Histamine is widely known as a substance that contributes to allergies, asthma, eczema, and coughs.

In addition, histamine is also a neurotransmitter with very important roles both in the brain and in the gut. Read this post to learn more about histamine.

Contents

Introduction

Histamine is a biogenic amine (R,R).

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 Production

Histamine is produced from the amino acid histidine, by the enzyme HDC (histidine-decarboxylase) (R,R).

Cells that can produce and store histamine include (R,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).

Histamine Degradation

histamine_metabolism
http://ajcn.nutrition.org/content/85/5/1185.long

Two enzymes control histamine degradation: HNMT (histamine N-methyl transferase) and DAO (diamine oxidase) (R,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).

DAO also degrades other biogenic amines such as putrescine and spermidine (R).

Histamine 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.

Histamine Receptors

hr_brain
http://www.nature.com/nrn/journal/v14/n7/fig_tab/nrn3526_F2.html

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

  • 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

  • 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

  • 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

  • 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).

Basically, histamine is usually not detectable (less than 1 ng/ml) in normal plasma samples (liquid part of the blood) (R), while it is higher in whole blood samples (a study reports ~45 ng/ mL) (R).

Health Benefits of Histamine

1) Histamine Increases Alertness and Wakefulness

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Histamine maintains wakefulness by activating H1R (R).

Early H1 antihistamines, that readily enter the brain (pass the blood-brain barrier), such as chloropyraminediphenhydramine, 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).

H3R has an opposite effect, it decreases histamine levels and promotes sleep (R,R). Therefore, blocking H3R induces wakefulness (R,R,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) Histamine Reduces Appetite

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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).

Leptin, the “satiety hormone” elevates brain histamine turnover (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) Histamine 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) Histamine 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) Histamine Increases Water Intake

bigstock-glasses-of-water-on-a-wooden-t-153277640-min

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) Histamine Improves Cognitive Performance

bigstock-d-rendering-of-human-brain-o-163987757-min

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).

Blockade of H3R generally improves memory, attention and cognitive performance (R,R), and this is associated with both histamine and acetylcholine increase (R).

However, there are also cases in which H3R activation enhances learning and memory (R,R).

7) Histamine 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) Histamine 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) Histamine 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).

In humans, histamine can improve erectile function, while H2R antihistamines reduce sexual function (R,R).

In females, histamine increases the release of hormones such as estradiol, prolactin and LH (R).

10) Histamine 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).

Decreased H1R activity was found in Alzheimer’s disease (R,R), and it was associated with the severity of cognitive symptoms (R).

On the contrary, increased levels of histamine were found in the blood and cerebrospinal fluid in Alzheimer’s disease patients (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).

Clinical trials tested H3R inhibitors in subjects with mild-to-moderate Alzheimer’s, but they proved mostly ineffective (R,R).

11) Histamine 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).

However, in some studies, H1R, H2R and H3R activities were also shown to cause hyperthermia (elevated body temperature) (R,R).

Histamine Negatives

histamine_action
http://ajcn.nutrition.org/content/85/5/1185.long

1) Elevated Histamine Causes Skin Itchiness

bigstock-woman-scratching-her-back-clos-102334589-min

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).

H1R blockers (antihistamines) are widely used to manage and alleviate itch symptoms (R,R).

On the other hand, H3R inhibitors aggravate itch symptoms (R). Blocking H3R increases scratching behavior in mice (R).

In mice, blocking both the H1R and H4R gave the best results, almost completely blocking the itch response (R,R).

2) Histamine 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) Histamine Contributes to Asthma

h1andh4inallergy
http://www.nature.com/nrd/journal/v7/n1/fig_tab/nrd2465_F4.html

Histamine generally promotes Th2 responses (R), which are implicated in the development of asthma (some types).

Furthermore, histamine causes airway contraction and coughing (R).

The level of histamine in the airways correlates with the severity of asthma (R), and histamine can be found in the lungs of asthma patients even during asymptomatic periods (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).

H4R-deficient mice, or those given H4R inhibitors, have reduced lung inflammation and a reduction in Th2 and inflammatory cytokines (R,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) Histamine 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 Histamine 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) Histamine Causes Motion Sickness

Histamine plays a role in keeping balance, which involves hair cells in the inner ear (R).

