA-DRB4 gene:

Human leukocyte antigens (HLA) are part of our immune system and help the body recognize foreign invaders. People have many different variants of these genes, giving rise to protection against different pathogens. Different HLA types lead to an increased ability to fight off diseases and also lead to increased susceptibility to autoimmune diseases and allergies.

rs7775228  (v4, v5)

  • CC: more likely to be allergic to grass pollen[ref]
  • CT: more likely to be allergic to grass pollen
  • TT: normal (most common genotype)

FLG gene:

Filaggrin, a protein encoded by the FLG gene, increases the epithelial integrity. Variants that decrease filaggrin have been tied to different types of allergies.

rs61816761 R501X (v4, v5):

  • AA: (rare) more likely to be allergic to grass pollen [ref]
  • AG: more likely to be allergic to grass pollen
  • GG: normal (most common genotype)

IL2 gene:

Interleukin 2 (IL2) is involved in the body’s immune system response to foreign invaders. It is a cytokine produced by Th1 cells when they are stimulated by, in this case, an allergen.

rs2069762 -330T/G (v4, v5):

  • AA: normal (most common genotype)
  • AG: normal risk of grass allergy
  • GG: 2.6x increased risk of grass allergy, [ref]

IL33 gene:

Interleukin 33 is involved in the body’s immune system response, also.  IL-33 drives the production of Th2 cytokines, acting on mast cells (among others).  It is thought to be responsible for itching sensations from allergies.[ref]

rs928413 (v4, v5)

  • AA: normal
  • AG: increased risk of hay fever, allergy
  • GG: increased risk of hay fever [ref]


A study on children with seasonal pollen allergies compared the effects of 1,000 IU of Vitamin D daily vs. placebo. The study found that the vitamin D group had reduced allergy symptoms compared to the placebo group. Another study looked at vitamin D combined with Lactobacillus rhamnosus GG (probiotic) on children’s allergies and found that the combo was also effective.

Nasal rinsing has been shown to be effective for grass pollen allergies.[ref]  The easiest way to nasal rinse is using a sinus rinse kit or with a neti pot.

Spirulina, a new favorite of mine, has been found in studies to reduce the symptoms of allergic rhinitis.[ref][ref]  You should be able to find spirulina in any health food store, or you can get it online.  Look for an organic version.

Bifidobacterium lactis reduced grass pollen reactions (taken for 8 weeks). [ref]

If you normally take antihistamines for pollen allergies, this study suggests that taking the antihistamines for three days before the exposure prevented the histamine 1 (H1) receptors from increasing expression in the nose. In an allergic response, your body releases histamine as a signaling molecule and then the receptors for histamine cause the reaction to occur.  H1 receptors are the ones involved in your typical seasonal allergy reaction with a runny nose and itchy, watery eyes. So the study showed that without the increase in histamine receptors, there were few allergy type symptoms. The antihistamine prevented the body from upregulating the H1 receptors.

Notes and studies related to histamine and mast cells

histamine and mast cellsInflammation, allergies, and histamine issues seem to be rampant today, and getting to the bottom of my own histamine related problems prompted me to search for my own personal ‘root cause’ for histamine intolerance. Below are my notes on different ways our body produces and deals with histamine.

Possible root causes of high histamine 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 just exacerbated 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 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 H4 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:

  • 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]

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]
  • 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.
  • 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 CGMCC0313-1 inhibits mast cell degranulation [study]
    • Lactobacillus GG [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.

Low Histamine Salsa Recipe

Low Histamine SalsaSalsa without tomatoes?  Yes!  Here is a quick recipe for a low histamine salsa using roasted red peppers instead of tomatoes.

Low Histamine Salsa

Roasted red peppers (2)

1/2 onion, diced

1/2 fresh red or yellow pepper, diced

small can of diced green chiles (optional)

cumin (to taste)

salt (to taste)

fresh cilantro, chopped

Blend the roasted red peppers in the blender or food processor until somewhat smooth.  Add diced onion, red pepper, green chiles.  Mix in cumin and salt to taste.  Stir in chopped cilantro.

