‘Histamine intolerance’ is a condition that results in high histamine levels. It is technically caused by a deficiency of an enzyme that breaks histamine down called diamine oxidase (DAO). Anything that causes histamine to increase contributes to this condition.

Often, a variety of food chemicals can cause a spike in inflammation and histamine, as was the case in myself.

In addition to my own battle with histamine intolerance, I have had quite a few clients who deal with histamine intolerance. This protocol is dedicated to them. Read on to learn about histamine intolerance, how it affects your health, and what you can do to treat it.

What is Histamine Intolerance?

The clearest sign of histamine intolerance is a bad reaction after eating fermented foods like sauerkraut.

One of the biggest contributors to histamine intolerance is chronic HPA activation.

If you have histamine intolerance, some potential therapeutic options include:

If you have histamine issues in general, then do the following:

  • Use Cromolyn as a mast cell stabilizer. It is effective when used right before or during a reaction
  • Take 1 capsule of Forskolin as a mast cell stabilizer [R]
  • Take 1 capsule twice a day of EGCG to inhibit histidine decarboxylase and stabilize mast cells
  • Experiment with other substances below and in the Th2 dominance page

To help combat histamine intolerance, I came up with the lectin avoidance diet to minimize food sensitivities, along with a cookbook.

What Does Histamine Intolerance Come From?

Histamine intolerance comes about as a result of too little histamine-degrading enzymes in your gut (DAO).

The result is accumulated histamine. This causes numerous symptoms that resemble an allergic reaction.

It can come from gut damage, alcohol, drugs/supplements, or a microbial imbalance.

If a lack of DAO is the sole cause of your histamine issues, then all you need to do is take the enzyme.

I suspect, however, that many people who complain of histamine intolerance don’t always have issues with the enzyme in particular. Rather, I believe such people are Th2 dominant and just produce excess histamine after meals.

For this post, I will discuss all the ways in which you can reduce histamine overall, not only ways to increase the enzyme.

Do You Have Histamine Intolerance

Reduced DAO levels can also lead to the following symptoms:

Scientific Evidence for Harm Caused by Histamine and Biogenic Amines

When blood histamine levels are raised above the normal range (0.3 to 1.0 ng/mL) this produces certain effects. For example, a level of 1 to 2 ng/mL causes increased stomach acid secretion, with flushing, headache, hives (urticaria), and itching skin (pruritus). At a level of 3 to 5 ng/mL), patients experience a high heart rate.. At a level of 7 to 12 ng/mL, bronchospasm is experienced, and cardiac arrest occurs at levels of 100 ng/mL [R].

Thus, large amounts of ingested histamine can cause significant symptoms in otherwise well individuals. For example, symptoms of flushing, sweating, hives (urticaria), GI symptoms, palpitations, and in severe cases bronchospasm, may occur following the consumption of spoiled fish [R].

This condition, known as scombroid poisoning, occurs due to the high level of histidine in certain fish species being converted into histamine by marine bacteria [R].

Due to the nature of the symptoms caused, reactions involving vasoactive amines may be incorrectly diagnosed as a food allergy.

One study found that a diet low in vasoactive amines alleviated chronic headaches in 73% of patients [R].

Another study reported that 27 out of 44 (61%) subjects had a significant improvement in idiopathic urticaria, angioedema, and pruritus on a diet low in dietary amines, although foods containing additives or high in natural salicylate were also restricted [R].

Subjects with chronic hives or angioedema had a marginally significant reduction in their use of antihistamines on a histamine-reducing diet, compared to a control group who eliminated artificial sweeteners from their diet [R].

Fifty-eight percent of adult patients with irritable bowel syndrome (IBS) considered foods rich in vasoactive amines, such as wine, beer, salami, and cheese, to be a cause of their symptoms [R].

Although 75 mg of liquid histamine can provoke symptoms in healthy volunteers, defining a safe threshold level for sensitive individuals is difficult [RR].

In a placebo-controlled study, no correlation was found between wine histamine content and wine intolerance. It also concluded that other vaso-active amines or sulfites may be more relevant in intolerance to wine [R].

