Diamine Oxidase and Histamine Intolerance: A Clinical Guide

If certain foods leave you with headaches, bloating, or skin reactions, diamine oxidase (DAO) may be a reason why. DAO is the enzyme responsible for breaking down histamine in the gut, and when it’s not working properly, histamine builds up and symptoms follow. Here’s what you need to know.

What Is Diamine Oxidase (DAO) and Why Does It Matter?

Diamine oxidase (DAO) is a digestive enzyme produced primarily in the small intestine. Its main job is to break down histamine from the food and drinks you consume before it can accumulate in the body.

When DAO levels are low, or the enzyme is not functioning well, dietary histamine passes into the bloodstream instead of being broken down. Low DAO activity is the primary driver of histamine intolerance.

What Is Histamine Intolerance?

Histamine is a natural compound that plays important roles in immune function, digestion, and the central nervous system. The body produces it, and it is also present in many common foods and drinks, such as canned meat and fish, tomatoes, aged cheese, alcoholic beverages, and fermented foods.

When histamine accumulates faster than the body can break it down, symptoms can appear across multiple systems. These may include 1 2 3:

• Bloating
• Diarrhea or constipation
• Abdominal pain
• Skin rashes, hives, or itching
• Runny, congested nose, and/or sneezing (rhinitis)
• Headaches or migraines
• Dizziness
• Heart palpitations
• Flushing
• Swelling
• Brain fog
• Itchy eyes
• Reflux
• Fatigue

Histamine intolerance is estimated to affect 1 to 3% of people in the United States, though that number is likely higher given how frequently it goes undiagnosed. It may also be a factor in 30 to 55% of people with nonspecific gastrointestinal (GI) symptoms, like chronic abdominal pain 4 5.

What Causes Low DAO Enzyme Activity?

While it is not fully understood why some people have lower DAO activity than others, there are several factors that are known contributors 6. 

Genetics and age may play a role, with DAO deficiency becoming more common after the age of 40. Gut inflammation and dysbiosis, a disruption in the balance of healthy gut bacteria, are also likely contributors 7. Many patients who address underlying gut dysfunction see meaningful improvement in their histamine intolerance symptoms as a result.

Certain medications are also known to reduce DAO levels or interfere with how the enzyme functions. These include 8:

• NSAIDs, like aspirin or ibuprofen
• Prokinetics, like metoclopramide
• Antibiotics, like doxycycline or neomycin B
• Antidepressants, such as MAO inhibitors or amitriptyline
• Anxiety medications, like diazepam or barbiturates
• Opioids, such as morphine or codeine

Hormonal fluctuations can be a factor as well. When estrogen drops before menstruation, DAO levels tend to fall alongside it. This may explain why some women experience worsened symptoms during their period 9.

How to Test for DAO Deficiency

There are actually two enzymes that break down histamine: diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT).

DAO is found mainly in the lining of the small intestine and plays the primary role in breaking down histamine from foods. HNMT, in contrast, is the main histamine-degrading enzyme in the brain and other tissues, where it regulates histamine’s activity as a neurotransmitter. Although researchers have investigated whether reduced HNMT activity may influence neurological symptoms, its clinical role in histamine intolerance remains much less established than that of DAO.

While we don’t routinely recommend them to clients, test kits that check for serum diamine oxidase activity are available online. If you decide to buy a diamine oxidase test kit, you’ll typically just need to perform a simple finger prick to provide a small blood sample.

Opinions vary on the interpretation of DAO levels, but a common guideline suggests that levels below 10 U/mL may indicate an increased risk of histamine intolerance 4.

A DAO test, or an assay, is just a small piece of the puzzle when treating histamine intolerance. We can usually make more progress and spend less time and money by evaluating a client’s symptoms and seeing if a low-histamine diet is beneficial.

Do DAO Supplements Work? Benefits and Limitations

Given DAO’s role in histamine intolerance, supplementing with the enzyme has attracted growing interest as a way to help manage symptoms triggered by high-histamine foods.

While the research on DAO supplementation is still evolving, early findings are promising and suggest it may help reduce symptoms in some people with histamine intolerance. Here’s what we currently know about its potential benefits, limitations, and who may be most likely to benefit.

Benefits of DAO Supplements 

Randomized controlled trials (RCTs), considered the gold standard of human research, have suggested that DAO supplements may help people with conditions potentially linked to too much histamine.

The findings of the benefits of DAO supplementation are summarized in this table:

Limitations of DAO Supplements

Current research suggests DAO supplements are safe and generally well tolerated. While these findings are encouraging, they are based on a limited number of well-designed human studies, and additional research will help clarify their full potential 8. 