Fresh corn tortilla chips:

I served this low histamine salsa with corn tortilla chips fried in coconut oil.  While unrefined, cold pressed coconut oil is nutritionally best, I’ve found that the cheaper, refined coconut oil leaves no coconut taste on the tortilla chips.  Just heat the coconut oil in a pan, cut up corn tortillas into wedges, and drop the wedges into the hot oil for a quick fry.  Be sure to turn the chips once while frying, and drain them on a paper towel or cookie rack.  Salt the chips while they are still hot.

Interested in the genetics of histamine intolerance?  Check out these two posts for more information: Histamine Intolerance & Genetics, Part 2 and High Histamine and Methylation (MTHFR defects).

Low Histamine Mint Shake

Low Histamine Mint Milkshake with Luteolin and Pea Shoots
Low Histamine Mint Milkshake with Luteolin and Pea Shoots

Not only is this shake low in histamines, but it is an excellent source of luteolin, a mast cell stabilizer.  So for anyone wanting a delicious, summery desert option, grab your blender and some ice cream.   I added some pea shoots for an extra boost of DAO enzyme.

Low-histamine Mint Shake

  • Fresh peppermint – about 25 grams or two big handfuls
  • 3/4 cup milk
  • ice cream
  • pea shoots (optional, natural source of DAO)

Blend together peppermint, milk and just one scoop of ice cream until smooth.    Then add in several more scoops of ice cream and blend to milkshake consistency.


Now for the science…

Dr. Theoharis Theohardies is a leading researcher on mast cell disorders and has written several papers on natural options for blocking the release of histamines from mast cells.  Much of his research and papers can be found on his website,

Luteolin is one bioflavinoid compound that has mast cell stabalizing (and thus anti-histamine releasing) properties.  Additionally, some studies have shown that it inhibits the production of estrogen and is being studied in regards to breast cancer. [ref]  Per 100 g of peppermint, there are 11 mg of luteolin.  [ref]  Parsley, oregano, thyme and celery are also high in luteolin.

mint and pea shoots

Histamine Intolerance & Genetics: Check Your 23andMe Raw Data

Histamine is a molecule that plays many roles in the body. It is involved in allergic reactions, plays a role in our immune defense system, acts as a vasodilator, and is a neurotransmitter.  While most of us think of histamine only when reaching for an anti-histamine during allergy season, it is a vital part of our body’s everyday functions.

Histamine that is out of balance with the body’s ability to break it down can cause symptoms that are collectively known as histamine intolerance. Histamine intolerance symptoms include headaches, migraines, anxiety/irritability, acid reflux, nausea, arrhythmia, sinus drainage, and more.

Genetics plays a role in how well your body breaks down histamine.  Read on to find out how to check your genetic data for genes involved with histamine levels…

Histamine Intolerance:
The main causes of histamine intolerance are too little of the enzymes that are needed to break down histamine, and/or too much histamine being produced (gut microbes or mast cells).  This article digs into the genes involved in the production of the enzymes that break down histamine.

Histamine is broken down and excreted by the diamine oxidase (DAO) enzyme in the gut and the histamine methyltransferase (HMNT) enzyme throughout the body.

Genetics of Histamine Intolerance:
Genetic variants of the AOC1/ABP1 gene can affect how much DAO enzyme is produced, and HMNT variants can cause variations in the production of that enzyme also. Some of the variants that are included with 23andMe results are listed below. Note that there are rarer mutations that influence DAO production not included with 23andMe data, so the information below may not give you the complete picture.[ref][ref]

AOC1 Gene:

Check your23andMe results for rs10156191 (v.4 only):

  • CC: normal
  • CT: reduced production of DAO
  • TT: reduced production of DAO[ref]

Check your 23andMe results for rs2052129 (v.5 only):

  • GG: normal
  • GT: reduced production of DAO
  • TT: reduced production of DAO [ref]

Check your 23andMe results for rs1049742 (v.4 only):

  • CC: normal
  • CT: reduced production of DAO
  • TT: reduced production of DAO

Check your 23andMe results for rs1049793 (v.4 only):

  • CC: normal
  • CG: reduced production of DAO
  • GG: reduced production of DAO [ref]


HNMT Gene:
Histamine n-methyltransferase is an enzyme that regulates histamine through metabolizing it from histamine to N-methylhistamine.

