 This week (3/27/25) I hosted a class on histamine intolerance & mast cells activation syndrome at the Vermont Center for Integrative Herbalism. I gave an overview of the latest research on the pathophysiology of these disorders, how to differentiate them from one another, and how to address their symptoms and root causes with dietary changes, herbal medicine, and supplementation. You can purchase the recording of this class at this link here. But I also wanted to post a transcript of this information here on my website, so that I can cite my sources more closely and spread this information to a wider audience. A couple people in the class had mentioned that my presentation was the most detailed and comprehensive they'd ever seen, which I was surprised by since histamine intolerance is such a hot topic and so many alternative practitioners want to share their opinions about it online (often without grounding their claims in scientific research). As my regular readers know, this website is all about empowering people to take charge of their own health by deepening their knowledge of health and disease. So in that vein, here is a write up of the discussion we had in class. It will be long but I still had to cut out things for time! So please tell me what sub-topics you'd like to hear more about related to histamine intolerance & MCAS. I care about the issues of histamine intolerance (HI) and mast cell activation syndrome (MCAS) because I developed HI myself about a year and a half ago after going on new medications for my double lung transplant. As a clinical herbalist, I have also assisted clients with histamine intolerance. It can be really frustrating for those of us with histamine issues to try to understand our disorders, not only because the symptoms can be so diverse and so uncomfortable, but because there is a lot of contradictory information online about this issue and conventional modern medical practitioners are often not educated on the subject, or dismiss our concerns as being all in our head. Only in the last couple decades has histamine intolerance and MCAS been recognized as real medical disorders, and due to the conservatism of modern medicine, it takes an average of 17 years for new medical knowledge to reach the doctor’s office. In the mean time, alternative and functional medical practitioners plus the wellness industry have taken up the issue, but this has led to a confusing amount of information online, some of which is false or profit-motivated when they’re trying to sell us fancy, expensive supplements. So in this class I want to try to cut through all that and review the latest scientific research on the pathophysiology of histamine and mast cell disorders, and then lay out a holistic approach to addressing them from an herbalist’s perspective. I will also mention the limitations of alternative or complementary modalities, and when we should seek medical assistance. In part one of this class I will discuss what histamine intolerance and mast cell activation disorders are, what causes them, and how they differ from one another. In part two I will discuss how to address the symptoms and root causes of these disorders with dietary changes, medicinal herbs, and a few supplements. How A Healthy Immune Response Works Before we dive into the pathophysiology of histamine and mast cell disorders, I want to briefly describe the way that the immune system should optimally function in relation to histamine production and mast cell activation. Our story begins with mast cells, which are a type of immune-active cell that lives in our connective tissue in essentially every part of the body. In a healthy immune system mast cells help the body fight off infections and recover from exposures to toxins such as insect bites or snake venom. They also promote pain sensations, wound healing, and the creation of new blood vessels. When triggered by pathogenic microbes, toxins, or other environmental stimuli, Mast cells release inflammatory compounds like histamine, serotonin, cytokines, prostaglandins, heparin, and other molecules [5] that flag other immune cells to clean up injured tissue, kill harmful pathogens, or grow new tissue. In the graphic below you can see the mass cell releasing these compounds in a process called degranulation.  Of the many compounds released by mast cells, today we’ll focus primarily on histamine. It’s a biogenic amine, which means that it’s synthesized from the metabolism of an amino acid called histidine via an enzyme called L-histidine decarboxylase [1]. Our bodies produce this enzyme, as do bacteria that ferment upon proteins. Amino acids are the building blocks of protein, therefore histamine can be created from the fermentation of proteins present in both vegetables and animals. When released inside the body, histamine serves many purposes including stimulating stomach acid secretion, muscle contraction, relaxation & contraction of blood vessels, and also serves as a neurotransmitter by activating certain processes in our nervous systems. And most important for our discussion, histamine causes inflammation, that is heat, redness, pain, and swelling of the tissues under normal circumstances this inflammation is positive, although sometimes painful, and leads to tissue healing. So histamine is a pretty important molecule