In general, evidence on DAO supplements has yet to clarify:

• If DAO can directly help with histamine intolerance
• How much DAO is ideal to take
• Whether DAO may cause negative side effects with long-term use

Something else to bear in mind is that most (if not all) diamine oxidase supplements are made from pig kidneys 8. This could be a problem if your religious affiliation or diet restricts pork or animal products in general.

Although DAO supplements can be a helpful tool for managing symptoms, we typically use them alongside other strategies that support long-term improvements in histamine tolerance. This may include addressing gut health, identifying dietary triggers, and targeting factors that contribute to histamine-related symptoms.

The 5-Step Clinical Protocol for Histamine Intolerance

DAO supplements alone can be very helpful for some people with histamine intolerance. But in the clinic, we often find a more root-cause approach is essential for managing the condition. For long-term relief, we focus on addressing the underlying causes with the following five steps.

Step 1: Start a Low-Histamine Diet and Support Gut Health

When we suspect histamine intolerance, the best way to reach a diagnosis is usually to have clients try a low-histamine diet. For a period of time, they avoid these four main categories of histamine-rich food:

• Any aged food, such as mature cheese or aged meat, or leftovers
• Any fermented food or drink, such as sauerkraut or red wine
• Various types of cured and canned meat or fish
• Shellfish

Compared with many strict elimination diets, a low-histamine diet isn’t too difficult to follow. The table below shows how we advise clients to make wholesome switches that can reduce histamine, all while ensuring happy tastebuds and enough nutrients:

* In the case of those with gluten sensitivity or celiac disease.

** In case this looks different from other high-/low-histamine lists you’ve seen, know that not every food listed in the “avoid” column is a histamine-rich food. Some foods listed may stimulate histamine production or inhibit DAO activity, leading to a similar outcome: an increased likelihood of histamine intolerance symptoms. 

These dietary swaps are the ones I’ve found to be most effective in my clinical practice.

When following a low-histamine diet, it’s important not to stress over the occasional high-histamine meal, whether it is planned or accidental. For most people, an 80:20 approach (staying on target 80% of the time) is enough to manage symptoms effectively.

Histamine-intolerant people usually notice their symptoms improve within 1–2 weeks of starting a low-histamine diet. If not, and depending on their symptoms, we may move into trialing a low FODMAP diet or a Candida diet.

Take Care of Your Gut Microbiota

Alongside a low-histamine diet it’s also helpful to support the health of the gut microbiota by taking probiotics. Though research is in its early stages, it’s thought that dysbiosis, or a disrupted balance of healthy bacteria in the gut, may play a role in histamine intolerance 1. 

For example, people with histamine intolerance may have reduced microbiota diversity and lower Bifidobacterium counts 14. Their gut may also contain more bacteria that are capable of producing histamine 15. Such changes in healthy gut bacteria may contribute to inflammation of the gut lining (intestinal mucosa) and less effective DAO. 

In the clinic, we’ve found that the most effective probiotic is one that combines different species, such as a blend of Lactobacillus and Bifidobacterium species, a beneficial yeast, and a soil-based probiotic.

Some out-of-date claims still lurking on the internet suggest that probiotics produce histamine and should be avoided in histamine intolerance. However, the only study we’ve found on probiotic histamine production showed that a multistrain probiotic made very little histamine in a Petri dish 16. 

What’s more compelling, though, is a meta-analysis (highest quality study of studies) that found that multi-strain probiotics can improve allergy symptoms (namely rhinitis) related largely to histamine 17.

In addition to probiotics, a few other gut supports we’ve found clinically useful for patients with stubborn histamine-like symptoms include: 

• An elemental diet 
• Herbal antimicrobials, such as oregano oil, garlic, and wormwood
• L-glutamine at 10–15 g/day

Step 2: Stabilize Mast Cells with Supplements

Mast cells play a key role in histamine intolerance. Found especially in the skin, lungs, and digestive tract, they are immune cells that store and release histamine when they come into contact with certain stimuli. 

Common triggers of histamine release by mast cells include allergens, infectious organisms like bacteria or viruses, physical stimuli like heat or friction, certain foods, and stress. 

Overactive mast cells can contribute to excess histamine, which worsens symptoms. But it’s possible to stabilize mast cells by reducing their histamine release and the inflammation that follows.

More research is needed, but both lab studies and human trials have found that the following may be effective mast cell stabilizers 18:

• Quercetin 
• Resveratrol 
• Curcumin
• Vitamin D
• Benifuuki green tea (contains EGCG, a polyphenolic compound)

I’d also add luteolin and melatonin to this list given that: 

• The anti-inflammatory compound luteolin outperformed cromolyn (a mast cell stabilizing medication) at reducing histamine release and inflammatory cytokines in a study 19. 
• The sleep hormone melatonin showed potential for reducing mast cell activity by blocking inflammatory pathways in a lab study 20.

