~ Histamine intolerance is caused by an imbalance of too much histamine in the body that overwhelms your capacity to break it down.
~ The imbalance of histamine can be caused by your body producing too much histamine or by not being able to break down histamine from foods properly. Or both!
~ Genetic variants impact how well you break down histamine.
~ Understanding which variants you have can help you target the right diet and supplements to help with symptoms.
This article goes in-depth on the research into histamine intolerance, including the genetic variants that impact histamine levels. It concludes with diet, lifestyle, and supplements solutions. Everything is fully referenced, so you can easily dig into the research yourself. It’s a long article (and thorough!), so you may want to bookmark it now to come back to read again.
Members will see their genotype report below, plus additional solutions in the Lifehacks section. Consider joining today.
Histamine intolerance: causes, symptoms, and treatment
Do you deal with sinus drainage after you eat? Periodic itching and hives? Migraines, irritability, anxiety, brain fog? The weird and seemingly unrelated symptoms of histamine intolerance can drive you nuts trying to figure out the root cause.
Classified as a biogenic amine, histamine is a molecule that plays many roles in the body.
Histamine’s many functions include:
- causes allergic reactions,
- acts within our immune defense system,
- dilates blood vessels (vasodilatation)
- acts as a neurotransmitter
- works as a signaling molecule in the stomach to release acid
While most of us think of histamine only during allergy season, histamine is a vital part of how your body works. The key is that you want the right amount – not too much!
What are the symptoms of histamine intolerance?
Histamine intolerance symptoms impact many different systems in the body, including[ref]:
- Head: headaches & migraines
- Mood: anxiety, irritability, brain fog
- Stomach: acid reflux, nausea, stomach pain
- Intestines: bloating, diarrhea, constipation
- Heart: heart arrhythmia, dizziness
- Sinuses: drainage, congestion
- Skin: hives, itching, flushing,
- Sleep: insomnia, early waking
People with histamine intolerance usually have several of the symptoms above, but they likely won’t have all of the symptoms.[ref]
Too much histamine has been known for decades to cause scombroid poisoning – the type of food poisoning from eating fish that isn’t fresh.[ref]
Here’s a visual overview of what we are going to cover here:
Causes of histamine intolerance:
The two leading causes of histamine intolerance are:
- not enough of the enzymes needed to break down histamine (DAO and HMNT)
- too much histamine being produced (gut microbes producing histamine, leaky gut, mast cells degranulating too easily, HDC variants, chronic exposure to allergens).
Clearing histamine from the body:
There are two ways your body breaks down and clears histamine: the DAO enzyme or the HMNT enzyme.[ref]
- Diamine oxidase (DAO) enzyme: Histamine from foods or bacteria in your gut is broken down or metabolized using the DAO (diamine oxidase) enzyme. The DAO enzyme is produced in the villi lining the small intestines and is released to metabolize histamine.[ref]
- Histamine methyltransferase (HMNT) enzyme: The HMNT enzyme works throughout the body, including in the brain, to deactivate and break down histamine created by your cells.[ref]
Diamine Oxidase (DAO) enzyme:
Diamine oxidase is encoded by that AOC1 gene. It is mainly produced in the intestines to counteract histamine from foods and histamine created by intestinal bacteria. Foods containing a lot of histamines include aged cheeses, aged meats, fermented foods, and more.
Certain bacteria in the gut (including those from some probiotics or fermented foods) can also increase histamine levels in the body. People with histamine intolerance show altered gut microbiome composition as well as elevated levels of zonulin, which regulates tight junctions in the intestines (leaky gut).[ref] A recent study of histamine intolerance patience found that they had “a significantly higher abundance of histamine-secreting bacteria…”[ref]
The DAO enzyme is also used by the body to break down other biogenic amines, including tyramine, putrescine, cadaverine, spermidine, and spermine. High levels of other biogenic amines can reduce the ability of DAO to break down histamine.[ref]
DAO degrades histamine into imidazole acetaldehyde, which is then quickly oxidized into imidazole acetic acid.[ref]
The HMNT enzyme breaks down histamine in the central nervous system.
