The Low-Down on Histamine

Histamine is an organic molecule produced in the body that is involved with immune response, gastric acid production, vasodilation, cardiac stimulation, and most smooth muscle contraction (ileum, bronchi, and uterus) or acting as a neurotransmitter in the brain. It is derived from the decarboxylation of the amino acid histidine via the enzyme L-histidine decarboxylase with B6 as a cofactor.

Most histamine is generated, stored, and released by mast cells or basophils as part of an immune response against foreign invaders, but non-mast cell histamine is found in the brain where it functions as a stimulatory neurotransmitter. As a neurotransmitter, it is involved in regulating aspects of the sleep/wake cycle, body temperature, appetite, mood, learning, memory, homeostasis of the endocrine system, pain sensitivity, libido (sexual desire and arousal), encoding and processing harmful stimuli in the nervous system, and regulating the release of serotonin, dopamine, and norepinephrine. It counterbalances dopamine levels. Histamine is also produced by enterochromaffin-like cells in mucosa underneath the epithelium, where it plays a role in the stimulation of hydrochloric acid and pepsinogen (pepsin) and it is also what causes tears to flow.

Histamine Receptors

Histamine exerts its effects by acting on H1, H2, H3, and H4 receptors. Histamine is synthesized all over the body, but it is more highly concentrated in the lungs, gastrointestinal tract, and skin. The action exerted depends on which type of receptor that histamine reacts with and the receptor it interacts with depends on where histamine is released.

H1 receptors are located in most smooth muscles (ileum, bronchi, uterus,) endothelial cells (blood vessels), and the brain. (Critical for the sleep-wake cycle e.g sleepiness or insomnia. Associated with motion sickness, vasodilation, hives, bronchoconstriction, hay fever, seasonal allergies, and possibly increased peristalsis with food allergies.)

H2 receptors are located d in gastric parietal cells, heart, uterus, and vascular smooth muscle. (Associated with gastric acid production, heart rate, cardiac output, abdominal pain, nausea, gastroenteritis, ulcers.) H2 receptors are also found on neutrophils where they can inhibit the production of antibodies and cytokines.

H3 receptors are located in the central nervous system. (Modulate neurotransmission and the synthesis of histamine.)

H4 receptors are located in mast cells, thymus, spleen, bone marrow, colon, small intestine, and basophils. (Associated with the inflammatory response, regulating white blood cell release from bone marrow.)

Histamine Balance

Problems with abnormally high levels of brain histamine (known as histadelia), were first presented to us by Dr. Carl Pfeiffer in his book Nutrition and Mental Illness many years ago. It can lead to headaches and migraines, anxiety, insomnia or disrupted sleep, hyperactivity, attention deficit, depression, obsessive-compulsive tendencies, high libido (excessive sexual arousal and desire), sexual addiction, gambling addiction, abnormal fears, a racing brain, crying easily, aggressiveness and schizophrenia. Alcohol, heroin and other narcotics block histamine, providing some temporary relief from the high histamine symptoms, thus why many high histamine people become addicted to drugs and alcohol.

Low levels of brain histamine, also made known to us by Dr. Pfeiffer and referred to as histapenia, may result in paranoia, ear ringing, visual or auditory hallucinations, fatigue, low libido, sensitivity to medications, irritability, and grandiose plans without the energy to see them through. If histamine is too low, then dopamine levels become elevated and high levels of dopamine can produce many psychological disturbances. Histamine levels are found to be lower in the brains of people with Alzheimer’s and elevated in people with Parkinson’s.

High histamine in other parts of the body produces watery eyes, runny nose, congestion, sneezing, wheezing, itching, hives, inflammation, gastrointestinal disturbances (e.g. nausea, vomiting), heart palpitations, fainting, changes in blood pressure (up or down), and motion sickness to name a few. While too little could lead to insufficient gastric acid secretion that could contribute to microbial overgrowth and gastrointestinal problems.

So like all things in the body, the key is balance; too much or too little histamine will lead to negative effects. However, it seems that excess histamine is a more common problem than low, so that is what we will focus on the most in this discussion.