HR1 and H2R activity contribute to motion sickness (R,R). H1R antihistamines, such as cyclizine and meclizine, are effective in the treatment of motion sickness and vomiting (R).

Betahistine, a drug frequently prescribed for motion sickness and vertigo, strongly inhibits H3R and weakly activates H1R (R).

7) Elevated Histamine Causes Headaches

bigstock-woman-with-headache-139862198-min

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) Histamine 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) Histamine Causes Scombroid Poisoning

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Scombroid poisoning, also called histamine fish poisoning, is caused by ingesting high levels of histamine from fish that are not fresh (R,R). The histamine in the fish is produced by bacteria (R).

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 Histamine 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).

Estrogen increases histamine (R). Histamine-intolerant women often suffer from headache that is dependent on their menstrual cycle and from dysmenorrhea (R).

Histamine degradation can be supported by the administration of vitamins C and B6, which increase DAO activity (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 Histamine 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) Histamine 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) Histamine May Contribute to Schizophrenia

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Increased histamine release and turnover were observed in patients with schizophrenia (R,R).

Famotidine, a H2R blocker, reduced negative symptoms in schizophrenics (R).

14) Histamine 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) Histamine May Contribute to Parkinson’s

Parkinson’s disease patients have increased brain histamine levels (R,R), and abnormally high H3R activity (R).

16) Histamine May Contribute to Multiple Sclerosis

Gene variants for H1R increase susceptibility to autoimmune disease (R).

T cells from H1R-deficient mice produce significantly less IFN-gamma, and these mice develop less severe autoimmune diseases (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).

Both H1R and H2R deficient mice develop less severe symptoms in animal models of multiple sclerosis (R,R).

However, the disease is exacerbated in mice with global histamine deficiency or H3R deficiency (R,R,R).

Also, H4R activity was anti-inflammatory in a mouse model of multiple sclerosis (R,R), where inhibiting H4R exacerbated the disease (R).

17) Histamine Contributes to Rheumatoid Arthritis

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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) Histamine 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) Histamine May Cause Irritable Bowel Syndrome

Histamine has been associated with symptom severity in IBS (R).

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) Histamine 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).

H2R deficient mice have reduced infarct size (R) and heart damage (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).

3) Pain

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

Histamine is highly elevated in ulcerative colitis and Crohn’s disease (CD) patients. In CD, the increase in histamine production was related to disease activity (R,R).

Inhibition of H1R had protective effects in some patients with IBD (R).

Rats treated with H4R inhibitors were protected from colitis-related intestinal injury and tissue damage (R,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).

It was shown that H2R activation by a probiotic bacterium L. reuteri suppresses acute inflammation within the mouse colon (R).

5) Cancer

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).

Also, a treatment combining IL-12 and histamine is used to prevent a relapse in acute myeloid leukemia (R,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

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SNPs in the HDC gene:

Some HDC gene variants increase the risk of developing allergic rhinitis (R).

  1. RS16963486
  2. RS17740607
  3. RS2073440

SNPs in the HNMT gene:

A variant of HNMT increases the risk of developing atopic dermatitis in children twofold, while another variant is associated with chronic urticaria (R).

  1. RS1050891

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 the artificial colors.

SNPs in the Diamine Oxidase gene (AOC1):

  1. RS1005390
  2. RS1049793
  3. RS17173637
  4. RS10156191
  5. RS1049742 
  6. RS2052129
  7. RS2071517

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)

rs1049742 (DAO Gene): Each T allele means you have reduced DAO activity. (R)

SNPs in the H4R gene:

Variants of H4R gene have been associated with increased risk of atopic dermatitis (R), and infection-induced asthma (R).

The number of H4R copies correlates to the incidence of arthritis, proteinuria, and antinuclear antibody abnormalities in systemic lupus erythematosus (SLE) (R).

  1. RS11662595
  2. RS11665084

SNPs in the H1R gene:

A variant in H1R has been associated with Parkinson’s disease (R).

  1. RS4684059
  2. RS7651620

SNPs in the MS4A2 gene:

The MS4A2 (Membrabe spanning 4-domains A2) gene codes for a subunit of the IgE-receptor protein. The IgE-receptor protein is found of the surface of mast cells and plays an important function in allergen response. [R]

Mutations in this gene have been associated with asthma [R] and fibromyalgia [R], among other conditions.

