When your body has too much histamine, it can cause symptoms collectively known as histamine intolerance. This can be due to excess production of histamine by your body or not being able to break down histamine from foods very well. OR… both!
Genetics plays a big role in how well your body breaks down histamine! You can use your genetic data to figure out if your genes are part of the reason why you have histamine intolerance. Knowing which genetic variants you carry leads to targeted solutions that are more likely to work for you.
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 when reaching for that anti-histamine during allergy season, it is a vital part of our body’s everyday functions.
What are the symptoms of histamine intolerance?
Histamine intolerance symptoms impact many different system 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
Most people with histamine intolerance have several of the symptoms above.[ref]
Causes of histamine intolerance:
The two main causes of histamine intolerance are:
- too little of the enzymes needed to break down histamine (DAO and HMNT)- and/or-
- too much histamine being produced (gut microbes producing histamine, mast cells degranulating too easily, chronic allergies).
Breaking down histamine:
There are two ways that your body clears out histamine: using the DAO enzyme or using the HMNT enzyme.[ref]
Diamine oxidase (DAO) enzyme: Histamine from foods or from bacteria in your gut is broken down using the DAO (diamine oxidase) enzyme. DAO is produced in the villi lining the small intestines.[ref]
Histamine methyltransferase (HMNT) enzyme : The HMNT enzyme works throughout the body to deactivate and break down histamine created by your body. Thus, histamine that is used as a signaling molecule in the stomach or as a neurotransmitter in the brain will be broken down via a reaction that incorporates the HMNT enzyme.[ref]
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 Parkinson’s disease. Studies also link HNMT variants to an increased risk of migraines or ADHD.
You may be wondering 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 certain 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), central nervous system, and mast cells. Activating the H1 receptors causes allergy-type symptoms such as itching, swelling, nose running, and skin reactions. H1 receptors are also important in asthma reactions.
- H2 receptors: When histamine activates the H2 receptors in the stomach, acid is released. H2 receptors are also found in the intestinal tract and in the walls of blood vessels. Mast cells also have H2 receptors, which when activated, causes the release of more histamine. In the heart, H2 receptors are important in controlling the rhythm.
- H3 receptors: The central nervous system and the peripheral nervous system 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 inflammatory response. H4 receptors are found in the bone marrow, basophils (a type of white blood cell), thymus, small intestine, spleen, colon, and mast cells.[ref]
In the intestines, which is actually the body’s largest immune organ, three types of histamine receptors are found: 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
A type of immune cell, mast cells store histamine in most tissues in the body.
Allergens cause mast cells to burst (degranulate) and release histamine. Large numbers of mast cells are in the skin, bronchial tree mucosa, and intestinal mucosa. Mast cells are also activated by viruses, bacteria, and fungi.[ref]
Some think that histamine intolerance is a subset of MCAS (read more about 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]
Benadryl, a commonly used antihistamine, has a side-effect of making people sleepy. This is due to the actions of histamine in the brain.
In mice, knocking out the histamine receptors in the brain shows that it alters sleep patterns a little bit. Without histamine, mice were slower to wake up. They also had fragmented sleep and decreased Non-REM sleep.[ref]
In another mouse study, researchers decreased the number of mast cells in the brain, reducing histamine production there. This did not affect the amount of time that the mice slept overall, but it did affect their brain waves in sleep as well as their ability to bounce back after sleep deprivation.[ref] Obviously, we can’t do these types of studies in humans, but it is important to know that altered histamine levels can impact sleep quality.
A recent study in people who had ‘suspected histamine-intolerance’, the researchers found that about 1/4 of the patients had a circadian change in histamine levels that was different from a control group. These patients had significantly reduced DAO enzyme levels during the day and subsequently higher histamine levels. [ref]
Genetics of Histamine Intolerance:
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DAO (diamine oxidase) is the enzyme produced by the intestines, breaking down histamine from foods. The AOC1 gene codes for the production of the DAO enzyme. Genetic variants in AOC1 can increase or decrease the production of the enzyme.
AOC1 genetic variants (diamine oxidase):
Check your genetic data for rs10156191 (23andMe v4; AncestryDNA):
- C/C: typical
- C/T: reduced production of DAO, increased risk of migraines due to histamine[ref]
- T/T: reduced production of DAO[ref][ref], increased risk of migraines due to histamine[ref]
Members: Your genotype for rs10156191 is —.
Check your genetic data for rs2052129 (23andMe v.5 only):
- G/G: typical
- G/T: reduced production of DAO, increased risk of migraines due to histamine[ref]
- T/T: reduced production of DAO[ref], increased risk of migraines due to histamine[ref]
Members: Your genotype for rs2052129 is —.
Check your genetic data for rs1049742 (23andMe v4 only):
- C/C: typical
- C/T: reduced production of DAO
- T/T: reduced production of DAO[ref]
Members: Your genotype for rs1049742 is —.
Check your genetic data for rs1049793 (23andMe v4; AncestryDNA(older)):
- C/C: typical
- C/G: reduced production of DAO
- G/G: reduced production of DAO[ref]
Members: Your genotype for rs1049793 is —.
HNMT genetic variants:
Histamine n-methyltransferase (HMNT) is the enzyme that regulates histamine in the body via converting it from histamine into N-methylhistamine, which can then be eliminated from the body.
