Histamine is a neurotransmitter with very important roles both in the brain and in the gut. Read this post to learn more about histamine.
What is Histamine?
Its name is derived from the Greek word ‘histos’, meaning tissue. Histamine got its name based on the fact that it can be found in various tissues [R].
Histamine was discovered in 1910 by the winner of the 1936 Nobel Prize in Medicine, Sir Henry H. Dale [R].
Since then, there has been a multitude of research involving histamine. However, there is still a lot we don’t know about histamine and its various functions.
Histamine is produced from the amino acid histidine, by the enzyme HDC (histidine-decarboxylase) (R, R].
- Mast cells and basophils, which are white blood cells responsible for allergic reactions
- Enterochromaffin-like cells in the stomach
- Histamine-releasing neurons (histaminergic neurons) can both produce and store histamine
Other cell types (such as dendritic cells (DCs) and T cells), can also produce histamine, but at much lower levels. These cells cannot store histamine, so they release it as soon as it is produced [R, R].
Certain microbes, such as some of our gut bacteria, also have the HDC enzyme, which allows them to produce histamine from the amino acid histidine [R].
HNMT degrades histamine inside the cells [R].
HNMT is the main enzyme degrading histamine in the brain [R].
It is also present in various tissues, such as the liver, spleen, gut, prostate, ovary, kidneys and lungs [R].
Blockers of HNMT reduce histamine degradation and increase histamine levels [R].
DAO is the main histamine-degrading enzyme in peripheral tissues (gut, connective tissues, placenta, kidneys) (R, R]. This enzyme can be released into the blood, and can therefore degrade histamine found outside of the cells [R].
Functions – Overview
Histamine has many different roles in the body.
Histamine acts as a messenger molecule in the nervous system (neurotransmitter) [R]. In the brain, it plays a key role in the sleep–wake cycle, appetite, motivation, learning, memory and sexual behavior [R, R].
In the stomach, histamine stimulates stomach acid secretion [R].
In the rest of the body, histamine is involved in the immune response, it causes smooth muscles and airways to contract, blood vessels to dilate and activates itch and pain-associated nerve cells [R]. These are all symptoms commonly found in allergies and other conditions in which histamine is increased.
The diverse functions of histamine are carried out through four specific histamine receptors: H1R, H2R, H3R and H4R [R]. These are proteins that histamine binds to on the cells. They are important, because histamine often has opposing roles, depending on which receptor it activates.
- H1R is found in the brain, airways, blood vessels, white blood cells and in various other tissues [R].
- In the brain, H1R activity results in increased wakefulness, reduced appetite and increased thirst [R].
- H1R activity can cause symptoms of allergy, such as redness, itching, swelling [R], runny nose, airway constriction, anaphylaxis, conjunctivitis (pinkeye), and hives [R].
- H2R is found in the brain, stomach, smooth muscles, white blood cells, heart and other tissues [R].
- Histamine binding to H2R inhibits immune system activities (both Th1 and Th2) [R, R], stimulates stomach acid secretion and increases heart rate [R].
- H2R activity causes smooth muscle relaxation of blood vessels, uterus and airways [R].
- H2R reduces bone density [R].
- H3R activity prevents the release of histamine [R]. This means that H3R often (but not always) has roles that oppose the activity of other histamine receptors.
- H3R is found in the brain, mainly in histamine-releasing nerve cells [R, R]. It is also present in other tissues, such as the stomach’s enterochromaffin-like cells [R].
- H3R activity promotes sleep, reduces itching and stimulates alcohol preference [R, R, R).
- In the brain, apart from decreasing histamine, H3R activity also decreases acetylcholine, dopamine, serotonin, noradrenaline, GABA, and glutamate [R, R, R].
- H4R is found in the bone marrow and white blood cells. It is also present in the spleen, thymus, lung, small intestine, colon and heart [R, R].
- H4R when activated recruits and activates white blood cells involved in inﬂammatory responses (such as eosinophils, mast cells, neutrophils, T lymphocytes and dendritic cells (DCs)) [R, R, R].
- H4R is also responsible for cytokine release. H4R activation increases IL-17 [R], and Th2 cytokines IL-4, IL-5, and IL-13 [R].
Histamine Blood Test
Reports of normal histamine levels vary between studies.
