Histamine Intolerance: Understanding the Science

In this post we take an in-depth look at the science behind the food sensitivity reactions caused by histamine. We’ll explore:

• the fascinating world of biogenic amines
• how histamine forms inside and outside of our bodies
• how histamine affects our physical and mental health
• why some people, especially women, are more sensitive to histamine than others
• and why reactions to high-histamine foods can be so unpredictable and confusing

To read about the practical aspects of histamine intolerance, such as diagnosis, prevention, treatment, food choices, food handling/storage, and medications to avoid, please see my companion post: "Freshness Counts: Histamine Intolerance."

The alchemy of biogenic amines

Histamine belongs to an important class of molecules called biogenic amines—potent signaling molecules made from amino acids (amino acids are the building blocks of all proteins—see my protein page for more information). HistAMINE, for example, is made from the amino acid HistIDINE.

Biogenic amines are used by all kinds of plants and animals to regulate important bodily functions. Cells capable of making biogenic amines generate and release them in very tiny quantities to attach to specific receptors on nearby target cells, triggering unique responses within those cells. As soon as their message is delivered, biogenic amines are destroyed by neutralizing enzymes to keep their influence under control.

In order to turn a garden variety amino acid into a powerful biogenic amine, all you have to do is remove its carboxyl group. This unceremonious amputation requires special enzymes called decarboxylases (fancy word for “enzymes that chop off carboxyl groups”).

That’s all well and good, but biogenic amines like histamine aren’t just created by special cells within our bodies to do good deeds. Many species of bacteria and yeast also contain decarboxylases, and they enjoy using them to make biogenic amines out of the proteins in foods we like to eat. Meats, fish, poultry, and dairy products are rich in protein, so they are chock full of amino acids. Whenever a high-protein food like meat, poultry, or fish is not immediately consumed or frozen, microorganisms in the environment get straight to work munching on it, fermenting it, breaking down its proteins into ever-smaller, stranger, and often smellier compounds, including biogenic amines. In living organisms, biogenic amines are destroyed by neutralizing enzymes almost immediately after they are created. Unlike in living tissues, biogenic amines produced during meat fermentation are not destroyed—so they accumulate. This is why the older a food is, the higher its biogenic amine level becomes.

Some biogenic amines have strong unpleasant odors, which can be useful in figuring out whether a food has gone bad, but histamine itself has no flavor and is odorless, so you can’t use the “smell test” to detect its presence.

To make matters worse, we silly humans actually go out of our way to ferment foods on purpose. We add bacteria to milk to make cheese and yogurt. We add yeast to grapes to make wine. We add bacteria to meat to make salami. In the process, foods like milk, grapes, and meat—which in their fresh forms are virtually histamine-free—can become very high in histamine and other biogenic amines.

So, histamine can come from inside our bodies or from outside our bodies—from the foods we eat. They can also come from bacteria in our gut as they ferment the foods we digest.

Here is a list of the most common biogenic amines and the amino acids they are made from. Those in italics are the major players in food sensitivities. You’ll notice that a couple of them have ghastly names, worthy of a Vincent Price voiceover: putrescine and the perfectly ghoulish cadaverine—mwaa ha hah . . .

Say hello to histamine

Histamine is an important messaging molecule responsible for a staggering number of biological effects in our bodies, helping to regulate bodily functions as diverse as digestion, sleep, sexual function, blood pressure, and brain function. How does this one molecule do so many different things? The secret to histamine’s versatility is that it can cause a variety of different responses in neighboring cells, depending on what kinds of cells are nearby, and which receptors are on their surfaces.

Only certain cells in our bodies are capable of making histamine:1

• Immune system: mast cells and basophils
• Digestive system: gastric enterochromaffin cells and certain gut bacteria
• Nervous system: histaminergic neurons (in the brain and body)

Histamine can bind to four different kinds of receptors, and each receptor responds in its own special way to histamine. The histidine decarboxylase enzyme (HDC) transforms histIDINE into histAMINE. The histamine molecule then binds to one of four different receptor types—H1, H2, H3, and H4—located in different places and performing different functions throughout the body.

By mixing and matching cell locations, receptors, and target cells, tiny histamine can accomplish a wide variety of tasks.1

Adapted from Maintz L and Novak M 2007; Illustration by Suzi Smith

For example, when histamine binds to special cells in the stomach called parietal cells, stomach acid is produced. When histamine binds to receptors on the surface of large blood vessel cells, arteries dilate, lowering blood pressure. When it binds to smaller vessels called capillaries, they become leaky and fluids ooze out of them, which can lead to runny nose, watery eyes, and puffy skin/fluid retention.

