Histamine Intolerance: 14 Facts You Need to Know

Genes Mentioned

• AOC1
• HNMT
• GAD1

As evidenced by this excellent paper in the American Journal of Clinical Nutrition, histamine intolerance is a condition that is starting to gain more awareness in the medical community.

It’s a problem that can seriously degrade anyone’s quality of life. Based on my experience with histamine issues, and after our research team spent over 100 hours combing through all the relevant peer reviewed studies on histamine and histamine metabolism, there are 14 things we’d like you to know about this condition.

It is our team’s hope that the information in this post will help anyone  battling through this difficult time, but before we get started, some words of optimism.

First, it is possible to  get a handle on histamine intolerance, it may not be easy, but with a personalized approach it can be conquered.  

Next, and this is crucially important – do not fear the fridge! Histamine intolerance is bigger than food. Ultra restrictive diets with 100 foods to avoid aren’t the solution long term. In order to be healthy, you must eat. This doesn’t mean that low histamine diets can’t help, but food isn’t the whole story, there are multiple factors that contribute to histamine overload.

With those preliminary notes out of the way, let’s get into the list.

#1. Histamine is a neurotransmitter

Yes, that is correct, no one is actually “histamine intolerant,” we all need histamine, it’s an essential neurotransmitter. ¹ However, as with anything, too much of a good thing can cause problems. Each of us has a histamine bucket. As our bodies make histamine, and as we ingest it in food, it is cleared by an enzyme known as diamine oxidase. When more histamine accumulates than our diamine oxidase levels can handle, symptoms begin which leads to the condition known as “histamine intolerance.”

#2. Histamine is released from mast cells

We can eat histamine, our brains use histamine, and the immune system also releases histamine from a special class of cells, called mast cells. Think of mast cells as the military sentinels of the immune system.

When these cells see a foreign invader, like a virus, or allergen, they react by “degranulating” and releasing cytokines that can seek out and kill the invader. Histamine is released from mast cells as part of this process. It acts as a vasodilator to facilitate blood flow to injury sites in the body.

The key thing to understand when experiencing histamine intolerance is that mast cells can become chronically irritated, causing the near constant release of histamine. We need mast cells for a properly functioning immune system, but they also need rest. When bacteria, an environmental toxin, or an allergy continuously  trigger mast cells, the resulting cytokine activity can start to cause tissue damage. Increased levels of tissue damage leads to  chronic inflammation.

Based on the commonly reported symptoms of histamine intolerance, it probably won’t come as a big surprise that mast cells are found in greatest numbers at the site of mucous membranes: skin, nose, throat, gut, lungs, and bladder.

In a very real sense, the quest to get over histamine intolerance is the quest to discover what is irritating the immune system and to remove it from the equation. Histamine intolerance can also be misdiagnosed as mast cell activation disorder.

#3. Excess histamine causes food poisoning

You may have heard the expression – “the dose makes the poison.” If you have one bourbon, you have a great time. If you have the whole bottle, you end up in the hospital. The same principle applies to dietary histamine. At a high enough dose, every one of us is histamine intolerant, as large doses of histamine cause food poisoning.

#4. One percent of people suffer from histamine intolerance

The American Journal of Clinical Nutrition estimates that 1% of the population suffers from histamine intolerance and 80% of those patients are middle-aged. Because the symptoms of histamine intolerance overlap with many other conditions, struggles with histamine often go undiagnosed. One possible way to catch a histamine intolerance is through inspection of a bug bite. Weird? Maybe, but when a “normal” bug bite swells out of control, it could be a sign that histamine levels aren’t where they should be in the body. If this is a normal occurance for someone, visiting a primary care physician might be a good next step to explore.  

#5. Seasonal allergies can contribute to histamine intolerance

This factor is not discussed as much as it should be. Food gets all the attention, but histamine intolerance goes well beyond food. Allergy to the environment triggers the immune system to produce histamine, which starts to fill the histamine bucket.

Consider this quote from the American Journal of Clinical Nutrition: 

Underlying conditions for increased availability [of histamine] may be an endogenous histamine overproduction caused by allergies…

The production of histamine by air-borne allergens can unknowingly take up a large portion of the  histamine bucket, leaving reduced wiggle room with food. This means that location alone can be a cause of histamine intolerance.

To this point, Dr. Janice Joneja wrote an excellent blog on the subject of histamine that everyone should read. This quote, in particular, stands out:

A person with histamine intolerance will typically experience a constant fluctuation in the signs and symptoms of histamine excess in response to changing conditions. For example, when a person is experiencing allergy to air-borne allergens such as seasonal pollens, the histamine released in the allergic response alone might put them into the symptom range. In such a case, avoiding histamine-associated foods will no longer relieve their symptoms because their total level of histamine will remain above their limit of tolerance. This explains the observation that during their “pollen allergy season” many people find themselves reacting to foods (usually histamine-rich foods) that they could normally eat with impunity.

#6. Histamine intolerance has a genetic component

An enzyme called diamine oxidase is responsible for cleaning up histamine in the gut. ² The AOC1 genes are coded to make this important enzyme, but not everyone is born with the same enzyme activity, which makes some of us genetically more susceptible for developing histamine intolerance.

So as not to confuse the DAO enzyme with the DAO gene (which many online forums do) take a look at Aaron’s post: You say DAO, I say DAAO.

DAO breaks down “free histamine,” like the histamine found in the gut, while HNMT, another histamine gene, processes histamine in the cell.

Variants in the AOC1 genes have been associated with reduced DAO activity. For example, this Italian study found that 10 out of 14 patients with histamine intolerance had very low levels of serum DAO.