Histamine Producing Bacteria

Some types of bacteria have the ability to convert the amino acid histidine into histamine as well, so when they are present on certain foods, they may generate histamine. If the level of histamine they create on the food is high, it can lead to excessive levels of histamine within the body in susceptible people when the food is eaten and often referred to as histamine intolerance. A variety of different strains within the following species of bacteria may produce histamine. Lactobacillus, Clostridium, Escherichia coli, Staphylococcus, Streptococcus, Klebsiella, Morganella, Enterobacter, Proteus, Acinetobacter, Pseudomonas, Aeromonas, Vibro, Plesisomanas, Pediococcus, and Micrococcus. If the level of some of these bacteria in your colon that have this ability is elevated or those bacteria have migrated to the small intestine as is the case in SIBO, then they may produce an excess of histamine.

It is believed that histamine intolerance is caused by insufficient levels of an enzyme called diamine oxidase (DAO) that breaks down histamine and when too many high histamine foods are eaten, it causes an excess of histamine that may lead to a wide variety of symptoms like migraines or vascular headaches, gastrointestinal disturbances (constipation, diarrhea, flatulence, distention, heartburn, indigestion, acid reflux), fatigue, throat tightening, autonomic nervous system dysregulation, dizziness, restless leg syndrome, joint and muscle pain, hiccups, low blood pressure, anxiety or panic attacks, heart racing, nasal congestion, runny nose, itching of eyes, ears and nose, hives, watery and red eyes, tinnitus, and on rare occasion a loss of consciousness for brief periods and much more. One of the most common symptoms is flushing, known as a histamine flush. This feels similar to a hot flash. A wave of heat flushes through the body, usually beginning at the waist area and traveling up to the top of the head. It may also just present in the chest, neck, or face area and may be accompanied by a red and prickly rash.

Reducing the consumption of foods that are high in histamine can provide significant relief from symptoms. However, diamine oxidase is produced by enterocytes (cells) in the small intestine. Therefore, one of the factors that can cause a deficiency in diamine oxidase is damage to the small intestine caused by small intestinal bacterial overgrowth (SIBO), Candida, or other microbes. If the gut is damaged, then DAO may not be secreted in sufficient amounts.

Furthermore, since some species of bacteria can convert histidine into histamine, the overgrowth of these types of bacteria in the gastrointestinal tract itself can contribute to higher levels of histamine within your body, as they will convert the histidine in your diet into histamine. So when you have bacterial overgrowth in the small intestine, your histamine levels may already be elevated, and then when foods that are high in histamine are eaten, then it becomes even more excessive. When that is the case, then histamine intolerance may improve, if one achieves some healing in the gut and reduces the level of microbial overgrowth.

From what I have experienced in my own life and witnessed in my clients’ lives, SIBO is one of the leading causes of high histamine or histamine intolerance. The more severe the overgrowth, the worse the histamine issue becomes.

After some healing has taken place, then one may try to bring some high histamine foods back into the diet slowly and see how they do. However, until the gut and bacteria issues are resolved, then high histamine foods need to be limited. On the other hand, even if you are producing enough of these enzymes, if you’re eating a diet high in histamines and have Candida or bacterial overgrowth, the enzymes may not be able to keep up with the level of histamine that is present. Intolerance develops when there is an imbalance between what’s coming in and the ability to break it down. Furthermore, the pH of the gut is important for both high or low histamine, because histamine release in the gastrointestinal tract is inhibited when the pH of the gut is too low, which means the production of hydrochloric acid will be impaired.

However, a deficiency in DAO can be caused by a variety of other factors like a genetic polymorphism that impairs one’s ability to produce the enzyme, low levels of copper and vitamin C which are needed for the production of the enzyme, or B6 which is needed as a cofactor with DAO to break down histamine, and impairment of the lymphatic system which carries the enzyme into circulation. Therefore, in some cases, like a genetic polymorphism in the gene for the enzyme itself, histamine intolerance will be lifelong, and limiting high histamine foods will be needed ongoing.