Histamine’s destiny

Histamine is promiscuous, lives fast and dies young. As soon as it delivers its special chemical message to its target cell it is instantly destroyed to keep it from running amok. No respect–but that’s what it gets for being the cad that it is.

If we eat something with histamine in it, say an aged steak or a piece of ripened cheese, we have special enzymes in our gut ready to destroy the histamine in that food before it can be absorbed into the bloodstream.

The cells lining the small intestine and the upper stretch of the colon (ascending colon) are constantly releasing a histamine-busting enzyme called Diamine Oxidase (DAO) into the gastrointestinal tract, creating the first line of defense against excessive histamine exposure from foods and beverages.

Any histamine that makes it past DAO will have to contend with another histamine-destroying enzyme, histamine-N-methyltransferase (HNMT), which is located inside of the cells lining the gut.

Most of the histamine that we consume is neutralized by DAO released into the gastrointestinal tract or HNMT located in the cells that line the gut. These enzymes prevent excess histamine from entering the bloodstream. [Illustration by Suzi Smith; Adapted from Kovacova-Hanuskova 2015 Allergol Immunopathol (Madr) 43(5):498-506.]

Most cases of histamine intolerance are thought to be due to inadequate levels or activity of these enzymes, most importantly DAO.1 If enzymes are deficient, histamine can cross into the bloodstream and cruise around the body willy-nilly, having its way with our cells.

Histamine reactions

Under normal circumstances, tiny amounts of histamine are quietly, safely conducting the daily business of the body. But there are plenty of scenarios that can lead to excessive, abnormal histamine exposure.

As with any toxin, “the dose makes the poison.” Healthy individuals are supposed to be able to handle foods that contain about 50 to 100 mg/kg of histamine,1 but people with histamine intolerance generally react to much lower levels. The kinds of reactions we have to histamine depend primarily on how much histamine we are exposed to and which area of the body is affected. Reactions fall into five general categories; the first four scenarios can happen to anyone:

1. Anaphylaxis—massive internal release of histamine into the bloodstream by an allergic trigger
2. “Scombroid poisoning”—food poisoning caused by eating spoiled fish (typically containing >500 mg/kg histamine)
3. Localized allergic reactions (sinus congestion, hives, etc.)
4. Histamine overload—eating too much histamine at once and overwhelming healthy defenses (typically >50 mg/kg)
5. Histamine intolerance—uncomfortable symptoms with exposure to histamine even at low doses (<50 mg/kg). This only happens to sensitive individuals.

Anaphylaxis

If you are allergic to peanuts and you sink your chompers into a peanut butter cup, your immune cells will throw a fit and flood your bloodstream with histamine, wreaking all kinds of havoc—from hives to low blood pressure to difficulty breathing. This is histamine in crisis mode. Histamine isn’t supposed to be coursing recklessly through your bloodstream in large quantities, and it can be deadly.

Scombroid poisoning

Most of us have at some point in our lives gotten sick with food poisoning after eating bad seafood. Scombroid poisoning is an extreme reaction to spoiled fish that is very high in histamine, typically greater than 500 mg/kg:1

“The onset of Scombroid poisoning is typically from 10 min to 1 h following consumption of poisonous fish. The symptoms are variable and include peppery or metallic taste, oral numbness, headache, dizziness, palpitations, rapid and weak pulse (low blood pressure), difficulty in swallowing, and thirst. Noteworthy as allergy-like are symptoms such as hives, rash, flushing and facial swelling. Symptoms involving the central nervous system (CNS) such as anxiety are less frequently observed. Less specific symptoms such as nausea, vomiting, abdominal cramps and diarrhea are also experienced. Recovery is usually complete within 24 hours.”1

However, the relationship between histamine levels and degree of toxicity is not straightforward; it seems that two other biogenic amines may also play a role in these severe reactions: putrescine and cadaverine. [It figures . . . leave it to Smelly and Spooky.] Both of these ghastly biogenic amines interfere with DAO activity, and therefore make it easier for histamine to get into our bloodstream.

Certain species of fish are more likely to be associated with scombroid poisoning, and the majority of them are dark-fleshed fish which are especially rich in the parent amino acid histidine:3

[*Salmon and swordfish are also commonly associated with Scombroid poisoning despite not having particularly high levels of histidine in their tissues.]

Localized allergic reactions

In humans, histamine is best known for its role in the body’s allergic response. If you are allergic to pollen, and you go romping through a field of flowers, the cells lining your sinuses will overreact and release too much histamine, causing watery eyes, sneezing, and so forth. Or if your skin is exposed to an irritating product you may develop hives. Many people with allergies take an antihistamine medication to block the effects of excess histamine.

