High Histamine Food List

Histamine is a type of biogenic tissue amine – L-histidine decarboxylase (HDC) and the cofactor pyridoxal 5’-phosphate or the active form of vitamin B6 mediate the conversion of histidine into histamine (its chemical reaction is represented in figure 1). The key enzymes such as diamine oxidase (DAO) and histamine N-methyltransferase (HNMT) degrade histamine into different by-products.

As per the International Union of Pure and Applied Chemistry (IUPAC)nomenclature, the chemical name of histamine is 2-(1H-imidazol-4-yl) ethanamine.

Essentially, the biogenic amines such as histamine, tyramine, putrescine and cadaverine at low concentrations have been reported to possess hazardous adverse effects on the human body. The storage of histamine is principally in lymph nodes, basophils, mast cells, gastric enterochromaffin cells and thymus. There are four histamine receptors, namely, H1, H2, H3 and H4, distributed in various parts of the human body. Histamine binds with respective receptors and displays the pharmacological effects.

Enzymes such as diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT) are actively involved in the metabolism of histamine by negating high levels of histamine in the human body.

Other names of DAO are histaminase and amiloride-binding protein that facilitates the oxidative deamination of histamine. The critical role of DAO is to eliminate the excess histamine and regulate the levels of histamine entering the blood circulation from the digestive tract. The expression of DAO is found in a few specific tissues such as the placenta, kidney, small intestine and ascending colon.

The primary function of HNMT controls histamine expression and its biosynthesis by N-methylation of histamine in various organs including kidney, liver, colon, spleen, spinal cord cells, ovaries, bronchi and trachea.HNMT selectively metabolizes histamine in the central nervous system. DAO can metabolize not only histamine, but it also metabolizesother biogenic amines like cadaverine and putrescine.

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Histamine unveils its pharmacological effects through binding to various histamine receptors (H1, H2, H3 and H4), thereby initiating appropriate pharmacological activities.

• H1 histamine receptor – it is ubiquitously present in the peripheral nervous system and smooth muscle. H1 receptor has been known to have an important role in allergic response and its activation on smooth muscle leads to vasoconstriction. Other activities such as increased vessel permeability, blood vessel dilatation, stimulation of sensory nerves in the airways and bronchoconstriction have resulted in the activation of the H1 receptor. Also, its activation further facilitates the chemotaxis of eosinophils, followed by few symptoms including nasal congestion, rhinorrhoea and sneezing. The stimulation of the H1 receptor in the cerebral cortex could interrupt potassium channels in neuronal cell membranes, followed by the depolarization of the neurons and an increase in neuronal excitation. As a neurotransmitter, histamine maintains wakefulness and conducts nociceptive pain impulses.
• H2 histamine receptor – parietal cells in the stomach, heart, immune cells and vascular smooth muscle have an H2 receptor. Activation of the H2 receptor results in vasodilation and gastric acid secretion that is essential for digestion.The binding of histamine with the H2 receptor also causes activation of neutrophils and basophils, a reduction in the chemotaxis, stimulation of suppressor cells, natural killer cell activity and lymphocyte proliferation. The combination of H1 and H2 receptors leads to rhinorrhoea and inflammation of nasal airways.
• H3 histamine receptor – it is referred to as a presynaptic auto receptor, mainly present in nerve cells and broadly distributed in all regions of the central nervous system. However, it is highly expressed in the hippocampus, cortex, caudate nucleus, thalamus, hypothalamus and olfactory tubercle. The availability of H3 receptor throughout the cortex plays a critical role in the modulation of several neurotransmitters such as GABA, acetylcholine, norepinephrine and dopamine in the central and peripheral nervous system.
• H4 histamine receptor – it is found on immune cells and tissues that include the thymus, bone marrow, the spleen and peripheral blood leukocytes. Besides immune cells, the H4 receptor is present in the lung, liver, colon and epicanthus. Activation of the H4 receptor leads to the chemotaxis of eosinophils and the upregulation of adhesion of biomolecules.