Furthermore, DAO is not the only mechanism used by the body to break down histamine, it is also achieved by another enzyme called N -methyltransferase (HMT) and the methylation process. In most tissue throughout the body, histamine is deactivated by DAO or N-methyltransferase. However, in the central nervous system, it is deactivated with N-methyltransferase only, because DAO is not found in the central nervous system. Therefore, high brain histamine (histadelia) is generally a biochemical imbalance with this enzyme and the methylation process, particularly under-methylating. In people who have low brain histamine, then it is believed to be due to over-methylation. However, HMT is also produced by enterocytes in the small intestine, so bacteria or Candida or anything contributing to a damaged gut could affect this enzyme as well.

Additionally, when a leaky gut is present due to this damage to the gut, then histamine can get into the bloodstream without being acted upon by DAO or HMT. Furthermore, histamine is released when undigested food particles escape through the leaky gut into the bloodstream and the immune system goes after them, so the leaky gut itself can generate higher levels of histamine. Plus, the toxins released by Candida or bacteria can also incite the release of histamine, thus making the histamine load even higher. Each time the immune system launches an attack against the toxins, protein, or microbe then inflammation is generated, which then perpetuates the whole cycle. Additionally, Sara Ballantyne, author of The Paleo Approach, explains that if basal cells are activated because of an autoimmune disorder or environmental allergy, then one’s baseline level of histamine may be elevated, which would make one more susceptible to histamine in their food.

Since methylation can be impaired by Candida, bacteria, and other microbes, then SIBO or Candida overgrowth could potentially contribute to histadelia or histamine intolerance in this manner as well, but methylation is a very complex issue that can have many contributing factors like deficiencies in nutrients like folate, B12, B6, magnesium or SAMe, a mutation in the MTHFR gene or other polymorphisms in the HNMT gene (codes for the enzyme N-methyltransferase) itself. Therefore, histadelia (high brain histamine) may also require an ongoing restriction of high histamine foods as well as a variety of other nutritional supplements like methionine to correct the imbalance in methylation.

Additionally, since both enzymes needed to break down histamine (DAO and HMT) are produced within enterocytes, then other things that damage the gut besides bacteria and Candida could be potential contributors and should be avoided as well to promote healthy enterocytes, like caffeine, wheat, and other grains, legumes, alcohol, NSAIDS, chlorinated drinking water, proton pump inhibitors, etc.

A mutation in histidine decarboxylase, the gene that encodes for the enzyme L-histidine decarboxylase that is needed to synthesize histamine, is possible as well; which could result in low levels of histamine. This mutation has been found to be associated with Tourette’s. The bacteria known as H pylori can also inhibit DAO.

High Histamine Foods

Some of the foods that are high in histamine will already be eliminated when one is following the basic Paleo principles as I encourage, which include alcoholic beverages, cured meats, coffee, chocolate, cocoa, soy products, peanuts, and some other legumes, wheat; and other foods that release histamine like wheat germ, food additives and preservatives like nitrates, food dyes, benzoate, sulfites, and yeast; or substances that inhibit DAO like green tea, black tea, mate tea, and energy drinks. However, there are quite a few foods that are Paleo or Primal friendly that may be high in histamine or stimulate the release of histamine, which includes the following:

• Kefir
• Cultured vegetables
• Bone broth
• Yogurt (depending on what bacteria present)
• Sour cream
• Vinegar (and foods that contain vinegar like olives, mayonnaise, and pickles)
• Anything cured or fermented
• Dried fruit
• Grapes
• Aged cheese
• Walnuts
• Cashews
• Avocados
• Eggplant
• Spinach
• Tomatoes
• Olives (However, olive oil contains less, so might be tolerated by some. Additionally, olive oil can increase the DAO enzyme, so not black and white. Can test and see how you do. Olives in any form give me a histamine reaction, but may not in someone with a lower level.)
• Pork
• Chicken liver
• Chicken skin and bones (use boneless and skinless). I’ve also found that thighs are higher than breasts.
• Beef liver
• Some species of fish are more prone to histamine (mackerel, mahi-mahi, tuna, anchovies, herring, sardines, shellfish, or any fish that is stored for extended periods of time, including those in the can)
• However, most other forms of fish or seafood in general have the potential as well, depending on how it is handled and processed.
• Kelp and other sea vegetables or seaweed, algae
• Smoked fish or smoked meats
• Leftovers (particularly meat.) The longer the leftover meat sits, the more histamine will accumulate.
• Anything that utilizes microbial fermentation

Alcohol contains histamine and it inhibits the DAO enzyme and feeds bacteria and Candida overgrowth.

