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Could Your Histamine Intolerance Really Be Mast Cell Activation Disorder?


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Reviewed by Laura Beth Schoenfeld, RD, MPH

Do you have trouble with histamine? Have you struggled to get a diagnosis? In Mast Cell Activation Disorder (MCAD), part of the innate immune system becomes hyperactive, releasing histamine and other chemicals that affect every organ system in the body. Read on to learn more about MCAD, and how you can address the root cause.

Histamine intolerance
Do you have trouble with histamine? Mast cell activation syndrome can contribute to the release of histamine. istock.com/Ugreen

Histamine intolerance has become a popular term in the natural health community.  Characterized by symptoms that appear to worsen with the intake of foods that are high in histamine or that stimulate the release of histamine, histamine intolerance is not really a diagnosis as much as it is a description of symptoms.

Most clinicians, including myself, now believe that Mast Cell Activation Disorder is a more accurate description of what patients with so-called “histamine intolerance” are suffering from. There are a number of factors that can contribute to, or cause, histamine intolerance, including excess histamine production, diamine oxidase (DAO) enzyme deficiency, HMNT mutation, and poor methylation in the liver; however, my experience has been that MCAD is responsible for a large number of cases of histamine intolerance. This article will serve as an introduction to MCAD – what it is, what causes it, and how to treat it.

Mast Cells: Sentinels of the Immune System

Mast cells are white blood cells found in all human tissues, especially at places where the body interfaces with the environment, like the gut and skin. Though best known for their role in allergies, mast cells are also involved in the formation of new blood cells, wound healing, the development of immune tolerance, defense against pathogens, and the maintenance of blood-brain barrier function. (1, 2)

Mast cells are the sentinels of the innate immune system, on the lookout for environmental changes or insults to the body. They respond by releasing mediator molecules that influence the behavior of other cells and tissues in an effort to maintain normalcy, or “homeostasis.”

There are over 200 of these mediators stored within the granules of mast cells, including tryptase, prostaglandins, leukotrienes, and histamine. (3)

Histamine often gets a particularly bad rap, but it has many important physiological functions in the body: acting as a neurotransmitter, regulating stomach acid secretion, and playing a role in the local and systemic immune response. (4) The key takeaway here is that we need mast cells and their mediators for normal body function. The issue arises when these cells become overactive, as they do in individuals with MCAD.

Mast Cell Activation Disorder: The Hidden Diagnosis

Mast cell activation disorder is characterized by the accumulation of mast cells that are genetically altered (mastocytosis) and/or the abnormal release of mast cell mediators (Mast Cell Activation Syndrome). Because mast cells are found in all human tissues, and mast cell mediator receptors are found on almost every cell in the body, MCAD has the potential to affect every organ system. (5)

MCAD presents clinically as a chronic, multisystem pathology of a generally allergic and inflammatory theme, and has been associated with obesity, diabetes, skin conditions, irritable bowel syndrome (IBS), depression, and more. (6) MCAD does have a genetic component, and tends to cluster in families (7), though related individuals may present with very different symptoms. (8)

Trouble with histamines? Get to the root of the problem.

MCAD is estimated to be more prevalent (9) than other diseases of mast cell dysfunction, but also more difficult to recognize. This is at least in part due to the fact that it often does not cause abnormalities in routine lab testing. MCAD was not named as a condition until 2007 (10) and diagnostic criteria weren’t proposed until 2010. (11)

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Finding the Root Cause of MCAD

In the functional medicine model, we always seek to address the root cause of disease, as opposed to just treating symptoms. We still have a lot to learn about MCAD, but I believe it is likely the result of deeper pathologies, including:

Heavy metal toxicity: Heavy metals like aluminum and mercury have been shown to destabilize mast cells. This makes sense, as the very purpose of using these as vaccine adjuvants is to elicit a heightened inflammatory immune response. Lead, cadmium, and bismuth have also been found to activate mast cells and cause mast cell mediator release. (12)

Infections or gut dysbiosis: The gut is home to 70% of the immune system (13), including a large number of mast cells. Parasitic infections, bacterial/viral infections, or bacterial/fungal overgrowth activate mast cells. (14) Helminth parasites and Candida have been shown to be potent stimulators of mast cell activation. (15, 16) Mast cells regularly interact with microbes, and gut dysbiosis itself may lead to MCAD. (17)

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CIRS: Chronic Inflammatory Response Syndrome could also play a role. Those who are particularly susceptible to mold and have a reduced ability to clear mycotoxins from the body, which leads to a constant activation of mast cells.