Recent studies show exactly how important HNMT is in controlling brain histamine levels. Genetic variants that change HNMT levels in the brain are linked to an increased risk of neurodegenerative disorders such as Parkinson’s disease. Studies also link HNMT variants to an increased risk of migraines and ADHD.[ref] Rare mutations that inactivate the HNMT enzyme are linked to intellectual disability.[ref]
The HNMT enzyme acts throughout the body. Genetically decreased HNMT is also linked to atopic dermatitis or eczema.[ref] While DAO can also circulate in the periphery, HNMT is the only enzyme breaking down histamine as a neurotransmitter in the central nervous system.
When histamine is degraded with the help of the HNMT enzyme, it forms N-methylhistamine, which is unable to bind to histamine receptors. Note that a methyl group is needed in the reaction. The N-methylhistamine is further broken down with the MAO-B enzyme, forming N-methylimidazole acetaldehyde.[ref]
Creation of Histamine:
Histamine is made from the amino acid histidine. It is an essential amino acid, meaning humans cannot make it in our bodies and must obtain it from diet. Histidine can be used in the body for several different purposes, including histamine production.
Histidine decarboxylase (HDC gene) is an enzyme that catalyzes the reaction of histidine into histamine. It does this inside various cell types, including creating histamine in large amounts in mast cells.
Not enough histamine:
Without enough histidine decarboxylase (HDC), animal studies show behavior that resembles Tourette syndrome.
Genetic studies show that people with Tourette’s (vocal and motor tics) may have rare HDC gene mutations as a cause. The loss of histamine in the basal ganglia causes too much dopamine in that region of the brain, resulting in tics.[ref]
Too much histamine and the heart:
Histamine is also essential in the way that the heart muscle functions. Too much histamine here can be detrimental, and people with chronic heart failure have higher average plasma histamine levels. In fact, a genetic variant in the HDC gene that reduces histamine levels is linked to a significantly decreased risk of chronic heart failure.[ref]
Additionally, clinical trials show that blocking the H2 receptor is beneficial for chronic heart failure. Famotidine improved cardiac symptoms and ventricular remodeling. In the heart, histamine increases the force of contraction, and even as far back as 1913, histamine has been known to induce heart arrhythmias.[ref][ref]
Histamine receptors explain the different effects of histamine
You may wonder why one molecule can cause so many different actions in the body…
How can histamine cause headaches and heartburn and hives?
The function of histamine in a specific part of the body depends on the receptor it binds to.
Different histamine receptors are found in different parts of the body:[ref]
- H1 receptors: Found in smooth muscle, endothelial cells (lining the blood vessels), the central nervous system, and mast cells. Activating the H1 receptors causes allergy-type symptoms such as itching, swelling, vasodilation, nose running, and skin reactions. H1 receptors are also important in asthma reactions.
- H2 receptors: Acid is released when histamine activates the H2 receptors in the stomach. H2 receptors are also found in the intestinal tract and the walls of blood vessels. Mast cells also have H2 receptors, which, when activated, cause the release of more histamine. In the heart, H2 receptors are essential in controlling the rhythm.
- H3 receptors: The central and peripheral nervous systems contain H3 receptors, which act as a feedback loop for histamine levels in the brain. Activating the H3 receptors impacts serotonin, norepinephrine, and acetylcholine release.[ref]
- H4 receptors: These histamine receptors are at the core of the inflammatory response. H4 receptors are found in the bone marrow, basophils (a type of white blood cell), the thymus, small intestine, spleen, colon, and mast cells.[ref]
Three types of histamine receptors are found in the intestines: H1, H2, and H4. Interestingly, a study showed that people with food allergies and IBS had significantly higher levels of H1 and H2 receptors in their intestines.[ref]
Mast cells and histamine release
Mast cells are a type of immune cell that stores histamine. They are found in most tissues in the body, especially in areas of the body exposed to the outside world.
Allergens cause mast cells to burst or degranulate and release histamine. Large numbers of mast cells are found in the skin, bronchial tree mucosa, and intestinal mucosa.
In addition to allergens, viruses, bacteria, and fungi also activate mast cells.[ref]
Some researchers categorize histamine intolerance as a subset of mast cell activation syndrome (MCAS).
