According to some researchers, histamine intolerance can cause headaches, rashes, anxiety, ulcers, and even arthritis. But how can you tell if you’re sensitive, and what can you do about it? Read on to discover if histamine could be behind your troublesome symptoms.
What is Histamine Intolerance?
Histamine intolerance is something of a misnomer; it isn’t really a sensitivity to histamine. Rather, people with histamine intolerance have too much histamine: they either create it in excess or they can’t break it down quickly enough [1].
One culprit might be low diamine oxidase (DAO), the enzyme that breaks histamine down in the gut [1].
When people with low DAO eat foods that contain histamine, it crosses into their blood, and they experience inflammation; by contrast, a healthy person would break down most dietary histamine before it ever reaches the bloodstream [1, 2].
Approximately 1% of the population has symptoms consistent with histamine intolerance. In contrast to food allergies, in which even a small amount of the allergen causes a reaction, the cumulative amount of histamine is crucial to inducing a reaction [1].
In many ways, histamine intolerance mimics an allergic reaction. Symptoms may include diarrhea, headaches, stuffy and runny nose, eye redness, asthma, low blood pressure, arrhythmia, hives, itching, and flushing [3].
Aside from foods and drinks high in histamine, other potential triggers include histidine dietary sources, certain bacteria, and DAO-blocking drugs, to name a few [1].
Causes
Histamine intolerance can emerge as a result of one or more factors including genetics, gut damage, alcohol, drugs/supplements, or microbiome imbalances; if there are too many bacteria producing histamine and not enough that degrade it, intestinal enzymes may have a hard time keeping up [1, 4].
Histamine also increases estrogen during menstruation. Histamine-intolerant women often suffer from menstrual cramps and headaches. The reverse is also true: peaks in estrogen during ovulation can lead to flare-ups by increasing histamine [5].
In pregnancy, DAO is produced at very high concentrations by the placenta, and its concentration may become elevated by 500 times. This increased DAO activity may be the reason why women with food intolerance frequently go into remission during pregnancy [5].
Symptoms
Histamine intolerance and reduced DAO levels can lead to allergy-like symptoms, including:
- Skin problems such as rashes, itching, hives, flushing, eczema, psoriasis, and even acne [6]
- Chronic headaches [7]
- Painful menstruation (dysmenorrhea) [7]
- Flushing [7]
- Gastrointestinal symptoms [7]
- Reactions to histamine-rich food and alcohol [7]
- Nasal mucus [5]
- Asthma attacks [5]
Note that these symptoms are not exclusive to histamine intolerance, nor is this necessarily a comprehensive list. If you experience these symptoms, we recommend talking to your doctor about whether you might have histamine intolerance, or if another underlying condition may be responsible.
How Much Histamine is Too Much?
Blood histamine levels above the normal range (0.3 to 1.0 ng/mL) produce certain negative effects.
For example, levels of 1 to 2 ng/mL increase stomach acid secretion and heart rate. A level of 3 to 5 ng/mL leads to flushing, headaches, hives (urticaria), and skin itching (pruritus). The airways dangerously tighten causing bronchospasm at 7 to 12 ng/mL, and heart attacks occur at 100 ng/mL [8].
Thus, large amounts of ingested histamine can cause significant symptoms in otherwise healthy individuals. For example, eating spoiled fish can lead to flushing, sweating, hives, gut symptoms, palpitations, and in severe cases bronchospasm [9].
This condition, known as scombroid poisoning, occurs when bacteria in the fish convert high levels of histidine into histamine. These bacteria thrive during improper storage and high temperatures, gradually spoiling the fish. Cooking the fish destroys the bacteria but not the histamine. Tuna and mackerel are common culprits [10].
Tolerant vs. Intolerant People
Although 75 mg of liquid histamine can provoke symptoms in healthy volunteers, defining the safe threshold level in sensitive individuals is difficult. Canned sardines, which are very likely to trigger symptoms in intolerant people, have as much as 20 mg per 100 g, but some people react to foods that contain much less [11, 12, 13, 1].
Some foods may also provoke the release of histamine from mast cells; such foods may increase blood and tissue histamine even if they don’t contain very much [8].
Negative Effects of High Histamine
The following effects are associated with high histamine, but should not be considered a comprehensive list of possible consequences of histamine intolerance. Furthermore, the presence of these symptoms does not necessarily implicate histamine as the underlying cause. Work with your doctor for an accurate diagnosis and appropriate management plan.
Itching, Pain & Inflammation
1) Skin Itchiness
Histamine is released from mast cells (a type of white blood cell) when tissues are inflamed or stimulated by allergens. Once released, histamine causes itching [14].
Activation of H1R and H4R induces itching, whereas activation of H3R decreases itching. By the same token, drugs that block H1R or H4R (antihistamines) can be used to manage itch, while H3R blockers generally aggravate the itch [14, 15].
