What is Histamine? Definition, Function, Receptors & DAO

The Horror of Histamine!

What is Histamine? Definition, Function, Receptors & DAO

After a long, cold winter we are finally starting to see the early signs of spring. The snow has melted. The temperatures are warming. Birds once again tweet happily from the trees. There are lovely green buds forming on all the trees and the daffodils are once again starting to pop up their cheerful yellow splendor.

Everything is perfect! Well, almost everything. That’s right; it is hay fever season again.

Your eyes are itchy and watery, you can’t stop sneezing, and the congestion is driving you nuts! Sound familiar? If so, before you reach for your antihistamine let’s take a look at how our body breaks down histamine and the functional medicine way of dealing with allergies.

Histamine is actually a neurotransmitter (brain chemical). This means that it has functions well beyond just allergies. There are four types of histamine receptors (H1R-H4R). The two types of histamine that are best understood and most relevant are histamine one (H1) and histamine two (H2).

H1 is found in the intracellular pathway and is generally related to symptoms of nasal allergies, hives, and asthma. H2 is found in the extracellular pathway and is primarily found in the gut where it regulates the release of hydrochloric acid (HCL). H1 blockers are medications such as Benadryl, Zyrtec, Claritin and Allegra.

H2 blockers are medications including Pepcid and Zantac.

When looking at how best to help with allergies, it is important to look at the biochemistry of histamine, particularly how it is broken down. This is true because in order to break down histamine we require specific enzymes. All enzymes require cofactors which are generally vitamins and minerals. This means that there are nutritional solutions to histamine problems.

First, let’s explore diamine oxidase (DAO). This enzyme is necessary for the breakdown of histamine in both the intracellular and extracellular pathways.

This enzyme is highly polymorphic, meaning that genetic single nucleotide polymorphisms (SNPS—pronounced “snips”) sometimes referred to as mutations are relatively common (to look at your own genetics you can purchase a direct-to-consumer test such as the one offered by 23andme).

When people have SNPs to this enzyme it causes histamine intolerance (HIT). Ingestion of foods that are high in histamine including alcohol, fermented foods, mature cheeses, smoked foods, shellfish, beans, nuts, chocolate, vinegar, wheat, tomatoes and citrus may exacerbate HIT.

This results in symptoms including gastrointestinal complaints, migraines, fatigue, dizziness, runny nose, flushing, asthma and hives. Interestingly, elevated histamine levels also inhibit DAO causing worsening of the histamine intolerance. The DAO enzyme requires flavin adenine dinucleotide (FAD) as its cofactor.

FAD requires the B-vitamin riboflavin (B2) for its synthesis. Therefore, those with this SNP require more riboflavin than the average person and therefore supplementing this vitamin may help decrease histamine intolerance. Another possible solution would be to take a supplement containing the DAO enzyme (there are several on the market).

Histamine methyltransferase (HNMT) is another enzyme that is required to breakdown histamine in the intracellular pathway. It requires S-adenosyl methionine (SAM) as its cofactor.

SAM is available as a supplement, but taking it can be problematic for many as it is a strong methyl donor and will greatly increase serotonin, dopamine, norepinephrine and epinephrine which can cause anxiety.

Instead, supplementing with vitamin B12 as the active methylcobalamin or folate as the active L-methylfolate can help improve methylation issues and help HNMT to work better.

Alcohol Dehydrogenase (ADH) is the final step in histamine breakdown. This is the same enzyme that breaks down alcoholic beverages. This explains why some individuals flush when they drink. It is also a good reason to perhaps skip cocktails, beer, and wine during hay fever season.

This enzyme actually has four different cofactors including zinc, vitamin C, thiamine (B1) and nicotinamide adenine dinucleotide (NAD—a niacin-based flavoprotein). Therefore taking supplemental zinc, vitamin C, thiamine, and/or niacin might also improve your allergy symptoms. Vitamin in particular is often used to help with allergies.

You can safely take up to 2 grams of this vitamin daily. However, it is best to take it in smaller doses (500 mg) throughout the day for better absorption.

Additional Natural Allergy Remedies
Histamine is released by mast cells, a type of white blood cell that is involved in allergy and anaphylaxis. Certain substances can help stabilize the mast cells so that they do not lose their histamine load. Pharmacologically, the medication chromolyn sodium is used in this way.