Make sure your meat is fresh or frozen. Meat accumulates histamine the longer it sits without being frozen. Check the expiration date on your meat products when buying fresh and don’t eat any that has an impending expiration date. Frozen is a better option, but this can vary from manufacturer to manufacturer depending on how the meat was handled when it was processed. If it was frozen immediately after processing, or if there was a long period before the meat made it to the freezer, its histamine content will be affected. You may be able to eat meat from some producers but not others, depending on their procedures. You may have to experiment with many different brands to find one that is tolerable for you.

The following foods can cause histamine to be released.

• Bananas
• Pineapple
• Papaya
• Strawberries
• Raspberries
• Shellfish
• Most nuts
• Egg white (when raw)
• Pumpkin (and its seeds)
• Most other berries
• Citrus (oranges, tangerines, mandarin, lemon, lime, grapefruit, kumquat, tangelo)
• Thyme
• Cinnamon, chili powder, cloves, anise, nutmeg, curry powder, cayenne
• Anything with benzoates or sulfites
• Fat ( but you don’t want to get rid of fat, so just moderate it to whatever level is comfortable)

Tyramine and Histamine

Most people who are sensitive to histamine are also sensitive to tyramine, a by-product of tyrosine breakdown, which produces similar symptoms as excess histamine. Many of the foods that are high in histamine are also high in tyramine. These include all fermented, pickled, or cured foods, aged cheese, fish, aged meat, all nuts and seeds, avocado, and citrus fruits. Other foods high in tyramine include olives, yeast extracts, sweet potato, potato, and pineapple.

Cooking Methods and Histamine

Grilling, frying, and cooking for long periods (slow cooking) increase amines and glutamate. Boiling does not. And some people find that cooking at lower temperatures is helpful. I find that I must keep my cooking length at no longer than 1 hour and 15 minutes. I do best with boiling.

Probiotics that Increase Histamine

As mentioned previously, there are a variety of bacteria that can produce histamine and some of these species are commonly found in the most popular and widely used probiotic supplements or probiotic foods. If one has high histamine, it would be best to avoid probiotics that contain these.

• Lactobacillus casei
• Lactobacillus reuteri
• Lactobacillus bulgaricus

The following bacteria degrade histamine, so they can be used to help lower one’s histamine level. However, do be aware that Bifidus can be a bully sometimes too and can try to take over and become overgrown as well if Lactobacillus is not present in sufficient amounts.

• Bifidobacterium infantis
• Bifidobacterium longum
• Lactobacillus plantarum
• Some soil based organisms

The following bacteria are neutral

• Streptococcus thermophiles
• Lactobacillus rhamnosus (down-regulates histamine receptors and up-regulates anti-inflammatory agents)

Other Factors that Increase Histamine

There are a variety of other factors that can elevate histamine levels which include the following:

Drugs
There’s an array of drugs that can inhibit the activity of DAO, which include some NSAIDs like ibuprofen and aspirin; antidepressants like Cymbalta, Zoloft, Effexor, and Prozac; muscle relaxants; diuretics; histamine 2 blockers like Tagamet, Pepcid, and Zantac; antihistamines like Allegra, Zyrtec, and Benadryl; immune modulators, antiarrhythmics; local anesthetics; antihypertensives, and others.  The supplement n-acetylcysteine (NAC).

High-Intensity Exercise
High-intensity exercise, particularly when done in a warm environment, can trigger the release of histamine.

Sunshine
Research indicates that ultraviolet light can stimulate the release of histamine. People who feel they are “allergic” to the sun are most likely having a histamine response. If you sneeze when you look towards the sun, this is also a sign. Heat, with or without the sunshine stimulates release as well.

