6 Steps to Naturally Treat Histamine Intolerance (Science-Based Protocol)

Diamine oxidase (DAO) and histamine n-methyltransferase (HNMT) are two enzymes that breakdown histamine. R

DAO is dependent on P5P and HNMT is dependent on SAM-e to break down histamine. R

Histamine is usually excreted via urine and metabolites (such as n-methylhistamine). R

In the brain, histamine is highly dependent on MAO-B. R

Histamine-releasing factor (HRF), or B cell growth factor, can stimulate histamine release and IL-4 and IL-13 production from IgE-sensitized basophils and mast cells. R

IL-4 acts on a positive feedback loop causing more release of IL-4 by TH2 cells. R

This makes the body shift towards a TH2 dominant immune system. R

HRF can also stimulate secretion of IL-8 (similar to CRH).  R

With my clients I will go for the root cause and look at a Gut Zoomer, Organic Acids Test, and a Toxicology test.

N-methylhistamine (urine) is the most prominent marker that will tell you if you have problems with histamine metabolism and very necessary to get to determine if your problem is histamine related or not. R

Common Biomarkers Of Histamine Intolerance:

• Alpha-MSH (this is necessary to make sure it's histamine and not overactive a-MSH levels, since MSH can cause flushing similar to histamine) R

• Complement C4a R

• DAO (in blood) R

• Estrogen

• IL-6 R

• IL-8 (this chemokine causes release of histamine attracting neutrophils) R R

• Leptin R

• Neurotensin R

• N-Methylhistamine R

• Progesterone

• Tryptase R

• TGF-b1 R

1. Eat a Low Histamine Diet

Avoid all these:

• Additives (in general may cause mast cell response) R

• Alcohol R

• Casein R

• Carnosine R

• Cheese R

• Chocolate R

• Citrus R

• Coffee R

• Cimetidine R

• Dietary Haptens

• Fermented foods (lactic acid producing bacteria produce biogenic amines) R R

• Fish, Shellfish, and other seafood (crustaceans too, fish oil capsules are fine) R

• Imidazoles - such as caffeine (promoting glutamate release in hypothalamus), nicotine, and theobromine R R

• Gluten R

• Lectins R R R R

• Leftover Meats (including long-cooking, cured, crockpot cooking, bone broth, collagen, etc) R

• Legumes R

• Licorice R

• Nightshades (like tomatoes, potatoes, etc) R

• Nuts R

• Papaya R

• Peanuts R

• Pineapple R

• Red Wine Vinegar R

• Sausage R

• Soy R

• Spices R

• Spinach R

• Strawberries R

• Turmeric (curcumin) R

• Yeast R

Essentially, eat very fresh and lower inflammatory foods.

Cooking/browning food with sugar (via Maillard reaction) may help reduce histamine on meats and fish. R R

2. Increase Enzymes to Break Down Histamine

DAO is the main enzyme that helps break down histamine in the gut and blood.  R

Increase DAO:

• Chronic high doses of Vitamin C (liposomal/IV maybe? - if you have h. pylori, it will inhibit the absorption of vitamin C) R R

• DAO Enzymes R

• Heparin R

• Progesterone (to balance estrogen if it is high)

• P5P (but can also increase histidine decarboxylase) R

Inhibiting histidine decarboxylase (HDC) will help break down histamine faster, since it is the enzyme that converts histidine into histamine (from strongest to weakest):

• Cortisol R

• Carnosine (although inhibits DAO) R R

• EGCG (although it promotes NGF growth) R

• Homocysteine (but not great to have elevated) R

• L-DOPA R

• Mucuna R

• NAC (although can increase histamine) R R R

• Naringenin R R

There are four different histamine receptors, named H1R through H4R. R

H1R is involved in the allergic response, smooth and endothelial muscle contraction, and neurotransmission. R R

H2R is expressed in many immune cells, parietal cells and nerve cells. It is mostly targeted for gastric, neurological, and cancer therapies. R R

H3R regulates histamine production in the central nervous system (CNS), regulating neurotransmitters. R R

H4R is regulates the immune system in blood and the CNS. R

Targeting histamine receptors with anti-histamine need to be specific for the right one - for example increasing antagonizing the 3rd Histamine Receptor (H3R) causes an increase of histamine in the brain, as H3R has auto/hetero-receptor properties. 

Technical R

• All four receptors belong to class A family of G-protein coupled receptors (GPCRs).

• H1R couples Gαq/11 proteins, leading to phospholipase C activation, production of inositol phosphate and calcium mobilization.

• H1R is also expressed in nerve cells, vascular smooth and endothelial cells among others, and takes part in neurotransmission and cellular adhesion respectively.