Histamine has a lifespan of a few minutes in the blood. Usually, it is rapidly degraded [R].
Health Benefits of Histamine
1) Increases Alertness and Wakefulness
Histamine maintains wakefulness by activating H1R [R].
Early H1 antihistamines, that readily enter the brain (pass the blood-brain barrier), such as chloropyramine, diphenhydramine, and cyclizine, diminish alertness, slow reaction time, and cause drowsiness and sedation (R, R].
On the other hand, drugs that block H1R, such as propiomazine and diphenhydramine, were reported to improve sleep quality [R].
Histamine-releasing neurons are associated with circadian rhythms. They are active during the day, stop working during drowsy states before sleep and resume activity only at high vigilance after waking-up [R].
Low brain histamine can cause excessive daytime sleepiness or prolonged nighttime sleep (hypersomnolence) [R].
Human narcoleptics have decreased brain histamine [R]. Narcolepsy is a disorder that affects the control of sleep and wakefulness. People with narcolepsy experience excessive daytime sleepiness and uncontrollable episodes of falling asleep during the daytime.
In narcoleptic patients, tiprolisant – an H3R inhibitor, increased wakefulness [R].
2) Reduces Appetite
Brain histamine decreases appetite via H1R and controls eating frequency (circadian rhythm). Increasing brain histamine suppresses appetite and decreases caloric intake, body weight, and blood triglycerides in rodents and monkeys [R].
In contrast, decreasing brain histamine, by blocking H1R, increases appetite, and increases both meal size and duration [R].
H1R deficient mice have disrupted feeding rhythms, and are prone to develop metabolic syndrome and obesity [R]. Similarly, mice with global histamine deficiency develop stomach fat, high insulin and have impaired glucose tolerance [R, R).
Chewing your food well may help reduce appetite. It was shown that chewing induces histamine release and activates H1R in the brain [R].
Depending on the study, H3R both increased and decreased appetite and obesity [R, R]. This may be because apart from decreasing histamine, H3R also decreases a variety of other substances in the brain [R].
During pregnancy, histamine content decreases, so appetite and food consumption increases [R].
Anorexia nervosa patients have more H1R receptors in the brain [R].
3) Increases Motivation and Exploration
Histamine is increased during goal-directed actions, where it plays a central role in motivation [R]. This is related to histamine’s role in decreasing appetite. By reducing the drive to eat, histamine helps you focus on the task.
Brain histamine is also required for the exploration of novelty [R].
Mice globally deficient in histamine have less interest in novelty and explore less [R].
Mice lacking H1R also explore less when put in a new environment. Furthermore, they have reduced emotional responses to new environments [R].
4) Helps Deal with Stress
Histamine is part of the body’s protective system designed to respond to danger.
In danger, brain histamine increases alertness and focus, decreases pain and the desire to eat [R].
Various types of stress increase brain histamine [R]. Examples include dehydration, loss of blood, severe infection or emotional stress.
5) Increases Water Intake
Prolonged (24 or 48 h) dehydration increases the production and release of histamine in the brain [R].
High histamine levels in the brain cause thirst and elicit drinking [R].
Histamine in the brain also increases water retention, by increasing the release of the hormone vasopressin. Decreasing histamine, by reducing its production, blocking H1R and H2R, or activating H3R, strongly decreases dehydration-induced vasopressin release [R].
6) Improves Cognitive Performance
Histamine stimulates certain types of memory and learning, while inhibits others [R].
H1R is important for memory, learning, and wakefulness [R]. H1R deficient mice show general learning and memory impairment. They have impaired spatial memory, and fail to integrate space- and time-related information [R].
H1 antihistamines can impair cognitive performance in humans [R]. Some of these effects may also be related to sedation.
Activation of H1R improves object recognition [R], while H2R activation enhances memory consolidation in rats [R].
However, there are also cases in which H3R activation enhances learning and memory (R, R].
7) May Combat Depression
Loss of histamine or histamine receptors in animals results in depression [R].
Reduced H1R activity correlates with the severity of clinical depression [R].
8) Protects from Seizures
Treatments that increase brain histamine improve a form of hereditary temporal lobe epilepsy, while H1R antihistamine diphenhydramine aggravates seizures in this setting [R].
