Histamine intolerance and the methylation cycle

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/ABP1 Gene:

Check your genetic data for  rs10156191 (23andMe v4; AncestryDNA):

  • C/C: typical
  • C/T: reduced production of DAO
  • T/T: reduced production of DAO[ref]

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

  • G/G: typical
  • G/T: reduced production of DAO
  • T/T: reduced production of DAO [ref]

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

  • C/C: typical
  • C/T: reduced production of DAO
  • T/T: reduced production of DAO

Check your genetic data for rs1049793 (23andMe v4; AncestryDNA):

  • C/C: typical
  • C/G: reduced production of DAO
  • G/G: 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 genetic data for rs1050891 (23andMe v.4 and v.5):

  • A/G: reduced breakdown of histamine compared to G/G
  • A/A: reduced breakdown of histamine compared to G/G [ref]

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

  • T/T: reduced breakdown of histamine
  • C/T: reduced breakdown of histamine compared to C/C
  • C/C: typical [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.

Check to see if you have impaired folate metabolism – MTHFR variants and MTR/MTRR variants.  Also, check to see if you have problems with the choline pathways.


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 a 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

Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.