used in a lot of bodily processes, and we can't do without it. The problem is that sometimes the body produces too much or has a difficult time breaking it down, and this can lead to the uncomfortable or dangerous symptoms of histamine intolerance, allergy, or histamine toxicity. The body produces two enzymes to break down histamine so that we don’t experience the negative side effects of a runaway histamine reaction. The first enzyme is histamine-N-methyltransferase (HNMT), which only deactivates histamine inside of our cells [1]. The second is diamine oxidase (DAO) which has broader functions across the body. It breaks down not just histamine but also other monoamines like tyramine, putrescine and cadaverine which can similarly cause negative symptoms when they build up in the body. DAO is produced mainly in the small intestine, ascending colon, placenta and kidneys. In the intestine, DAO is produced by the intestinal villi [1] which are little hair-like parts of the intestinal cells that produce a lot of different enzymes to help us digest our foods, and also we absorb nutrients through the villi.  Intestinal villi. So in a healthy immune system the body produces enough HNMT and DAO enzymes to deactivate histamine at the appropriate time, both when its produced by our own cells and when it’s contained in the foods we eat. Something interesting to note is in pregnancy the placenta produces huge amounts of DAO, releasing about 500x more of it than in non-pregnant people, which explains why allergies, asthma, and other histamine-related disorders can go into remission during pregnancy (and then come back afterwards). [7] Differentiating histamine intolerance from mast cell disorders So let’s talk about what happens when histamine and mast cells get out of whack and start to cause problems. Histamine receptors are located all over the body and mast cells are active in almost every organ system, therefore symptoms of histamine overload can be very diverse. These can include:
The most dangerous type of histamine reaction is called anaphylaxis. This is when so much histamine is released into the body all at once that the throat swells up so that breathing can become difficult and the blood pressure can drop suddenly as the body goes into shock. This is an emergency situation that requires immediate medical attention. For those prone to anaphylaxis, carrying an epipen with them is an important safety measure. An epiPen contains a shot of epinephrine (adrenaline) which counter-acts the effects of histamine and reduces tissue swelling in emergencies. Now, these symptoms are generally thought to fall within two categories: histamine intolerance and mast cell activation disorders; but there is also some overlap between the two, as you can see in the top left of the graph below. Because both of these categories have been researched and described only in the last 20 years or so, there is not yet universal consensus on how to differentiate and diagnosis these disorders. And as new research is coming out we’re discovering more all the time about the underlying causes.  I made this graph to visualize my understanding of how to differentiate histamine issues and mast cell disorders based on how the mast cells are acting. The two axes of this graph are the presence of clonal vs non-clonal mast cells, and allergic versus non-allergic mast cell activation. So let’s start with clonal vs non-clonal on the vertical axis. Certain genetic and epigenetic mutations can cause a body to produce too many mast cells, which is called clonal mast cell disease, or mastocytosis. People with mastocytosis are at very high risk for anaphylaxis because there are too many mast cells that are hyper-sensitive to harmless stimuli, and can therefore flood the body with a lot of histamine all at once [5]. Mastocytosis is very rare and can be diagnosed with a blood test. Herbs and supplements on their own will not be enough to treat this disease, and pharmaceuticals are needed to prevent anaphylactic attacks and control the overproduction of mast cells. On the horizontal axis we have allergic vs non-allergic mast cell activation. An allergy develops when the immune system has learned to over-react and release a ton of histamine when it encounters a specific substance from the environment (such as pollen, certain food like peanuts, or insect venom). In autoimmunity the body can also learn to become allergic to its own tissues. An allergy causes the body to respond the same way every time when exposed to that particular substance, even in very small amounts. Like mastocytosis, the most severe allergies are at higher risk for anaphylaxis, and allergies can worsen overtime if they’re not treated. So, in the bottom right of the graph, we can see that people with both clonal mast cells (mastocytosis) and allergies are at highest risk of experiencing anaphylaxis. Others may have mastocystosis with no allergies (bottom left of graph), allergies with no mastocytosis (top right), and lastly, disordered mast cell activation or histamine intolerance with no allergies and no mastocytosis (top left with red arrow). This last category is where histamine intolerance and what is usually called mast cell activation syndrome (MCAS) overlap. The term MCAS is generally used to refer to the presence of hyper-sensitive