2) Inflammation
Through H1R activation in the blood vessels and airways, histamine can quickly cause acute rhinitis, airway constriction, conjunctivitis, cramping, diarrhea, and skin inflammation. Unsurprisingly, then, blocking H1R with antihistamines can decrease inflammation before and during an allergic reaction [16].
Through H4R activation, histamine also contributes to chronic inflammation [16].
3) Asthma
Histamine generally promotes Th2 responses, which are involved in some types of asthma; it also causes airway narrowing and coughing [17].
People with asthma have histamine in their lungs even during periods without symptoms; those with more severe asthma have more histamine in their airways, and vice versa [16].
Inhaled and intravenous histamine causes airway constriction that can be inhibited by H1R antihistamines [16].
Regardless, antihistamines are not very effective in asthma treatment compared to anti-inflammatory corticosteroids. Some research suggests that antihistamines may still help by decreasing the Th2 immune response and suppressing the accumulation of inflammatory cells, but better alternatives are available [16].
4) Eczema
Patients with severe eczema (atopic dermatitis) tend to have higher blood histamine. In one study, they also spontaneously released more histamine in response to environmental cues and food; furthermore, when they consumed histamine, it worsened their symptoms. When people with atopic dermatitis followed a histamine-free diet for 2 weeks, their symptoms reduced [1].
In addition, some patients with atopic dermatitis have lower diamine oxidase (DAO) activity, which is to say that they can’t break down histamine as effectively as a healthy person [1].
5) Anaphylaxis
Anaphylaxis is a severe, whole-body allergic reaction that can be fatal without medical intervention. Histamine contributes to this response by opening up blood vessels and increasing heart rate [17, 18].
Headache
6) Headaches
Histamine causes headaches by releasing nitric oxide and increasing inflammation. It can induce headaches in healthy people as well as in those with migraine [5].
Many migraine patients have histamine intolerance, reduced DAO activity, and elevated histamine during both attacks and symptom-free periods. Food rich in histamine triggers headaches, while histamine-free diet and therapy with antihistamines alleviate headaches in these people [5].
Bones & Joints
7) Bone Density
Histamine may decrease bone density. Patients with osteoporosis tend to have higher levels of histamine; in mice, histamine deficiency increases bone density and reduces the rate at which bone tissue is broken down [19].
8) Arthritis
Histamine increases inflammation, and thus may contribute to the development of arthritis. In mice, histamine deficiency reduces the symptoms of inflammatory arthritis [20].
Paradoxically, rheumatoid arthritis patients actually have lower histamine levels in their circulation and joint fluid. Some researchers have suggested that they “consume” more histamine, preventing its levels in the blood from getting too high. It could also be that other inflammatory markers (such as TNF-a) are much more important than histamine in rheumatoid arthritis [20, 21].
Mental Illness & Neurological Disorders
9) Anxiety
Histamine is a danger response signal; increased brain histamine promotes anxiety. The activity of histamine-releasing nerves is increased in stressful situations, and blocking this activity reduces anxiety [22].
Blocking H1R reduces fearful behaviors in animals, while blocking H3R increases anxiety. Strangely, however, global histamine deficiency increased anxiety in mice [22].
10) Schizophrenia
People with schizophrenia tend to have increased histamine activity in their brains. Famotidine, an H2R blocker, may reduce so-called “negative” symptoms of schizophrenia, such as the inability to feel positive emotions or pleasure [23, 24, 25, 26].
11) Parkinson’s Disease
Parkinson’s disease patients tend to have increased brain histamine levels and abnormally high H3R activity [22, 27, 28].
In a mouse model of Parkinson’s, blocking H3R with thioperamide can restore a normal sleep cycle, improve memory. This drug also increases wakefulness in mice with narcolepsy. Disrupted sleep worsens cognitive deficits, so H3R blockers may help prevent these symptoms [28].
12) Multiple Sclerosis
Certain gene variants for H1R have been linked to autoimmune disease, and H1R production is increased in patients with multiple sclerosis (MS) [16, 17].
T cells from H1R-deficient mice produce significantly less IFN-gamma, and these mice develop less severe autoimmune diseases. Both H1R- and H2R-deficient mice with multiple sclerosis develop less severe symptoms [16, 17, 20].
By contrast, H4R activity reduced inflammation in mice with multiple sclerosis, while inhibiting H4R made the disease worse [29, 30].
However, MS is worse in mice with global histamine deficiency or H3R deficiency. Therefore, the relative abundance of the histamine receptors 1, 2, and 4 may cause harm, rather than histamine or H3R [20, 17].
13) Balance
HR1 and H3R activity contribute to motion sickness. H1R antihistamines, such as cyclizine, meclizine, and dimenhydrinate (Gravol) effectively treat motion sickness and vomiting. Betahistine, a drug frequently prescribed for motion sickness and vertigo, strongly inhibits H3R and weakly activates H1R [31, 32].