High Estrogen
People with elevated levels of estrogen (estrogen dominance) may have a higher level of histamine response.

Stress
Stress increases histamine and decreases the body’s ability to metabolize it.

Niacin
Causes the release of prostaglandin D2 and histamine.

Hypothyroidism and Hyperthyroidism

Both hypothyroidism and hyperthyroidism can increase histamine levels. Low thyroid may increase MAST cells (cells that produce histamine) and thus more histamine production. While high thyroid levels may increase histamine receptors resulting in a heightened histamine response.

Histamine Threshold

The level of histamine that is present in each type of food can vary dramatically, depending on how it was handled and processed and some foods are more prone to histamine build-up than others. For example, bacteria colonize the gut of fish as soon as it dies. If the fish is not gutted soon after the catch, the fish will be high in histamine. Histamine will continue to build until they are cooked or frozen, especially if they are not kept cool enough before cooking. Many reactions to fish that are believed to be an allergy are a reaction to histamine.

Additionally, histamine intolerance can vary in severity from one individual to another, depending on a variety of different factors like the level of DAO or HMT one is producing, the level of bacterial overgrowth involved, whether genetic polymorphisms or autoimmune disorders are present, the health of the gut, methylation function, or how much was ingested. Not only that, one’s threshold for histamine can also waver from day to day depending on these same factors and anything else that might have been consumed or engaged with that affected histamine levels like stress, pollens, exercise, and sunshine. You may be able to eat a particular high histamine food at certain times of the year, but incapable if it is hot and you are in the sun, or being exposed to pollens, or experiencing a high-stress event.

One person may only have problems with foods that are exceptionally high in histamine, while another may not be able to tolerate any of them. Sometimes it’s a matter of accumulation; you may have no problems with one high histamine food, but be pushed over your threshold if three are eaten in that same day. Additionally, you may be able to consume a high histamine food by adjusting the serving size. For example, in my own life, I can’t do kefir, bone broth, or chicken liver due to their histamine and glutamate content. However, I can do a little strawberry and yogurt. I can’t eat half of an avocado or I get a migraine, but I can do 1/4 of an avocado without symptoms. Therefore, just because one has high histamine does not mean they will have problems with all the foods on the list or completely avoid the food. The oil from a food may be lower in histamine than the food itself, so some people may be able to do oils from high histamine foods, where the very sensitive ones cannot.

Additionally, since histamine is produced naturally in the body from histidine, which is an amino acid that will be present in animal protein, and bacteria can convert the histidine into histamine, it is possible when histamine is excessively high from bacterial overgrowth or foods high in histamine, that animal protein could contribute to the problem. If that is the case, then one could experiment with the serving size of animal protein, but I certainly wouldn’t recommend removing this from the diet. In most cases, reducing Candida and bacterial overgrowth and anything else that damages the gut, improving methylation, and avoiding the high histamine foods will be sufficient and that is primarily where the focus should be directed.

Since many of the high histamine foods can be beneficial for our health, one does not necessarily want to eliminate all of them without testing to see how their body responds and then adjusting accordingly. Furthermore, since conditions can change over time, then one will want to re-access how they are responding to them periodically to see if some of them can be reintroduced.

A variety of nutritional supplements may be used to reduce histamine levels depending on the underlying problems. For example, methionine, calcium, and magnesium are often used to address high histamine caused by undermethylation. Vitamin C has a mild antihistamine effect, so it can be used to help alleviate symptoms. Flavonoids (molecules found in some plant foods) like quercetin, have been found to inhibit the release of histamine and pro-inflammatory cytokines in mast cells. There are DAO supplements on the market that some people find to be helpful, but do keep in mind this would only apply to the situation where DAO is the sole problem; this would not address all the other issues that can cause high histamine that we discussed. If one is experiencing a severe histamine reaction, then a pharmaceutical-based antihistamine could be used, but naturally, these are not something we want to use on a daily basis, as it would perpetuate the problem since they inhibit the DAO enzyme. Additionally, anti-histamines also block the action of another neurotransmitter, acetylcholine, which is critical for brain function and regulation of the autonomic nervous system.