We’re waiting for more research to confirm which of these supplements can actually relieve histamine intolerance in people. But they’re generally safe to try, and we’ve had good clinical results using one or more of them, as outlined in the following protocol:

The doses are based on what studies have reported as successful results and what our histamine-intolerant clients report as helpful.

Step 3: Boost the Body’s Ability to Metabolize Histamine

Having an optimal intake of vitamins and minerals is important for metabolizing histamine. The following micronutrients may help DAO break down histamine:

• Vitamin C (2,000 mg/day decreased blood serum histamine by 38%) 21
• Vitamin B6 (especially the pyridoxal-5-phosphate form) 8
• Copper 8
• Zinc 8

Although a healthy, balanced diet should supply these nutrients, supplements can help you achieve the higher intakes we find useful for histamine intolerance. To avoid over-supplementing, and to know which vitamins your body may be deficient in, a blood test is something to consider with the support of your clinician.

When we use supplements to support a faster, more efficient breakdown of histamine, these are the micronutrients and doses we use:

If you want to add these supplements to your own regimen, taking them with, or after, a meal is usually the best to avoid stomach pain. However, you should check with your own healthcare provider about which products and doses are right for you.

Step 4: Directly Break Down or Block Histamine

If my clients are still troubled by high-histamine symptoms after implementing steps 1–3, we will try a DAO supplement. At this point, it becomes clear when someone needs direct enzymatic help to break down histamine.

When diamine oxidase is called for, we have clients take at least 10,000 HDU (histamine-degrading units) before meals 8.

For those who are open to conventional medications, antihistamines are also an option. Usually available over the counter, these drugs block histamine receptors and can be good for short-term support, taken as needed.

The two types of antihistamines are:

• H1 blockers: Zyrtec, Claritin
• H2 blockers: Pepcid, Zantac

You should check with your own doctor about proper dosing, but our clients who need them usually take both an H1 blocker and an H2 blocker each day.

Step 5: Address Other Culprits

If other factors could be contributing to your histamine intolerance symptoms, it’s important to address them.

For example, female hormonal imbalances, stress, environmental toxins, and infections may all play a part.

Female Hormone Imbalances

I already alluded to the fact that the menstrual cycle can affect diamine oxidase, with levels declining alongside estrogen and progesterone hormones before menstruation 9. 

To support a healthy hormone balance in women who get histamine symptom flares (manifesting mainly as bloating, fatigue, or mood swings), we often recommend using the following herbs, or a curated combination of them:

• Black cohosh
• Dong quai
• Licorice root extract
• Chaste berry extract
• DIM (Diindolylmethane)

It’s best to check with your practitioner to figure out which hormone-balancing herbs might be best for your own symptoms of histamine intolerance.

Unmanaged Stress

Stress may also play a role in histamine intolerance. For example, in lab studies, stress hormones like CRH (corticotropin-releasing hormone) can activate mast cells 22. 

Science-based ways to manage stress include:

• Yoga
• Meditation
• Cognitive behavioral therapy (CBT)
• Time in nature (if allergies aren’t a concern)
• Limbic system retraining, like The Gupta Program

Environmental Exposures

Mold, chemicals, and allergens can trigger mast cells to release histamine 23. To manage this, it’s important to identify and reduce exposure to these triggers whenever possible.

Infectious Organisms

Infectious organisms can also stimulate mast cells and contribute to histamine-like symptoms. Examples include:

• Vector-borne microbes like Borrelia, Babesia, and Bartonella 23
• Viruses
• Parasites
• H. pylori
• Candida
• Small Intestinal Bacterial Overgrowth (SIBO)

Addressing any infections that might be triggering mast cell activity is an important step toward managing symptoms of histamine intolerance.

Diamine Oxidase Isn’t the Only Factor in Histamine Intolerance

Diamine oxidase (DAO) plays a key role in breaking down histamine, but it’s only one piece of the puzzle. Factors like gut health, mast cell activity, stress, hormonal imbalances, and environmental triggers may all contribute to histamine intolerance and its symptoms.

By adopting a holistic approach, including dietary adjustments, gut support, targeted supplements, and lifestyle changes, you can reduce your histamine load at the root and regain control over your symptoms. DAO supplements and antihistamines can provide additional relief, but they’re most effective when used in combination with strategies that address root causes.

If you need help walking through the 5-step process outlined in this article, you can subscribe to and download our Histamine Intolerance Handout. Alternatively, you can book a consultation with the clinic here. We’d love to help.

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