Blockade of H1R promotes seizures in humans [R]. Proconvulsant (seizure-causing) effects of H1R antihistamines have been observed particularly in children [R].
H2R inhibitors (such as famotidine) can also cause seizures [R].
On the other hand, blockade of H3R, which facilitates histamine release, is anticonvulsant (protects from seizures) [R].
9) Promotes Sexual Behavior and Reproduction
Sexual behaviors are compromised by the loss of histamine and histamine receptor function [R].
Histamine deficiency and H1R inhibition impair mating behaviors and sexual arousal in mice. These mice have elevated androgen levels but smaller testicles [R].
10) May be Beneficial in Alzheimer’s
Some of the cognitive deficits associated with Alzheimer’s disease may be explained by lowered brain histamine [R].
Alzheimer’s disease patients have decreased brain histamine levels and a lower number of histamine-releasing neurons [R, R).
The Alzheimer’s disease drug tacrine is an inhibitor of acetylcholine esterase, but it also inhibits HNMT, thereby, increasing brain histamine levels [R].
11) Helps the Body Cool Down
It was shown that heating the body activates histamine-releasing neurons, and activated H1R then decreases body temperature [R].
Histamine promotes airway dilation and rapid breathing (R, R). Increased airway surface releases more heat.
Elevated histamine in the brain causes hypothermia (below-normal body temperature) [R].
1) Elevated Levels Causes Skin Itchiness
Histamine is released from mast cells (a type of white blood cells) when tissues are inflamed or stimulated by allergens. Once released, histamine causes itching [R, R).
Activation of H1R and H4R induces, whereas activation of H3R decreases itching [R].
2) Increases Inflammation
Histamine can act rapidly in blood vessels and airways, causing acute rhinitis, airway constriction, conjunctivitis, cramping, diarrhea or the skin wheal and ﬂare responses, mostly via H1R activation [R].
Pre-treatment of the nose and eyes with H1R antihistamines can decrease the inﬂammation locally after an allergen challenge [R].
However, histamine also contributes to chronic inflammation [R].
H4R activity has chronic inﬂammatory effects that can be decreased by administration of H4R inhibitors [R].
3) Contributes to Asthma
Histamine generally promotes Th2 responses [R], which are implicated in the development of asthma (some types).
Furthermore, histamine causes airway contraction and coughing [R].
Inhaled and intravenous histamine causes airway constriction that can be inhibited by H1R antihistamines [R].
However, although histamine does play a role in asthma, antihistamines are not very effective in asthma treatment [R], compared to corticosteroids. Antihistamines can still help by decreasing the Th2 immune response and suppressing the accumulation of inﬂammatory cells [R].
It has been shown that treatment with cetirizine, an H1R inhibitor, over a period of 18 months delayed the onset of asthma in some young children with atopic dermatitis [R].
In patients with concurrent symptoms of allergic rhinitis and asthma, treatment with H1R antihistamines decreased rhinitis and asthma symptoms, and improved airway function [R].
However, in some cases, H4R activity was protective in mice with asthma [R].
4) Aggravates Atopic Dermatitis
Orally ingested histamine aggravates eczema in atopic dermatitis patients [R].
Patients with severe atopic dermatitis have higher blood histamine. They also have increased spontaneous histamine release in response to different cues such as food [R].
In addition, reduced DAO activity was found in some patients with atopic dermatitis [R].
Reduction of atopic dermatitis was observed in patients with low DAO activity who followed a histamine-free diet for 2 weeks [R].
5) Elevated Levels Causes Anaphylaxis
Histamine plays a role in anaphylaxis – a severe, whole-body allergic reaction.
In anaphylaxis in mice, histamine in response to an allergen decreases breathing frequency and body temperature [R].
6) Causes Motion Sickness
Histamine plays a role in keeping balance, which involves hair cells in the inner ear [R].
Betahistine, a drug frequently prescribed for motion sickness and vertigo, strongly inhibits H3R and weakly activates H1R [R].
7) Elevated Levels Causes Headaches
Histamine causes headache by releasing nitric oxid [R], and/or increasing inflammation [R].
Therefore, histamine can induce headaches dose-dependently in healthy people as well as in patients with migraine [R].
In migraine patients, histamine is elevated both during attacks and during symptom-free periods [R].
