Histamine and Mast Cell Activation Disorder - Your weird symptoms finally answered

I like to think of Mast Cell Activation Disorder (MCAD) as the “weird” and “strange” symptoms disorder. Since MCAD can affect nearly any organ in the body, the symptomology is incredibly vast, diverse, and unique to the individual. If you or your doctor are not aware of this illness, then your symptoms may appear seemingly unrelated, as did mine.

*Check with your doctor before trying any of the diets, supplements, and strategies discussed

What is Mast Cell Activation Disorder (MCAD)?

MCAD is the broad term used to describe a number of disorders related to mast cells functioning improperly. Just like there are different forms of Inflammatory Bowel Disease (Crohn’s and ulcerative colitis), there are different forms of MCAD, including the following: systemic mastocytosis (SM), mast cell activation syndrome (MCAS), and mast cell leukemia (MCL). Systemic Mastocytosis tends to show up in middle age or early adulthood, while MCAS tends to present symptoms in childhood or adolescence. MCAS symptoms usually shows up early in life, and then after a stressful event, symptoms may begin to get worse.

To understand what MCAD is, it’s best to understand what mast cells are.  Mast cells are a type of immune cell that play central roles in adaptive and innate immune responses. Mature mast cells can be found all over the body, including but not limited to vascularized tissue, skin, airways, bone marrow, and the gastrointestinal tract. When activated, they have the ability to release over 200 mediators, which can cause a variety of responses in the body. One of the most well-known responses is the activation of mast cells role in allergic reactions.

Tryptase is the most abundant mediator and secretory granule released from mast cells, which is why it is the gold standard for diagnosing mast cell activation disorder. Tryptase itself has the ability to stimulate mast cell degranulation and histamine release, which could be a vicious cycle. (R)

Tryptase plays a major role in allergic and inflammatory conditions like rhinitis, conjunctivitis, and asthma. It’s also likely a factor in gastrointestinal, dermatological, and cardiovascular disorders. (R)

Mast cells also have the ability to produce and release histamine, prostaglandins, leukotrienes, and other inflammatory cytokines. The complexity of the mediators released from mast cells and the location in which they act leads to diverse symptoms.

This is not a complete list, but here are some clinical signs and symptoms of MCAD:

Abdominal pain, cramping, bloating, diarrhea, nausea, chest pain, gastritis, malabsorption, cough, asthma-like symptoms, rhinitis, sinusitis, conjunctivitis, difficulty focusing vision, splenomegaly, elevated liver enzymes, hypercholesterolemia, blood pressure irregularity, headache, neuropathic pain, difficulty concentrating, forgetfulness, brain fog, lightheadedness, tinnitus, hives, urticarial pigmentosa, pruritus, flushing, muscle pain, osteoporosis, osteopenia, bone pain, arthritis, fatigue, fever, environmental sensitivities. (R)


Histamine and Histamine Intolerance

I believe that histamine and histamine intolerance is what people first learn about when they are feeling sick and trying to figure out why certain foods or environmental triggers cause reactions.  From there, they may try a low-histamine diet and feel better. However, symptoms may continue to progress, and then later on, possibly months or years later, they learn that the real culprit to their illness is MCAD. Since histamine plays such a huge role in the symptomology of MCAD, it’s important to discuss it here.

Histamine is synthesized by the B6 dependent enzyme L-histidine decarboxylase (HDC) from the amino acid histidine. Histamine is synthesize by not only mast cells, but also basophils, platelets, and other cells, and it’s well known for triggering mast cell degranulation.

Histamine elicits effects by binding to 4 different histamine receptors (H1, H2, H3, H4) located on cells of various tissues. Histamine causes many physical changes, including muscle cell contraction, vasodilation, increased vascular permeability, mucus secretion, tachycardia, arrhythmias, gastric acid secretion, and plays various roles in biological processes such as wound healing and circadian rhythm. 

Short summary on each of the histamine receptors:

H1: found in smooth muscle and endothelial cells. Some functions include allergic responses, vasodilation, and circadian rhythm.

H2: found in gastric parietal cells. Major function in stimulating the secretion of gastric acid.

H3: found in the central nervous system. Major function includes neurotransmitter release.

H4: found on mast cells, eosinophils, T cells, dendritic cells. Major function includes regulating immune responses.