Related article: Mast cell activation syndrome
For more in-depth info on mast cells and histamine, check out Research Studies on Mast Cells and Histamine Intolerance, where I dive into all the different ways histamine can affect you.
Histamine, Sleep, and Circadian Rhythm:
Histamine acts in the brain as a neurotransmitter. It is an alerting neurotransmitter, rising in the morning hours to wake us up. About 50% of the histamine in the brain is from mast cells.[ref]
Diphenhydramine, a commonly used antihistamine, has the side effect of making people sleepy. It is due to blocking the actions of histamine in the brain.
Altering histamine levels in the brain changes sleep:
- In mice, eliminating the histamine receptors in the brain alters sleep patterns. Without histamine, mice were slower to wake up. They also had fragmented sleep and decreased non-REM sleep.[ref]
- In another animal study, researchers decreased the number of mast cells in the brain, reducing histamine production. It did not affect the amount of time the mice slept overall, but it did affect their brain waves in sleep and their ability to bounce back after sleep deprivation.[ref]
In a recent study of people with suspected histamine intolerance, the researchers found that about 25% of the patients had a circadian change in histamine levels that differed from a control group. These patients had significantly reduced DAO enzyme levels and higher histamine levels during the day.[ref]
Histamine Intolerance Genotype Report:
Lifehacks for histamine intolerance:
Below are the research-backed solutions for histamine intolerance. You may need to try several different ‘lifehacks’ to see which works best for you.
A low-histamine diet restricts foods with high levels of histamine or that cause the body to release histamine. To experiment with a low-histamine diet, eliminate all of the higher-histamine foods for a period of time to see how your body responds.
In general, foods that are fermented or aged are higher in histamine. A quick overview of high histamine foods includes processed meats, cheeses (except farmer cheese), fish and seafood that isn’t completely fresh, spinach, chocolate, tomatoes, strawberries, wine, sake, and more.
High histamine foods list:
If you are considering a low histamine diet, I find this histamine food list to be the most thorough: Complete list of foods that are high in histamine (pdf).
Note that alcohol can cause mast cells to release histamine. For some, this may cause flushing when drinking. But for people with histamine intolerance, even alcoholic drinks that are lower in histamine may still cause a reaction.[ref]
Related article: Alcohol, mast cells, and histamine
What does a low-histamine diet do?
- Decreasing the amount of histamine you take into your body will lower the overall amount of histamine circulating in your body.
- Research studies show that a low histamine diet helps with chronic urticaria (itchiness, hives), migraines, stomach problems, and asthma.[ref][ref]
Should you maintain a low histamine diet long-term?
Trying a low-histamine diet for a period of time can give you a lot of insight into how histamine affects your body, but it may not be a diet you want to continue long-term. A low-histamine diet restricts many healthy foods that you may enjoy, such as spinach, strawberries, and avocados.
Use a low histamine diet as a tool to learn which histamine-containing foods bother you the most. It can also be a short-term way of getting histamine responses under control.
Low FODMAPs diet: histamine and gut problems
Interestingly, a randomized controlled study for people diagnosed with IBS found that a low FODMAPs diet reduced symptoms and reduced histamine levels.
It could mean that a FODMAPs diet works because IBS is related to histamine intolerance – or – it could mean that the people diagnosed with IBS were really dealing with gut-related histamine symptoms.[ref] Additionally, the low FODMAPs diet may help to decrease intestinal barrier permeability.
A low FODMAPs diet cuts out a lot of high histamine foods, so it could reduce histamine levels by eating fewer foods high in histamine. On the other hand, a low FODMAPs diet impacts the gut microbiome and histamine-producing bacteria. Animal studies also link IBS to mast cell activation in the colon, so changing the gut microbiome with a FODMAPs diet may also impact colonic mast cells.[ref]
Learn more about what is included in a low FODMAPs diet: Starting a Low FODMAPs diet
Supplements for Histamine Intolerance:
Related Articles and Topics:
Mast cells: MCAS, genetics, and solutions
Mast Cell Activation Syndrome, or MCAS, is a recently recognized disease involving mast cells that misbehave in various ways. Symptoms of MCAS can include abdominal pain, nausea, itching, flushing, hives, headaches, heart palpitations, anxiety, brain fog, and anaphylaxis. Dive into the research into mast cells, genetics, and solutions.
