High histamine: what it does and why it’s so complicated

Histamine is an amine; a biologically active molecule based on the structure of ammonia (NH3). It’s formed by the decarboxylation (the removal of a carboxyl group) of the amino acid histidine.

The highest concentrations of histamine are found in the intestinal mucosa, skin, and bronchial tissues. Basophils and mast cells secrete histamine as part of a local immune response when your body detects a foreign invader. These cells reside in connective tissue and act as potent effector cells of the innate immune system.

Mast cells are the major producer of histamine and express many receptors on their surface. These receptors are activated through stimulants such as allergens, complement peptides, and neuropeptides, which cause the mast cells to release various inflammatory mediators including histamine.

Histamines play a crucial role in protecting your body from potentially harmful invaders. They act like armed guards, sounding the alarm to let your body know that something foreign has entered and that it needs to be attacked. This causes your immune system to respond with inflammatory chemicals that help get rid of the invader - known as an allergen - that’s bothering you.

When produced during a local immune response, histamine’s main role is to cause inflammation. Its release causes your capillaries to become more permeable to white blood cells and other proteins, which allows the white blood cells to target and attack foreign bodies in the affected tissue.

This inflammatory response is designed to help protect the body against pathogens. Your immune system sees these things as a threat and responds. If it has encountered a particular substance before, it immediately recognizes it as a trigger and launches a chain reaction to defend you.

Histamine also has a few other important functions in the bowel and is also known to act as a neurotransmitter (chemical messenger). It’s also involved in the secretion of gastric acid, inflammation, and the regulation of vasodilation and bronchoconstriction.

While your body’s objective is to keep you safe from what it believes could be harmful, these allergic reactions can be quite difficult to bear.

1. You encounter the trigger (pollen, dust, food, chemical, etc.). 
2. Your immune system recognizes the ‘invader’ and sends a chemical signal to your mast cells in your skin, lungs, nose, mouth, gut, and blood. The message is: “Send out histamines!”
3. The histamines leave the mast cells and increase the flow of blood to the affected area of your body. 
4. The increased blood flow causes inflammation, alerting even more chemicals in your immune system to head to the site and start repairing any damage. 
5. Histamines then dock themselves at their respective histamine receptors.

If you’ve breathed in the allergen, histamines will lodge themselves in your nose, causing the membranes lining your nostrils to make more mucus. This leads to a runny or stuffy nose, along with sneezing. The inflammation will also irritate your throat and chest, causing you to cough or make breathing more difficult. Histamines can also make your eyes watery and itchy.

When histamine is present in your bloodstream, it can affect your gut, lungs, skin, brain, and entire cardiovascular system. This results in a variety of unpleasant symptoms. It can also make it difficult to pinpoint histamine as a cause of the symptoms, which complicates the diagnosis.

In most cases, histamine is broken down by enzymes in your body, which prevents it from building up. But if these enzymes aren’t working properly histamine quickly accumulates. This can lead to histamine intolerance.

Because histamine plays so many different parts in how your body functions, symptoms of an intolerance are broad and can easily be confused for other things, such as food allergies.

According to Dr. Ben Lynch, there are numerous causes for histamine intolerance, including:

• Genetic susceptibility (MTHFR, DAO, MAO, HNMT, PEMT)
• Pathogens (a number of which produce histamine or block methylation)
• Nutrient deficiencies (B12, folate, B6, B2, B1, Zn, Cu, C, methionine)
• Nutrient excesses (histidine, excess of protein in the diet)
• Medications
• Nutrient demands (stress, anxiety, lack of sleep)
• Hormonal insufficiency (adrenal fatigue)
• Hormonal excess (estrogen)
• Lifestyle (excessive exercise, alcohol)
• Diet (fermented foods, aged foods, citrus, fish)
• Environment (pollen, mold, mildew, dust mites)
• Gastrointestinal conditions (leaky gut syndrome, IBD, IBS)

One prevailing theory for high histamine is that symptoms are made worse due to sensitivity. If your tolerance level for histamine is naturally low, you might react when you eat or drink something containing histamine.

In other words, your symptoms can be brought on by eating high histamine foods, or foods that trigger the release of histamine.

Histamine levels in foods increase with maturation, which means those most likely to cause a reaction have been fermented in some way. This includes aged cheeses, yogurt, kefir, sauerkraut, processed meats, aged meats, and alcoholic drinks such as wine, champagne, and beer. Reactions also appear to correlate with the degree of processing.