and unstable mast cells that are non-clonal. So someone can have both HI and MCAS, and it can be pretty hard to differentiate the two clinically because the symptoms are often the same. So I’m focusing our class today on this category where MCAS overlaps with HI, because this category is lowest risk for anaphylaxis and it’s where we are most likely to benefit from nutritional, herbal, and supplemental support. What is Histamine Intolerance? So let’s describe histamine intolerance in more detail. Histamine intolerance (HI) is a term that describes a symptom picture, not necessarily a disease with a specific cause (similar to gluten intolerance). It might even be considered a diagnosis of exclusion when other mast cell disorders or allergies have been ruled out. Histamine intolerance does not have a universal way of being diagnosed, but it is generally agreed that a person can be said to have HI if:
This is considered the gold standard diagnostic criteria for HI. We can also get blood tests to figure out someone’s particular root cause, but that may not be necessary for the majority of HI cases. Histamine intolerance results primarily from eating foods high in histamine, or ingesting substances that block the enzymatic break down of histamine. The symptoms are generally more mild than in diseases related to abnormal mast cells, although the symptoms can still be really uncomfortable or chronic. Histamine intolerant people can also have allergies, but that they are two different issues. Histamine intolerance is thought to result from one or more of these factors:
Diamine Oxidase (DAO) Deficiency Because DAO deficiency is one of the most common causes of HI, I want to talk about this in a little more detail. Several things can cause us to become deficient in DAO:
 We can improve the activity of DAO in our bodies by avoiding substances that inhibit DAO, addressing dysbiosis or gut inflammation with healing foods, herbs, and supplements, and also taking a supplement of the DAO enzyme itself. What is Mast Cell Activation Syndrome (MCAS)? Now let me describe MCAS in a little more detail. In an imbalanced immune system that has become hyper-reactive, mast cells can become unstable, meaning that they can be too-easily triggered to degranulate and release inflammatory compounds including histamine, cytokines, and prostaglandins. Unstable mast cells can be triggered by heat exposure, latex, toxins, stress and anxiety, exercise, surgery, certain, chemicals, certain medications, alcohol and fermented foods, and more [7]. There is not yet universal consensus on diagnosing MCAS, however it’s generally agreed that there must be histaminic symptoms in at least two organ systems (for example, in both the gut and the skin), the symptoms are made worse by predictable triggers, and other causes are ruled out [3]. MCAS can occur without sensitivity to histamines in foods (HI), although many times MCAS and HI occur together. Research done over the last several years is revealing connections between MCAS and many other disorders, including:
Epidemiology: Understanding the Big Picture So why do so many illnesses seem to be linked to mast cell disorders and histamine intolerance? What’s the bigger picture here? Well, Since the middle of the 20th century the prevalence of immune disorders like allergies, asthma, autoimmunity, and now mast cell activation disorders has been steadily increasing in modern/ capitalist-colonial, and industrialized countries like those in Western Europe and North America. The map below shows in red the regions that have the highest prevalence of food sensitivities and allergies [16].  Map of global prevalence of allergies and food sensitivities [16]. Nowadays approximately a third of us in these countries have these histamine-related disorders [11] and over 20% of us have food sensitivities [12]. Research over the last several decades has come to blame modernity’s obsession with cleanliness, its overuse of antibiotics, chronic exposure to toxic compounds, unhealthy diets that include refined carbohydrates and industrial vegetable oils, and its disconnection from the more-than-human world and the means of our subsistence (that is, farming, hunting, and gathering) [31]. The human microbiome is negatively impacted by our modern lifestyles which reduce the diversity of the bacteria and fungi in our guts and lead to an overabundance of harmful pathogens. Our gut ecosystems are made up of several trillion bacteria, fungi, and viruses that provide essential services to the human body. This gut microbiome is responsible for educating and modulating our immune responses, digesting dietary fibers, regulating gut motility, absorbing nutrients from our food, defending us against pathogens, defending and repairing the gut mucosal barrier, producing vitamins including the B and K vitamins, producing essential neurotransmitters like serotonin [14]. When this internal ecosystem gets out of balance all sorts of problems can come up, including mast cell hyper-sensitivity and overgrowth of certain bacteria and fungi that produce excess amounts of histamine. In addition, imbalanced gut flora and inflammation from food sensitivities can cause the junctures between our intestinal cells to loosen and allow food-derived molecules, toxins, and pathogens to pass into the blood