It is thought that other foods may be able to cause histamine release directly from tissue mast cells, although evidence for this is lacking [R].

Amine and Histamine-Rich Foods

Histamine is considered a biogenic amine. Biogenic amines are commonly found in fish, fish products, meat, dairy products, wine, cider, and beer, as well as spinach, tomatoes, and yeast products [R, R].

Biogenic or vasoactive amines are produced by bacteria during fermentation, storage, or decay [R].

They include beta-phenylethylamine, tyramine, tryptamine, putrescine, cadaverine, spermine, and spermidine, but histamine is the one most frequently linked to food-related symptoms [R].

Citrus fruits are histamine “liberators” and should likewise be avoided [R].

In general, foods likely to contain high levels of these biogenic amines are fermented foods or foodstuff exposed to microbial contamination during storage [R].

Histamine, tyramine, cadaverine, spermine, spermidine, putrescine, tryptamine, and agmatine are considered to be the most important biogenic amines occurring in foods [R].

Biogenic amines have a negative reputation, but in reality, some like spermidine are quite healthful.

Spermidine prolongs the lifespan of several model organisms including yeast, nematodes, and flies, and reduces oxidative stress. Spermidine induces autophagy in cultured cells and flies [R].

The main bacteria responsible for biogenic amine production in fermented food are lactic acid bacteria (LAB) [R].

These bacteria can break down amino acids into amine-containing compounds. Bacteria produce these compounds as defense mechanisms to withstand acidic environments [R].

Biogenic amines play critical roles within the human body [R].

Some countries place limits for histamine in wine such as Germany (2mg/l), Holland (3mg/l), Finland (5mg/l), Belgium (5 to 6mg/l), France (8mg/l), Switzerland, and Austria (10mg/l) [R].

According to one study, the average levels of histamine in wine were 3.63 mg/L for French wines, 2.19 mg/L for Italian wines, and 5.02 mg/L for Spanish wines [R].

The histamine content varies widely even in foods with supposedly high histamine levels [R].

The following foods generally have high histamine levels:

  • Fermented products: Sauerkraut, kombucha, alcoholic beverages (except distilled), pickles, fermented soy products, yogurt, buttermilk, kefir, mature cheese
  • Cured, smoked, and fermented meats: Sausage, pepperoni, salami, etc.
  • Canned fish products [R]
  • Tomato paste [R]
  • Spinach and yeast products [R]
  • Citrus fruits are histamine “liberators,” which increase histamine release, and should likewise be avoided [R]

Introduction to Mast Cells

Other than histamine, mast cells release:

Mast cells are present in most tissues surrounding blood vessels and nerves. They are especially present in areas that interact with the outside world: the skin, lungs, digestive tract, mouth, eyelids, and nose.

Mast cell activation plays a central role in asthma, allergic rhinitis, anaphylaxiseczemaitching (pruritus), hives, pain, and autoimmunity. It also suppresses fertility and sperm motility in males.

Mast Cells, Histamine, and Stress

Whenever your stress response is set off, your hypothalamus releases Corticotropin Releasing Hormone (CRH), which results in an increase in cortisol release.

People think that cortisol is the villain. Chronically elevated cortisol is certainly bad, but chronically elevated CRH is even much worse.

Mast cells get activated by CRH, which leads to histamine release [R].

On the other hand, cortisol inhibits histamine secretion [R].

So, we see that activation of your stress pathway has opposing effects on histamine. But eventually, you become insensitive to cortisol and the histamine-reducing effects of cortisol are diminished, while CRH stays elevated.

CRH also activates brain mast cells to release inflammatory cytokines such as IL-6 and IL-8. [R]. Activation of mast cells by CRH increases brain barrier permeability [R].

Some people produce high levels of CRH and lower levels of cortisol, and this causes a lot of histamine issues.

Through my consults, I’ve realized that a majority of people’s histamine issues are most impacted by chronic stress response activation, i.e., too much HPA activity.

Psychological stress is only one of the dozens of reasons why your stress response is overactive. However, it’s often the most significant factor.