  1. RS512555
  2. RS569108
  3. RS983392

SNPs in the GABRB3 gene:

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).

  1. RS25409
  2. RS3212335
  3. RS4906902
  4. RS61996546
  5. RS8043440
  6. RS878960

Factors that Increase Histamine

bigstock-a-sampler-of-fermented-food-gr-148127186-min

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).

Histamine can also result from bacterial contamination of food when stored improperly. Heat and cold don’t affect histamine, so once it’s produced, it is basically irremovable from the food (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
  • trauma
  • alcohol
  • 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 avoiding histamine-rich food, 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.

Technical

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).

Hormones

  • 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.

Methylation

  • 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.

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

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13 COMMENTS

  • carol close

    Usually where there are high histamine levels, there are also high tryptase levels.

    To lower histamine levels, eat only fresh foods- eggs, chicken, rice, gluten free pasta/crackers, cream cheese, butter, coconut oil, olive oil, non-citrus juices, milk, herbal teas (not coffee, black tea), fresh/frozen fish, fresh/frozen fruits and vegetables. No tomatoes, strawberries, vinegar, matured cheeses, pickled/canned foods, shellfish, salami and other cured meats, sausages, ham, bologna, etc. No beans, nuts chocolate, peanut butter, ready meals, deli food because its been sitting ,energy drinks, as these are all high in histamines, so the key to low histamine is fresh.

    To reduce high tryptase levels, take lactoferrin. (Should be a link back to lactoferrin here). Colostrum is another supplement with lactoferrin.

    https://en.wikipedia.org/wiki/Lactoferrin Human colostrum (“first milk”) has the highest concentration, followed by human milk, then cow milk (150 mg/L).[3]

    https://www.ncbi.nlm.nih.gov/pubmed/10197050 “Inhibitors of tryptase for the treatment of mast cell-mediated diseases.” (These inhibit tryptase elevated in Mast Cell Activation Disorders, Ehlers Danlos and POTs which are linked together in a disease called Familial Tryptasemmia, which also includes these symptoms- chronic skin flushing, itching, or hives, bee sting allergy, dizziness and/or difficulty maintaining a normal pulse and blood pressure, sometimes diagnosed as dysautonomia or postural orthostatic tachycardia syndrome (POTS), chronic head, back, and joint pain, hypermobile joints, scoliosis, retained primary teeth or other skeletal abnormalities, sometimes diagnosed as Ehlers-Danlos syndrome, Type III, hypermobile type, GI disturbances including heartburn, IBS, and numerous food and drug reactions and intolerances, anxiety, depression, and/or behavioral disturbances). The first three drugs to inhibit tryptase are synthetic and the last is lactoferrin also found in the supplement colostrum: 1) peptidic inhibitors (e.g., APC-366), 2) dibasic inhibitors (i.e., pentamidine-like), 3) Zn(2+)-mediated inhibitors (i.e., BABIM-like), and 4) heparin antagonists (e.g., lactoferrin). They have implicated tryptase as a mediator in the pathology of numerous allergic and inflammatory conditions including rhinitis, conjunctivitis, and most notably asthma. A growing body of data further implicates tryptase in certain gastrointestinal (IBS), dermatological (excema), and cardiovascular disorders as well.

    https://arupconsult.com/content/mast-cell-disorders “Mast Cell Activated Disorders” These disorders include these symptoms- 1) Wheezing/pulmonary signs and symptoms -Asthma, Anaphylaxis, Carcinoid tumors. 2) Hives/itching/rash- Atopic dermatosis, Chronic urticaria, Angioedema, Scleroderma, 3) Autoimmune disorders- Vasculitis, Diarrhea/abdominal pain, Allergic reaction to food, Eosinophilic GI disorders, Celiac disease, IBS, VIPoma
    4) Hematologic disorders- Myelodysplastic syndrome/myeloproliferative neoplasms, Chronic eosinophilic leukemia.

  • Linda

    Hi Joe,
    Do you know the mechanism behind why I am reacting so strongly ( get a terrible rash all over my face and scalp) to histamine/ histamine liberators including lectins and oxalates even though my DAO is normal and both blood and urine levels of histamine are REALLY low? My reactions suddenly started 10 years ago after overconsumption of painkillers for 5 years.

    Thank you!

    1. Nattha Wannissorn

      There’s another enzyme that breaks down histamine called HNMT. Also, painkillers can cause leaky gut.