stream where they shouldn’t be. This is called leaky gut, and it’s common in people with histamine intolerance, mast cell activation disorders, and many other inflammatory diseases [15]. But the new research on mast cell disorders coming out over the last couple of years linking chronic stress with histamine disorders [19], is causing a bit of a paradigm shift for me. That is, I’m coming to understand that all of these immune disorders are signs that the way our society is structured is intrinsically harmful to human and more than human life. And that’s a political issue. Although this class/article is focused on what we can do on an individual level to heal these illnesses, the issues we’ve been discussing are ultimately caused by the socioeconomic exploitation and inequality we experience under capitalist-colonialism, and that needs to be tackled at a more collective and systemic level. I could say a lot more about that, but I know we have limited time. So let’s get into the practical stuff now. An Integrative Approach to Treating MCAS In a 2023 paper, Weinstock, Nelson, and Blitshteyn [2] offered a comprehensive treatment protocol developed from their clinical experience working with MCAS and histamine intolerance in their patients. These patients primarily had neuropsychiatric symptoms like anxiety, bipolar disorder, ADHD, panic disorder, and so on. Weinstock et al. outline several tiers of treatment depending on the severity of the case and how the person responded to each stage. In the first tier they have patients go on a gluten-free, dairy-free, and low histamine diet for at least 3 weeks. Gluten and dairy are removed because studies and clinical experience have shown that MCAS can be triggered by these two food sensitivities [6,12]. Also in this tier they prescribe daily use of H-1 and H-2 histamine receptor blockers (H1 antihistamines are anti-allergy meds like allegra, claritin, and so on; H2 antihistamines are those that block the production of stomach acid). Now, as an herbalist I would prefer at this stage to use herbal medicine, probiotics, and nutritional supplements before resorting to the use of antihistamine drugs. But of course, these medications are necessary to control the acute onset of symptoms. Personally, I use anti-histamine medication only when I suspect I’ve eaten too much histamine that day or when I feel symptoms of histamine overload coming on. I use Allegra or Xyzal, both of which are over the counter H1 anti-histamine drugs. I primarily control my symptoms with a low histamine diet, but for those who are more sensitive than me or have additional hyper-sensitivities like allergies, then daily use of antihistamine drugs may be needed to control sx. And we do want to control our sx, however we can! In the second tier, if patients still don’t have their symptoms under control then Weinstock and friends added mast cell stabilizing supplements, specifically vitamin C, vitamin D3, and quercetin (which is a flavonoid derived from plants). I think we herbalists would add these in stage one. Then, if tier two is not enough, Weinstock and friends add low-dose naltrexone (LDN), which is a microdose of an opioid receptor antagonist that can have profound immunomodulating effects. Again, if that’s still not enough, they prescribe more intense immunomodulating drugs to stabilize or shut down mast cell activity, including a chemotherapeutic drug called hydroxyurea. Obviously herbalists are not going to prescribe any medications, and we’ll instead prefer to use herbs and supplements. But I just wanted to mention this integrative approach because it’s clearly effective and I like that it’s tailored to each individual’s needs. So being in collaboration with a conventional healthcare provider that’s knowledgeable about histamine intolerance and MCAS would be a really good thing, though I know they’re all too rare. How to Implement a Low Histamine Diet So let’s talk now about our most important step in a holistic protocol: a low histamine diet. Histamine is present in any food containing proteins that have been fermented by bacteria which convert histidine to histamine. Sometimes we ferment foods and drinks on purpose, like with yogurt or tempeh or beer. Foods that are cured, smoked, or canned can also be very high in histamine. Sometimes histamine is produced accidentally though, like when food spoils or gets contaminated (usually during long transportation). There is noting inherently wrong with fermented foods, and actually under normal circumstances, they’re really really good for us! Fermented foods can increase the diversity of our gut microbiome, help educate our immune systems, and encourage proper digestion. But for those of us who are histamine intolerant, unfortunately the histamines in fermented foods can be too much for us and lead to sx of histamine overload. So for a certain period of time people with HI need to avoid fermented foods while the root cause of the problem is addressed. But during this time period, it’s important to take a probiotic supplement that is high in bacterial species that don’t produce histamine, which I’ll talk about later. In addition, to reducing histamine in the diet, some folks also experience negative symptoms from eating the other biogenic amines present in aged or fermented foods, specifically