Many migraine patients have histamine intolerance and reduced DAO activity. Food rich in histamine triggers headaches, while histamine-free diet and therapy with antihistamines alleviate headaches in these people [R].
However, antihistamines are generally not effective in treating headaches [R].
8) Decreases Bone Density
Histamine decreases bone density [R].
Patients with osteoporosis tend to have higher levels of histamine [R].
Global histamine deficiency increases bone density and reduces bone break-down in mice (R, R].
9) Causes Scombroid Poisoning
Major histamine-producing bacteria in the fish are Morganella morganii, Enterobacter aerogenes, Raoultella planticola, Raoultella ornithinolytica, and Photobacterium damselae [R].
The proper handling and storage of fish is the most effective preventive measure, as cooking does not decrease histamine levels [R].
The symptoms of scombroid poisoning are variable and include a peppery or metallic taste, oral numbness, headache, dizziness, palpitations, rapid and weak pulse, low blood pressure, difficulty in swallowing, thirst, hives, rash, flushing, and facial swelling. Sometimes nausea, vomiting, and diarrhea also occur [R].
These symptoms are typically rapid in onset, and recovery is usually complete within 24 h, but in rare cases can last for days [R].
Scombroid poisoning is treated by antihistamines. Corticosteroids are ineffective in this case [R].
10) Some People Develop Intolerance
Histamine intolerance results from the imbalance between accumulated histamine and histamine degradation [R].
Approximately 1% of the population has histamine intolerance [R].
In contrast to food allergy, in which even a small amount of the allergen causes a reaction, in histamine intolerance, the cumulative amount of histamine is crucial [R].
Histamine can be increased by internal histamine overproduction or increased ingestion of histidine or histamine (in food, alcohol, or from bacteria). However, most often, the main cause of histamine intolerance is the impaired degradation of histamine by DAO or HNMT [R].
Histamine intolerance mimics an allergic reaction. Symptoms may include diarrhea, headache, rhino-conjunctival (congestion and runny nose accompanied with red eyes) symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, and flushing [R].
For histamine-intolerant patients, alcohol and long-ripened or fermented (and therefore histamine-rich) foods, for example, aged cheese, cured meat, yeast products, spinach, tomatoes, and histamine liberators, such as citrus fruit, should be avoided [R, R].
In pregnancy, DAO is produced at very high concentrations by the placenta, and its concentration may become elevated 500 times. This increased DAO activity may be the reason why, in women with food intolerance, remissions frequently occur during pregnancy [R].
You can find more information about histamine intolerance and ways to deal with it in the histamine intolerance post.
11) Elevated Levels Causes Ulcers
Histamine increases stomach acid secretion through H2R activity (R, R].
H2R inhibitors are used for treating peptic ulcer disease [R].
Additionally, treatment with an H4R inhibitor was protective in animals with gastric ulcers [R].
12) Increases Anxiety
Histamine is a danger response signal and increased brain histamine promotes anxiety [R].
The activity of histamine-releasing nerves is increased in stressful situations, and blocking this activity reduces anxiety [R].
Blocking H1R reduces fear-related behaviors in animals, while blocking H3R increases anxiety [R].
However, global histamine deficiency increased anxiety in mice [R, R).
13) May Contribute to Schizophrenia
Increased histamine release and turnover were observed in patients with schizophrenia (R, R).
Famotidine, a H2R blocker, reduced negative symptoms in schizophrenics [R].
14) Contributes to Alcoholism
Rats preferring alcohol have increased brain histamine levels and turnover, more histamine-releasing nerves, but lower H1R and H3R activity [R].
Blocking H3R activity decreases alcohol intake and alcohol preference in both mice and rats [R, R), while activation of H3R increases alcohol intake, suggesting that H3R increases alcohol preference [R].
A variation in the HMNT gene has been linked to alcoholism in humans [R].
15) May Contribute to Parkinson’s
Parkinson’s disease patients have increased brain histamine levels [R, R), and abnormally high H3R activity [R].
16) May Contribute to Multiple Sclerosis
Gene variants for H1R increase susceptibility to autoimmune disease [R].
H1R production is increased in patients with multiple sclerosis (MS) [R]. H1R was elevated 4.6-fold in chronic silent cases of MS [R].