Nutritional Deficiencies: Some nutrient deficiencies can trigger MCAD. Vitamin D is required to maintain the stability of mast cells, and a deficiency has been shown to activate them. (18) Zinc is involved in regulating mast-cell function, and there may be a link between magnesium deficiency and inflammation. (19, 20)

Treatment for MCAD

Conventional treatments for MCAD are pharmacological agents that block the action of mast cell mediators. While these may provide much-needed relief to patients, they are not a long-term solution and can have unwanted side effects. Safer short-term action steps that you can take to provide some relief include:

  • Adopting a low-histamine diet: For some people with MCAD, a low-histamine diet provides significant relief. Supplemental diamine oxidase can also help by increasing histamine breakdown.  But, it’s important to keep in mind that this is only reducing exogenous (outside) histamine, and not altering the amount produced by your mast cells endogenously (within the body). Histamine is also only one of many mediators produced during mast cell degranulation.
  • Focus on nutrients and foods known to stabilize mast cells: Many nutrients, including selenium (21) and vitamin C (22), have been shown to stabilize mast cells. A number of herbs and spices, like holy basil (23), peppermint (24), ginger (25), thyme (26), and turmeric (27) also have this effect. I have also seen good results with supplemental forms of quercetin (28), bromelain, nigella sativa (29), nettle (30), and butterbur. (31)
  • Reducing stress: Corticotropin hormone, released in response to physical or psychological stress, destabilizes mast cells and causes them to release their mediators. (32)
  • Entraining circadian rhythms: Mast cell activity closely mirrors circadian rhythms (33), so getting enough sleep and avoiding blue light at night is crucial.

Ultimately though, we need to address the root cause:

  • Remove heavy metals from your system: Chelating agents can help to remove heavy metals from your system. This is best done under the guidance of a healthcare practitioner. Removal of old mercury fillings by a trained professional can also reduce the burden of heavy metals in the body.
  • Treat infections: A comprehensive stool test can help identify parasites and other infections that could be contributing to mast cell activation.
  • Heal your gut: Remove inflammatory foods and focus on nutrient density. Include plenty of probiotic, prebiotic, and healing foods in your diet.
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Join the conversation

  1. Chris, there is a great book by Dr. Lawrence B. Afrin, a well known hematologist in the field of mast cell diseases called: “Never Bet Against Occam, Mast Cell Activation Disease and The Modern Epidemics of Chronic Ilness and Medical Complexity ” 2016. I just finished reading it and it has really helped my understanding of this difficult to diagnose disease. I have suffered from this since I was young, the doctors. It knowing what it was. My son also has it and we have the genetics.

  2. I have genes that prevent methylation as well as variants in Dao genes. I cannot get rid of cellular waste effectively or deal with the heavy metals. Have Hashimoto’s and chronic fatigue, recurrent SIBO, leaky gut, many different food sensitivities including all grains, dairy, legumes, sugar, eggs, and most nuts. Am working now to try support methylation. Been a battle for many years. Am 69. Suspect MCAD is an issue as well. Haven’t found an answer yet but am constantly working on it. Feel fairly good ne day and sleep well then terrible the next with no sleep. Nose runs most of time and chronic sinus drainage that itches my throat.

    • Ah Judy, I felt like I was reading about myself! That’s great that you continue to work on it. That’s what it takes to battle this disease. Even with a diagnosis of MCAS, the burden of finding what helps us is on us. And the interesting thing is that sometimes what helps one doesn’t help another. Best of luck on your journey.