Notes about Histamine and Mast Cells
A compilation of notes and reference studies on the functioning of mast cells and histamine receptors.
Tyramine: The Cheese Effect and Your Genes
Tyramine is another biogenic amine found in a lot of the same foods as histamine. An inability to break down tyramine can cause a variety of symptoms.
Recipes and Foods for Histamine Intolerance
Interested in low histamine foods and recipes? This article focuses on foods high in histamine so you can easily eliminate them from your diet.
Systemic symptoms such as gastrointestinal issues or fatigue can be caused by eating foods higher in nickel.
Agúndez, J. A. G., Ayuso, P., Cornejo-García, J. A., Blanca, M., Torres, M. J., Doña, I., Salas, M., Blanca-López, N., Canto, G., Rondon, C., Campo, P., Laguna, J. J., Fernández, J., Martínez, C., & García-Martín, E. (2012). The diamine oxidase gene is associated with hypersensitivity response to non-steroidal anti-inflammatory drugs. PLoS ONE, 7(11), e47571. https://doi.org/10.1371/journal.pone.0047571
Andersen, L. P. H., Werner, M. U., Rosenkilde, M. M., Harpsøe, N. G., Fuglsang, H., Rosenberg, J., & Gögenur, I. (2016). Pharmacokinetics of oral and intravenous melatonin in healthy volunteers. BMC Pharmacology & Toxicology, 17, 8. https://doi.org/10.1186/s40360-016-0052-2
Association of diamine oxidase and histamine N-methyltransferase polymorphisms with presence of migraine in a group of Mexican mothers of children with allergies. (2017). Neurología (English Edition), 32(8), 500–507. https://doi.org/10.1016/j.nrleng.2016.02.012
Ayuso, P., García-Martín, E., Martínez, C., & Agúndez, J. A. G. (2007). Genetic variability of human diamine oxidase: Occurrence of three nonsynonymous polymorphisms and study of their effect on serum enzyme activity. Pharmacogenetics and Genomics, 17(9), 687–693. https://doi.org/10.1097/FPC.0b013e328012b8e4
Che, D. N., Cho, B. O., Shin, J. Y., Kang, H. J., Kim, Y.-S., & Jang, S. I. (2018). Fisetin inhibits IL-31 production in stimulated human mast cells: Possibilities of fisetin being exploited to treat histamine-independent pruritus. Life Sciences, 201, 121–129. https://doi.org/10.1016/j.lfs.2018.03.056
Chikahisa, S., Kodama, T., Soya, A., Sagawa, Y., Ishimaru, Y., Séi, H., & Nishino, S. (2013a). Histamine from brain resident mast cells promotes wakefulness and modulates behavioral states. PLoS ONE, 8(10), e78434. https://doi.org/10.1371/journal.pone.0078434
Chikahisa, S., Kodama, T., Soya, A., Sagawa, Y., Ishimaru, Y., Séi, H., & Nishino, S. (2013b). Histamine from brain resident mast cells promotes wakefulness and modulates behavioral states. PLoS ONE, 8(10), e78434. https://doi.org/10.1371/journal.pone.0078434
García-Martín, E., Ayuso, P., Martínez, C., Blanca, M., & Agúndez, J. A. G. (2009). Histamine pharmacogenomics. Pharmacogenomics, 10(5), 867–883. https://doi.org/10.2217/pgs.09.26
García-Martín, E., Martínez, C., Serrador, M., Alonso-Navarro, H., Ayuso, P., Navacerrada, F., Agúndez, J. A. G., & Jiménez-Jiménez, F. J. (2015). Diamine oxidase rs10156191 and rs2052129 variants are associated with the risk for migraine. Headache, 55(2), 276–286. https://doi.org/10.1111/head.12493
Hon, Y. Y., Jusko, W. J., Zhou, H.-H., Chen, G.-L., Guo, D., Zhou, G., Spratlin, V. E., & Jann, M. W. (2006). Endogenous histamine and cortisol levels in subjects with different histamine n-methyltransferase c314t genotypes. Molecular Diagnosis & Therapy, 10(2), 109–114.