It’s really important to understand that while H1 and H2 antihistamines are a standard treatment for MCAD, you can see that histamine will still be able to bind to H3 and H4 receptors and create havoc. It’s even more important to understand that mast cells themselves have H4 receptors, and when histamine binds to an H4 receptor on a mast cell, it can cause them to release more mediators.  We currently don’t have a suitable H4 blocker drug yet, at least that I’m aware of.

Headaches can be induced by giving both healthy and susceptible patients certain doses of histamine. Histamine headaches are vascular headaches, and caused by the binding of histamine to H1 receptors. Increased numbers of mast cells in the brain is associated with migraine, cluster headaches, and multiple sclerosis. Low histamine diets and antihistamines reduce or alleviate headaches. (R)

Histamine intolerance “might” be different than MCAD, since histamine intolerance has more to do with the ability to breakdown and metabolize histamine. If the body can’t break down histamine effectively and efficiently, then histamine levels can increase and lead to symptoms.

Common symptoms of histamine intolerance include:

diarrhea, headache, nasal congestion, hypotension, arrhythmia, urticarial, pruritis, flushing, urticarial pruritus, flushing. These symptoms are also synonymous with MCAD for obvious reasons. It’s estimated that about 1% of the population has histamine intolerance.


Metabolizing Histamine (DAO and HNMT)

Diamine oxidase (DAO) is the main enzyme that degrades ingested histamine. Histamine N-methyltransferase is the enzyme that helps to degrade histamine inside of cells. Reduced DAO activity can lead to higher levels of histamine in the body. Eating foods that are high in histamine can stimulate mast cell activation, or eating foods that block DAO may lead to increased symptoms in those that are susceptible. Following a low-histamine diet and/or taking antihistamines can reduce or eliminate some symptoms.

Histamine intolerance is generally caused by genetic mutations or some other impairment of the enzymes that help metabolize histamine. Genetic mutations in DAO or HNMT may lead to increased histamine levels. Certain single-nucleotide polymorphisms (SNPs) in the gene that codes for DAO is associated with inflammatory diseases, such as food allergies, gluten-sensitivity, Crohn’s disease, ulcerative colitis, and colon adenoma. Histamine intolerance mostly seems to present itself through inhibited DAO activity, and not so much HNMT. (R)

Gastrointestinal diseases that are characterized by altered and damaged enterocytes may cause a decrease in the production and availability of DAO to degrade histamine. So, while you may not have any genetic mutations for the genes that code for DAO or HNMT, you may still have lower levels of DAO if your gut is damaged.


Criteria for Diagnosing MCAD

The criteria for diagnosing which form of MCAD (i.e. Systemic Mastocytosis vs. MCAS) a patient has is slightly different from one another. Without going in to too much detail here, I will briefly discuss what doctors will mostly be looking for.

The first thing that needs to be carefully and diligently reviewed, is a complete patient medical history starting from birth. Doctors and patients need to discuss every single symptom a person has had through their entire life, but mostly focusing on what seems unusual, such as lots of ear infections, nasal congestion, stomach issues, headaches, hives, itchiness, etc; things that stick out when comparing to other people of the same age. Usually with MCAS, inflammatory symptoms start during early childhood and adolescence, and progress through age. If a patient has Systemic Mastocytosis, it’s more likely that symptoms came on rather suddenly, and usually somewhere around middle age or a little sooner. However, this is just generally speaking, so this thinking isn’t set in stone.

After going through a complete and thorough health history, the next step is testing, and lots of it. During a physical examination, the doctor will likely do a scratch test to look for dermatographism. 

 By JAguayo18 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=48386362

By JAguayo18 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=48386362

The blood and urine testing is detailed and specific. One of the hallmarks of MCAD is a persistent elevated serum total tryptase greater than 20 ng/ml. Other elevated mediators include histamine, prostaglandins, heparin, chromogranin A, and leukotrienes.

The other tests are a bit more complicated and more invasive. One test is looking at biopsies taken from different tissues. In my case, I’ve had a few colonoscopies with biopsies and they were able to get samples taken from 6 years ago, restain them, and check for abnormalities in the quantity and/or quality of mast cells. If there are dense aggregates of mast cells or irregularities seen, this would be another indication of MCAD.

