When your body has too much histamine, it can cause symptoms 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.
- involved in allergic reactions,
- acts within our immune defense system,
- causes vasodilation (dilates blood vessels)
- acts as a neurotransmitter
- works as a signaling molecule in the stomach
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 include[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,
- Circadian Rhythm: sleep problems, 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 that are needed to break down histamine- and/or-
- too much histamine being produced (gut microbes, mast cells degranulating, allergy).
Breaking down histamine:
There are two ways that your body clears out histamine: using the DAO enzyme or using the HMNT enzyme.[ref]
DAO: Histamine that enters the body from foods or is made by the bacteria in your gut is broken down using the DAO (diamine oxidase) enzyme. DAO is produced in the villi lining the small intestines.[ref]
HNMT: The histamine methyltransferase (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 a neurotransmitter in the brain – will be broken down in those tissues 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. Other studies link HNMT variants to an increased risk of ADHD and migraines.
Looking at the function of the different histamine receptors illustrates the many actions of histamine within the body.
- H1 receptors: Smooth muscle, the endothelium (cells lining the inside of blood vessels and lymph vessels), central nervous system, and mast cells all can have H1 receptors on the surface of their cells.
- 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.
- 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 CNS.
- 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 have been 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 called 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.
Some think that histamine intolerance is a subset of MCAS (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 and Sleep:
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 on 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]
Another mouse study 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.
Genetics of Histamine Intolerance:
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 –.
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
A low histamine diet restricts the foods that contain high levels of histamine or that cause the body to release histamine.
A low histamine diet restricts a lot of ‘healthy’ foods that you may enjoy, such as spinach, strawberries, and avocados. 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. 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.
Dietary Options, Vitamins & Supplements
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 vitamin B6 content of foods.
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]
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.
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]
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 prep 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.
Medications that decrease DAO
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 Genes and Topics:
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.
Originally published April, 2015.