Histamine overload

Most healthy individuals can tolerate a total of about 50 to 100 mg/kg of histamine in foods per sitting,1 but consuming more than that can cause symptoms even in people with healthy histamine defenses. Our natural capacity to neutralize histamine varies widely, so some people can get away with lots of high-histamine foods while others are more sensitive.

Histamine intolerance

“The term ‘histamine intolerance’ was introduced as common denominator for symptoms such as abdominal pain, flatulence, diarrhoea, headache, pruritus (itching), blepharedemas (puffy eyes), urticaria (hives), rhinorrhea (runny nose), dysmenorrhea (menstrual cycle problems), respiratory obstruction (difficulty breathing), tachycardia (racing heart), extrasystoles (palpitations) and hypotension (low blood pressure) occurring after the consumption of histamine-rich foods.”2

Histamine intolerance affects at least 1% of the population, and 80% of those affected are (ahem) . . . middle-aged.3

What causes histamine intolerance?

Most cases of histamine intolerance are thought to be due to abnormally low levels/activity of diamine oxidase (DAO), an enzyme that destroys histamine.

DAO is located only in certain organs in the body: the small intestine, ascending colon, kidney, liver and placenta. Therefore, anything that causes temporary or permanent damage to any of these organs could potentially affect DAO function, particularly damage to the intestines, because that is where DAO is most active (in non-pregnant individuals). Examples include chemotherapy, Crohn’s Disease, Celiac Disease, kidney disease, liver failure, or surgery. Genetic abnormalities in DAO also play a role in certain cases of histamine intolerance.1

DAO requires vitamin B6, vitamin C, copper, and zinc in order to function properly, so if you are deficient in any of these, you may experience histamine intolerance.

DAO supplements are available and can be effective in limiting the effects of histamine in food when taken 15 minutes before eating. The one I use is Seeking Health's Histamine Block.

HNMT, by contrast, is found in almost all organs in the body, including in the brain and red blood cells. Problems with HNMT function are not thought to play a significant role in most cases of histamine intolerance.

SIBO (small intestine bacterial overgrowth) can lead to high levels of histamine in the gut, overwhelming our enzymes.

HER-stamine?

About 80% of people with histamine intolerance are women.1 This may be because estrogen and histamine reinforce each other, meaning that estrogen increases histamine levels and vice versa. Since women have higher levels of estrogen than men, they also naturally have higher levels of histamine than men. It stands to reason then that it would take smaller amounts of high-histamine foods to overwhelm histamine-destroying enzymes.

Histamine is known to increase estrogen production. This is very important to think about, because eating different amounts of histamine from day to day can put women on a hormonal roller coaster of fluctuating estrogen levels.

Women may be more sensitive to histamine in foods during the points in their cycles when estrogen levels are higher (ovulation and pre-menstrual phase) or if they are taking estrogen supplements. Histamine triggers nitric oxide release in the arteries surrounding the brain, which can lead to migraine headaches. “Menstrual migraines” may be due to the fact that estrogen levels peak during the pre-menstrual phase, stimulating a rise in histamine.

Women have a higher number of H1 receptors in their brains than men do, which means that women’s brains are naturally more sensitive to histamine (see mental health section below).2

One of the many natural roles of histamine in the body is to stimulate contraction of the uterus. This explains why histamine intolerance can cause or worsen pre-menstrual cramps.3

Especially fascinating is that pregnant women typically experience relief from allergies and histamine intolerance during pregnancy because the placenta produces up to 500 times the normal amount of DAO, the enzyme that destroys histamine, in order to protect the fetus from histamine toxicity.

Histamine and mental health

Histamine acts as an important neurotransmitter in the brain, where it helps to regulate the stress response, alertness, sexual function, sleep-wake cycles, attention, learning, and memory.

While I am not aware of any scientific findings specifically proving a formal connection between histamine intolerance and mood disorders, people with histamine intolerance commonly experience symptoms such as panic, insomnia, anxiety, and fatigue. It is intriguing to think about, because histamine is not thought to cross the blood-brain-barrier.1 Therefore, if you eat a high-histamine diet, and some of that histamine makes it into your bloodstream, it shouldn’t be able to enter your brain. How then do we understand the psychological symptoms associated with histamine intolerance?

One possible explanation is that the majority of the anxiety symptoms people with histamine intolerance notice are not generated in the brain, but rather in the body, via histamine’s ability to raise levels in the bloodstream of other important signaling molecules, most importantly adrenaline.