If it looks like your MCAD is leaning towards Systemic Mastocytosis, the doctor may order a bone marrow biopsy and aspiration. However, it’s pretty quick and over in about 10 minutes. The pain comes in short bursts every 15 seconds or so and lasts a few seconds at a time, so it’s manageable. You’ll likely need bone marrow biopsies from each side of the hip (iliac crest), and then in my case, I had 4 bone marrow aspirations from each side. Again, they are looking for abnormalities in mast cells, but also checking for different genetic mutations such as the Kit codon 816 mutation.

In order to be diagnosed with MCAD, 2 or 3 of the tests need to be positive (abnormal), as well as a medical history that points towards the illness. Also, it’s common for testing to come back negative, which is why retesting is usually a good idea. Even if all of your tests come back negative for MCAD, it doesn’t necessarily mean you don’t have the condition. It’s a pretty detailed a long process, but it’s worth it.

Mast cell leukemia (MCL) is rare and is characterized by higher levels of mast cells in the bone marrow and in circulation (≥20%). MCL has a poor prognosis, and most patients who are diagnosed with MCL have less than 1 year to live. While both Systemic Mastocytosis and MCL are rare disorders, MCAS may actually be relatively common.


Treatment for HI and MCAD

*You need to talk to a doctor before starting any of the mentioned supplements or drugs, whether they are OTC or not. MCAD is a complicated illness, and you don’t want to be making things worse.


Unfortunately, MCAD is not curable. Some patients are lucky to find therapies that work within the first few months of trying them, while other take years to figure out what medications and treatments work for them. Avoiding triggers, antihistamines, and mast cell stabilizers are the main treatments. It takes about 4 weeks to see results once a therapeutic dosage tailored to the individual is reached. (R)

Mast cells produce and release over 200 mediators, and currently, only a few of these mediators are being targeted by drug or herbal therapy. This makes it difficult because if lab test results show elevated prostaglandins, then logically, one would believe that non-steroidal anti-inflammatory drugs (NSAIDS, i.e. ibuprofen) would greatly improve symptoms. However, this isn’t the case, because of the complexity and nature of MCAD. This is why I believe mast cell stabilizers are so important. 

Due to the nature of MCAD, patients can react to just about anything, which is why it can be difficult to find exactly which medications and treatments work for them.  As an example, one person may have reactions to all of the brands selling loratidine (generic Claritin), except for the children’s version of loratidine sold at CVS. The antihistamines and active ingredients in medications generally aren’t the cause of reactions, the fillers, binders, dyes, etc. are what cause reactions. It’s important to try out different brands of the same drug, because they all tend to use different inactive ingredients, which can be helpful for those with MCAD.

Avoid Triggers

The first line of treatment is to identify all of the triggers (chemical, food, environment, physical, etc.), and avoid them as much as humanly possible. This can take a long time. It requires you to know you’re body very well, and be mindful of how you feel each day. I recommend keeping a health journal for quite some time (6 months, 1+ year), until you have a good grasp of what causes reactions or makes symptoms flare up. You’ll need to pay attention to exactly what you eat, the quantities, how much sleep you’ve gotten, the smells you’ve encountered, physical activity, pretty much anything and everything. Over time you’ll know what you can and can’t do. At some point after “successful” treatment, it’s likely that you’ll be able to tolerate more of the things that trigger reactions.


 Pretty much what you see here is a big no-no if you've got MCAD.

Pretty much what you see here is a big no-no if you've got MCAD.

 and Diet is going to be your best treatment option. However, diets should be treated as an intervention, and it’s important to avoid extreme dieting if possible. If a diet, (i.e. low-histamine diet) does not seem to be helpful after a month or so, then it should be discontinued. With MCAD, low-histamine diets generally help, but people can react to other things besides high histamine foods, like gluten or whole grains due lectin sensitivities. Sometimes it’s not even the food itself, it might actually be the pesticides and herbicides; even if it’s organic pesticides.  Also, if the diet does not seem reasonable and attainable, in which it completely interferes with life, then it may be a good idea to not follow it or not follow it 100% of the time. In most cases, I believe that a lower histamine diet will help, but if possible, be sure that you are getting all of the nutrients (vitamins, minerals, calories) you need. Extreme diets and elimination diets are just that, eliminating foods, which means that’s less options of getting all of the nutrients.