Read the full list of reasons for chronic stress pathway activation and see how many factors apply to you.

You can take a salivary cortisol rhythm test to get a better idea of what your stress response is like.

Mice who were exposed to acute stress more quickly developed multiple sclerosis, a disease with a leaky brain barrier. When these mice were lacking mast cells or CRH, the effects disappeared [R].

Read why stress is bad.

Histamine and IgE Allergies

If you’re Th2 dominant, you will likely have issues with histamine.

This is because B-cells produce IgE antibodies, which in turn stimulates mast cells to release histamine.

Therefore, you should think about taking supplements to suppress your Th2 system.

Histamine and Biotoxin Illness/CIRS

People with biotoxin illness generally have issues with histamine-rich foods, such as cured or fermented foods.

The most common biotoxin is mold, which is in all of our homes to one degree or another.

Mold is a broad category that includes the actual mold itself like Aspergillus, Stachybotrys, and others.

However, it’s important to note that it’s usually not just the mold, but also the algae, bacteria, VOCs, and chemicals from the mold that can be mass activators of inflammation, causing histamine issues as a side effect.

The most common markers of biotoxin illness are elevated C4a and TGF-beta. These inflammatory responses activate mast cells, which cause blood histamine levels to rise [R].

Mast Cells and Infections

Sometimes, if people have chronic infections, they can have histamine/mast cell issues. Mast cells get activated by parasites through IgE responses, for example.

Histamine and Lectins

Lectins can bind to the lining of the gut wall and make it leakier [R].

Undigested lectins can enter the bloodstream [R].

Lectins such as ConA are probably the best-studied food components in triggering mast cells and basophils [R].

IgE antibodies contain sugar molecules that are a target of lectins. Lectins can then cause histamine to be released. (This works by cross-linking the glycans of cell-bound IgE.)

In the picture below, the Ys are IgE antibodies, the red dots are the sugar molecules, and the purple egg is a lectin. This is what’s called “cross-linking the glycans of cell-bound IgE.”

Misc_fig_2 (Condensed)

The cited study was performed with potato lectins, but many other lectins would likely have a similar effect.

Potato lectin is present in amounts of 5 to 8 mg per 100 g raw potatoes, and ∼0·5 mg per 100 g when cooked [R].

Cooked potatoes still retain about half of the biological activity of lectins, so even cooking them won’t get rid of the problem, but it does improve it to a large extent [R].

The following lectins increase histamine release:

  • White potatoes and certainly unmodified potato starch (STA): “As potato lectin activates and degranulates both mast cells and basophils by interacting with the chitobiose core of IgE glycans, higher intake of potato may increase the clinical symptoms as a result of non-allergic food hypersensitivity in atopic subjects” [R]
  • Tomatoes: “Tomato lectin behaves similarly to potato lectin in a glycoprotein-binding assay, based on their structural homology and identical sugar specificity” [R]
  • Soy (SBA) [R]
  • Gluten-containing grains (WGA): However, this evidence is contradictory. It could be that WGA increases histamine release, but when histamine is released the stores get used up for a bit, and histamine is inhibited [R, R, R]
  • Legumes (ConA) [R]

Leptin, Mast Cells, and Histamine Intolerance

Leptin may have to do with histamine intolerance.

Leptin and leptin receptors are in mast cells in human skin, lungs, gut, and urogenital tract, suggesting that leptin has some effect on mast cells [R].

In metabolic syndrome patients, there was a positive correlation between leptin levels and the number of fat tissue mast cells, suggesting that leptin may stimulate mast cells [R].

It seems like leptin causes mast cells to be more inflammatory [R].

Leptin correlates with, and probably increases, mast cell activation in children with asthma who exercise [R].

See my post on leptin: All About Leptin: Its Role in Chronic Inflammation, CFS, and Weight.

Nerve Growth Factor (NGF) Activates Mast Cells

Nerve Growth Factor (NGF) activates mast cells, which causes the release of histamine. BDNF, and other neurotrophins, However, it does not activate mast cells [R].

This may contribute to histamine intolerance.

