When it comes to food, age discrimination is a very good thing.
I am grateful to Dr. Judy Tsafrir for calling my attention to this important aspect of food sensitivities. I recently wrote a series of blog posts documenting in (some would say horrifying) detail my personal attempt at an extreme ketogenic diet. Given that I have an extraordinary number of food sensitivities, that experiment was even more challenging than it would have been for a normal person…
You see, for the past few years I have gravitated towards a mostly-meat diet–usually fresh or frozen poultry and fish supplemented with small amounts of the plant foods that bother me least–cucumbers, lettuce, etc. However, the ketogenic diet put strict limits on how much protein I could eat, so I found myself turning to some foods that are unusual for me, such as pork and beef, which tend to have more fat and less protein than poultry and fish. While travelling, I sometimes had to resort to smoked, cured, or other processed meats. I have known for a long time that these do not agree with me, which is why I prefer to eat fresh meats whenever possible. So there I was, having all kinds of difficulty tolerating these foods, and driving my readers crazy.
Then one day, Dr. Tsafrir commented beneath one of my posts that I might have histamine intolerance. She had removed foods high in histamine from her own diet and written on her own site about the many benefits she’d experienced. So, I decided to learn more about the science behind this topic in hopes of better understanding my own bizarre food reactions, as well as helping those of you out there who may be struggling with similar issues.
Histamine is found lurking primarily in aged, cured, fermented, cultured, and spoiled foods. Reactions to histamine described in the literature vary from subjective reports of a wide variety of variable symptoms to full-blown toxicity. We will dive in to the details soon enough, but first: what is histamine?
Say Hello to Histamine
Histamine is a tiny messaging molecule that some cells use to communicate with each other. It is naturally found in all kinds of plants and animals. Histamine is best known for its role in the body’s allergic response. If you are allergic to peanuts and you sink your chompers into a yummy peanut butter cup, your immune cells will flood your system with histamine, wreaking all kinds of havoc–from hives to low blood pressure to difficulty breathing. But this is histamine in crisis mode. Under normal circumstances, tiny amounts of histamine are quietly conducting the daily business of the body. It is not typically cruising recklessly through your bloodstream in large quantities, the way it is during an allergic emergency (anaphylactic shock).
Histamine is versatile–it helps to regulate body 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 multi-faceted nature lies in which type of cell and which type of receptor it binds to. For example, when histamine binds to special cells in the stomach called parietal cells, they respond by producing stomach acid. When histamine binds to receptors on the surface of blood vessel cells, blood vessels dilate, dropping blood pressure. Small vessels called capillaries become leaky and fluids ooze out of them, which can lead to runny nose, watery eyes, and puffy skin/fluid retention. In the brain, histamine acts as a neurotransmitter, carrying chemical messages between nerve cells.
Histamine is promiscuous, lives fast and dies young. As soon as it delivers its special chemical message to its target cell it is then instantly destroyed to keep it under control. No respect–but that’s what it gets for being the cad that it is. So, if histamine doesn’t hang around in plants and animals, why should we worry?
We all get old…but we do not rot. As long as oxygen and blood are flowing, we stay fresh as a daisy. Meat used to be alive, but it’s not anymore. As soon as it stops being alive, bacteria start eating it–decomposing it—fermenting it–breaking its proteins down into ever-smaller, stranger, and often smellier compounds. Many of these by-products are biogenic amines. Histamine is just one example of a biogenic amine. Unlike in living tissues, the histamine that is produced during meat fermentation is not instantly destroyed—so it accumulates. The longer meat is left out, the higher the biogenic amine content. Histamine itself has no flavor and is odorless, so you can’t use the smell test to detect its presence.
What are Biogenic Amines?
A biogenic amine is a potent signaling molecule made from an amino acid. Histamine, for example, is made from the common amino acid histidine (amino acids are what proteins are made of). Meat and fish are rich in protein, so they are chock full of amino acids. [For more information about amino acids, see my protein page].
Here is a list of the most common biogenic amines and the amino acids they are made from. You’ll notice that a couple of them have ghastly names, worthy of a Vincent Price voiceover: putrescine and the perfectly ghoulish cadaverine—mwaaah ah ah…
Parent amino acids are in green and their biogenic amine products are in red:
- Arginine—Agmatine, Putrescine, Spermine, Spermidine
- Ornithine—Putrescine, Spermine, Spermidine
- Tryptophan—Tryptamine, Serotonin
To turn a garden variety amino acid into a powerful biogenic amine, you need to remove its carboxyl group. To accomplish this you need a special enzyme called a decarboxylase (fancy word for “enzyme that chops off carboxyl groups”).
Many species of bacteria and yeast contain the enzyme histidine decarboxylase (HDC), which turns histidine into histamine. So, when meat (or fish) is not immediately consumed or frozen, bacteria get straight to work breaking down the amino acids within it, and one of the by-products is histamine.