However, there are several natural mast cell stabilizers. Quercetin, a natural compound found in apples, onions, and capers is a wonderful natural mast cell stabilizer. Unfortunately, it is poorly absorbed (about 1%) to increase its absorption rate it is best to take it on an empty stomach about half an hour before a meal.

It may be taken up to four times per day. The herb holy basil also works as a mast cell stabilizer. This is available in capsules, tinctures and even as a tea (Tulsi Tea). It also has the benefit for helping the body cope with stress.

Milk thistle, an herb often used to help improve detoxification and support the liver is another mast cell stabilizer. EGCG, a constituent found in green tea is also quite helpful in stabilizing mast cells.

Ellagic acid found in raspberries, strawberries, walnuts, longan seeds, mango kernel, and pomegranate may also inhibit histamine release. Feverfew, a botanical that is both anti-inflammatory and helpful for migraines, may also be helpful for stabilizing mast cells.

When mast cell stabilizers are insufficient, H1 blockers may be helpful. If you prefer to avoid medication, the herb butterbur is a wonderful natural antihistamine.

In clinical trials, this herb was found to be as effective as the over-the-counter medications Zyrtec, Claritin and Allegra. As in many H1 blocking antihistamines, butterbur may cause drowsiness.

Unfortunately, if you have an allergy to ragweed, chrysanthemums, marigolds, and/or daisies you will ly find that you are also allergic to butterbur as it is in the same family.

In addition to mast cells, leukotrienes are also implicated in asthma and allergies. This substance causes contractions of smooth muscle in the respiratory tract that cause symptoms of asthma and allergic rhinitis.

Medications such as monteleukast (brand name Singulair) are used as leukotriene agonists and are often used to help these symptoms. Fish oil (omega-3 fatty acids) is a wonderful natural leukotriene agonist.

Not only will fish oil improve your allergies, but it is a fantastic natural anti-inflammatory.

This spring I hope that experimenting with the various vitamins, minerals, and botanicals helps to decrease your hay fever so that you may enjoy the beauty of this wonderful season. You may be amazed at just how good you feel. Consider reducing dietary histamine as well as decreasing your total histamine load is really helpful.

Jessica Pizano is the owner of Fit to You, LLC, which offers clinical nutrition and nutrigenomic counseling, as well as personalized training programs. She earned a master’s degree in human nutrition that emphasizes functional medicine at the University of Bridgeport.

She is a certified nutrition specialist through the Board for Certified Nutrition Specialists. She is continuing her studies at Maryland University of Integrative Health where she is pursuing a doctor of clinical nutrition and is also an adjunct faculty member teaching nutritional genomics.

A certified personal trainer and a corrective exercise specialist through the National Academy of Sports Medicine, she is also certified in mat Pilates through PHI Pilates and earned her Clinical Exercise Specialist and Longevity Wellness Specialist through the American Council on Exercise.

She may be contacted at (860) 321-7234 or online at www.fittoyouct.com.

Source: https://naturalnutmeg.com/the-horror-of-histamine/

What is Histamine? Definition, Function, Receptors & DAO

What is Histamine? Definition, Function, Receptors & DAO

As the most important biogenic amine, histamine regulates sleep, appetite, motivation, learning, and sexual behavior through its four receptors. Read on to discover its function and the genes that affect it.

What is Histamine?

Most people know about histamine because of antihistamines, drugs commonly used to manage allergy symptoms. Too much histamine for too long brings about a long list of unwanted effects: redness, itching, swelling, runny nose, hives, and others.

Anyone looking to overcome their histamine issues has to start with understanding what histamine is and how it functions in the body.

Histamine is not just detrimental, it also has some protective roles. Problems usually arise if it’s not being broken down fast enough or if it’s being produced in excess and targeting the wrong receptors.


Histamine is a biogenic amine: that is, a compound made in your body that includes an amine group. Other biogenic amines include tyramine, tryptamine, putrescine, cadaverine, spermine, and spermidine; these are produced by bacteria during improper food storage. Most are detrimental, while others (especially spermidine) can be highly beneficial [1, 2, 3, 4].