tyramine, putrescine, and cadaverine [17]. These other amines can cause similar symptoms, but are especially correlated with headaches and migraines [2,4]. For example, aged cheese and cured meat is high in histamine plus these other amines, so it’s pretty important to avoid those types of food. In table 1 below is a list of high histamine foods to avoid [17]. You may see lists on the internet that give contradictory information in this regard, because many of them are not backed up by legit data. Remember to only trust information online that correctly cites its sources! Also, other lists online sometimes lump in foods that are not high in histamine but can cause mast cells to destabilize and release histamine. These so-called histamine-releasing foods and substances are listed in table 4 [17]. Be aware that there is not consensus on the idea of certain foods triggering histamine release, so you’ll need to assess this for yourself based on your own experience.    These tables are from source [17]. Here is a link to a PDF document that I’ve found to provide the most detailed and accurate list foods to avoid and other foods to replace them with. You can try to memorize these lists, or you can remember how histamine builds up in foods and make inferences based on that logic. So that's:
The Overflowing Pot Metaphor It’s also very important to keep in mind that histamine exerts a cumulative effect in the body. This means that eating histaminic foods won’t have a negative effect on you until you reach a critical load, beyond which your body can’t break down. I like to think of this as a pot full of water. You can keep adding water to the pot little by little, But at some point just one more drop will cause a bunch of water to spill out of the pot. That’s what it’s like for histamine reactions. I can eat half an avocado, a bite or two of yogurt, and maybe a few left overs, but if I eat a cured meat stick on top of that, especially if I do this a couple days in a row, I’ll definitely get red, flushed, and itchy within a couple hours. Another thing to mention is that depending on a few factors such as the speed of your gastric motility and your daily activities, you may experience a histamine response from a food within ten minutes or ten hours, or sometimes even a day or two later. Some conventional practitioners have a misconception that histamine intolerance only happens within 30 min of eating a high histamine food, but when we understand how histamines build up until they reach a critical threshold, we’ll understand why that’s an incomplete understanding. Low Histamine Foods That Are Fine to Eat It’s also important to pay attention not just to what we eat but how we eat and cook our foods. Because our goal is to minimize bacterial fermentation of foods, we need to emphasize eating fresh foods and staying away from aged and processed foods. It also means we need to change our food storage habits a little bit. Refrigerated leftovers should be eaten within 12 hours or less (depending on your level of sensitivity and the type of food), and it’s a good idea to freeze any foods at risk of spoiling, for example, raw or cooked meats and fish, fresh berries, and so on. For example, before I became histamine intolerance I used to keep a pound of raw beef in the fridge and cook bits of it over a few days. But now I cook the whole pound at once, divide it into servings, and freeze the servings that I am not eating that day. Then if I plan to eat some meat the next day, I defrost a serving overnight in the fridge. I also now cook foods in batches and freeze them, then defrost stuff in individual servings. In general we may need to make smaller amounts of things so that we can keep it fresh, like I make my own salad dressing and I should really not make more than a cup at a time so that I can keep turning over the jar. Below is a list of acceptable foods and substitutes for high histamine foods:
Because everyone is a little different you may find that some foods on the high histamine list don't trigger you, or that in small doses they’re fine. It’s a good idea in the beginning of using a low histamine diet to also remove other hard to digest and inflammatory foods. The most common of these are gluten, dairy, and sugar. There are many studies showing how each of these foods increases gut inflammation or triggers mast cell activation. Last week I taught a class on how to navigate multiple food sensitivities and how to use an elimination diet – you can access the recording of that on VCIH’s website here. Herbal Medicine In general, modern diets and lifestyles are deficient in the plant compounds we have coevolved with to maintain our health. These plant compounds include bioflavonoids, catechins, carotenoids, and so on. Most of us are deficient in these compounds due to our modern diets being too rich in processed foods and not including enough fresh whole veggies and fruits. Many times this is a socio-economic issue since capitalism makes it hard for us to access and afford whole, fresh foods, while it makes it too easy and cheap to get ahold of processed junk food. So in addition to adding more whole vegetables and fruits to our diets, I want to talk about a few classes of herbs that will be particularly helpful with regard to histamine intolerance and mast cell activation.