17) Contributes to Rheumatoid Arthritis
Histamine can contribute to the development of arthritis by increasing inflammation [R].
Paradoxically, rheumatoid arthritis patients actually have lower histamine levels in their circulation or joint fluid [R].
Inflammatory arthritis is reduced in mice with global histamine deficiency. It was shown that H3R and H4R activities contribute to arthritis development [R].
Inhibiting H4 has a protective effect in mice with arthritis [R].
18) Contributes to the Hardening of the Arteries
Histamine increases inflammation and causes small blood vessels, such as capillaries, to swell, but large arteries to contract [R].
In addition, histamine induces blood vessel wall thickening [R], a process that contributes to the hardening of the arteries.
In humans with hardening of the arteries (atherosclerosis), histamine blood levels are increased [R].
Mice with global histamine deficiency had reduced arterial wall thickening [R].
19) May Cause Irritable Bowel Syndrome
IBS patients with abdominal pain have more mast cells which spontaneously release high amounts of histamine in proximity to gut-associated nerves [R].
In one study, 58% of the patients with IBS experienced GI symptoms from histamine-releasing food items and foods rich in biogenic amines. The use of carbon absorbent (which adsorbs histamine from the gut) has been beneficial for some of these patients [R].
Elevated levels of H1Rs and H2Rs are found in stomachs of patients with IBS [R].
H1R inhibitor ketotifen was shown to reduce some of the IBS symptoms [R].
20) Is Harmful in Heart Failure
Blood histamine was more than two-fold higher in patients with myocardial infarction [R].
H2R activity increased, whereas H2R blocker (famotidine) reduced infarct size after heart injury in mice [R].
Histamine can Both Help and Aggravate These Conditions:
1) Bacterial Infection
Histamine is involved in the immune response to bacterial infection [R].
It was shown that blocking H2R or H3R/4R can impair the immune response in mice [R].
H2R blockade enhanced bacterial colonization in mice [R].
Conversely, a global deficiency of histamine in mice resulted in a stronger cytokine response and these mice more effectively cleared tuberculosis [R].
2) Food Allergy
People with food allergies have increased histamine production and increased numbers of mast cells (that produce and release histamine) in the gut. Administration of DAO can help in food allergies by degrading histamine in the gut [R].
However, some histamine activity is beneficial in allergies, because the treatment with H2R inhibitors increased the IgE production against food antigens, contributing to the development of IgE-mediated food allergies [R].
Brain histamine decreases pain [R]. Increasing brain histamine by increasing histamine production, or inhibiting H3R has analgesic effects (R, R].
Accordingly, reductions in brain histamine levels by decreasing histamine production or activating H3R increases pain [R].
However, activation of H1R or H2R increases the sensitivity to pain [R]. H1R and H2R deficient mice have decreased pain sensitivity [R]. Also blocking H1R or H2R reduced the pain responses (to thermal and mechanical triggers) in mice [R, R, R].
H1R inhibition improved pelvic pain, and H2R inhibition improved painful bladder syndrome (PBS)-related pain in humans [R].
Moreover, activation of H4R also contributes to pain, because blocking H4R decreased pain sensitivity in animals [R].
4) Inflammatory Bowel Disease
Inhibition of H1R had protective effects in some patients with IBD [R].
On the other hand, histamine activity through H2R may have protective effects in IBD, because the inhibition of H2R increased the risk of hospitalization or surgery in patients with Crohn’s disease [R].
Histamine has both growth-promoting and cancer-preventing effects [R, R).
It was shown that blood histamine levels are decreased in cancer patients [R].
Mice globally deficient in histamine are more susceptible to skin and colon cancer [R].
Histamine reduced lymphoma growth in mice [R].
Furthermore, it was shown that histamine in the blood merges with cholesterol, to produce dendrogenin A (DDA), a compound with antitumor properties. DAA prevents breast cancer and melanoma in mice [R].
On the other hand, histamine in general shifts the immune system from a Th1 to a Th2 pattern [R]. This is bad because Th1 cells fight cancer.
Histamine production is increased in tumor tissues, such as breast cancer, colon cancer, melanoma, lymphomas, and leukemia [R]. Histamine within tumors can enhance tumor growth, by suppressing Th1 responses (LT-α, TNF-α, and IFN-γ) via the H2R [R].