• Alcohol
• Eggplant
• Pickled or canned foods, including sauerkraut
• Matured cheeses
• Smoked meat products (salami, ham, sausage)
• Shellfish
• Beans and pulses (chickpeas, soy)
• Long-stored nuts (peanuts, cashew nuts, almonds)
• Chocolates and other cocoa-based products
• Seitan
• Rice vinegar
• Instant meals
• Snacks and sweets with preservatives and artificial additives

As mentioned above, a specific enzyme is required for your body to process histamine properly. If something is preventing your body from doing this, or the enzymes aren’t as active as they should be, you may end up with higher than desirable histamine levels.

The three main genes involved in processing histamine include:

• HNMT – which requires SAMe as a cofactor (and this requires an effective MTHFR enzyme to help produce SAMe)
• DAO – which requires vitamin B6 and copper
• MAO – which requires vitamin B2 and iron
• NAT2 – which requires CoA which stems from vitamin B5

If any one of these genes is slowed or burdened, then the removal of histamine is slowed – and symptoms of histamine intolerance occur.

The main enzyme required for helping your body metabolize histamine in foods is diamine oxidase (DAO). DAO is produced in the mucosa of your small intestine and then moves into your bloodstream.If the amount of ingested biogenic amines is high and/or they can’t be broken down in the body, histamine levels can cause multiple gastrointestinal (GI) symptoms.

It has been suggested that DAO is secreted to scavenge extracellular histamine leftover from a release. If DAO activity is reduced, histamine will not be broken down properly, resulting in numerous allergy-like symptoms. For this reason, histamine intolerance is thought to be caused by a DAO deficiency.

One of the many functions of histamine in the body is to act as a neurotransmitter, where it helps regulate important brain functions such as alertness, attention, learning, memory, stress response, sleep-wake cycles, and sexual function.

When histamine levels are out of balance, mood and behavioral problems can result. It’s been found that those with high histamine levels often experience mood disorders such as hyperactivity, obsessive-compulsive behavior, panic, anxiety, and depression.

Mast cells in the brain contain granules of histamine along with numerous mediators that are released in response in certain situations, particularly stress. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states, which suggests that they can influence neural systems underlying behavior.Histamine has four kinds of receptors: H1R, H2R, H3R, and H4R. The first three of these are present in the brain. H1 and H2 receptor-mediated actions are mostly excitatory, while H3 receptors act as inhibitory auto- and heteroreceptors. These receptors interact with other transmitter systems involved in brain functions such as sleep-wake regulation, circadian rhythm, appetite, immunity, learning, and memory in health and disease.

Animal studies have suggested that histamine may be implicated in anxiety disorders. One study showed that mice without mast cells had greater anxiety-like behavior than mice with normal mast cells. But when mast cell activation was blocked, the researchers noticed an increase in anxiety-like behavior. It appeared that a mast cell deficiency caused a reduction in the levels of histamine in the mice’ brains, which led the researchers to suggest that central mast cells are involved in the modulation of anxiety-like behavior.

This finding may highlight the influence of histamine in the brain. It may also explain why people with mast cell-related conditions such as inflammatory bowel disorders and food allergies tend to have higher levels of anxiety. It’s also known that antihistamines can affect mood, causing irritability, sleep disturbances, and grogginess.

Further to the psychiatric influence of histamine is its involvement in the methylation process. It’s now known that defects of the MTHFR gene can result in a malfunctioning MTHFR enzyme, which can result in imbalances in methylation status. MTHFR helps regulate methylation which is needed to reduce intracellular histamine.

Histamine levels correlate with the functionality of the methylation process. In other words - if your histamine levels are low, you may be ‘overmethylated’. If your histamine levels are high, you will be undermethylated.

Research suggests that a MTHFR mutation that compromises your body’s ability to carry out methylation can lead to a buildup of excess histamine.

• Diet
  A histamine-free diet is your first step. Cut out fermented and processed foods, citrus, alcohol, aged foods, and cheeses. Increase the intake of healthy fats such as fatty fish, avocado, and nuts. 
• DAO supplementation
  One study showed that when high-histamine patients took DAO supplements before meals, their symptoms improved significantly.
  Avoiding DAO-blocking foods is also advised.
• Methylation support
  Many mental health conditions (particularly depression) can be effectively treated with supplementation of the right vitamins, minerals, and amino acids. Methyl-Life’s™ Methylfolate 15 best-selling product contains a high dose (15 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. This highly-recommended product is formulated specially for people with a heightened need for bioavailable folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.). This product is particularly targeted at raising serotonin levels which can aid in depression and mood-related challenges.

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