I recommend trying a low histamine diet for a month or so to see if you have any improvements. If you are unsure if you have issues with histamine or mast cell activation, then a low histamine diet can actually be a tool to help diagnose MCAD.

Although there are a few different lists and guides for eating low histamine, I like the one created by the Mastocytosis Society Canada. Click here to download the pdf.

This is not a complete list of foods to avoid, but this will give you an idea:

  • citrus fruits
  • berries: blueberries are probably the safest
  • fermented foods
  • yeast containing/risen foods
  • pineapple
  • bananas
  • avocados
  • eggplant
  • spinach
  • tomatoes
  • chocolate
  • cinnamon and spicy seasonings
  • smoke foods
  • shellfish, and fish not fresh
  • aged foods
  • pickled foods
  • preservatives, additives, artificial ingredients
  • dried fruits/foods
  • most nuts and seeds
  • cow's milk
  • mushrooms
  • alcohol
  • teas: white tea is probably the safest

Not a complete list, but an idea about foods might work for you:

  • grains: but be careful, because many people with inflammatory issues react to certain grains; white rice is probably the safest (just be careful with blood sugar)
  • potatoes, sweet potatoes and yams might be better than white potatoes
  • rutabaga, parsnips, carrots
  • green beans, broccoli, kale, brussels sprouts, asparagus
  • fruits are a hit a miss, but apples are pretty safe, and blueberries are the least likely berry to cause a reaction
  • fresh fish, or fish that was immediately gutted and frozen
  • fresh meats and poultry
  • salt is the safest seasoning
  • fresh herbs are safer than dried herbs


Track your food and symptoms thoroughly. Also, enter your daily intake into a nutrient tracker like cronometer. This way, you'll be able to see what nutrients you may be missing out on. Nutritional supplements might be needed, but remember, with an elimination diet, we are trying to avoid any possible triggers, and even multivitamins can be triggers.

After 30 days or so, it is then recommended to start adding back one food at a time to see if you react to them. Add back one food every 4-7 days. This will give your body enough time to react and eliminate each individual food.


Nutrients of Concern

ALL nutrients are of concern.

While you need to be sure you are getting enough of ALL the vitamins and minerals, there are a few which require more focus. It might even be a good idea to have some blood work to check for deficiencies in these specific nutrients.

I highly recommend focusing on getting all of your nutrition from whole food sources before resorting to supplementation. Supplements often contain a lot more than you probably need, which can affect the balance of some vitamins and minerals.

Vitamin C

Vitamin C is very important in reducing histamine, inflammation, and mast cell issues. Vitamin C inhibits mast cell production, increases the breakdown and degradation of histamine, and decreases histamine synthesis by inhibiting histidine decarboxylase (the enzyme that forms histamine) (R) Vitamin C is a cofactor for DAO. (R)


Copper is a cofactor for DAO. (R)

Recommended article: Copper


Magnesium deficiency may increase histamine levels and mast cells (R, R).

Recommended article: What You Need to Know About Magnesium

Vitamin B6

B6 is also a cofactor for DAO. (R)

Vitamin B12

Vitamin B12 is important for the methylation cycle, which may help reduce histamine levels.


Folate is also important for the methylation cycle.



I'm not big on supplements, unless the benefits are greater than the risks. There are a variety of supplements that have been shown to stabilize mast cells, inhibit histamine by some mechanism, and/or decrease inflammation.

As far as supplements go, quercetin is probably the most likely to help you.

*As always, consult your doctor before trying any of these supplements. Also, be careful. With MCAD you can react to just about anything.

Quercetin and other Flavonoids

Flavonoids are known for their antioxidant and anti-inflammatory roles.  Some flavonoids have been found to inhibit histamine release from mast cells. Quercetin and rutin have been found to inhibit histamine release and prevent elevated intracellular calcium, and decrease the production of proinflammatory cytokines. (R)

Quercetin is also a mast cell stabilizer. In human cultured mast cells, luteolin inhibits the release of histamine, leukotrienes, and prostaglandins from mast cells, and decreases the production of TNF-α and other proinflammatory cytokines in bone marrow cultured murine mast cells. (6)

Vitamin C

I highly recommend getting all of your vitamin C from food if possible. However, you may want to try supplemental vitamin C to see if you have any noticeable benefits. A lot of people have a difficult time finding a vitamin C supplement that works for them. Ascorbyl palmitate may cause less reactions than ascorbic acid. You also might find that increasing your intake of vitamin C from whole foods is enough. The food that contains the most vitamin C is camu camu, which may be an option for some. Be careful with ascorbic acid and supplemental vitamin C, because higher intakes can mess with copper metabolism.

