Histamine Intolerance and MTHFR

Histamine is a compound made naturally in the body from the amino acid histidine. Histamine is primarily stored in mast cells and basophils, but also in lymph nodes, intestinal cells and the thymus.

Histamine is mostly associated with allergic reactions. These effects occur through four different receptors (H1, H2, H3 and H4) located throughout the body. When histamine binds to these receptors, it triggers symptoms such as sneezing, congestion, itchy and watery eyes, skin rashes, fatigue, headaches, and bloating or diarrhea.

Histamine is synthesised from the amino acid histidine by the enzyme L-histidine decarboxylase (HDC). HDC requires pyridoxal-5′-phosphate (P5P), the active form of vitamin B6, as a cofactor. Once released, histamine is metabolized mainly by the enzymes diamine oxidase (DAO) and histamine N-methyltransferase (HNMT), which produces several metabolic by-products.

Although known for its involvement in allergies, histamine has many different roles in the body.

Immune functions 

• Mediates the inflammation process and immunomodulation
• Increases vascular permeability and cytokine production
• Induces smooth muscle contraction and vasodilatation
• Stimulates haematopoiesis
• Supports wound healing, cell proliferation and angiogenesis

Gastrointestinal and metabolic functions

• Stimulates gastric acid secretion and nociceptive nerve fibers
• Helps regulate appetite

Cardiovascular effects

• Alters blood pressure
• Promotes vasodilation

Neurological

• Promotes wakefulness, alertness, and arousal
• Supports learning and memory
• Influences anxiety
• Modulates day and night rhythms

Diamine oxidase (DAO) and histamine N-methyltransferase (HNMT) are the two primary enzymes required for breaking down histamine. DAO acts primarily in the gut and intestinal mucosa, where it breaks down histamine ingested in food. HNMT acts on histamine within tissues, particularly in the brain and liver.

• DAO
  The main role of DAO is to keep histamine levels in balance and prevent excess histamine from entering the blood circulation from food or released into the digestive tract. DAO exists outside the cells and is mainly located in the intestinal mucosa, placenta, kidneys and thymus.
  DAO acts like a chemical ‘gatekeeper’ in the gut. It breaks histamine down by removing part of its nitrogen-containing structure, turning it into inactive by-products (including imidazole acetaldehyde) which the body can eliminate safely. This prevents the histamine from being absorbed into the bloodstream, which in turn prevents histamine from accumulating and triggering symptoms elsewhere in the body.
  If DAO is not able to function properly (whether due to genetic variants, health conditions or medications), histamine can build up, often resulting in histamine intolerance.

• HMNT
  HNMT is an enzyme inside the cells that controls histamine levels where DAO can’t reach, particularly in the liver, kidneys, lungs and brain. HNMT inactivates histamine by methylation, a process that requires S-adenosylmethionine (SAMe) as a methyl donor.
  If the methylation pathway is impaired, histamine may remain inside cells, causing inflammation, allergic-type reactions or overstimulation in sensitive tissues.¹

The H1 (G-protein-coupled) receptor is widely present in blood vessel linings, smooth muscle, sensory nerves and the central nervous system (CNS). The binding of histamine to H1 causes:

• Allergic and inflammatory responses such as itching, swelling, redness and increased mucus secretion seen in allergic reactions
• Dilation of blood vessels and increased permeability, allowing immune cells to enter tissues more easily
• Bronchoconstriction, contributing to asthma symptoms
• Wakefulness and hypersensitivity to pain

Blocking H1 receptors is the most familiar clinically: 

• Reduced allergic symptoms: less itching, redness, swelling and mucus production
• Decreased vasodilation and permeability → reduced tissue swelling (e.g., hives)
• Minimal effect on bronchoconstriction; not primary therapy for asthma
• CNS effects (mainly first-generation antihistamines): sedation and reduced wakefulness

Examples of H1 blockers:

• First-generation (sedating): diphenhydramine, chlorpheniramine
• Second-generation (less sedating): cetirizine, loratadine, fexofenadine

H2 receptors are located in the stomach lining (parietal cells), heart, blood vessels and certain immune cells. Histamine binding causes: 