Cardiovascular Disease
14) Atherosclerosis
Histamine increases inflammation and causes small blood vessels, such as capillaries, to swell, but large arteries to contract. In addition, histamine thickens blood vessel walls, a process that contributes to the hardening of the arteries. People with hardened arteries (atherosclerosis) tend to have more histamine in their blood [17].
15) Damage After Heart Attacks
In the six days after a heart attack, blood histamine may rise to more than twice as high as normal, while H2R activity increases [33].
Famotidine, a drug that blocks H2R, reduced the damage to the heart tissue after a heart attack in mice [33, 34].
Stomach Ulcers
16) Ulcers
Through H2R activation, histamine increases stomach acid secretion, thereby damaging the stomach lining and increasing the risk of gastric ulcers; H2R inhibitors are used to treat peptic ulcer disease [30].
Additionally, H4R inhibitors were protective in animals with gastric ulcers [30].
Oral Toxicity
17) Scombroid Poisoning
You may get scombroid poisoning, also called histamine fish poisoning, if you eat fish that are not fresh. Bacteria in fish produce toxic quantities of histamine over time [17, 2].
A number of bacteria in fish produce histamine (including Morganella morganii, Enterobacter aerogenes, Raoultella planticola, Raoultella ornithinolytica, and Photobacterium damselae) [2].
To avoid scombroid poisoning, fish must be carefully handled and stored. Cooking spoiled fish won’t help; high temperatures kill the bacteria but don’t destroy the histamine [2].
The symptoms of scombroid poisoning are variable and may include [2]:
- A peppery or metallic taste
- Mouth numbness and difficulty swallowing
- Headache
- Dizziness and low blood pressure
- Palpitations and rapid and weak pulse
- Thirst
- Hives, rash, flushing, and facial swelling
- Nausea, vomiting, and diarrhea
These symptoms are typically rapid in onset, and recovery is usually complete within 24 hours, but in rare cases can last for days [2].
Scombroid poisoning is treated with antihistamines. Corticosteroids are ineffective. If you have food poisoning symptoms for over 24 hours or if your symptoms are severe, seek medical attention [2].
18) Irritable Bowel Syndrome
Histamine has been associated with symptom severity in irritable bowel syndrome (IBS). IBS patients with abdominal pain have more mast cells and more histamine activity near gut-associated nerves [2].
In one study, 58% of patients with IBS experienced gut symptoms from histamine-releasing food items and foods rich in biogenic amines. In some of these patients, a new carbon-based adsorbent (which binds to histamine in the gut, preventing it from crossing into the bloodstream) reduced symptoms [2].
Furthermore, elevated levels of H1Rs and H2Rs are found in the stomachs of people with IBS. The H1R inhibitor ketotifen reduces some IBS symptoms [2].
Testing for Histamine Intolerance
If you believe that you have excess histamine, talk to your doctor about the options for testing and appropriate management.
Markers to Check
Tryptase is a marker of mast cell activation, so you should test for tryptase if you want to see how active your mast cells are. Doctors can also test for blood histamine shortly after a reaction [35, 36].
Sensitivity to vasoactive amines is usually diagnosed through history and dietary exclusion; however, some studies have suggested that the measurement of diamine oxidase (DAO) levels may be helpful [37].
In one study, people with DAO levels under 3 kU/mL were more likely to negatively react to high-histamine foods, whereas histamine intolerance was unlikely when DAO was over 10 kU/mL [38].
According to another study, the size of the wheal in the “histamine 50-skin-prick test” is a useful diagnostic indicator: 82% of people with histamine intolerance maintained a wheal size greater than 3 mm, compared with 18% of controls [39].
It might also be a good idea to get a breath test to check if you’ve got H. Pylori. H. pylori infects about 52% of Americans; infection increases histidine decarboxylase, which in turn increases histamine [40].
Takeaway
Histamine intolerance symptoms emerge when there’s too much histamine for your body to handle, either because production is too high or breakdown isn’t happening fast enough. People who don’t break down histamine well enough often have low diamine oxidase (DAO) enzyme activity.
Histamine can trigger itching, rash, pain, gut inflammation, and headaches in the short term. If histamine levels are high for a long period of time, they may contribute to mental illness, brain damage, weak bones, and heart disease.
Diets low in both histamine and mast cell triggers can help manage intolerance, as can natural and pharmaceutical antihistamines.
Learn More About Histamine
This is the third post in a six-part series on histamine, histamine intolerance, and how to manage it. To learn more, click through the links below.
- Part 1: What is Histamine? Definition, Function, Receptors & DAO
- Part 2: 17 Histamine Health Effects: Cognition, Inflammation & Sleep
- Part 4: Low Histamine Diet: Does It Work? + Who Should Try It
- Part 5: Foods High & Low in Histamine + Other Mast Cell Triggers
- Part 6: Natural Antihistamines to Prevent Histamine Reactions