#7. Histamine intolerance can cause gut issues

Mast cells reside in large numbers in the gut, so a chronic allergic response paired with an inability to clear the histamine (due to reduced DAO) will irritate the gut over time.

Aaron’s research indicates that histamine issues often coincide with gut problems. Histamine, when chronically elevated in the gut, can cause an increase in zonulin, which is a protein shown to break apart the epithelial wall; the lining that keeps the contents of the gut from entering the bloodstream.

For more on gut health and histamine, take a look at the podcast episode we did on the subject.

Decreased DAO levels are linked to a number of inflammatory bowel conditions, including Crohn’s disease and ulcerative colitis. This small study, which evaluated tissue samples from the intestine of 20 patients struggling with Crohn’s, found that all of the patients had very low levels of DAO.

To make matters worse, many fermented foods, marketed for “gut repair,” are very high in histamine. Collagen is a bad one. 

#8. Our microbiome can produce histamine

Changes to the flora in our guts may be a contributing factor to histamine intolerance, which is why some of us develop histamine problems after a severe infection and multiple rounds of antibiotics.

Small scale studies have shown that the microbiomes of those with histamine intolerance are altered in noticeable ways. Again, the studies aren’t enormous, but patients with histamine intolerance have been found to have elevated levels of Proteobacteria above what is considered normal.  Proteobacteria are a type of microbe found commonly in disease states.

Further, healthy microbes in the gut, like many Bifidobacterium species can degrade histamine, while other unhealthy microbes, such as Escherichia, can produce histamine. ³

#9. NSAIDs may aggravate histamine intolerance

Certain variants in the AOC1 genes are associated not only with lower levels of diamine oxidase, but with NSAID allergy as well. The SNP in question is rs10156191.

Carriers of the T allele, which is also linked to lower DAO activity, are likely to have a hypersensitive reaction to NSAID drugs.

#10. Alcohol makes histamine intolerance worse

As we’ve established, one factor in the body’s ability to deal with histamine is genetic, however, lifestyle also plays an important role.

You may have read that alcohol degrades DAO activity, which further worsens histamine issues. This is a widely reported “fact” on the internet, but the evidence is limited. Having said that, drinking alcohol is not good for you under normal circumstances, but it’s especially bad if you are suffering from histamine intolerance.

Most alcohol, and especially beer and wine, is fermented and very high in histamine. If you’re looking for a drink to quickly fill and overflow the histamine bucket, it’s alcohol  of any kind. Some people report success sticking to clear liquor rather than beers, wines, and liquors with more additives.

This study, which appeared in the Journal Allergy and Asthma Proceedings, evaluated the histamine levels of 28 wine intolerant subjects before and after drinking red wine. Within 30 minutes, 22 of the subjects saw their histamine levels sky rocket.

#11. All food has histamine

In some cases, especially when medical supervision is present, a low histamine diet can be just what the doctor ordered to help curb a problem with histamine intolerance. However, it’s important to recognize that almost all food has some histamine. Known as a “biogenic amine” histamine in food accumulates the longer food sits out, and is especially bad in aged and fermented foods. However, it is impossible to completely avoid dietary histamine. 

#12. Freshness of food is key

A glass of wine at the end of the day is like a cup of coffee in the morning for some people. Necessary. So it may be upsetting to hear that red wine is a no go for those with unbalanced histamine levels. But why?? In part because it’s aged and fermented. Though these factors are what makes it delicious, it is also what makes it high in histamine. The same is true for:

• Leftovers
• Smoked meat and fish
• Deli meat
• Aged cheese
• Meal prep services
• Fish that is not fresh
• Avocado and banana

Any food given time to ripen or age will only increase in histamine the longer it sits out. Keeping an eye on the freshness of food is key if your goal is to defeat histamine intolerance.

#13. Elimination diets can be easier than you think

If the thought of cutting out 100 foods to adhere to  a low histamine diet scares you, you’re not alone.

Even the list cited above seems rather large, doesn’t it? Well, if you want to experiment with food triggers, and go low histamine, start by cutting out the least nutrient dense foods and move on from there.

What does this look like?

It means ditching the condiments. Pickles, sauerkraut, ketchup, salsa. These foods are notoriously high in histamine, and although they are tasty, they confer very little in the way of nutrient density.

Next, eliminate alcohol, especially the heavily fermented variations. Additionally, and unfortunately, no more cold cuts, leftovers, aged cheese, and smoked salmon.

Oh, and take a break from coffee and tea. They are both histamine liberators, but more simply, they contain caffeine which increases cortisol. Most people with histamine issues need to balance stress as a first priority because…

#14. Stress can histamine intolerance worse

At the beginning of this post,the role that mast cells play in histamine intolerance was discussed. There are a myriad of factors that can trigger mast cells, but stress is one of them.

High stress environments will make a case of histamine intolerance worse. Consider this review by world renowned mast cell expert Dr. Theoharis Theoharides in which he discusses the stress response and its impact on the immune system.

For interested readers, we interviewed Dr. Theoharides on the podcast last year.

Key Takeaways

• Histamine intolerance is multifactorial – starting to react to food is a sign that some other upstream factor is amiss.
• Physical location plays a role in histamine intolerance.
• Ruling out mold toxicity and examining the health of the microbiome are worthwhile exercises when histamine intolerance strikes.
• Alcohol, antibiotics and NSAID drugs are kryptonite for those suffering from histamine intolerance.
• Some people are at a genetic disadvantage in clearing histamine.