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Functional Medicine Histamine Intolerance Support Protocol

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Functional Medicine Histamine Intolerance Support Protocol

Histamine is a natural amine produced in the body that causes many effects on the body. Histamine is not inherently bad, but when an imbalance develops between the body's total histamine load and its ability to eliminate it, histamine intolerance develops. Despite how it sounds, histamine intolerance is not an allergy to histamine; but, the symptoms it creates appear allergy-like, given histamine's physiologic actions in the body. Because of this, diagnosing histamine intolerance can be difficult. This article will discuss a functional medicine approach to diagnosing histamine intolerance and identifying its root causes. It will also outline a treatment protocol to consider for histamine intolerance. (3, 4)


What is Histamine Intolerance?

Histamine is a chemical that plays a role in brain function, digestion, and immune responses. As a neurotransmitter, it acts on receptors in the brain to increase wakefulness. It stimulates parietal cells in the stomach to secrete gastric acid required for digestion. Histamine's most notorious role in the body is its ability to elicit inflammatory immune responses. (2)

Much of histamine is made in the body by granules in specific types of immune cells: mast cells and basophils. After exposure to foreign allergens, these cells release histamine at mucosal surfaces to induce an inflammatory immune response. Typically, histamine is then degraded by specific enzymes. If, however, you cannot break down histamine efficiently, it will build up in the body, causing histamine intolerance. Histamine intolerance results from dysequilibrium in accumulated histamine and the body's capacity to degrade and eliminate it. (1, 2)

Histamine Intolerance Signs & Symptoms

The symptoms of histamine intolerance are linked to the physiological functions of histamine in the body. Typically, histamine intolerance symptoms present after ingesting a high-histamine food or exposure to an allergen that triggers a histamine-mediated immune response. Symptoms strongly resemble allergy symptoms, sometimes making diagnosis difficult. Common symptoms include (1):

  • Gastrointestinal symptoms
  • Sneezing
  • Nasal congestion and runny nose
  • Headache
  • Flushing
  • Hives
  • Itching
  • Fatigue

More severe cases of histamine intolerance can present with abnormal and painful menstrual cycles, insomnia, irregular heart rate, asthma, anxiety, difficulty regulating body temperature and blood pressure, and dizziness. (3)

What Causes Histamine Intolerance?

Histamine intolerance results from factors that induce excess histamine production and deficiencies in the enzymes that break it down.

Reasons for Enzyme Deficiencies

Two main enzymes break down histamine in the body: diamine oxidase (DAO) is primarily responsible for eliminating histamine in the gut, and histamine-N-methyltransferase (HNMT) is responsible for the conversion of histamine intracellularly. (4)

Impaired enzymatic function and reduced levels of enzymes are two main reasons why a person may not have sufficient enzyme activity to eliminate histamine from the body. Genetic variations and certain medications can cause decreased enzymatic function or block the enzyme from doing its job. Medications that block DAO's activity include (3, 5):

  • Antiarrhythmics
  • Antibiotics
  • Antidepressants
  • Antihypertensives
  • Muscle relaxants
  • Narcotics
  • Non-steroidal anti-inflammatory drugs (NSAIDs)

Because DAO is synthesized in the gut, gastrointestinal disorders, including leaky gut, IBS, SIBO, and IBD, can also contribute to enzyme deficiency.

Reasons for Histamine Overproduction

Dietary histamine from histamine-rich foods or foods that trigger histamine release in the body will contribute to the overproduction of histamine. (3)

Exposure to environmental and dietary allergens causes IgE-mediated immune reactions and histamine release from immune cells. Some people have mast cell disorders, resulting in mast cell overactivation and overproduction of inflammatory chemicals, including histamine.

Mold exposure, leaky gut, SIBO, or other intestinal dysbiosis can contribute to immune dysregulation, shifting the immune balance to favor allergic-type responses and causing overproduction of histamine.