A number of autoimmune conditions have high NGF as well as more mast cells [R].

NGF is one mechanism by which stress increases histamine intolerance, inflammation, and autoimmunity [R].

Ghrelin Activates Mast Cells

Ghrelin and obestatin induce hunger, anxiety, and mast cell activation [R].

This hormone is another reason why anxiety often goes together with histamine intolerance.

Mast Cells and Fluoride

Fluoride potentiates mast cells to trigger more easily. People are exposed to more fluoride in the US because of the fluoridation in water.

Histamine and Mast Cell Stabilizers

Histamine is released by immune cells called mast cells. When you stabilize these cells, histamine doesn’t get released.

When mast cells are activated, they release much more than histamine.

People with mast cell activation from food allergies can experience brain fog. I believe this is because mast cells release superoxide, which is the central cause of brain fog [R].

Various herbs within the Th2 list are mast cell stabilizers, and therefore prevent the release of histamine.

Mast cell Stabilizers/Histamine Reducers

A relatively safe and effective drug that stabilizes mast cells is called Cromolyn. This drug works via multiple mechanisms in combating allergies. It’s available over the counter in the US.

The following also stabilize mast cells:

Mast cells have a circadian rhythm [R].

Most of the supplements for Th2 dominance decrease histamine release from mast cells.

Histamine and Antihistamines

Antihistamines (H1-receptor antagonists) block histamine receptors so that with a given amount of circulating histamine, the effects will be less severe.

Fexofenadine or Allegra seems like a safe drug that doesn’t cause drowsiness because it doesn’t cross the blood-brain barrier much. First generation antihistamines (Benadryl) do cross the brain barrier and cause fatigue.

Research on humans taking Allegra at normal dosages shows no significant adverse effects when compared to a placebo. No deaths occurred in testing on mice who took 110 times the maximum recommended dose for an adult human. I recommend speaking to your doctor to get a prescription.

Benadryl is good to take at night since it induces sleepiness. It’s actually an FDA-approved sleep medication.

Benadryl has other positive effects besides blocking histamine receptors. It decreases anxiety, increases serotonin, increases dopamine, and is useful for the treatment of OCD [R, R, R].

Histamine and Bradykinin

Bradykinin is a protein that causes blood vessels to dilate (enlarge) and therefore causes blood pressure to fall.

It is used in studies to increase histamine levels [R].

One potential mechanism by which it increases histamine is via an increase in calcium within our cells [R].

ACE inhibitors or blood pressure-lowering drugs increase bradykinin.

ACE inhibitors also constrict our airways, which makes sense because histamine causes such effects.

Therefore, people with histamine issues would be wise to stay away from ACE-inhibiting drugs, unless absolutely needed.

Click here to see a list of natural ACE inhibitors, which are weaker than drugs.

Supplements that inhibit bradykinin:

Histamine and Histidine Decarboxylase

Histidine decarboxylase (HDC) is the enzyme that speeds up the reaction that produces histamine from the amino acid histidine. This enzyme is helped by vitamin B6.

If you inhibit the enzyme HDC, you decrease the production of histamine.

Inhibitors of HDC are:

It might be a good idea to check if you’ve got H Pylori (breath). H pylori infect about 52% of the American public. H pylori infection increases histidine carboxylase, which increases histamine [R].

Histamine and Probiotics

Some probiotics degrade histamine and are recommended for histamine-intolerant people.

Histamine degrading bacteria:

People with histamine intolerance generally do better with Bifido probiotics.

Supplements That Increase DAO Production

Besides taking an enzyme, some supplements increase DAO.

The following increase DAO:

  • Vitamin C: In one study, 1 g of vitamin C also directly decreased histamine in everyone it was given to, and histamine levels increased exponentially as the ascorbic acid level decreased. Take 500 to 2,000 mg of vitamin C periodically throughout the day, as it is rapidly excreted [R, R]
  • Vitamin B-6: Caution, this also increases histidine decarboxylase) [R]
  • Benadryl [R]
  • Pancreatic enzymes: Don’t know if it increases DAO, but it supposedly helps [R]

H Pylori inhibits absorption of vitamin C [R].