Table 1. Effects of various concentrations of histamine.

Histamine intolerance or enteral histaminosis is an imbalance between the histamine degradation system and metabolism of ingested histamine. Basically you’ve eaten more histamine-producing things than your body can get rid of, so you’re dealing with an imbalance. Histamine intolerance is also known as a medical condition that occurs due to reduced diamine oxidase (DAO) activity, which leads to the accumulation of histamine in plasma and creates damaging effects.

Histamine intolerance affects at least 1 percent of the global population. It’s interesting to note that, of those, around 80% are middle-aged women.

With an abundant presence of histamine receptors throughout the human body, histamine intolerance presents most of the clinical manifestationsin various organs such as cardiovascular (tachycardia, palpitations and collapse), gastrointestinal tract (abdominal pain, constipation, diarrhea, emesis, bloating, distention, flatulence, nausea, diarrhea and postprandial fullness), nervous system (dizziness and headache), respiratory system (dyspnea, nasal congestion, rhinorrhea and rhinitis) and skin (eczema, flush, inflammation, pruritus and urticaria).

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Tolerated amounts of ingested histamine tend to produce an untoward reaction in the human body. The clinical manifestations are directly related to the presence of histamine, not with other substances or conditions. This type of intolerance is due to the deficiency of either DAO or HNMT enzymes where the equilibrium between the histamine degradation system and levels of histamine in the body get disrupted.

It is caused or aggravated due to another disease condition or any drug/substance that interrupts the metabolism of histamine. Celiac disease is an example of this and causes histamine intolerance - it is an intestinal disease triggered by gluten.

Single nucleotide polymorphisms (SNPs) in any gene often create an inactive state of a particular protein. The genes encoding enzymes L-histidine decarboxylase, diamine oxidase and histamine N-methyltransferase have been extensively studied for their SNPs. These SNPs result in the formation of aprotein with altered activity, followed by histamine build up and therefore produce the symptoms of histamine intolerance.

Single Nucleotide Polymorphisms in HDC:

1. rs17740607 and rs2073440. 

Single Nucleotide Polymorphisms in DAO:

1. rs45558339, rs35070995, rs10156191, rs1049742, rs2268999and rs1049793. 

Single Nucleotide Polymorphisms in HNMT:

1. rs1801105, rs11558538, rs1050891, rs758252808, rs2052129 and rs745756308.

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Structurally similar drugs with histamine could bind with the active site of either DAO or HNMT and decrease its enzymatic activity. Some medications that block the DAO enzyme induce histamine intolerance; a list of drugs and medications is given below.

• Amitriptyline
• Anaesthetics (Thiopental and prilocaine)
• Analgesics such as (Morphine, pethidine, acetyl salicylic acid, metamizole and diclofenac sodium
• Antibiotics (Isoniazid, amoxicillin, cefuroxime, cefotiam, pentamidine, clavulanic acid, chloroquine and paromomycin)
• Antihypertensives (Verapamil, Dihydralazine and alprenolol)
• Cimetidine
• Clonidine
• Colistimethate
• Cyclophosphamide
• Expectorants such as acetylcysteine and ambroxol
• Metoclopramide
• Muscle relaxants (Pancuronium, D-tubocurarine and alcuronium)
• Pentamidine
• Promethazine
• Propafenone
• Quinidine
• Suxamethonium
• X-ray contrast media

Table 2. Different food categories with high histamine content.

• Alcohol
• Black tea and mate tea
• Energy drinks

As per the guidelines of the German Society for Allergology and Clinical Immunology (DGAKI), a 3-step dietary adjustment can be followed to reduce the adverse effects of histamine intolerance.

1st step (avoidance) – 10-14 days:

• This step is to reduce the symptoms to a large extent
• A mixed diet focusing on vegetables and less biogenic amine containing food intake, nutrient optimization, modification in meal composition and a balanced diet are the key recommendations.