Histamine was discovered in 1910 by the winner of the 1936 Nobel Prize in Medicine, Sir Henry H. Dale. Its name is derived from the Greek word histos, meaning tissue, as many tissues throughout the body express it [5, 2].


People talk about problems with mast cell activation, allergies, and other conditions of histamine release. But what exactly is going on in the body?

The following cells in your body produce, release, and store histamine [2, 5, 6]:

  • Mast cells andbasophils, types of white blood cells responsible for allergic reactions
  • Enterochromaffin- (ECL) cells in the stomach lining
  • Histamine-releasing (histaminergic) neurons

In people with histamine intolerance, food allergies, IBD, and IBS, the histamine system may become dysfunctional. Histamine builds up and strays from its typical behavior. As these changes gain momentum, they may shift the balance in immune cells and reduce barrier integrity in the gut. This triggers all the inflammatory symptoms most people recognize all too well [2].

Other cells can also produce histamine, but at much lower levels. These cells cannot store histamine, so they need to release it straight away [2, 6].

An enzyme called histidine decarboxylase (HDC) makes histamine from the amino acid histidine. Certain microbes, including some gut bacteria, also have the HDC enzyme and can produce histamine from histidine. This may sound a problem, but researchers think specific histamine-producing probiotic bacteria (such as Lactobacillus rhamnosus) could be beneficial [2].


Two enzymes control histamine breakdown: histamine N-methyltransferase (HNMT) and diamine oxidase or DAO. These enzymes are extremely important. If either one starts malfunctioning, histamine can increase dramatically throughout the body [7, 2].


HNMT is the main histamine-degrading enzyme in the brain. It breaks down histamine inside the cells without being released into the bloodstream. The liver, spleen, gut, prostate, ovaries, kidneys, and lungs also contain it [8, 2, 9].


HNMT breaks down histamine bymethylating it. this, various blogs claim that people with high blood histamine are “undermethylators” and those with low blood histamine “overmethylators” [2].

The trouble here is that over- and undermethylation is unly to take place in all tissues and organs across the body at the same time. People may have low gut HNMT and normal brain HNMT. This doesn’t always make someone an over- or undermethylator; any individual’s reaction to histamine may be tissue or organ dependent [10, 11].

Additionally, several causes other than low HNMT activity/undermethylation can raise histamine, such as [12]:

  • Reduced DAO activity (the most common cause of histamine intolerance)
  • Higher histamine production, and
  • Increased histamine intake


DAO is the main histamine-degrading enzyme in the gut, connective tissues, placenta, and kidneys. This enzyme is released into the blood; it can, therefore, break down histamine found outside of the cells [13, 2, 14].

DAO also degrades other biogenic amines such as putrescine and spermidine [14].

Many sources claim DAO deficiency underlies histamine intolerance and sensitivity. This is possible, but it’s only one ly cause. To make matters worse, testing DAO in the blood tells us little about its activity in the gut [10].

Histamine Function & Receptors Overview

In the nervous system, histamine acts as a messenger molecule or neurotransmitter. It plays key roles in the sleep-wake cycle, appetite, motivation, learning, memory, and sexual behavior [1, 5, 6].

In the stomach, histamine stimulates acid secretion. In the rest of the body, histamine intensifies the immune response, contracts smooth muscles and airways, dilates blood vessels, and activates itch and pain-associated nerve cells. These resemble symptoms common to allergies and other conditions in which histamine is increased [5, 2].


On the surface of target cells, histamine binds to four specific histamine receptors – H1R, H2R, H3R, andH4R – which carry out its functions. Histamine often has opposing roles, depending on which receptor it activates [15].


  • H1R is mainly found in the brain, airways, blood vessels, and white blood cells [2].
  • In the brain, it increases wakefulness, reduces appetite, and increases thirst [2].
  • H1R activity can produce allergy symptoms, such as redness, itching, swelling, runny nose, airway constriction, anaphylaxis, pinkeye (conjunctivitis), and hives [2].


  • H2R is mostly found in the brain, stomach, white blood cells, heart, and other internal organs (smooth muscles) [2].
  • It relaxes smooth muscles in the blood vessels, uterus, and airways [6].
  • Activated by histamine, H2R inhibits both Th1 and Th2 immune responses, stimulates stomach acid secretion, increasesheart rate, and reduces bone density [1, 2, 5].