So, take-home lesson: eat your meat/fish either very fresh or confirm that it was frozen quickly. Seems simple enough, right? But wait, there’s more. We silly humans actually go out of our way to ferment foods on purpose. People like to play with food—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, these fresh foods—milk, grapes, and meat—which in their fresh forms are essentially histamine-free, become very high in histamine and other biogenic amines.
Foods High in Histamine
The lists below are not meant to be complete, just representative of what I found in the literature. Levels exceeding 2 mg/L in beverages and 100 mg/kg in foods are considered risky:
Red wine up to 24 mg/Liter
Most (fresh) vegetables are very low in histamine, with levels ranging from 0 to 16 mg/kg. The notable exceptions are tomatoes, eggplant, and spinach:
Ketchup 22 mg/kg
Eggplant 26 mg/kg
Spinach 30 to 60 mg/kg
Sauerkraut (fermented cabbage) up to 229 mg/kg
Uncultured dairy products such as milk and cream tend to be very low in histamine, with levels of less than 1 mg/kg. The same is true for fresh, unripened cheeses with short shelf-lives, such as fresh mozzarella and ricotta.
Sour cream up to 7 mg/kg
Yogurt up to 13 mg/kg
Ripened cheeses 2.21 – 2500 mg/kg (whoa…)
Most fresh meats are very low in histamine, with the exception of ground/chopped beef products:
Raw ground beef stored in refrigerator for 12 days 31.8 mg/kg
Cooked ground beef stored in refrigerator for 12 days 85.4 mg/kg
Dry sausages such as salami, pepperoni, and chorizo, are the meat products highest in histamine content.
Dry fermented sausages up to 357.7 mg/kg
Like other animal foods, fresh fish is very low in histamine, whereas levels in canned tuna range from zero to as high as 40.5 mg/kg.
However, improperly handled fish is notorious for causing “scombroid poisoning”—an extreme reaction to spoiled fish:
“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 h.” [Hungerford 2010]
Fish samples that have caused scombroid poisoning tend to be very high in histamine, typically with levels of greater than 100 mg/kg. 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.
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:
- Cape yellowtail
[*Salmon and Swordfish are also more commonly associated with “scombroid poisoning” despite not having particularly high levels of histidine in their tissues.]
Some foods are suspected of triggering histamine release within some people’s bodies, even though they may not contain any histamine of their own:
- Citrus fruit
- Egg white
However, there isn’t much evidence to support the theory that these foods can trigger histamine reactions:
“We could not find any study on histamine-releasing effects of most of the foods suggested of having histamine-releasing capacities…there are no DBPCFC (double-blind placebo-controlled food challenge) studies in human beings supporting the widely held belief that foods should have histamine-releasing capacity. The hypothesis that foods may have a histamine-releasing capacity is based on several older in vitro studies, animal studies in other diseases demonstrating histamine-releasing effects of foods, and on studies in which pharmacological substances were incubated directly with digestive tract mucosal tissues. Thus, the normal digestive influences on foods are eliminated and the significance of these findings is doubtful.” [Vlieg-Boerstra 2005]
What is 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.” [Komericki 2010]
According to a 2007 review article [Maintz and Novak], histamine intolerance affects at least 1% of the population, and 80% of those affected are (ahem)…middle-aged.
Women seem to comprise the majority of people who complain of histamine intolerance. This may be because estrogen and histamine reinforce each other—histamine can increase estrogen levels and vice versa, which may explain why histamine intolerance is associated with pre-menstrual cramps and menstrual migraine. Even more fascinating is that pregnant women may experience relief from food sensitivities during pregnancy because the placenta secretes very high amounts of diamine oxidase, or DAO, the enzyme that destroys histamine.
Histamine intolerance may be caused by abnormally low levels of DAO. DAO is found, among other places, in the membranes of cells lining the small intestine and the upper portion of the colon, therefore people with damaged gastrointestinal systems seem to be at higher risk for histamine intolerance.
Is Histamine Intolerance Real?
There is considerable controversy around this diagnosis, and many scientists think of histamine intolerance as only weakly grounded in scientific evidence or perhaps even psychosomatic in nature.
A 2003 analysis of biogenic amines and food intolerances, which included two studies of histamine and red wine reactions, concluded:
“Of the studies performed on the adverse effects of biogenic amines, only a few are methodologically acceptable. Although this limits the conclusions that may be reached, the current scientific literature does not show a relation between the oral ingestion of biogenic amines and food intolerance reactions. There is therefore no scientific basis for dietary recommendations concerning biogenic amines in such patients.” [Jansen 2003]
A more recent consideration of the evidence suggested:
“The concept of histamine intolerance as a metabolic disease is in need of more experimental and clinical evidence and affected patients will benefit from a clear, evidence-based, diagnostic and therapeutic regime.” [Schwelberger 2010].