2nd step (testing) – for up to 6 weeks:

• This phase should be an expansion of food choices under the consideration of individual risk factors such as stress, medications, menstruation and other biological parameters.
• The recommended objectives are the re-introduction of suspected foods and the establishment of individual histamine tolerance patient records and history.

3rd step (Long term diet):

• A balanced supply of nutrients and better quality of life would be considered in this phase and individual nutritional recommendations can be created and implemented.

Few diagnostic methods are available to detect histamine intolerance because a reliable procedure has yet to be discovered. Generally, through patient history and self-diagnosis by the patient, the adverse events of histamine intolerance can be uncovered and evaluated. The following questions should be resolved in order to understand histamine intolerance thoroughly.

• What are the expected clinical manifestations and the implementation ofappropriate diagnostic methods for histamine intolerance?
• Any substantial evidence for the pathomechanism of histamine intolerance should be collected, documented and further researched?
• Which are the parameters best utilized in the diagnostic work-up and what is their reliability?

Several parameters have been proposed and used for the diagnosis of histamine intolerance. The reliability of such parameters is discussed below.

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As per recent research studies conducted on histamine intolerance, the diagnostic method using the measurement of DAO enzyme activity in blood serum is not conclusive. DAO-specific monoclonal antibodies can be used to detect the DAO activity in the kidney, intestine and placenta, but not in blood serum. On another hand, a recent study has specified the reliability of verifying DAO enzyme activity in blood serum.

Kofler et al., (2011) have discovered a diagnostic tool for histamine intolerance and slowed histamine degradation. Administration of 1% histamine solution in our human bodies that leads to the occurrence of a wheal and the measurement of the wheal size is key in the Histamine 50-skin-prick testing. Persistent wheal size after 20 – 50 minutes assumes a sign of slowed histamine degradation. But this method does not give us any conclusions for the diagnosis of histamine intolerance. The slowed degradation of administered histamine as a diagnostic tool has been under debate before a final decision on histamine intolerance can be made.

Measurement of DAO and HNMT enzyme activities in the intestinal mucosa (the most critical organ for the metabolism of histamine that comes from sources outside the body) could be of potential diagnostic significance. Current studies reveal that blood DAO or HNMT concentration in humans does not provide any conclusions on enzyme activities in the small intestine. Additional research should be carried out to establish whether the evaluation of DAO enzyme activity in the small intestine corroborates the information on the degradation of histamine.

Few bacteria (lactobacilli) in the intestinal microbiota secrete large quantities of histamine. This may result in misleading pathological information when high levels of histamine concentration in stool samples are observed. Therefore, the validity of stool analysis in the diagnosis of histamine intolerance is questionable, since the histamine in stools is typically the metabolite of intestinal bacteria. 

Assessment of plasma levels of histamine for determining histamine intolerance has always been in the debate. Thus, histamine in the plasma cannot be considered as a diagnostic tool at the moment.

The presence of methylhistamine in urine must be carefully studied as the levels of methylhistamine is dependent on histamine. It’s also worth noting that high protein content foods lead to a surge in methylhistamine in the urine, so this could convolute the histamine analysis.

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Methylation is a vital process that catalyzes many physiological processes such as cell growth and repair, detoxification of harmful toxic substances, and regulation of brain functions as well as the immune system. The methylation process is a key component in one-carbon metabolism that possesses the attachment of a one-carbon unit, like a methyl group, by different types of donor molecules onto acceptor molecules. Chemically, a methyl group contains one carbon attached to three hydrogen atoms. Generally, methylation depends upon the availability of 5-methylfolate and is regulated by folate and methionine cycles. These two cycles result in the biosynthesis of S-adenosyl methionine (SAMe) and 5-methylfolate.

Methylation is involved in many biological processes detailed below – in essence, it acts at the very core of our ‘life-force’:

Cardiovascular System:

• Biosynthesis of carnitine, CoQ10, nitric oxide and metabolism of homocysteine.

Detoxification:

• Mainly involved the phase II metabolic pathway that facilitates the detoxification of catecholamines, hormones and heavy metals.
• Also, supports the production of glutathione and the sulphation process.