  • H3R is found mainly in histamine-releasing nerve cells in the brain and enterochromaffin- cells in the stomach [1, 15].
  • H3R prevents histamine release and often opposes the activity of other histamine receptors [2].
  • H3R activity promotessleep and reduces itching [2, 16].
  • In different parts of the brain, it also lowers acetylcholine, dopamine, serotonin, noradrenaline, GABA, and glutamate [1, 6, 17].
  • It promotes alcohol preference; that is, H3R activity may make you want a drink [18].


  • H4R is found in the bone marrow and white blood cells. It is also present in smaller amounts in the spleen, thymus, lung, small intestine, colon, and heart [6, 1].
  • It activates white blood cells involved in inflammatory responses [6, 1, 19].
  • H4R is also responsible for cytokine release (increases IL-17 and Th2 cytokines IL-4, IL-5, and IL-13) [1].


HDC codes for histidine decarboxylase, the enzyme that produces histamine. Some HDC gene variants are associated with allergic rhinitis [7].

Diamine Oxidase (DAO)

DAO codes for diamine oxidase, the enzyme that breaks down histamine in the gut and tissues. Here are some important DAOgene SNPs you can look into:

  1. rs1005390
  2. rs1049793
  3. rs17173637
  4. rs10156191
  5. rs1049742
  6. rs2052129
  7. rs2071517

In both rs10156191 and rs1049742, the T allele is associated with lower DAO activity, migraines, and sensitivity to NSAID painkillers (aspirin, ibuprofen). Two T alleles have a stronger association than one T allele [21, 22, 23].


The MS4A2 gene codes for a subunit of the IgE-receptor protein that affects allergic responses and is found on the surface of histamine-producing mast cells and [24].

Mutations in this gene are associated with asthma and fibromyalgia, inflammatory conditions with overactive mast cells [25, 26, 27, 28].

More About Histamine

This is the first post in a six-part series on histamine, histamine intolerance, and how to manage it. To learn more, click through the links below.

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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.

Source: https://selfhacked.com/blog/histamine/

DAO Deficiency and Histamine: The Unly Connection

What is Histamine? Definition, Function, Receptors & DAO

We live in a time when we can choose what to eat. But in our endeavour to be healthy, what are we doing to histamine levels? How is this affecting us?

For most of us, histamine is just another chemical compound that we associate with allergies.  It’s good for the most part but for others, a serious threat to their health and daily living.

But there is more to histamine than allergies.

In fact, histamine may be a factor to what triggered last night’s migraine, the upset stomach or the itch you’re having right now. On a molecular level, what is a superfood for one person might be poison to another.

This is where a thing called histamine intolerance comes in.

What does it do?

Although one of the main functions of histamine is associated with allergic reactions, it is also an in important neurotransmitter and immune messenger molecule. Histamine is stored in mast cells and subsequently released when these cells are activated.

Even though histamine is small compared to other biological molecules (containing only 17 atoms), it plays an important role in the body. It is known to be involved in over 23 different physiological functions and it’s all thanks to histamine’s flexible chemical binding structure.

When histamine is formed, it is broken down by specific enzymes. In the central nervous system, it is metabolized by histamine N-methyltransferase (HNMT), while in the digestive tract it is broken down by diamine oxidase (DAO).

DAO? What is that?

Diamine oxidase (DAO) is the major enzyme involved in histamine metabolism and is responsible for ensuring a steady histamine level required for the balance of numerous chemical reactions taking place in the body.

DAO is the key enzyme responsible for the degradation of extracellular (free) histamine, regardless of whether the histamine originates from allergy-induced processes in the body or is consumed with food.

What happens is histamine is degraded to imidazole acetaldehyde which, after methylation as a methylhistamine, is eliminated via the kidneys. This allows the body to retain optimal amounts of histamine all the time.

