Histamine is a bioactive compound involved in immune inflammatory reactions, allergies, vasoactivation, gastric acid secretion, and blood cell formation.
High histamine levels can cause classic symptoms such as sneezing, congestion, rash, bloating, nausea, vomiting, diarrhea, headache, dizziness, and low blood pressure. Histamine intolerance is associated with GI disorders, including IBD, IBS, celiac disease, and reduced production or activity of diamine oxidase, the enzyme that breaks down intestinal histamine. A low histamine level may not be considered clinically relevant.
Standard Range: ≤1.8 ng/mL (16.19 nmol/L)
The ODX Range: <1.0 ng/mL (9.00 nmol/L)
Standard Range: 12-127 ng/mL (107.96 - 1142.62 nmol/L)
The ODX Range: 12-127 ng/mL (107.96 - 1142.62 nmol/L)
Low histamine levels suggest the absence of histamine intolerance and may not be considered clinically relevant.
High histamine levels are associated with histamine intolerance, allergic reactions (Patel 2023, Smolinska 2022, Kakolyri 2020), mast cell activation syndrome (MCAS), eosinophilic gastroenteritis, celiac disease (Schnedl 2021), abdominal bloating, nausea, vomiting, diarrhea, dizziness, palpitations, hypotension, headache, dermatitis, urticaria, pruritic, edema, local inflammation (Comas-Basté 2020), migraines (Jochum 2024, Comas-Basté 2020, Haimart 1987), increased heart rate, flushing, headache, increased pulse pressure, decreased diastolic blood pressure (Kaliner 1982), food allergy, IBS, IBD, gut microbial histamine production, fermented food histamine (Smolinska 2022), hypersensitivity to NSAIDs (Kakolyri 2020), and an insufficiency of vitamin C (Jochum 2024, Clemetson 1980), copper, and diamine oxidase (DAO) (Jochum 2024).
Histamine, a bioactive amine, is synthesized from the amino acid L-histidine using the pyridoxal-5’-phosphate form of vitamin B6 as a cofactor. Histamine is found in most tissues, including gastric mucosa, parietal cells, and neurons, but is found in the highest concentrations in mast cells, basophils, and the lungs. Macrophages, neutrophils, platelets, and dendritic cells can produce large amounts of histamine, but only mast cells and basophils store significant amounts. Most histamine is broken down by histamine-N-methyltransferase (HNMT) (50-80%) and diamine oxide (DAO) (15-30%). Histamine has potent vasoactive activity, plays a role in immunoregulation and the inflammatory response, and is a mediator of allergic reactions, autoimmune conditions, gastric acid secretion, and new blood cell formation in the bone marrow, e.g., RBCs, WBCs, and platelets. It is also a significant activator of neutrophils and eosinophils (Patel 2023).
Mast cell histamine release is associated with celiac disease, eosinophilic gastroenteritis, and mast cell activation syndrome (MCAS). Histamine intolerance (HIT), often related to insufficient DAO, was found in 55% of celiac disease subjects who did not respond to a gluten-free diet (Schnedl 2021).
Histamine is also produced by bacterial fermentation and, therefore, can be found in fermented foods and even produced by GI bacteria. An insufficiency of gastrointestinal DAO, the enzyme responsible for breaking down ingested or microbiota-generated histamine, can lead to histamine intolerance. HIT is associated with bloating, postprandial vertigo, headache, diarrhea, abdominal pain, and constipation. A serum DAO below 10 U/mL may be related to HIT. A low-histamine diet and DAO supplementation may help relieve HIT symptoms (Schnedl 2021).
DAO insufficiency may be temporary if caused by substances that inhibit it, including alcohol; competing bioactive amines such as putrescine and cadaverine found in citrus, mushrooms, soybeans, nuts, and bananas; and certain medications, including chloroquine, clavulanic acid, verapamil, clonidine, and metoclopramide. Other amine-containing foods, including papaya, kiwi, strawberries, plums, and pineapples, may trigger histamine release, contributing to histamine intolerance (Comas-Basté 2020).