Check your 23andMe results for rs1050891 (v.4 and v.5):

  • AG: reduced breakdown of histamine compared to GG
  • AA: reduced breakdown of histamine compared to GG [ref]

Check your 23andMe results for i3000469 (v.4 , rs11558538):

  • TT: reduced breakdown of histamine
  • CT: reduced breakdown of histamine compared to CC
  • CC: normal [ref]

Methylation Cycle:
The methylation cycle plays a role in breaking down monoamine neurotransmitters including histamine.  So looking at your methylation cycle genes can also help with balancing out a histamine intolerance.


Most people with histamine intolerance find that a low histamine diet can help manage symptoms while getting to the root cause. There are many lists online for foods that are high in histamine or cause the release of histamine. Here is the list that I like to use.

A low histamine diet can be difficult to incorporate at first, but it should only take a few days to a week to know if it is helping your histamine intolerance type symptoms.  There are several research studies showing that a low histamine diet helps chronic urticaria (itchiness, hives), migraines, and asthma. [ref][ref]

There are DAO supplements available that may help some people who don’t produce enough of the enzyme. Additionally, pea shoots are supposed to be naturally high in DAO.[ref] You can easily grow pea shoots at home!

Quercetin has also been shown in studies to inhibit mast cells from degrading and increasing histamine levels.[ref]

A new study looked at the correlation between symptoms of histamine intolerance and gluten intolerance.  It concluded that there was significant overlap in symptoms and that it is possible that a low histamine diet may help people with gluten sensitivity. [ref]

How food is prepared makes a difference in the histamine levels.  A recent study concluded “Frying and grilling increased histamine level in foods, whereas boiling had little influence or even decreased it. The boiling method might be helpful to control the effect of histamine in histamine-sensitive or susceptible patients, compared with frying and grilling.”

In addition to foods, drug interactions can cause a decrease in the DAO enzyme production. Metformin has been shown to decrease the DAO enzyme.

For anyone taking nicotinamide (also called niacinamide or B3), here is an interesting research paper looking at the increase in plasma histamine level after taking 100 mg of nicotinamide.


More background information:

Histamine Receptors:
The other side of the histamine equation is the histamine receptors to which histamine binds.

  • H1: smooth muscle, endothelium (cells lining the inside of blood vessels and lymph vessels), central nervous system tissue, mast cells   (discovered in 1966)
  • H2: Gastrointestinal, vascular smooth muscle tissue (walls of blood vessels), mast cells  H2 receptors are blocked by Tagamet. (discovered in 1972)  “H2 receptors mediate histamine stimulation of gastric acid secretion and may be involved in cardiac stimulation”
  • H3: Central nervous system and some peripheral nervous system, mast cells (discovered in 1987)   “feedback inhibitors in CNS”
  • H4: Bone marrow, basophils (a type of white blood cell), thymus, small intestine, spleen, colon, mast cells  (discovered in 2001) “considered to have a role in a number of inflammatory disorders such as allergy, asthma, chronic pruritus and autoimmune diseases” [ref]

In the intestines, which is the body’s largest immune organ, three types of histamine receptors have been found: H1, H2, and H4. Low levels of H3 were found in intestinal samples in a few of the study participants. Interestingly, those with food allergies and IBS had significantly higher levels of H1 and H2 receptors in their intestines.  [ref]

Mast Cells:
Mast cells are the storage site for histamine in most tissue. Allergens cause mast cells to burst (degranulate) and release histamine. Large numbers of mast cells are in the skin, bronchial tree mucosa, and intestinal mucosa. Some think that histamine intolerance is a subset of MCAS (mast cell activation syndrome).