Estrogen promotes the degranulation of mast cells and basophils, mediating the release of histamine and other inflammatory cytokines. States of estrogen excess or dominance can increase histamine burden and worsen histamine-mediated symptoms.

Functional Medicine Labs to Test for Root Cause of Histamine Intolerance

Functional medicine labs help practitioners personalize treatment options for their patients. Below are some of the most common labs ordered for patients suffering from histamine intolerance.

Gut Health Assessment

A comprehensive gut assessment should include a comprehensive stool analysis, a SIBO breath test, and a leaky gut panel.

A comprehensive stool analysis measures biomarkers in stool that provide insight into digestion and malabsorption, intestinal inflammation, and the makeup of the large intestinal microbiome.

A SIBO breath test is performed at home by the patient. It measures gas levels exhaled through the breath that can indicate the overgrowth of bacteria within the small intestine and archaeal overgrowth in the small or large intestines.

The advanced intestinal barrier assessment (IBA) measures direct markers of leaky gut: zonulin, DAO, and LPS. Histamine is also measured to determine the histamine-to-DAO ratio.

Genetic Testing

Genetic polymorphisms of the DAO and HNMT genes can be identified with a genetic panel. Additional polymorphisms identified can also guide treatment recommendations, like the best form of vitamins to use and additional detoxification support.

Female Hormone Panel

A female hormone panel measures sex hormones essential to women's health, primarily estrogen, progesterone, and testosterone. When evaluating a women's hormonal balance, it is important to look at each form of estrogen and the estrogen-to-progesterone ratio.


The most accurate way to screen for and diagnose mold toxicity is to measure mycotoxins in the urine.


IgE-mediated allergies (environmental and dietary) should be ruled out as histamine intolerance mimics and potential triggers of histamine overproduction in the body.

Functional Medicine Treatment Protocol for Histamine Intolerance

Addressing histamine intolerance's root cause(s) is critical to overcoming symptoms. This article will not discuss this in depth due to the complexity of the many possible causes. Lab findings should guide this aspect of the treatment protocol, often including addressing gut health, balancing hormones, eliminating mold exposure, and treating allergies. You can check out the Rupa Health Magazine for articles about these issues.

Therapeutic Diet and Nutrition Considerations for Histamine Intolerance

Implementing a low-histamine diet is foundational in the treatment of histamine intolerance. Foods with high histamine content and those that stimulate the release of endogenous histamine should be eliminated or limited from the diet. Studies show that improvements in gastrointestinal and dermatological symptoms can be observed in 33-100% of patients as soon as four weeks after implementing dietary modifications. (4)

High Histamine Foods to Avoid

  • Hard and semi-hard cheeses
  • Fermented foods: pickled vegetables, sauerkraut, kimchi, yogurt, kombucha
  • Shellfish
  • Processed or smoked meats
  • Soy: tempeh, tofu, miso, soy sauce
  • Mushrooms
  • Avocado
  • Olives
  • Dried fruits
  • Canned food
  • Chocolate
  • Vinegar
  • Alcohol
  • Leftovers

Histamine-Releasing Foods to Avoid

  • Spinach
  • Eggplant
  • Tomato
  • Bananas
  • Plums
  • Pineapple
  • Citrus fruits
  • Strawberries

Low-Histamine Foods to Eat

  • Freshly caught and cooked fish, meat, and poultry
  • Cooked eggs
  • All vegetables except those listed above
  • Fruits: apple, cantaloupe, figs, honeydew, mango, watermelon
  • Unbleached and unprocessed grains and flours
  • Coconut
  • Dairy alternatives: coconut milk, rice milk, hemp milk, almond milk, macadamia milk

Supplements Protocol for Histamine Intolerance

Supplements are utilized in a histamine intolerance protocol to support histamine degradation pathways, stabilize mast cells, reduce inflammation, and palliate symptoms as needed.