  • carol close

    Re: Estrogen increases histamine. The reference actually says that histamine stimulates estrogen synthesis. Plus, research shows estrogen causes histamine to be excreted, progesterone has a nil effect on histamine excretion; however, testosterone reduces histamine excretion. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1665824/ “Alterations of histamine metabolism after injections of sex hormones in mice” .
    Re: Migraine headaches. http://www.ncbi.nlm.nih.gov/pubmed/26707041 “Is migraine a consequence of a loss of neurohormonal and metabolic integrity? A new hypothesis.” All patients received a complex program which included: hormonorestorative therapy (HT) with bio-identical hormones; correction of balance between sympathetic and parasympathetic systems and simultaneously calcium/magnesium balance; “resetting” the pineal gland; improvement of intestinal absorption through restoration of normal intestinal flora, and a cleanse from parasitic infestation (if necessary). Serum levels of total cholesterol (TC), pregnenolone, dehydroepiandrosterone sulfate (DHEAS), progesterone, total estrogen, and total testosterone were determined. results- All patients responded to this regimen. We do not have patients who still have migraine after they started to use this program. Laboratory finding prior to HT showed the significant deficiency in production of all basic steroid hormones (progesterone and pregnenolone production declined the most). Concurrent symptoms such as fibromyalgia, insomnia, depression, gastrointestinal disorders, and fatigue had disappeared. Total cholesterol completely normalized in (91.7%) patients. No adverse effects or complications related to this program were registered.

  • carol close

    Oops, mark alman, not mark allen, where is the edit button on replies

  • carol close

    Re: btrute on Feb. 9, 2017 and mark allen

    Joe should link his hormone blogs to this blog entry. Joe is on the right track in his interest of hormones as important signal molecules in autoimmune disorders and the brain gut connection with hormones influencing the initiation of the immune response which includes the maintenance of peripheral tolerance to self-antigens. Hormones, such as pregnenolone, vitamin D, DHEA, estrogens, prolactin, human growth hormone, and especially progesterone (raising it) and cortisol (usually lowering it), may profoundly affect dendritic cells differentiation, maturation and function leading to either a pro-inflammatory or an anti-inflammatory (or tolerogenic) phenotype. A better understanding of the role of sex hormones in the modulation of the brain-gut-microbiota axis should enable a more effective and sex-tailored therapeutic approach in IBS, and autoimmune disorders such as Lupus, Multiple Sclerosis, scleroderma, rheumatoid arthritis. Click on these links below for explanations of hormones affecting IBD, plus autoimmune disorders.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949254/ “Sex Hormones in the modulation of irritable bowel syndrome.”

    https://www.ncbi.nlm.nih.gov/pubmed/27931211 “Gonadectomy effects on the risk of immune disorders in the dog: a retrospective study.” (This study evaluated the prevalence and risk of atopic dermatitis, autoimmune hemolytic anemia, canine myasthenia gravis, colitis, hypoadrenocorticism, hypothyroidism, immune-mediated polyarthritis, immune-mediated thrombocytopenia, inflammatory bowel disease, lupus erythematosus, and pemphigus complex in neutered dogs. Neutered dogs had a significantly greater risk of atopic dermatitis, autoimmune hemolytic anemia, hypoadrenocorticism, hypothyroidism, immune-mediated thrombocytopenia, and inflammatory bowel disease.)

    https://www.ncbi.nlm.nih.gov/pubmed/27585815 “Hormonal Modulation of Dendritic Cells Differentiation, Maturation and Function: Implications for the Initiation and Progress of Systemic Autoimmunity.” (Estrogens, progesterone, prolactin and cortisol affect dendritic cells growth and function leading to either a pro-inflammatory or anti-inflammatory phenotype- An unbalanced hormonal status affects the production of pro-inflammatory cytokines, the expression of activating/inhibitory receptors and co-stimulatory molecules on conventional and plasmacytoid dendritic cells, conferring susceptibility to develop autoimmunity. Estradiol administration to lupus-prone female mice increased the expression of co-stimulatory molecules, enhanced the immunogenicity and produced large amounts of IL-6, IL-12 and TNF-α by bone marrow-derived dendritic cells. These data suggest that estradiol/estrogen receptor signaling may play an active role during lupus pathology.)