Histamine exerts its effects by binding to its 4 receptors: H1R, H2R, H3R, and H4R on target cells in various tissues. Histamine receptors are located all over the body and have many important functions including:

  • H1 receptors: Smooth muscle and endothelial cells affecting skin; blood vessels (Benadryl and Claritin block activity of these receptors)
  • H2 receptors: Cells in the intestines control acid secretion, abdominal pain, and nausea; heart rate
  • H3 receptors: Central nervous system controlling nerves, sleep, appetite and behavior
  • H4 receptors: Thymus, small intestine, spleen, colon, bone marrow and white blood cells; inflammatory response

The DAO gene is also involved in the metabolism of glutamate, an excitatory neurotransmitter found to be elevated in those with schizophrenia and bipolar disorders. ,,

I have a DAO SNP! What now?

Histamine becomes a problem when we have metabolic disturbances that do not allow us to effectively metabolize histamine properly specially for DAO. If DAO is inhibited, histamine will accumulate in the blood and would result in intolerance.

DAO deficiency can be caused by genetic factors (primary deficiency) when certain sequence variants (polymorphisms) in the DAO gene lead to a significantly reduced DAO enzyme activity. Individuals with a DAO gene mutation may have a tendency towards high histamine.

Having a polymorphism doesn’t mean you will have expression of the SNP and therefore histamine intolerance, but you are pre-disposed, particularly if your environment (food, stress, toxin exposure, gut function) are affecting the expression of the gene. In that case, given that histamine is present in our daily diet, we need to be careful what we’re consuming every day.

What to eat for DAO?

The DAO enzyme is dependent on vitamin B6, B12, iron, copper and vitamin C, so it makes sense to increase the intake of these compounds.

Copper and Vit C are crucial components of the DAO enzyme and B6 is a key cofactor that enables DAO to degrade histamine.

Copper deficiency is another possible cause for low DAO activity, as copper is a central atom of the DAO and thus essential for its function.

Because copper is essential to DAO function, copper levels should be monitored in patients with low DAO activity to avoid further DAO deterioration.

Zinc levels should be checked at the same time, as zinc prevents intestinal copper absorption.

DAO vitamins and minerals

  • Vitamin C is well-known for its antihistaminic working. In a lot of cases, blood histamine levels are directly correlated to the vitamin C levels, and intake of vitamin C will lead to less histamine in a matter of days. It functions as a cofactor of DAO, just vitamin B6 does. Vitamin C can be taken at doses of up to 3,000 mg to reduce histamine levels. Taking large amount of vitamin C is known as Megadosing.
  • DAO depends on vitamin B6 to function. If there is shortage of B6, the enzyme is practically useless. The intake of vitamin B6 often leads to a higher DAO activity. According to the NIH, doses of up to 2 mg should suffice for lactating mothers.
  • Magnesium is important in the histamine metabolism. A shortage increases the activity of histidine decarboxylase in some tissues. Histidine decarboxylase is the enzyme that makes histamine from histidine. While at the same time, a lack of magnesium intake leads to reduced DAO. The NIH recommends doses of up to 400 mg and Magnesium can be bought over the counter as 500 mg tablets.
  • Copper is another cofactor of DAO and able to reduce histamine levels. It’s not often recommended to supplement.
  • Zinc inhibits the release of histamine from mast cells. Supplementation is recommended.
  • Manganese also inhibits the release of histamine from mast cells much zinc.

Some individuals have altered DAO production due to a number of different factors including:

  • Small Intestinal Bacterial Overgrowth (SIBO): some gut microbes produce high amounts of histamines as a byproduct of their metabolism.
  • Leaky Gut Syndrome: Intestinal permeability creates major inflammatory stress in the body which can contribute to poor DAO function.
  • GI inflammatory conditions: Crohn’s, Inflammatory bowel disease (IBS), colitis
  • Celiac disease and those with gluten intolerance
  • Certain drugs: NSAIDs, acid-blocking medications, anti-depressants, immune suppressants.

Many different diuretics, hormone replacement drugs, statins (and others) reduce the amount of these nutrients, causing “medication induced SNP.” This kind of SNP can happen in the absence of an actual gene SNP, because the medication is acting worse than the homozygous polymorphism.