SAM-e may help break down histamine by methylating it.

Histamine N-methyltransferase is an alternative to DAO in breaking down histamine, using SAM-e to accomplish this.

Histamine and Erythropoietin

In a clinical trial with uremic patients, 8 out of 10 people with pruritus had marked reductions in their pruritus scores during erythropoietin therapy.

The patients with pruritus had elevated histamine (20.7 nmol/l), compared with the patients without pruritus (4.2) and normal subjects (2.1).

Therapy with erythropoietin decreased histamine, and discontinuation of erythropoietin was accompanied by increases in histamine [R].

Read a list of Ways to increase EPO.

Flushing: Histamine, MSH, or Both?

People with histamine issues are most often underweight, have low blood pressure, have increased pain sensitivity, and don’t display a fever generally, even though they exhibit inflammation.

While histamine has a role in these, activation of the melanocortin receptors can cause the same issues (MC4R) [R].

People with chronic stress and/or inflammation have the MC4R receptor activated, which then leads to flushing, weight loss, lower blood pressure, and increased pain [R].

My guess is that both histamine and MC4R cause flushing symptoms.

You can check your genes for MC4R.

Be Wary of These Supplements

Histamine-producing bacteria:

DAO inhibitors:

Other:

Genetics of Histamine Intolerance

SelfDecode is the best and most powerful genetic application, which helps you interpret your genes. You need to sign up and upload your genetics to see what versions of these genes you have.

SNPs in the HDC gene:

Some HDC gene variants increase the risk of developing allergic rhinitis [R].

Gene name SNP/variants Effects of snps/variants
HDC rs16963486 Decreases HDC activity, increases histamine levels
  1. RS16963486
  2. 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 gene known as C939T regulates histamine. “AA” will increase histamine.

If you have AA, don’t despair, as ~56% of the population has this gene.

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.

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.

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 and you’re also going to be more sensitive to NSAIDs (aspirin, ibuprofen) [R, R].

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

SNPs in the H4R gene:

Variants of the H4R gene are associated with an increased risk of atopic dermatitis, and infection-induced asthma [R, 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 (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].

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

  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

Testing for Histamine Intolerance

You can do a histamine test to check for elevated blood levels. You can also check your tryptase levels, which are markers for mast cell activation.

The diagnosis of sensitivity to vasoactive amines is usually made through history and dietary exclusion; however, some studies have suggested that the measurement of diamine oxidase (DAO) levels may be helpful.

One study found a DAO level <3 kU/mL was associated with reported symptoms to high histamine foods, whereas a level of >10 kU/mL indicated histamine intolerance was unlikely [R].

Patients with chronic idiopathic hives/urticaria and GI symptoms have reduced DAO activity [RR].

Another study reported that the size of the wheel used in the “histamine 50-skin-prick test”, was a useful diagnostic indicator: 82% of subjects with histamine intolerance maintained a wheal size greater than 3 mm, compared with 18 % of controls [R].

I suggest just taking the DAO enzyme and see how you feel.

SelfDecode Pages

To get full use out of these pages, it’s best to have your genetics uploaded to SelfDecode. For example, you can see if any of your related genes are flagged as “potentially problematic.” If you have many genes that are flagged as problematic, you might be susceptible to alterations with that biological process.

Here is an example of genes that I found were problematic for me related to mast cell degranulation.

Other/Anecdotal

Some people supposedly have trouble converting sulfur to sulfate (phenol sulfotransferase issue), and those who have a sensitivity to certain foods and chemicals because of this often times develop a high histamine level.

Avoiding certain phenolic and high salicylate foods may help the sulfation problem and subsequently lower the high histamine level.

MSM or Epsom salts also supply sulfur to the system and may be helpful. Some people cannot convert the sulfur in MSM to the needed sulfate form, although other people can.

Epsom salts supply sulfur in the sulfate form directly. Taking MSM or Epsom salts may alleviate a histamine reaction. You can also try glucosamine sulfate and chondroitin sulfate.

 

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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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