    • Wow you describing me. What foods do you eat then, specifically the nuts that you can tolerate? I am now doing my best to just eat foods that grow, no longer pre-packaged foods. But nuts are something I love and yet can cause kidney stones and Diverticulitis issues for me. I had my kids food sensitive tested a few years back called an Igf test.. they came back with issues with all gluten, eggs, dairy, shrimp and honey. I know I am similar to what they tested. My nose is always post nasal drip too no matter what time of year it is.

  3. This may be the answer to my issues. When not following a paleo diet, I struggle terribly with debilitating allergy attacks, so I’ve put together the link to my digestion and gut. How do I find out for sure whether this is the root cause? I can’t imagine having this conversation with my MD, and when I asked a gastroenterologist about candida, she looked at me like I was crazy. Thanks!

  4. I have gotten into a habit of taking anti-histamines daily because I feel less reactive to things, less itchy and puffy eyes and better on a whole.
    I react severely to insect bites which often tend to reappear and swell as if I have just been bitten on an annual basis
    I couldn’t believe your article because I was beginning to wonder if I just was imagining that I felt better but perhaps there is a deeper reason why.
    I would be really grateful to find out if I need to run tests …

  5. So is this why i all of a sudden have chronic hives? The hives coincidentally started the same time my thyroid levels dropped and my blood work showed hypothyroid and high antibodies? I tried gluten free/paleo for years and it doesn’t effect the hives at all. I go through cycles of where the hives get really bad and then go away for a while. Skin test on allergens all came back neg. So right now im getting the Zolair shot and taking zyrtec every day . The combo of the 2 is def helping. I do remember my allergist talking about mast cells when describing to me how the shot works. Would trying an anti histamine diet possibly assist too? Thanks!

    • I had really bad hives for years until I discovered that it was when I ate sweet things, especially fruit, so maybe a fructose problem? Alcohol also seems to trigger the hives but not so bad. I steer clear of anything with fructose I can tolerate a very small amount of ordinary sugar, so maybe the sucrose cancels it out to some extent, but mainly I eat nothing sweet at all, and so no hives. If I cheat the next day the hives are back!

  6. Which foods likely trigger histamine action more? and those that lower such activity? Thanks Chris.

  7. I got anti histamine eye drops, anti histamine pills, anti histamine nose drops and still it felt like it was going haywire, especially just before the period it is going berserk. But I have to say I went Paleo low carb a couple of months ago and my blood results came back perfect (I saw some huge improvements), my hair is in good condition, even after all the abuse, my menstruation has decreased (menorrhagia) and lost after so many fruitless attempts 24 pounds in 3 months! I hope my other issues will improve over time as well if I also keep an eye on the histamine levels in food.

    Thanks for the article!

  8. Copper is essential for the formation of the DAO enzyme.

    Many avoid it because of the fear of its toxicity.

    When I was copper deficient, I became intolerant of many foods, even beyond high histamine ones.

    • You can have high copper levels and low useful copper. There are different forms of copper you can purchase. Copper sebacate is more likely to increase useful copper. Personally, I was diagnosed has having low useful copper. I tried copper gluconate and it made me feel poorly. However, the sebacate form was helpful.

      I have since found out that you need a protein called ceruloplasmin to transport and use the copper. To make cerulopalsmin, you need boron. However, you lose your boron if you have been exposed to aluminum. I think my problem was a lack of boron, because I had also been diagnosed as having too much aluminum in my body. Boron / borax supplementation helped my health. I’ve been using Fiji and Volvic water to remove the aluminum. I can’t say that water has made a dramatic difference, but some subtle improvements in my health have occured.

      • Thanks for the info, Polly,

        I’ve tried both the copper sebacate and copper glycinate.
        Both seem effective.

        Interesting about boron.

        Metals can displace each other and cause deficiencies. It turns out that I have iron overload, which can cause copper deficiency.

        Copper enzymes and proteins, like ceruloplasmin, regulate
        iron metabolism. I’m hoping that dietary practices, etc., along with copper supplementation will mitigate the iron overload.

        Meanwhile, the high histamine symptoms have resolved.