Drugs that influence DAO

The changed production of DAO enzyme can be as a consequence of certain medications:

  • Non-steroidal anti-inflammatory drugs (ibuprofen, aspirin)
  • Antidepressants (Cymbalta, Effexor, Prozac, Zoloft)
  • Immune modulators (Humira, Enbrel, Plaquenil)
  • Antiarrhythmics (propanolol, metaprolol, Cardizem, Norvasc)
  • Antihistamines (Allegra, Zyrtec, Benadryl)
  • Histamine (H2) blockers (Tagamet, Pepcid, Zantac)

Some studies suggest considering the herb HOPS and quercetin (about 250 to 500 mg taken three times daily) in order to reduce histamine levels.

What to eat when you’ve got SNP in your DAO

No matter our intake of different supplements, medications or drugs, the most important thing in the end is how we behave with our body and what we are consuming to make it better.

Before you decide to take the next step (through pills), try directly going on a low-histamine diet first. Some foods naturally have more histamine content while others accumulate histamines while they age. Fermented and dried foods typically have the highest levels of histamines.

A low histamine diet must be focused around getting foods at their peak level of freshness.

Foods High in Histamines:

Here is a list of high histamine foods:

  • Fermented alcoholic beverages, especially wine, champagne and beer
  • Fermented foods: sauerkraut, vinegar, soy sauce, kefir, yogurt, kombucha, etc.
  • Vinegar-containing foods: pickles, mayonnaise, olives
  • Cured meats: bacon, salami, pepperoni, luncheon meats and hot dogs
  • Soured foods: sour cream, sour milk, buttermilk, soured bread, etc.
  • Dried fruit: apricots, prunes, dates, figs, raisins
  • Most citrus fruits
  • Aged cheese including goat cheese
  • Nuts: walnuts, cashews, and peanuts
  • Vegetables: avocados, eggplant, spinach, and tomatoes
  • Smoked fish and certain species of fish: mackerel, mahi-mahi, tuna, anchovies, sardines
  • Processed foods of all types – Preservatives are high in histamines

Histamine-Releasing Foods:

These foods do not necessarily contain histamine but they block the action of DAO and therefore they potentiate the effects of elevated histamines.

  • Alcohol
  • Bananas
  • Chocolate
  • Cow’s Milk
  • Nuts
  • Papaya
  • Pineapple
  • Shellfish
  • Strawberries
  • Tomatoes
  • Wheat Germ
  • Many artificial preservatives and dyes

DAO-Blocking Foods:

  • Alcohol
  • Energy drinks
  • Black tea
  • Mate tea
  • Green tea

Low Histamine Foods:

  • Freshly Cooked Meat & Poultry
  • Freshly Caught Fish
  • Extra Virgin Olive Oil
  • Pasture-Raised Eggs
  • Gluten-Free Grains: brown rice & quinoa
  • Fresh Fruits: Other than citrus, avocado, tomato, pineapple, bananas and strawberries
  • Fresh Vegetables (except spinach and eggplant)
  • Coconut milk, Rice milk, Hemp milk, Almond milk
  • Coconut oil & Grass-fed Butter/Ghee
  • Organic coffee
  • Almond butter
  • Leafy herbs
  • Herbal teas

Take note: some high histamine foods offer lots of health benefits so it is wise if you were to consider having a well-balanced diet but with low histamine foods prioritized.


  1. Histamine and histamine intolerance, Laura Maintz and Natalija Novak 2007 American Society for Clinical Nutrition
  2. Histamine Intolerance in Clinical Practice Laura Maintz, Thomas Bieber, Natalija Novak
  3. The Differential Diagnosis of Food Intolerance Zopf, Y; Baenkler, H; Silbermann, A; Hahn, E G; Raithel, M Dtsch Arztebl Int 2009; 106(21): 359-69; DOI: 10.3238/arztebl.2009.0359
  4. Allergies and Your Genes – Histamine, Autoimmunity and DAO SNPs, Suzy Cohen (http://suzycohen.com/articles/histamine_intolerance_dao_genes_hashimotos/)
  5. Histamine intolerance, IMD Labor Berlin-Potsdam(http://www.imd-berlin.de/en/special-areas-of-competence/food-intolerances/histamine-intolerance.html)

Source: https://mthfrsupport.com.au/2016/09/dao-deficiency-and-histamine-the-unlikely-connection/