Are You Histamine Intolerant?

Learn how to test for histamine intolerance or mast cell activation syndrome. What are the symptoms of mast cell activation?

Is histamine intolerance a real problem or the latest hype…?

Histamine is a necessary factor in various healthy biological reactions like wound healing, blood vessel function, and hormonal balance. However, histamine is also the stuff of allergic reactions and anaphylactic shock. Why then is histamine the talk of chronic disease including chemical sensitivity, ME/CFS, and others?

The balance of histamine production and degradation is vital. Histamine is naturally broken down by 2 important enzymes: histamine N-methyltransferase (HMNT) and diamine oxidase (DAO). While both enzymes have a high capacity to breakdown histamine, DAO is the most vulnerable. This is because DAO is found outside of the cell while HMNT is active only within cells. Various factors can throw off the balance of histamine breakdown, with further research needed to understand genetic or acquired triggers.

Too much histamine or not enough enzyme activity can result in body-wide symptoms which mimic complex chronic illnesses, such as ME/CFS. This includes:

  • Fatigue & brain fog

  • Chronic nasal congestion

  • Low blood pressure

  • Heart rate irregularities

  • Diarrhea

  • Chronic pain

  • Skin rashes & hives

  • Anxiety

  • Headaches

  • Difficult menstruation

  • Acid reflux

  • Alcohol intolerance

How can one tell if histamine is a problem? Some rather simple clues may first give reason to explore this avenue.

Food and Chemical Sensitivities

Sensitivities to many foods and/or supplements may be suggestive of histamine problems. A more detailed dietary strategy for low histamine diets can be found here. For now, alcohol and fermented foods have some of the highest levels of histamine. This is due to high production of the chemical by fermenting bacteria.

Other foods that have the potential to release high degrees of histamine are citrus fruits. Citrus-based compounds are common components of some supplements and may therefore worsen symptoms. So if otherwise “healthy” food options like sauerkraut and probiotics make you worse, consider the histamine load of your diet.

Of note, those with a history of gut dysbiosis or other intestinal disorder may be especially susceptible to histamine problems. The enzyme DAO is released in large part by cells that line the intestine. Long standing intestinal problems may reduce the production of DAO, making one more sensitive to histamine containing foods. This may improve as the health of the gut improves.

Considerations for Women

DAO activity is lowest during menstruation and histamine levels are augmented by estrogen. This may lead to an imbalance of histamine metabolism during menstruation that results in worsening of symptoms. Also, if your symptoms resolved during a pregnancy then returned, consider the fact that DAO is released in abundance by the placenta.


Certain medications may block the activity of histamine degrading enzymes. While short courses of these drugs may not be detrimental to DAO activity, chronic use may cause substantial shifts in histamine balance. Common medications include NSAIDs, amitriptyline (Elavil), contrast media from diagnostic imaging, morphine, second-line antibiotics like cefuroxime (Ceftin), and more.


How can I know for sure if histamine is a problem?

Testing for histamine intolerance is not routine. There are various approaches that should be taken together when interpreting the results. It is common and easy to measure plasma histamine using standard laboratories. The normal reference range for histamine is 0.3 to 1.0 ng/mL. This test is problematic however as it just represents a snapshot in time and may not be representative of food-related histamine problems.

A better test would be to look at the breakdown product of histamine, N-methylhistamine, which is standard in a urine test (Quest Diagnostic). This measure would give a better idea of how effectively histamine is being broken down. Yet, this still is an indirect measurement. Better still would be to measure the DAO enzyme activity itself. As of yet, a test for intracellular HMNT activity is not possible. DAO enzyme activity below 3 U/mL is indicative of histamine intolerance. Ideally, all 3 tests should be administered to get the whole picture of histamine metabolism.

Find treatment options for histamine intolerance in another post.

Dr. Craighistamine, mast cells