  9. This is very interesting. I have Hashimoto’s disease( which I am slowly healing naturally), high mold reactions, and high Candida Antibodies that are extremely difficult to get rid of. My body also tends to create abnormal skin celled moles, which I get scraped off often.I wonder if this all as something to do with MCAD?

  10. Could histamine be a problem if there is a lack of the typical respiratory symptoms? I never get cold like symptoms such as runny nose, etc., but I get seemingly random and sometimes intense itches in arms and other places that are pinpoint localized. I also get frequent migraines that I’ve never been able to identify triggers for.

  11. What about the relationship between folate deficiency and high histamine? Or insufficient methylation altogether, which can cause the body to have a higher toxic burden?

    And, do you know of a DAO product that doesn’t contain rice or corn (which I’m allergic to…)


    • +1 for that idea! I, too, have looked for a DAO supplement free of rice or corn without success.

      My functional MD inquired with a compounding pharmacy and they weren’t able to find an unadulterated source either. Apparently it is considered a drug in the EU, so we had hoped the enzyme might be available as a raw ingredient.

      Chris Kresser: product opportunity!

  12. As someone with diagnosed MCAD, I was wondering if you would talk about under the “Root Causes” section about MCAD’s relation to connective tissue disorders like Ehlers-Danlos Syndrome. Research suggests that MCAD can be caused by/secondary to Ehlers-Danlos Syndrome and faulty collagen. I’d love to hear your take on this as well. MCAD-EDS-POTS is a disease cluster that it seems little is known about, and I tend to see articles like this where the causes of MCAD are talked about as something that can be addressed and healed, but I become disappointed when I realize that my particular mast cell activation issues may not be caused by heavy metal, mold, or gut dysbiosis but because of a genetic condition.

    • I have MCAS-EDS-POTS and it is getting worse. I would also be very curious as to more research in this area.

  13. Hi Chris, At last, someone is talking about this debilitating problem.
    I’m 70, and have battled with Hashimotos & other auto immune issues all my life, and I’ve baffled, AND battled a LOT of doctors over the years! Now, thankfully, there are a few Integrative medical professionals who are thinking beyond the square and realizing that it is NOT all in our heads. I’ve tried everything to get rid of the inflammatory side of the disease, with very little success. I came across an article on histamine, as I was trying to find out why I can’t eat so many foods,…gluten, dairy, sugar, salicylates, and anything yellow, orange, red or purple. These foods produce violent leg cramps, and sometimes, hand cramps, numbness in one side of the face, dry eye and all sorts of nerve tingling and other weird problems. I’ve tried every recommendation to fix my gut, include. bone broth by the bucket, probiotics. etc. etc.
    I NOW read that one cannot have any of the lactobacillus varieties of probiotics with histamine intolerance, and various other supplements that I take are no no’s too.
    You have to look at everything, for instance ginger and tumeric are supposed to be helpful, but if I had either of those, I would be up all night, screaming with leg pain.
    Yesterday I had a $400 blood test, to check on methylation and histamine issues. Can’t wait for the answers!
    I suggest that once autoimmunity is activated, the body tries to compensate in any way it can, which throws the whole system out of wack, and it begins to over produce or under produce all sorts of mechanisms. As the years roll on, we suffer more and more from the breakdown. Hence, my body now reacts in some way to every food I put in my mouth because it sees it as a ‘foreigner’ and sends in a whole army to protect it. I’d like to know how many people who have histamine intolerance, ALSO have auto immune diseases, perhaps 100%? Also, what is the connection between histamine intolerance/Mast Cell issues and Methylation?
    Hope this helps someone!

  14. Chris and team, thank you for this article. I was wondering if you could recommend a functional medicine doctor in the southern California area …preferably the Torrance/Redondo/Hermosa/Manhattan Beach areas. (I see the practitioners in your clinic are located in Northern California.) I have Crohn’s (and other autoimmune conditions) which I have semi-successfully managed with Paleo and AIP. However, I’ve now developed some sort of angioedema with itching (on my face and eyes, which is especially concerning), and I would like to seek professional help for proper testing and treatment. I think it may be histamine intolerance (and may be related to mold and/or mercury exposure). I read that Chris is originally from Manhattan Beach and thought he might be able to recommend a good FMD down here. Any recommendations would be much appreciated. Thank you in advance!