Vitamin D

A lot of people do not live in parts of the world where they can maintain adequate levels of vitamin D during the colder months, due to the angle of the sun. Mast cells contain vitamin D receptors, and activation of the vitamin D receptor has been shown to decrease inflammation.  Some patients see improvement in taking vitamin D, and 1,000 IU per day seems to be a reasonable dose that should be safe. Also, changes in bone density is common in those with MCAD, such as osteopenia, osteoporosis, and/or osteosclerosis, and vitamin D can help maintain health bone structure.

You can read more about vitamin D on this post here.

Diamine Oxidase (DAO)

DAO supplements have helped some patients.  The supplements are dosed in terms of histamine-degrading units (HDU). HistDAO can be taken at 20,000-40,000 HDUs (1-2 caps) 15 minutes before a meal.


Curcumin is found in turmeric, and probably one of the most (if not the most) recognized natural anti-inflammatory.  The USDA has approved curcumin as GRAS (generally recognized as safe) status, so that’s always nice to hear.

A study on mouse bone marrow derived mast cells found that curcumin inhibits cyclooxygenase-2 (COX-2) dependent prostaglandin D2 (PGD2) and 5-lipoxygenase (5-LO) dependent leukotriene C4 (LTC4) in mouse mast cells. Curcumin also inhibits intracellular calcium influx and nuclear factor- κB (NF-κB). PGD2 plays an important role in inflammation and allergic diseases. Studies have shown that curcumin inhibits mast secretion of histamine, tumor necrosis factor-α (TNF- α) and interleukin-4 (IL-4). It also inhibits other IgE-induced reactions. (R) In rat models, curcumin improves rhinitis, and lowers histamine. (R) Curcumin also inhibits the production of interleukin (IL) -1, IL-2, IL-6, IL-8, and IL-12, and it’s good for ulcerative colitis and arthritis. (R)

Curcumin can help with wound healing and has antimicrobial activities. As you can tell, it is likely and has been shown to be beneficial for a wide variety of conditions, including cancer and autoimmune conditions. Piperine increases the bioavailability of curcumin by 2,000%. Meriva is a patented version of curcumin mixed with soy phosphatidylcholine that is 29 times more bioavailable than curcumin alone. This means that you need to take a lot less Meriva compared to regular curcumin in order to reach the same effect. Interestingly, curcumin becomes more bioavailable when it’s mixed back with some of the other components of turmeric, which means turmeric might be suitable or more suitable than curcumin. Either way, I recommend trying curcumin without added ingredients first, since those with MCAD can react to just about anything.

*PLEAE NOTE:  Curcumin was found to decrease DAO levels, so it may worsen things. (R)

As with all supplements and drugs, there’s the possibility of adverse effects. Some people who’ve taken curcumin experience nausea, diarrhea, abdominal pain, and increased serum alkaline phosphatase and lactate dehydrogenase. (R)

Epigallocatechin gallete (EGCG)

EGCG is found in green tea, and it decreases the level of mast cells and their activity, as well as decrease TNF-α and NF–κB in rats with colitis. (R)


A probiotic containing Bifidobacterium longum and Bifidobacterium infantis reduces histamine-mediated symptoms in rats. (R)


*There are other supplements that have been shown to inhibit mast cells degranulation, but I believe nutrition and lifestyle will help you the most.



Exercise is an important part of a healthy lifestyle. Unfortunately, exercise can actually be a major trigger for persons with histamine intolerance and MCAD. The intensity and duration of exercise should be your main focus, and it's much better to start very slow, document your workout and how you feel after and the next day after, and adjust accordingly. You should definitely avoid running/sprinting, and excessive strain during you workout (unless your body can handle it).