Digestive System:

• Assists the bile formation via phosphatidylcholine synthesis.

Energy:

• Provides the energy in the form of ATP through the biosynthesis of carnitine, CoQ10, creatine, adenosine and NADPH.

Immunity:

• Helps in antigen recognition, cell differentiation and maturation of immune cells.
• Regulates immune responses against antigens and histamine breakdown.
• Controls viral life cycles and tumor growth.

Sex Hormones:

• Involved in the oestrogen metabolism and production of sperm and ova, and maintaining fetal growth.

Nervous system:

• Production and breakdown of acetylcholine, adrenaline, dopamine, melatonin, myelin, noradrenaline and serotonin.

The malfunction in the methylation process has been implicated in Alzheimer’s disease, cancer, cardiovascular diseases, multiple sclerosis, chronic fatigue, fibromyalgia, autism, anxiety and depression. For instance, Single Nucleotide Polymorphisms (SNPs) lead to an inactive state of the MTHFRenzyme.

The MTHFR gene is responsible for the conversion of folic acid into the active form of folate (L-methylfolate or 5-methylfolate). This, L-methylfolate then actively participates in methylation. The impairment of MTHFR from mutated gene SNPs results in a reduced availability of 5-methylfolate, which ultimately interferes with the methylation reaction. This methylation disruption causes increased serum levels of homocysteine, followed by several chronic disease conditions.

Do the disruption of methylation and/or low levels of methylfolate affect histamine balance in the human body?

Yes, compromised methylation often causes excess serum levels of histamine. The methylation cycle aids in the breaking down (or metabolism) of monoamine neurotransmitters, including histamine. Thus, the interruption in the methylation cycle is one of the reasons behind histamine intolerance.

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Methyl groups from methylfolate are very important to facilitate methylation reaction and other biological reactions. It is suggested that methyl groups bind to the active site of the histamine receptor, this helps in restoring the histamine equilibrium and gets rid of excessive levels of histamine. In the case of low levels of methyl groups in the human body, the histamine escapes from the metabolism and the accumulation of histamine happens. This situation triggers histamine intolerance – it is the weakened ability of our bodies to metabolize or break down ingested histamine.

Histamine intolerance is referred to as enteral histaminosis, a condition caused by a sensitivity to dietary histamine. It is a disorder that starts from a reduced histamine degradation capacity in the intestine due to diminished HNMT and DAO activity, impaired methylation and low levels of methylfolate.

Because of the ubiquitous presence of four histamine receptors in different parts of the human body, especially abundant in the gastrointestinal tract and its surrounding regions, histamine intolerance mainly triggers gastrointestinal and extraintestinal related clinical symptoms such as allergic response, nasal congestion, rhinorrhoea, dilatation of blood vessels and inflammation of airways.

• Eating a low histamine diet
• Cutting out any probiotics or foods (yogurt) which contain lactobacilli strains (consider a spore-based probiotic for optimal effectiveness instead)and  
• Supplementing with L-5-Methylfolate to increase your body’s methylation and capacity to metabolize the excess histamine
• Taking a DAO enzyme supplement product to help metabolize the excess histamine

If you’re looking to avoid the hazardous effects caused by histamine intolerance, methylfolate supplementation could certainly help. But make sure you’re using a reliable source for the active L-5-MTHF (or L-Methylfolate) because as you can imagine, not all methylfolate products are equal. Some of the best methylfolate supplements for vegans, those with cardiovascular risks, histamine intolerance and MTHFR mutations include Methyl-Life® products (B-Methylated II, Methylated Multivitamin, and if you suffer from depression, consider Methylfolate 7.5+ or Methylfolate 15+ as a therapeutic option).

These have been created by a team of natural health experts and used successfully by hundreds of people all over the world. It’s worth noting that Methyl-Life® recently received data from a study that showed theirs to be the purest, stable, and most potent of four of the world’s industry-leading, patented L-Methylfolates. Check out the study comparison details to learn more.

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