Check your genetic data for rs1050891 (23andMe v4, v5):
- G/G: typical
- A/G: reduced breakdown of histamine compared to G/G
- A/A: reduced breakdown of histamine compared to G/G[ref]
Members: Your genotype for rs1050891 is —.
Check your genetic data for rs11558538 C314T (23andMe results for i3000469, v4; AncestryDNA):
- T/T: reduced HNMT activity[ref][ref]
- C/T: reduced breakdown of histamine compared to C/C
- C/C: typical[ref]
Members: Your genotype for rs11558538 is — -or- your 23andMe genotype for i3000469 is —.
The methylation cycle plays a role in breaking down monoamine neurotransmitters including histamine. It is also important in creating the methyl groups needed for the HMNT enzyme to work. So looking at your methylation cycle genes can also help with balancing out a histamine intolerance.
The MTHFR gene codes for an enzyme that is a key player in the folate cycle. This is one source of methyl groups for the methylation cycle. Decreased enzyme activity of MTHFR – combined with a diet lacking in folate or choline – may cause a reduced breakdown of histamine.
Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):
- G/G: typical *
- A/G: one copy of MTHFR C677T allele (heterozygous), decreased by 40%
- A/A: two copies of MTHFR C677T (homozygous), decreased by 70 – 80%
Members: Your genotype for rs1801133 is —.
Check your genetic data for rs1801131 (23andMe v4, v5; AncestryDNA):
- T/T: typical *
- G/T: one copy of MTHFR A1298C (heterozygous), slightly decreased enzyme
- G/G: two copies of MTHFR A1298C (homozygous), decreased enzyme by about 20%
*Given in the forward orientation to match your genetic data
Members: Your genotype for rs1801131 is —.
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.
Low-histamine diet, initially:
A low-histamine diet restricts foods that contain 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.
While there are many partial lists for low-histamine diets, I find this list to be the most thorough: Complete list of foods that are high in histamine
What does a low-histamine diet do?
- Decreasing the amount of histamine that you take into your body will lower the overall amount circulating in your body.
- Research studies show that a low histamine diet helps 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 is affecting your body, but it may not be a diet that you want to continue long-term. A low histamine diet restricts a lot of ‘healthy’ foods that you may enjoy, such as spinach, strawberries, and avocados.
Use it as a tool to learn which histamine-containing foods bother you the most and as a short-term way of getting histamine responses under control.
Low FODMAPs diet for gut histamine problems:
Interestingly, a randomized controlled study for people diagnosed with IBS found that a low FODMAPs diet reduced symptoms as well as reducing histamine. This 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]
A low FODMAPs diet cuts out a lot of high histamine foods, so it could be reducing histamine levels through eating fewer foods high in histamine. Or – more likely – the low FODMAPs diet is impact the gut microbiome and histamine producing bacteria.
Vitamins & Supplements for histamine intolerance:
Vitamin B6 is a cofactor in the reactions that degrade histamine. Pyridoxal-5′-phosphate is the active form of vitamin B6. Foods high in vitamin B6 include salmon, tuna, eggs, milk, beef, and carrots.(article) Not sure if you get enough vitamin B6? Cronometer.com is a free online app where you can record the foods you eat each day to determine the nutrient content – and it includes the vitamin B6 content of foods.
Quercetin has also been shown in studies to inhibit mast cells from degranulating. Mast cells are one way that the body releases histamine.[ref]
Luteolin has been shown in studies to inhibit histamine release from mast cells.[ref]
There are DAO supplements available that may help some people who don’t produce enough of the enzyme. A recent study found that histamine intolerance symptoms improved significantly when taking DAO capsules before meals.[ref]
Looking for an alternative to DAO supplements? Pea shoots – those first few inches of the pea plant that come up in the spring – are naturally high in the DAO enzyme.[ref] You can easily grow pea shoots at home, and they are a tasty addition to a salad.
Gluten sensitivity and histamine intolerance
A new study looked at the correlation between symptoms of histamine intolerance and gluten intolerance. It concluded that there was a significant overlap in symptoms and that it is possible that a low histamine diet may help people with gluten sensitivity.[ref]
Food preparation methods to reduce histamine levels
How food is prepared makes a big difference in the histamine levels.
A recent study concluded “Frying and grilling increased histamine levels in foods, whereas boiling had little influence or even decreased it. The boiling method might be helpful to control the effect of histamine in histamine-sensitive or susceptible patients, compared with frying and grilling.”
Additionally, leftovers kept in the fridge (especially meats!) can build up histamine. Instead, try putting your leftovers in the freezer and thawing them when you want to eat them.
As you will see on the list of foods high in histamine, fermenting and drying foods can increase histamine levels.
Personal note: smoked meats, such as BBQ pork or brisket, can contain high levels of histamine. Sometimes it is worth it.
Avoid medications that decrease DAO enzyme production
In addition to foods, drug interactions can cause a decrease in the DAO enzyme production.
Metformin has been shown to decrease the DAO enzyme.[ref]
Vitamin B3 (nicotinamide or niacinamide) may increase histamine levels at doses of 100 mg or higher.[ref]
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 on 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.
Top 10 Genes to Check in Your Genetic Raw Data
Wondering what is actually important in your genetic data? These 10 genes have important variants with a big impact on health. Check your genes (free article).
Originally published April, 2015.