Low-intensity exercises should be the cornerstone of you workout regime. Some ideas to get you started are:

  • Yoga
  • Walking (slow, fast/brisk)
  • Low intensity interval training
  • Weight lifting with light weights

If you have a hard time getting your body moving, just a simple stretching routine can help jump start and wake up the muscles.


Monitor Temperature

Both hot and cold exposure can be triggers. You should particularly pay attention and regulate the temperature of your shower/bath. Luke warm, meaning not hot, and not cold, is probably the best temperature. Taking a hot shower might be relaxing and feel great for a minute or two, but soon after, you will likely feel worse than you did before the shower. If you start to feel too warm in the shower, turn the heat down to cool yourself off.

Its likely that heat is more problematic than cold.

In general, don't let yourself get too hot or too cold.


Filter Your Water

Depending on where you live, the smell of unfiltered tap water might be enough to trigger a reaction. Get a water filter than you can keep in the fridge, or better yet, install one right on the faucet itself. Also, a filter for your shower head is a good idea.


Avoid Harsh Chemicals

Cleaning Supplies

Avoid harsh chemicals like window cleaners and bleach. Invest in some more natural chemicals. If you can, open the bottle while your shopping and smell it to see if it bothers you before you buy it.


Perfume/cologne also has a lot of chemicals in them. Don't wear any, and ask the people around to not wear any.


Use natural soaps to bathe and wash your hands with. You might find that making your own is the best option. It's pretty easy actually. Pure-castile soap, honey, olive oil, and essential oils of your choosing make a great body and hand wash.


Scents are troublesome. If you are breathing in a scent that you think is going to bother you, or it is already bothering you, then get away from that scent ASAP. Don't try to "tough it out". Just leave the area.


Reduce Stress

You will encounter stress provoking situations, and there will be times that you won't feel good, which may increase anxiety and stress. Emotional/mental stress can definitely be a trigger. Here are a couple of ways that can help build resilience to stress:

  • Breathing exercises
  • Meditation
  • Yoga



H1 and H2 Antihistamines

H1 and H2 blockers are used for baseline treatment.  Your doctor will likely have you start with these.

 By Phn003 at English Wikibooks [Public domain], via Wikimedia Commons

By Phn003 at English Wikibooks [Public domain], via Wikimedia Commons

H1 antihistamines – block the activation of mast cells and histamine mediated symptoms by antagonizing (blocking) H1-histamine receptors. Examples include: Claritin (loratidine), Benadryl (diphenhydramine), Zyrtec (cetirizine), Allegra (fexofenadine). Zyrtec (cetirizine) also possesses some mast cell stabilizing activity. (R)

H2 antihistamine – block the activation of mast cells and histamine mediated symptoms by antagonizing (blocking) H2-histamine receptors. Examples include: Zantac (ranitidine), Pepcid AC (famotidine), Tagamet (cimetidine)


In patients who experience anaphylaxis, epinephrine is advised to be carried with at all times (i.e. Epi-Pen), and readily and quickly absorbable forms of H1 and H2 blockers.

Cromolyn (Disodium cromoglycate)

Cromolyn is a very common drug used to stabilize mast cells, and can inhibit histamine, leukotrienes, and prostaglandins from mast cells. (R)

However, it isn’t absorbed well. Cromolyn can be purchased over the counter in a nasal spray (Nasalcrom) and in eyedrops (Opticrom). It can also be taken orally or inhaled. Interestingly, a Cromolyn cream can be made by mixing Nasalcrom and a skin cream like (Eucerin). *Talk to a doctor before trying these even though you can purchase different versions over the counter.

Glucocorticoids (steroids)

Glucocorticoids and other immunosuppressive drugs can be an effective treatment for cooling down the immune system and decreasing mast cell activation. (R)

Acetylsalicylic acid (ASA) (aspirin)

Acetylsalicylic acid (ASA) (aspirin) is sometimes used to inhibit cyclooxygenases and decrease levels of prostaglandins.  However, ASA can stimulate mast cells to degranulate. (R)



MCAD diagnosis is likely to increase over the coming years, as are the treatment options available. It’s pretty complex and diverse, and treatment requires patients, time, and diligence in taking one step at a time. If you think you’ve got MCAD, I recommend finding and seeing a doctor who either specializes in MCAD, or at least knows what it is to get formally diagnosed.