• Stomach acid production, which is essential for the digestion of proteins. H2 blockers can be used to treat conditions such as ulcers and gastro‑oesophageal reflux disease (GERD)
• Vasodilation, which can affect cardiovascular function
• Changes in immune cell activity, including control of cytokine production

The H3 receptor is mostly located throughout the central nervous system and peripheral nervous system (PNS) as a presynaptic regulatory receptor. Blocking H3 receptors causes:

• Increases in histamine and other key neurotransmitters (acetylcholine, dopamine, serotonin, noradrenaline)²
• Improvements in learning, memory (working, spatial, episodic), alertness and cognition
• Potential treatments for Alzheimer's, Attention Deficit Hyperactivity Disorder (ADHD) and schizophrenia

The H4 receptor is expressed on immune cells (eosinophils, mast cells, T cells and other leukocytes), so it is mostly linked to the immune system and inflammatory regulation. It causes:

• Directed movement (chemotaxis) of these cells toward sites of inflammation
• Adhesion of immune cells to blood vessel walls and migration into tissues
• Local inflammatory responses in the lungs, liver and colon

The H4 is a relatively recently characterized receptor and remains an active area of research. Preclinical and early clinical studies suggest that blocking H4 receptors may lead to:

• Reduced immune cell migration (chemotaxis)
• Decreased immune-mediated inflammation, particularly in allergic and chronic inflammatory conditions
• Potential reduction in itch (pruritus)

The H4 antagonists are not yet widely used in clinical practice, but several compounds are under investigation in clinical trials for:

• Atopic dermatitis
• Asthma
• Chronic pruritus and other inflammatory/immune disorders

From a clinical perspective, each histamine receptor is associated with different therapeutic approaches:

H1 → antihistamines (allergy medications)

H2 → acid reducers (e.g., for Gastroesophageal reflux disease (GERD), ulcers)

H3 → experimental / CNS-targeting drugs (wakefulness, cognition)

H4 → emerging immunomodulatory targets (still under research)

• Histadelia is a term used to describe high histamine levels, but it is not a recognized medical condition. The term originates from orthomolecular psychiatry, a form of alternative medicine developed in the 1950s based on the concept that histamine levels were linked to mood disorders. The concept has not been validated by clinical studies and should not be confused with histamine intolerance.
• Histamine intolerance
  Histamine intolerance (HIT) is a type of hypersensitivity caused by histamine in food. Reactions occur when the amount of histamine ingested from food exceeds the body’s ability to break it down.

Note that the terms ‘primary’ and ‘secondary’ histamine intolerance are not defined medical categories.

• Primary histamine intolerance is often used to describe the reaction when the DAO or HMNT enzymes are deficient or not functioning properly.
  Genetic polymorphisms in the AOC1 gene (which encodes DAO) have been associated with lower enzyme activity and greater susceptibility to histamine accumulation in some people.³ Functional deficiency of the enzymes can lead to a predisposition for histamine accumulation, even if the diet is normal. Accumulation of histamine leads to symptoms that affect the skin, gut, respiratory system and neurological system, causing skin rashes, headaches, asthma and bloating/diarrhea.
• Secondary histamine intolerance occurs when another condition or factor impairs the breakdown of histamine. This can include intestinal inflammation or barrier dysfunction, such as in dysbiosis, which reduces DAO release and activity. Medications or medical conditions can also inhibit or reduce DAO function or histamine metabolism.

Histamine intolerance can result in symptoms affecting either the gut or other parts of the body in which histamine receptors are located. Symptoms can be diverse and difficult to pinpoint, but can include:⁴

• Gastrointestinal symptoms: Bloating (most common), abdominal discomfort, gas, diarrhea or constipation, and other digestive issues
• Respiratory symptoms: runny nose, rhinitis, nasal congestion, dyspnea, sneezing
• Skin symptoms: Pruritus (itching) (most common), redness, urticaria (rashes), dermatitis, swelling
• Cardiovascular/nervous system: Dizziness, headache, palpitations, migraine, low energy
• Reproductive system: Menstrual cramps

The DAO enzyme helps control and protect against high levels of histamine ingested through food, and most research indicates that histamine intolerance is linked to factors that reduce DAO or impair its function. These can include:

• Genetic factors: Variants in genes encoding DAO and related enzymes can reduce (or sometimes increase) DAO activity.
• Gastrointestinal disorders: Conditions such as inflammatory bowel disease, malabsorption disorders and nonceliac gluten sensitivity can lower DAO activity.
• Medications and other substances: Some drugs (e.g., verapamil) and alcohol can temporarily inhibit DAO, leading to excess circulating histamine.
• Diet: High histamine levels in the body may be caused by consumption of high-histamine foods, particularly fermented or poorly stored foods.⁵

Diagnosis of histamine intolerance is difficult as symptoms are diverse and tend to overlap with other conditions.

Testing DAO levels can help to detect intolerance. A blood test can measure either the total amount of DAO or its functional activity (HDU/mL). A urine test assesses histamine breakdown, which can demonstrate DAO activity and overall histamine processing. However, some research has shown that histamine levels can fluctuate throughout the day (usually due to the intake of histamine-rich food) which can result in a misinterpretation of a high or low level.⁶

It’s also important to note that a DAO blood test will not show DAO levels in the gut. The standard diagnosis of histamine intolerance typically requires assessment of diet, symptoms, medical history, and whether symptoms reduce after following a low-histamine diet for 3-4 weeks.

Although MTHFR is not directly linked to histamine intolerance, mutations in the MTHFR gene may impair methylation, which can then affect the function of HNMT. HMNT is one of the two major enzymes involved in histamine metabolism, and requires the availability of S-adenosylmethionine (SAM-e) to eliminate histamine from the body. High histamine levels may be associated with low methylation and reduced SAMe synthesis, but this may be only one factor.⁷

Vitamin B12 is not directly linked to histamine levels, but it is also required for the methionine cycle that produces SAMe (the methyl donor HNMT uses to break down histamine). B12 deficiency may impair SAMe production, which may then affect the function of HNMT and result in poor histamine clearance.

Supplementing with B12 and other nutrients that support methylation may be advisable for people who are low in microminerals.

The main strategy to reduce symptoms of histamine intolerance is to follow a low-histamine diet. As this can be different for each person, individuals are advised to avoid foods known to trigger their own symptoms. It may be helpful to keep a food diary and note when reactions occur.

Foods high in histamine include:¹³

Some foods are known as ‘histamine liberators’ because they are believed to trigger the release of histamine stored in the body.

• Fruits: Citrus, kiwi, pineapple, strawberries, bananas, tomatoes, plums, papaya
• Vegetables: Spinach, eggplant
• Nuts: Walnuts and peanuts. 
• Chocolate and cocoa
• Food additives: Benzoates, sulfites, nitrites, glutamate, artificial colors.
• Legumes: Beans, soy, lentils.
• Vinegars

Although there is a lack of scientific evidence to support the theory of ‘liberating’ histamine within the body, these foods are generally excluded on a low-histamine diet.⁸

It’s important to note that the histamine levels of a food product vary due to multiple factors, including freshness and production processes. For this reason, meat and fish may be safe for someone with histamine intolerance as long as they are eaten fresh. Fermented foods, on the other hand, are generally considered the most problematic due to their high histamine content or DAO deficiency. 

• Fresh or frozen meats: Poultry, fish
• Fresh fruit: Blueberries, apricots, cranberries, apples, mango, peaches
• Fresh vegetables: Sweet potatoes, asparagus, broccoli, squash, cucumbers, beets
• Fresh herbs
• Grains: Rice and rice products, wheat products, millet, rye, corn, oats
• Dairy: Butter, cream cheese, pasteurized milk 
• Eggs (in limited amounts)

Some foods also contain amines (such as putrescine, cadaverine, and tyramine) that may slow down the body’s ability to break down histamine from food by competing for DAO. This can mean that histamine remains in the body for longer, potentially causing higher histamine levels.⁹

Although current research is limited, supplementation with DAO may be effective for people who have a known DAO deficiency. Several studies have suggested that DAO supplements may increase DAO levels, improve symptoms and reduce use of antihistamine medications. A 2018 study found that people affected by migraines who were supplemented with DAO enzyme over one month significantly reduced the duration of their migraine attacks by 1.4 hours.¹⁰