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570481/ “The Prevalence of Growth Hormone Deficiency and Celiac Disease.”

    https://www.ncbi.nlm.nih.gov/pubmed/17086608 “Lower adrenocortical and adrenomedullary responses to hypoglycemia is premenopausal women with systemic sclerosis.” (Evidence showing scleroderma as having decreased adrenocortical and adrenomedullary functions.)

    https://www.ncbi.nlm.nih.gov/pubmed/11155790 “Replacement therapy with DHEA, plus corticosteroids in patients with chronic inflammatory diseases– substitutes of adrenal and sex hormones.”

    https://www.ncbi.nlm.nih.gov/pubmed/27395031 “Network of nuclear receptor ligands in multiple sclerosis: Common pathways and interactions of sex-steroids, corticosteroids and vitamin D3-derived molecules.”

    https://www.ncbi.nlm.nih.gov/pubmed/28163248“Associations between Endogenous Sex Hormones and MRI Structural Changes in Patients with Symptomatic Knee Osteoarthritis.” (Low estrogen, testosterone and progesterone association in osteoarthritis.)

    https://www.ncbi.nlm.nih.gov/pubmed/25697984 “Hormonal modulation of the immune system – A spotlight on the role of progestogens.” (The immunomodulatory effects of progesterone, especially progesterone’s effect on T cells on the innate and adaptive immunity and its role in the pathogenesis of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.)

    A warning Regarding Benadryl and Anticholinergics- Many anticholinergic drugs cause drowsiness and thirst. Many anticholinergic drugs even those

    prescribed by doctors, inhibit Delta wave slow wave deep sleep allowing the brain’s glymphatic system to remove the brain’s toxins, cause dementia, inhibit neurotransmission, and disrupt the high cholinergic tone associated with REM sleep affecting procedural memory consolidation. Anticholinergic drugs decrease saliva increasing mouth bacteria and dental plaque, which dental plaque can be found in clogged carotid arteries. Drugs called anticholinergics, block acetylcholine, a nervous system neurotransmitter. They are used to treat gastrointestinal disorders such as gastritis, diarrhea, pylorospasm, diverticulitis, ulcerative colitis, nausea and vomiting. They also treat genitourinary disorders such as cystitis, urethritis and prostatitis. They treat respiratory disorders such as asthma, chronic bronchitis, and chronic obstructive pulmonary disease (COPD). They treat sinus bradycardia due to a hypersensitive vagus nerve. They are used to treat insomnia though usually only on a short term basis. They are used to treat dizziness including vertigo (aka the spins) and motion sickness related symptoms. They include such common over-the-counter brands as Benadryl, Dramamine, Excedrin PM, Nytol, Sominex,Tylenol PM, and Unisom and other decongestants. Other anticholinergic/antispasmodic drugs, which include certain antidepressants, meds to control incontinence, certain pain relievers, antihistamines, decongestants, barbituates, muscle relaxers, benzodiazepines, CNS stimulants, tricyclic antidepressants, and drugs available only by prescription such as Paxil, Detrol, Demerol, Wellbutrin, and Elavil can cause dementia. In total, there are more than 68 doctor prescribed and over the counter anticholinergic/antispasmodics which cause dementia and even some drugs that are prescribed for neurodegenerative disorders are anticholinergic exasperating neurodegenerative disorders! The Fix to undo anticholinergic effects causing dementia- Bacopa and huperzine which inhibit anticholinesterace which is the culprit that breaks down acetylcholine. Piracetam and choline are known to activate the cholinergic system and alleviate cognitive symptoms caused by extended use of anticholinergic drugs.

    1. btrute

      Carol, thank you so much for your insights. I take Alpha GPC each day to help cope with the Benadryl. I will look into starting Bacopa too as my short term memory is not good!

    2. tony

      Wouldn’t anticholinergic drugs like Benadryl up-regulate acetylcholine receptors over time tho??