If brain histamine is low, then a high protein diet would be necessary to help bring it up. Additionally, low histamine is usually accompanied by high copper. Since copper is one of the nutrients used in the degradation of histamine, if copper is high then histamine will be broken too much. Then the low histamine levels encourage more build-up of copper. Supplements that can help balance copper levels and increase histamine include zinc, manganese, niacin (B3), and Vitamin C. However, other steps may be needed to address high copper, which you can learn more about on my copper toxicity page. Additionally, research suggests that people with type A blood are more prone to sequestering copper.

As you can see, it is critical for your physical, emotional, and spiritual health to keep histamine in balance and important to understand all the interconnected facets that may be involved and need to be addressed.

Histamine Testing

There are a variety of different tests one may use when assessing histamine levels, but it depends on which factor you are wanting to investigate.

A genetic test would be needed to evaluate whether there are mutations in genes that are associated with the DAO enzyme, the N-methyltransferase gene, the MTHFR gene, or other genetic problems with methylation.  However, it’s important to be aware that just because one has a genetic vulnerability doesn’t mean it will always be expressed. Sometimes there is an inciting incident that sets it off, like exposure to an environmental toxin, a high-stress event, trauma, a chronic health condition, SIBO, degradation of the gut, adrenal fatigue, or others.

There’s a lab test that can analyze the ratio of histamine to DAO. A high histamine to DAO ratio would indicate that the DAO level is not sufficient for handling the histamine level.

A blood histamine test can identify high or low levels.

Testing copper levels could also be beneficial; if copper is high, then histamine is probably low.

However, by far, the easiest, most affordable, and effective way to assess whether your histamine is low or high is by your symptoms. A histamine challenge test, which is accomplished simply by consuming high histamine foods and monitoring your response, and then trying a low-histamine diet to see if it relieves some of those symptoms can provide a very clear indication if you are high in histamine or intolerant. Alternatively, you can do an elimination diet, where you simply remove the high histamine foods and see if symptoms improve, and then reintroduce them one at a time to see if symptoms reappear.

Furthermore, I can administer a very simple screening questionnaire that can provide a strong indicator of whether histamine is low or high, which can help you decide whether more lab testing would be advisable. Contact me today for a consultation if you’re interested.

References

Laura Maintz and Natalija Novak, Histamine and Histamine Intolerance. The American Journal of Clinical Nutrition 2007;85:1185–96.

Are You Suffering From Histamine Intolerance? (organiclifestylemagazine.com)

The role of histamine in food allergy, intolerance, and mood control. (foodsmatter.com)

R. Bowen. Enterochromaffin-Like (ECL) Cells. Coloroda State University. January 31, 2003
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Histamine and Histamine Receptors
https://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/otherendo/histamine.html

Histamine Receptors. University of Bristol
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HNMT histamine N-methyltransferase [ Homo sapiens (human) ]
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Brown DD, Tomchick R, Axelrod J (November 1959). “The distribution and properties of a histamine-methylating enzyme” (pdf). J. Biol. Chem. 234 (11): 2948–50. PMID 13804910.

Sarah Ballantyne, Ph.D. The Paleo Approach: Reverse Autoimmune Disease and Heal Your Body. Victory Belt Publishing; 1 edition (January 28, 2014)

Laura Maintz and Natalija Novak. Histamine and histamine intolerance. Am J Clin Nutr May 2007 vol. 85 no. 5 1185-1196

Castellan Baldan L, Williams KA, Gallezot JD, et al. Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. Neuron. 2014 Jan 8;81(1):77-90. doi: 10.1016/j.neuron.2013.10.052.

Park HH, Lee S, Son HY, Park SB, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct;31(10):1303-11. doi: 10.1007/s12272-001-2110-5. Epub 2008 Oct 29.

Joan Mathews Larson. Depression Free Naturally.  Wellspring/Ballantine (January 2, 2001)

https://jpet.aspetjournals.org/content/327/3/665

The Thyroid-Histamine Connection – Dr. Becky Campbell

https://orthomolecular.org/library/jom/2002/pdf/2002-v17n01-p017.pdf