Above are just a few photos of the medicinal herbs I've mentioned. From top left to right & down we have: calendula flower, American skullcap, artichoke leaf, chamomile, lemon balm, meadowsweet, stinging nettles, reishi mushroom, and goldenrod. Nutritional Supplements Gut healing: because most of us with mast cell or histamine issues also have gut inflammation or leaky gut, I suggest taking supplements that help the gut heal and improve barrier integrity.
Studies have shown that people with histamine intolerance and MCAS often have imbalances in the gut microbiome [7,11,15]. We tend to have too much Proteobacteria and not enough of the beneficial Bifidobacteria, and overall we have lower diversity in our gut ecosystems [15]. This in turn can create the conditions for developing leaky gut and reduced production of intestinal DAO [15]. For those without histamine intolerance I would recommend eating fermented foods like sauerkraut, yogurt, miso, etc. But we need to be a little more careful when choosing probiotic foods and supplements in our situations because some lactic-acid forming bacteria which we usually consider helpful can produce histamine, including some (but not all!) of the Lactobacillus strains that are commonly present in fermented foods and probiotic pills. Here are some strains shown to produce histamine: Lactobacillus hilgardii, Lactobacillus buchnerii, Lactobacillus curvatus, Oenococcus oeni [1], Lactobacillus reuteri, Lactobacillus casei, and Lactobacillus delbrueckii subsp. bulgaricus [15]. Most of the time this is not actually a problem, but for some super sensitive people they may notice they respond negatively to probiotics containing the above strains. In those cases, there is some clinical reports of people responding better to soil-based probiotics, though there has been very little research on this to date [26,27]. So for us, it may be a better idea to choose probitoics that are not histamine producing and are well-documented to be beneficial to the gut. These strains include Bifidobacterium bifidum [15], Lactobacillus rhamnosus GG, Lactobacilltus acidophilus, L. plantarum, Bifidobacterium infantis, E coli Nissle 1917, and Bifidobacterium animalis lactis BB-12 [14], and Bacteroides fragilis [28]. Because the supplement market is very loosely regulated, some probiotic supplements are totally useless, so here are some guidelines for how to choose a legit probiotic:
Other Suggestions An immense number of studies over the last several decades have shown that growing up on a farm and interacting with non-human animals regularly, including cows, horses, goats, and even dogs, improves the diversity and health of the human gut microbiome. Plus interspecies affection is very good nourishment for the soul! Growing your own food, digging in the garden, and being outdoors on a regular basis is also helpful as that exposes us to the beneficial soil based bacteria that help modulate our immune systems. Being less cleanly overall is actually good for our microbiomes, but especially with regards to exposure to animals and healthy soils. My rule of thumb is to stay hygienic when going into human environments like cities and hospitals (because harmful human to human pathogens thrive in these environments), but allowing for dirty hands in the garden and the forest; and extra snuggles with dogs, horses, goats, etc. Though, I know some of us, myself included, are immunosuppressed and need to be more careful with regards to microbial exposures, so be more careful in those cases (but still kiss dogs). 😙🐕 I hope this article is helpful. If you appreciate this info please please consider donating to me! I put an incalculable number of hours into this work and generally don't get well-paid for it. I'm disabled and very low income, so if you could support me I'd appreciate it! You can send me a donation via paypal here. Sources: [1] Comas-Basté, O., Sánchez-Pérez, S., Veciana-Nogués, M. T., Latorre-Moratalla, M., & Vidal-Carou, M. D. C. (2020). Histamine intolerance: The current state of the art. Biomolecules, 10(8), 1181. 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Mica (they/he) is a clinical herbalist, nutritionist, researcher, and writer living in Abenaki territory (Vermont). *************************** Disclaimer: The content of this website and blog is for educational purposes only and should not be considered medical advice. The information provided here is not intended to replace medical care. Archives
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