Read even more: Notes about Histamine and Mast Cells


Updated 2/2018


Histamine intolerance and the methylation cycle

Histamine Intolerance - The genes and pathways of breaking down histamine.
Histamine Intolerance – The genes and pathways of breaking down histamine.

Are you itching by the end of the day?  Miserable in the evening due to heartburn?  Nose constantly stuffy and drippy? Plagued by migraines? All of these (and more) can be related to histamine intolerance.

First, symptoms of histamine issues can be more than just watery eyes and sneezing when the pollen count rises each spring.

From The American Journal of Clinical Nutrition:

[Histamine] causes smooth muscle cell contraction, vasodilatation, increased vascular permeability and mucus secretion, tachycardia, alterations of blood pressure, and arrhythmias, and it stimulates gastric acid secretion and nociceptive nerve fibers. In addition, histamine has been known to play various roles in neurotransmission, immunomodulation, hematopoiesis, wound healing, day-night rhythm…

Symptoms of histamine intolerance can include:

  • headaches
  • migraines
  • dark circles under the eyes
  • itching, hives
  • congestion, sneezing, runny nose
  • acid reflux
  • anxiety, irritability, hyperactivity
  • digestive issues
  • tachycardia or arrhythmia
  • fatigue

I like the way the author of Peeling Back the Onion Layers explains it:

Everyone has a different tolerance for histamines. Some have serious mast cell disorders and need to be extremely vigilant about histamines in the diet. Some people need to restrict histamines in their diet to avoid migraines and terrible insomnia. Others just need to watch their histamine load to avoid crossing their threshold and feeling a little cranky or noticing a decline in their digestion.

A lack of the diamine oxidase (DAO) enzyme can cause issues with histamines.  The gene AOC1 codes for the production of diamine oxidase.  There are a couple of AOC1 polymorphisms included in 23andMe data that have been linked to reduced production of DAO.

Check your 23andMe results for rs10156191:

  •  CC: Normal DAO production
  •  CT: Reduced DAO production [ref]
  •  TT: Reduced DAO production


Check your 23andMe results for rs1049742:

  •  CC: Normal DAO production
  •  CT: Reduced DAO production [ref]
  •  TT: Reduced DAO production


So how does this tie together with the methylation cycle?  From Chapter 2: Nutrigenomics and the Methylation Cycle by Dr. Amy Yasko:

The functional areas impacted by improper methylation are in a dynamic relationship with one another—that is, they are mutually interactive. So it is with the relationship of your immune cells to digestive issues. Since many of your immune cells reside in the digestive tract, there’s a close relationship between methylation, immunity, and such digestive problems as leaky gut, allergies, and various forms of digestive distress that the children commonly experience. Briefly, if methylation is low and T cell production is low, then histamine levels tend to be high. Histamine is linked to inflammation, a contributing factors to leaky gut as well as allergies.

With the underactivity of T cells, B cell activity can take over, which can lead to autoimmune issues like allergies and food sensitivities.

This makes sense when you look at the big picture of how methylation cycle problems can affect the health of the whole body.  I do need to note, though, that this is not something for which I can find any research studies to back up Dr. Yasko’s position.

So for those who have MTHFR polymorphisms or other methylation cycle problems, histamine intolerance can be tied into overall immune health.   As your health overall improves, often histamines will become less of a problem.

A diet of low histamine foods can help to get you back on track and manage the symptoms that too much histamine is causing you.  But getting to the root of the matter will require a healthy gut.  For those with methylation cycle issues, a diet rich in green vegetables will help increase folate levels, and there are supplements for methylfolate and B12 that may help as well.* Another avenue to look at for gut health and inflammation is the role that surfactants in our foods play in our gut microbiome.

Additional Reading:

Updated Feb. 2017