Maintz, L., Yu, C.-F., Rodríguez, E., Baurecht, H., Bieber, T., Illig, T., Weidinger, S., & Novak, N. (2011). Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities. Allergy, 66(7), 893–902. https://doi.org/10.1111/j.1398-9995.2011.02548.x
McIntosh, K., Reed, D. E., Schneider, T., Dang, F., Keshteli, A. H., De Palma, G., Madsen, K., Bercik, P., & Vanner, S. (2017). FODMAPs alter symptoms and the metabolome of patients with IBS: A randomised controlled trial. Gut, 66(7), 1241–1251. https://doi.org/10.1136/gutjnl-2015-311339
Piliponsky, A. M., Acharya, M., & Shubin, N. J. (2019). Mast cells in viral, bacterial, and fungal infection immunity. International Journal of Molecular Sciences, 20(12), E2851. https://doi.org/10.3390/ijms20122851
Pinzer, T. C., Tietz, E., Waldmann, E., Schink, M., Neurath, M. F., & Zopf, Y. (2018). Circadian profiling reveals higher histamine plasma levels and lower diamine oxidase serum activities in 24% of patients with suspected histamine intolerance compared to food allergy and controls. Allergy, 73(4), 949–957. https://doi.org/10.1111/all.13361
Sander, L. E., Lorentz, A., Sellge, G., Coëffier, M., Neipp, M., Veres, T., Frieling, T., Meier, P. N., Manns, M. P., & Bischoff, S. C. (2006). Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract. Gut, 55(4), 498–504. https://doi.org/10.1136/gut.2004.061762
Schnedl, W. J., Lackner, S., Enko, D., Schenk, M., Holasek, S. J., & Mangge, H. (2019). Evaluation of symptoms and symptom combinations in histamine intolerance. Intestinal Research, 17(3), 427–433. https://doi.org/10.5217/ir.2018.00152
Simon, T., Semsei, A. F., Ungvári, I., Hadadi, E., Virág, V., Nagy, A., Vangor, M. S., László, V., Szalai, C., & Falus, A. (2012). Asthma endophenotypes and polymorphisms in the histamine receptor HRH4 gene. International Archives of Allergy and Immunology, 159(2), 109–120. https://doi.org/10.1159/000335919
Stevenson, J., Sonuga-Barke, E., McCann, D., Grimshaw, K., Parker, K. M., Rose-Zerilli, M. J., Holloway, J. W., & Warner, J. O. (2010). The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children’s adhd symptoms. American Journal of Psychiatry, 167(9), 1108–1115. https://doi.org/10.1176/appi.ajp.2010.09101529
Thangam, E. B., Jemima, E. A., Singh, H., Baig, M. S., Khan, M., Mathias, C. B., Church, M. K., & Saluja, R. (2018). The role of histamine and histamine receptors in mast cell-mediated allergy and inflammation: The hunt for new therapeutic targets. Frontiers in Immunology, 0. https://doi.org/10.3389/fimmu.2018.01873
Threlfell, S., Cragg, S. J., Kalló, I., Turi, G. F., Coen, C. W., & Greenfield, S. A. (2004). Histamine H3 receptors inhibit serotonin release in substantia nigra pars reticulata. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 24(40), 8704–8710. https://doi.org/10.1523/JNEUROSCI.2690-04.2004
Weng, Z., Zhang, B., Asadi, S., Sismanopoulos, N., Butcher, A., Fu, X., Katsarou-Katsari, A., Antoniou, C., & Theoharides, T. C. (2012). Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PloS One, 7(3), e33805. https://doi.org/10.1371/journal.pone.0033805
Yoshikawa, T., Nakamura, T., & Yanai, K. (2019). Histamine n-methyltransferase in the brain. International Journal of Molecular Sciences, 20(3), 737. https://doi.org/10.3390/ijms20030737
Yu, X., Ma, Y., Harding, E. C., Yustos, R., Vyssotski, A. L., Franks, N. P., & Wisden, W. (2019). Genetic lesioning of histamine neurons increases sleep–wake fragmentation and reveals their contribution to modafinil-induced wakefulness. Sleep, 42(5), zsz031. https://doi.org/10.1093/sleep/zsz031
Originally published April, 2015.