Histamine-rich foods include fish, seafood, fermented or aged foods (e.g., cheese, pickles, and sausage), and certain vegetables, including spinach, eggplant, and tomato. These foods should be limited in HIT. Supplementing with DAO enzyme cofactors vitamin C, copper, and vitamin B6 may be a beneficial adjunctive therapy (Smolinska 2022).
Symptoms begin to occur as histamine accumulates in the blood, often involving three or more organs, and average symptoms 11 per patient. Gastrointestinal symptoms are the most frequent and severe and include postprandial fullness, abdominal pain, diarrhea, and constipation, followed by nervous system and cardiovascular symptoms, including dizziness, headache, and palpitations. Respiratory and dermatological symptoms can occur as well (Comas-Basté 2020).
Additional symptoms of histamine intolerance include nasal congestion, sneezing, rhinitis, dyspnea, decreased muscle tone, itchy skin, fatigue, anxiety, depression, and collapse. Histamine can increase the synthesis and release of catecholamines, causing increased blood pressure, tachycardia, arrhythmias, nervousness, and sleep disturbance. Histamine produced by GI bacteria can pass through into the plasma and cause adverse reactions. Histamine-secreting bacteria include Staphylococcus, Proteus, Enterobacteriaceae, Clostridium perfringens, and Enterococcus faecalis (Smolinska 2022).
The activation of four types of histamine receptors determines symptomatology (Patel 2023):
H1 receptors
H2 receptors
H3 receptors
H4 receptors
Histamine can be measured in whole blood or in plasma. Early research in 12 subjects used histamine infusion to identify the level at which plasma histamine was associated with various symptoms. A level of 0.62 ng/mL (5.58 nmol/L) was related to basal histamine, an increase to 1.6 ng/mL (14.49 nmol/L) was associated with a 30% increase in heart rate; 2.39 ng/mL (21.50 nmol/L) was associated with significant flushing and headache; and 2.45 ng/mL (22.04 nmol/L) was associated with a 30% increase in pulse pressure. Antihistamine therapy increased the threshold at which the symptoms occurred. Dose-related symptoms included increased pulse rate, decreased diastolic blood pressure, cutaneous flushing, and pulsatile headache (Kaliner 1982). Migraine sufferers can have significantly elevated plasma histamine during and in between migraine attacks (Haimart 1987),
A review of data from 55 BioCenter Laboratory patients found the highest blood histamine in those with obsessive-compulsive disorder (OCD) and bipolar, organic brain syndrome. Researchers note that histamine itself functions as a neurotransmitter and elevated levels may be associated with headaches, personality disorders, and even schizophrenia (Jackson 1998).
Elevated histamine is seen in at least 50% of acute allergic reactions presenting to the emergency department. Plasma histamine levels above 1.11 ng/mL (10 nmol/L) correlate better with acute allergic reactions than tryptase levels. Clinical signs associated with elevated histamine include urticaria, extensive erythema, wheezing, and abdominal symptoms, while only urticaria was related to elevated tryptase above 15 ng/mL. The severity of urticaria appears to be the best predictor of plasma histamine. An elevation in histamine but not in tryptase suggests the involvement of basophils, which produce much less tryptase than mast cells do. Gastrointestinal symptoms are likely to be associated with elevated histamine and food allergies (Lin 2000).
Vitamin C breaks down the imidazole ring of histamine and can reduce elevated histamine in the blood. A dose of 2,000 mg of vitamin C can reduce plasma histamine by 40% (Ramanujan 2024). Whole blood histamine increases exponentially as plasma vitamin C levels fall below 1 mg/dL (56.78 umol/L, with a highly significant increase in histamine when plasma vitamin C falls below 0.7 mg/dL (39.75 umol/L) (Clemetson 1980).
Histamine intolerance may be associated with medication sensitivity. In a study of 34 subjects, plasma histamine, but not whole blood histamine, was significantly higher in those reporting hypersensitivity to acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs). Histamine was also significantly higher in those reporting sensitivity to COX-1 versus COX-2 selective inhibitors (Kakolyri 2020).
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