  15. Please include Copper as an essential component of the DAO enzyme.

    Copper deficiency may be part of the reason there is so much histamine intolerance these days.

  16. Yes, I have histamine intolerance. What I noticed at the age of 67 that Hormone Replacement therapy aggravates it. I was off HRT for 5 years and when I went back on it for my bones the migraines started back up. Also being on the computer with eye strain also triggers the response. Good article. Do you know anyone that has been cured of this condition? I would really like to know. I would like to eat fermented foods to heal my gut, but I can’t because it creates very bad high pitched tinnitis. I tried to take DAO but it wasn’t a good long term solution. Is there a Autoimmune connection? As I have Graves disease also.

  17. Great article…. I have a question though. Can taking histamine through pill form, such as hydroxyzine or benadryl, cause the same reaction in your body if your intolerant or even in a person who is not intolerant? Thank you!

    • Those drugs are ANTI-histamines. They work by blocking certain receptors that histamine binds to, thus temporarily stopping histamine based symptoms (itchiness, runny nose, etc). They don’t break down the histamine however, so if you have a build up of histamine in your body, it will likely still be high (but maybe not so bad) when the drugs wear off.

  18. Good information, Chris! I have Chronic Lyme disease in which I am being treated naturally. This sounds like it could be a problem that Lyme disease would help to occur. What are your thoughts?

      • Isn’t MCAD diagnosed by chronically high tryptase levels? MCAD was ruled out in my case because my tryptase levels routinely tested low normal. I think information about tryptase and other clinical and symptom indicators need to be included in this article surrounding the discussion of MCAD. If someone gets this diagnosis, they are going to have a hard time finding experienced practitioners to help them manage the condition when generic information like this does not work well enough.

        • Good point. Just finished with a hematologist. Tryptase was high, then low. The urine test was negative. And now my bone marrow biopsy came back normal. I think there isn’t even an agreement on the definition within the medical community. My allergist was the one who finally suggested the diagnosis, but no one knows what to do. I feel like I’m going crazy and the reactions just keep happening. I walk too much, I break out in hives. I get stressed, my face turns beet red, itchy and puffy. I spend more than 10 min in the sun, I get welts all over my arms, neck, chest and calves (even though they weren’t exposed to the sun). I can’t tolerate ginger, fish oil, corn (used in many supplements). Didn’t mean to rant but yesterday’s dr visit made me feel like I will never feel better again.

          • Restesting is a very good idea. Dr. Afrin recommends 3 rounds of testing. I think only 1 bone marrow biopsy and aspiration, but even then, bone marrow biopsies and aspirations miss MCAD 1 in every 6 times. This is because mast cells tend to aggregate in clumps, sometimes that is. So a sample may not show anything. The mediators tested in the urine and blood have a super short half life, so its difficult to get an accurate reading.

      • Given that MCAD is a disease of genetically altered mast cells and not an autoimmune disease…would the low histamine version of AIP still be a useful for those of us battling with this disease? Thanks!

    • I have chronic Lyme as well–which has welcomed SIBO and guy dybiosis. But yet I struggle to find relief, answers…. Do others with Lyme have MCAD? What are symptoms that would indicate this is something to look into?….. Do conventional doctors test for that then too?

    • I have Lyme disease with babesia infection and I have histamine intolerance issues along with mcs (multiple chemical sensitivities). A low histamine diet has been beneficial along with “pearls” histamine degrading probiotics. Sometimes I go days where my nose runs and inside of ears itch or roof of mouth also chest pressure and head and and neck swell up and ears are full and pop. Also severe brain fog and dizziness. I have methylation issues too. I take quercetin and vit c and organic sulphur. I will sauté several onions and eat them to help stop the nose from running. Dao enzymes are also my first defense. My blood pressure drops and I get the pass out feeling. I eat Celtic sea salt when this happens.