Cimetidine, an H2R inhibitor, has antitumor properties in the treatment of glioblastoma [R].
H3R inhibition was beneficial in glioma [R].
H2R or H4R inhibition can decrease the proliferation of colon cancer cells [R].
Genetics of Histamine
Some HDC gene variants increase the risk of developing allergic rhinitis [R].
SNPs in the HNMT gene:
rs1050891: The HNMT mutant causing the C939T amino acid substitution. “AA” will increase histamine.
If you have “AA”, don’t freak out, as ~56% of the population has it.
Food additives can exacerbate ADHD symptoms and cause non-IgE-dependent histamine release from basophils [R].
“AA” for this gene indicates an increase in ADHD behavior for children when they have been exposed to certain food additives: sunset yellow, carmoisine, tartrazine, ponceau 4R, quinoline yellow, Allura red AC, and sodium benzoate [R].
It’s believed that ”AA” increases histamine levels and this is responsible for the ADHD behavior [R].
Taking SAM-e should negate this gene, theoretically. In addition, just avoid artificial colors.
rs10156191 (DAO Gene): Each “T” allele means you have reduced DAO activity [R]. A “T” allele means you’re more likely to get migraines [R], and you’re also going to be more sensitive to NSAIDs (aspirin, Ibuprofen) [R].
The number of H4R copies correlates to the incidence of arthritis, proteinuria, and antinuclear antibody abnormalities in systemic lupus erythematosus (SLE) [R].
A variant in H1R has been associated with Parkinson’s disease [R].
The MS4A2 (Membrane spanning 4-domains A2) gene codes for a subunit of the IgE-receptor protein. The IgE-receptor protein is found on the surface of mast cells and plays an important function in allergen response [R].
This gene encodes a protein that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the nervous system. It is associated with epilepsy and autism [R].
Factors that Increase Histamine
Histamine is naturally present in some types of food at high concentrations. Cocoa, spinach, and tomatoes have high histamine [R].
A high content of histamine is also found in fermented foods such as alcoholic beverages (beer, wine), fermented vegetables, cheeses, meat, soy, and yogurt [R].
Histamine can be produced by fermenting bacteria, including the naturally occurring gut bacteria [R].
To prevent histamine production by bacteria, cooling of the food is insufficient, freezing and early removal of bacteria is necessary [R].
Additionally, some conditions and foods can increase the release of internal histamine in the body [R]:
- hypoxia (a lack of oxygen)
- extreme temperatures
- certain types of food such as citrus fruits
- nicotine (in cigarette smoke) triggers histamine release [R]
You will want to decrease histamine if you have histamine intolerance. Generally, you should be avoiding histamine-rich foods and food that promotes histamine release.
For more information about histamine-rich, histamine-releasing foods, and ways to decrease histamine, check the post on histamine intolerance.
Th1/Th2 Immune Response
- Histamine in general favors the Th2 response [R].
- H1R can promote Th1 [R, R].
- H2R can decrease both Th1 and Th2 responses [R].
- H4R activity promotes Th2 [R].
- Histamine decreases TRH and TSH levels through H2R [R].
- Histamine inhibits GH [R].
- Histamine increases vasopressin and oxytocin release [R].
- Histamine is responsible for estrogen-induced LH surges in females (mediated by GnRH) [R].
- Histamine increases suckling-induced PRL release. Histamine effects on prolactin release can be blocked by activating H3R [R].
- Histamine can stimulate the production of estradiol via H1R [R].
- Histamine stimulates the secretion of ACTH [R, R], aldosterone [R] and cortisol [R], mainly through H1R.
- Histamine is degraded by methylation (HNMT). That is why various blogs associate high blood histamine with undermethylation and undermethylators, and low blood histamine with overmethylation and overmethylators. Note, however, that under/over methylation as full body phenomena are not backed up by scientific research. High histamine may be a result of several causes other than decreased HNMT activity, such as reduced DAO activity, increased histamine production, and increased histamine ingestion.
Histamine levels are influenced by your genes. If you’ve gotten your genes sequenced, SelfDecode can help you determine if your levels are high or low as a result of your genes, and then pinpoint what you can do about it.
Irregular Histamine Levels?
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