Supplemental DAO taken no more than 15 minutes before meals can help break down dietary histamines in the digestive tract, preventing and alleviating digestive symptoms related to meals. Functional providers regularly prescribe Xymogen's HistDAO, dosed two capsules with meals.

Enzyme Cofactors

Nutrient cofactors are required to support the enzymes involved in histamine's breakdown and elimination pathways. Patients with histamine intolerance can be sensitive to supplements; dosing can vary between patients depending on their tolerance. Cofactors to consider supplementing in patients with histamine intolerance include:

  • Vitamin B1: 500-1000 mg daily
  • Vitamin B2: 400 mg daily
  • Vitamin B5 (Pantothenic Acid): 2-3 g daily
  • Vitamin B6 (P-5-P): 70-200 mg in the evening
  • Vitamin B12: 1000-5000 mcg daily
  • Vitamin C: 1000-5000 mg daily in divided doses; decrease the dose if the patient develops loose stool
  • Magnesium: start at 200 mg in the evening and increase to bowel tolerance; decrease the dose if the patient develops loose stool
  • Copper: 1-3 mg daily

Mast Cell Inhibitors and Antihistamines

Quercetin - found naturally in foods including garlic, onions, apple, and parsley - is known for its antioxidant activity and ability to inhibit histamine release. It is often dosed at 400 mg three times daily.

Stinging nettle leaf is also traditionally used in treating allergies, supported by research showing its ability to reduce clinical symptoms and eosinophil counts in patients with allergic rhinitis. Nettle leaf is commonly dosed at 400-600 mg three times daily.

Curcumin is the active component of turmeric and has anti-inflammatory, antioxidant, and anti-allergic properties. It has been studied and is often recommended for patients with mast cell disorders. It is typically dosed at 1 gram 2-3 times daily.

Omega-3 Fatty Acids

Omega-3 fatty acids (EPA and DHA) are known for their ability to enhance immune function and reduce inflammation. Using 3-5 grams of combined EPA and DHA daily can reduce inflammation and symptoms associated with histamine overload.


Supporting a healthy gut microbiome is important for patients with histamine intolerance to reduce intestinal inflammation and promote a healthy balance between histamine-producing and degrading bacteria. Certain strains of bacteria, like Lactobacillus casei, produce histamine. Probiotics that exclude histamine-producing and include histamine-scavenging bacterial strains can lessen the body's histamine burden. Seeking Health's Probiota HistaminX, dosed one capsule daily, is a popular option in treating histamine intolerance.

When to Retest Labs

The amount of time it takes to restore a healthy balance of histamine levels in the body varies from person to person, depending on the chronicity of symptoms, underlying factors, and ability to comply with treatment protocols. Many doctors and patients will opt to gauge the treatment plan's efficacy by monitoring patient symptoms, which can begin to improve anywhere from one week to a few months. If labs are being repeated, waiting 1-3 months from baseline is generally recommended to assess the patient's response to therapy accurately.



Histamine intolerance can cause uncomfortable symptoms. If you suspect that you suffer from histamine intolerance, work with a functional medicine doctor who can order the appropriate labs to rule out other disorders that can cause similar symptoms and identify the underlying contributors to histamine imbalance. By implementing dietary modifications and starting a supplement protocol, while addressing the root causes of dis-ease, it is possible to experience relief from histamine symptoms in a matter of weeks.

Lab Tests in This Article

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1. Maintz, L., & Novak, N. (2007). Histamine and histamine intolerance. The American Journal of Clinical Nutrition, 85(5), 1185–1196.

2. Mandal, A. (2019, February 26). What Does Histamine Do? News Medical.

3. Greenan, S. (2021, December 17). A Functional Medicine Approach to Histamine Intolerance. Rupa Health.

4. Shulpekova, Y.O., Nechaev, V.D., Popova, I.L., et al. (2021). Food Intolerance: The Role of Histamine. Nutrients, 13(9), 3207.

5. Huizen, J. (2021, April 16). Which foods are high in histamine? Medical News Today.

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