Adrenaline is the body’s “fight-or-flight” hormone. It does not cross the blood-brain barrier, but in the body, it can trigger panic symptoms such as racing/pounding heart, anxiety, nausea, sweating, insomnia, shortness of breath, shaking, etc.

Another interesting possibility: histamine raises estrogen levels in the body, and estrogen DOES cross the blood-brain barrier. As any woman knows, estrogen can have powerful effects on mood—sometimes positive, sometimes negative (the relationship between estrogen and mood is very complicated). Once inside the brain, estrogen stimulates histamine release, so this could be one way that a high-histamine diet in sensitive people might affect energy and concentration levels.

If you have anxiety or sleep problems and want to understand how your diet may be causing your symptoms, I recommend reading my Psychology Today article "5 Foods Proven to Cause Anxiety and Insomnia."

What about the other biogenic amines?

In foods, histamine is never alone. It is always accompanied by significant amounts of other biogenic amines. This makes symptoms and diagnosis of histamine intolerance complicated and sometimes rather unpredictable.

Putrescine and cadaverine in foods can cause trouble by interfering with DAO activity, making it harder for us to detoxify histamine in our gut. This can raise the level of histamine we are exposed to. The higher the levels of putrescine and cadaverine in a food, the higher the effective level of histamine.1

Tyramine is broken down not by diamine oxidase (DAO) but by a different enzyme called "monoamine oxidase" (MAO). Tyramine is therefore notorious for causing problems in people taking old-fashioned antidepressants called “MAO-inhibitors” like Nardil and Parnate, which block tyramine destruction. If tyramine accumulates, severe headaches and dangerously high blood pressure can occur.

True tyramine intolerance, unlike histamine intolerance, doesn’t seem to be a concern except in people taking MAO-inhibitor medications or in rare cases of genetic MAO deficiency. But here’s the rub: putrescine and cadaverine both interfere with MAO activity and therefore behave as mild MAO-inhibitors! Smelly and Spooky strike again…you just can’t trust those two . . . this is why aged foods can trigger migraines and high blood pressure even if you don’t have histamine intolerance.

It’s not just about histamine . . . other factors

It is no easy task figuring out whether or not you have histamine intolerance. In addition to the fact that other biogenic amines can influence how a particular food affects you, there are MANY other variables that determine how you will feel when you eat a high-histamine food:

It’s impossible to know how much histamine is in a given food, and the same food will contain different amounts of histamine under different circumstances:

• Some medications interfere with DAO activity, including NSAIDS such as Ibuprofen2
• Estrogen levels stimulate histamine production3
• Stress and physical injury trigger immune cells to release histamine and other pro-inflammatory substances4
• Alcohol interferes with DAO activity5
• Low-histamine “trigger foods” directly stimulate mast cells to release histamine6
• There is a handful of low-protein, low-histamine plant foods naturally rich in the amino acid histidine (which turns into histamine under the right conditions)3
• Some species of gut bacteria contain histidine decarboxylase and therefore can generate histamine from proteins in the foods we eat. This is more likely to occur with foods that are difficult for us to completely digest on our own, because such foods travel further down in our digestive system into the colon, where bacteria live. This is just one reason why it makes sense to minimize “fermentable” foods such as legumes and foods high in proteins such as gluten and casein, which humans don’t possess the capacity to break down.

People with histamine intolerance can even experience high blood pressure or low blood pressure, depending on the circumstances! Histamine itself lowers blood pressure in most cases. However, histamine also triggers the release of other substances in the body that affect blood pressure, most importantly adrenaline, which raises blood pressure.

It’s complicated.

People with histamine sensitivity and their doctors can easily become very confused. The same food can cause different symptoms, or no symptoms, from one day to the next, depending on the circumstances. It is not simply about how much histamine is in a food. Which other biogenic amines were in that food? Did you drink alcohol that day? Did you take an NSAID like Aleve or another medicine that can raise histamine levels? What else did you eat that day? Did you eat any histamine triggering foods? How stressed were you? If you are a woman, where were you in your monthly cycle?

I see you throwing your hands up in the air. How are you supposed to know whether you have histamine intolerance or not? If you suspect you have histamine intolerance, what should you do? Fear not, help is on the way!

Please see my companion post all about the practical aspects of histamine intolerance—diagnostic tests, food choices, food storage/handling, and medications to avoid: "Freshness Counts: Histamine Intolerance."

You can also listen to my podcast interview with Yasmina Ykelenstam, the Low Histamine Chef, about the connection between histamine intolerance and mental health.