  • Mark Alman

    …I’m surprised you didn’t highlight this role (I discovered) from one of your citations:

    “Thyroid functions play a role in energy metabolism, thermogenesis, and bone physiology. TRH is synthesized in preoptic, paraventricular, and periventricular neurons, from where it is transported and released into the hypophysial portal circulation. The majority of the TMN neurons are excited by TRH (673), and hypothalamic neuronal histamine in turn has predominantly inhibitory effects on the hypothalamo-pituitary-thyroid (HPT) axis (356). Histamine decreases TRH release and TSH plasma levels through H2R in both hypothalamic and pituitary targets (477). Cimetidine facilitates cold-induced and TRH-induced TSH responses (501, 771). Systemic l-thyroxine administration, along with rises in T3 and T4 levels, increases cortical 5-HT and histamine content, whereas carbimazole treatment lowers histamine, glutamate, and 5-HT levels, suggesting a T3/T4-mediated negative feedback on TRH production by histamine (778). TRH is also a cotransmitter of glutamatergic neurons located in DMH (110) and serotonergic neurons in the raphe implicated in TRH-induced suppression of food intake by histamine (215) and effects on behavioral state (612).”

    http://physrev.physiology.org/content/88/3/1183.long

    …a revelation to me

    1. Nattha Wannissorn

      thanks. we’ll add it to the post.

  • btrute

    Wow Carol, your knowledge and writing is very impressive. Do you blog or forum post where I might correspond with you? Is a baseline blood tryptase test going to be telling if I am taking Benadryl regularly. Benadryl changed my life after having IBD for many years. Best!

  • carol close

    Also, POTS, Ehler Danlos, and MCAS are linked to gluten intolerance. And, the food allergy is simply the warning sign that food intolerance is taking place in the gut. Again, the IgE is formed at the time the damage to the villi is taking place and the main culprits are the “big 4”- gluten (wheat, barley, rye), casein (dairy products), soy, and corn- the top 4 human allergens and the primary allergens. We know that most other food allergies are secondary to this damage, a condition known as the “leaky gut syndrome” in people. This fascinating process develops when the intestine releases a hormone called “zonulin”, which increases the flow of nutrients through the compromised bowel wall. Unfortunately, food proteins (and other things) pass though the wall in an abnormal fashion, setting the individual up for secondary food allergies to otherwise healthy foods (eggs, rice, chicken, tree nuts, tropical fruits, etc.). Celiacs are notorious for developing multiple secondary food allergies. This villous damage and atrophy then leads to the malabsorption of calcium, iron, iodine, B complex, C, and multiple trace minerals, nutrients essential in the formation and maintenance of our entire body including the enzyme systems that are so vital to its function. So, why doesn’t the collagen form properly in Ehler Danlos? Kinda falls into the “duh” category now, doesn’t it? And those with food intolerances such as celiac disease have staggering rates of immune-mediated disorders- Hashimoto’s and Graves disease, rheumatoid arthritis, type one diabetes, lupus, and other immune-mediated diseases. Why is that? Well, all we really have to understand is the concept of lectins and we’re off and running. Could it be that collagen is just another tissue type that the immune system decides to attack at some point, just as it does blood cells, kidneys, eyes, the pancreas, and the peripheral nerves? Could some of these spontaneous (and even some of the not-so-spontaneous cruciate ruptures be immune mediated? Where do lectins go when they enter the body? The same place that paramyxoviruses go…everywhere ! Have you ever thought of an immune-mediated disease as “house-cleaning”, with the immune assaults wiping out the lectins and the viruses they “broke out of jail” by changing the cell wall’s physiology and causing those viruses…embedded in the cells cytoplasm and those in our very DNA- to adapt to the challenge? You are right to tell people to get their DNA analyzed and they can avoid diseases epigenetically. You have figured out a lot and are helping a lot of people.

  • carol close

    Probably the major cause of high histamine is recently discovered Heriditary Alpha Typtasemia which 6% of the population has, inheriting extra copies of the alpha tryptase gene, and links three diseases. POTS, Ehler Danlos, and MCAS (Mast Cell Activation Disorder). One study actually shows tryptase keeps you from going into anaphylactic shock. Patients who suspect they may have hereditary alpha tryptasemia syndrome should first have a baseline blood tryptase test drawn by their doctor, if they haven’t already. It should not be drawn immediately after a major allergic reaction, as that can lead to an elevated tryptase for a different reason. A serum level greater than 10 ng/ml is suggestive of alpha tryptasemia, while a level lower than 8ng/ml makes this diagnosis far less likely. There is no commercially available test for the genetic duplication, and it cannot be identified through usual genetic testing including microarrays, whole exome sequencing, or whole genome sequencing. The research-based test that can diagnose alpha tryptasemia is under development.

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