• H2R is expressed in many immune cell types, parietal cells and nerve cells.

• H2R mediates its effects by coupling GαS proteins, stimulating adenylate cyclase and increasing intracellular cAMP levels.

• H2R in regulates histamine synthesis and cytokine production in immune cells.

• This prevents stem cells in the bone marrow from differentiating and can even induce stem cells to undergo apoptosis.

• Due to its broad localization, antagonists of this receptor have been used for treating gastric and neurological disorders, as well as in antitumour therapy.

• H3R, when located in the presynaptic membrane of histaminergic cells, regulates the production of Hia in the CNS.

• H3R also regulates the release of many neurotransmitters, acting as a presynaptic heteroceptor.

• H3R couples to Gαi/o proteins and inhibits cAMP accumulation.

• It has been demonstrated that several active isoforms of this receptor exist in humans, although their function remain unknown.

• H4R is expressed in certain immune cells of haematopoietic origin and in the CNS.

• H4R couples to Gαi/o proteins and inhibits cAMP formation.

• H4R has been recently targeted as a key component of the immune response as well as being responsible for the mobilization of immune cells.

• Histamine's regulates both IL-6 production and mRNA expression in mice mast cells via H4R activation.

Ketotifen Fumarate is a H1 antagonist with little side effects. R

DAO

D-amino acid oxidase is an enzyme that breaks down histamine into histadine. R

Mutations in this gene are associated with:

• Ulcerative Colitis R

• Schizophrenia R

• Migraines R

• Sensitivity to NSAIDs R

• Schizophrenia R

• Bipolar Disorder R

rs10156191 - Each T allele means you have reduced DAO activity. R
rs1049742 - Each T allele means you have reduced DAO activity. R
rs2052129 R
rs2268999 (reduced activity)
rs2071514 (protective)
rs1049748 (protective)
rs2071517 (protective)

HDC

Histidine decarboxylase converts L-histidine to histamine (via P5P). R

HDC is expressed by mast cells and other immune cells, gastric enterochromaffin-like cells (ECLCs) and histaminergic neurons. R

Mutations in this gene are associated with:

• Breast Cancer and Cancer Growth R R

• Chronic Heart Failure R

• Tourette Syndrome R

• Bile Acid Secretion R

• Atherosclerosis R

• Scleroderma R

• Rhinitis (TT allele of rs2073440)

HNMT

Histamine N-methyltransferase regulates histamine methylation. R

SAM-e should help increase this gene as a methyl donor. R

Mutations in this gene are associated with:

• Asthma R

• Allergic Rhinitis R

• Breast Cancer R

• Bronchiolitis R

• Pick's Disease R

• Down Syndrome R

• Intellectual disability R

• Huntington's Disease R

• Parkinson's disease R R

• Better Outcome in Ischaemic Stroke R

• Schizophrenia protection R

• Myasthenia gravis R

• Anxiety R

• Aspirin intolerant chronic urticaria R

• Alcoholism R

rs1050891 - AA will increase histamine and may worsen ADHD. R
rs758252808
rs17583889
rs1801105
rs11558538
rs745756308

Histamine Receptors

HRH1
HRH2
HRH3
HRH4

Histamine Transporters

SLC18A2/VMAT2
SLC22A3/EMT

MTHFR

Being heterozygous or homozygous for either C677T and/or A1298c will predispose you to further histamine problems.

Each allele for both mutations adds the burden for detoxing excess histamine.

For a deeper look at how the full methylation cycle works, why MTHFR is only one piece of the puzzle, and how to support it, see the complete methylation guide.

The connection between methylation and histamine is direct: HNMT (histamine N-methyltransferase) is the only enzyme that clears histamine inside cells, and it requires SAM-e as its methyl donor.

When SAM-e is depleted (from MTHFR variants, B12 deficiency, or high toxin burden), HNMT slows down and histamine accumulates in the brain, liver, and airways.

This is why so many people with MTHFR mutations present with histamine intolerance as their primary symptom.

Supporting the methylation cycle with methylfolate, methyl-B12, riboflavin, and TMG restores SAM-e production and directly improves histamine clearance through HNMT.

Creatine supplementation also helps: creatine synthesis consumes approximately 40% of all SAM-e methyl groups in the body, so supplementing creatine directly frees up SAM-e for histamine degradation.

VDR

The Vitamin D Receptor acts as a transcription factor and target for H1R (histamine 1 receptor). R

• For mackerel, at 0 degrees C, neither histamine former nor histamine production was detected up to 14 days of storage. R

• Mast Cell Activation Symptomatology (Part 1 of 3) V

• Histamine vs Tyramine producing bacteria in cheese. R