The way I tend to think about these things is this: if you notice that foods high in histamine and other biogenic amines bother you, you do not need a scientist or a doctor to prove you right or wrong.
How is Histamine Intolerance Diagnosed?
You may have histamine intolerance (HI) if you have at least 2 typical symptoms of HI and they go away either with a histamine-free diet or with the use of antihistamine medications. As with any food intolerance issue, keeping a careful food & symptom diary is very important in noticing patterns. People who suspect they may have HI should first be tested for food allergies to rule those out before undergoing more specialized testing.
Levels of DAO–the enzyme that destroys histamine–can be measured:
“Histamine intolerance is presumably highly likely in patients with DAO activity <3 U/mL, likely (but less likely) in patients with DAO activity <10 U/mL, and improbable in patients with DAO activity >10 U/mL.” [Maintz and Novak 2007]
The gold standard for diagnosis of histamine intolerance involves following a strict “histamine-free” diet for 4 weeks, and then undergoing a “histamine capsule challenge” in which you are given capsules filled with histamine and a clinician monitors your medical reaction.
Treatment of Histamine Intolerance
If you suspect you have HI, here are some options which may help you to feel better:
- Eat a low-histamine diet. Avoid cultured, processed, cured, fermented and aged foods. Choose fresh foods whenever possible. Ask your grocer what the “pack date” is of the meat or fish being sold. “FAS” (frozen-at-sea) fish may be your best bet. Unfortunately, grass-fed and pastured meats are often shipped from farther away, and may not be the best choice when it comes to histamine content.
- If you are someone who can tolerate small amounts of histamine-containing foods, pay attention to how often you eat them, because histamine can accumulate in the body over time.
- Occasional use of antihistamines or medicines called “mast cell stabilizers” may be helpful–if they don’t bother you.
- Vitamin C, vitamin B6 and copper can all increase DAO activity
- DAO supplements (isolated from pig) are available
- Some people, especially those with prominent gastrointestinal symptoms of HI may benefit from pancreatic enzymes.
- Avoid alcohol—alcohol reduces DAO activity
- Be aware of medications that interfere with DAO activity. If you take any of the following medicines, discuss with your clinician how they may be affecting your HI symptoms, to see if alternatives are available:
- Clavulanic acid
- NSAIDs (Ibuprofen/Advil, etc.)
Prevention of Histamine Intolerance
Of course, simple, natural, preventive measures are usually the wisest course of action. Understanding how histamine forms in foods can help you to minimize your exposure not just to histamine, but to all potentially irritating and/or toxic biogenic amines.
- Immediate storage of meats and fish on ice dramatically reduces the rate of histamine formation but does not stop it completely.
- HDC, the enzyme that turns histidine into histamine, can remain in foods even after the bacteria (or yeast) that produced that enzyme have died. Therefore, HDC can remain active, turning proteins into histamine, long after the micro-organisms are dead and gone, leading to continued accumulation of histamine. However, HDC can be inactivated by freezing for 1-2 weeks, and is destroyed by cooking.
- Histamine itself is NOT destroyed by cooking, freezing, hot smoking, or canning. Therefore, once it has been produced, you are stuck with it.
Al Bulushi I, et al. Biogenic amines in fish: roles in intoxication, spoilage, and nitrosamine formation—a review. Crit Rev Food Sci Nutr 2009; 49(4): 369-377.
Ancin-Azpilicueta C et al. Current knowledge about the presence of amines in wine. Critical Reviews in Food Science and Nutrition 2008; 48(3): 257-275.
Bodmer S et al. Biogenic amines in foods: histamine and food processing. Inflamm Res 1999; 48: 296–300.
Hungerford JM. Scombroid poisoning: a review. Toxicon 2010; 56: 231–243.
Jansen SC et al. Intolerance to dietary biogenic amines: a review. Ann Allergy Asthma Immunol 2003; 91:233–241.
Komericki P et al. Histamine intolerance: lack of reproducibility of single symptoms by oral provocation with histamine: a randomised, double-blind, placebo-controlled cross-over study. Wien Klin Wochenschr 2011; 123: 15–20.
Maintz L and Novak N. Histamine and histamine intolerance. Am J Clin Nutr 2007; 85:1185–96.
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Schwelberger HG. Histamine intolerance: a metabolic disease? Inﬂamm Res 2010; 59 (Suppl 2): S219–S221
Vlieg-Boerstra BJ et al. Mastocytosis and adverse reactions to food. The Netherlands Journal of Medicine 2005; 63(7): 244-249.
Wöhrl S et al. Histamine intolerance-like symptoms in healthy volunteers after oral provocation with liquid histamine. Allergy Asthma Proc 2004; 25(5): 305-311.