Understanding Histamines and Mast Cell Activation Syndrome (MCAS)

I recently encountered a 45 year old female in my clinic experiencing symptoms ranging from anxiety, depression and brain fog to nasal congestion, migraine headaches, watery eyes, runny nose, and bouts of tachycardia (racing heart). This patient was also struggling with debilitating chronic fatigue and acid reflux. Lastly, (and somewhat nonchalantly) the patient mentioned an annoying itching on her skin that had suddenly come on in the past year on her hands as well as frequent hives and rashes, which she was treating with daily over-the-counter antihistamines. I should also mention, she was diagnosed with Celiac Disease (biopsy confirmed) about 10 years prior.

As with pretty much all chronic health conditions, it’s always important to take a step back, look at the “Big Picture” and try to understand how various symptoms (and conditions) might be related. Interestingly, it was her allergy-type symptoms and itching skin (that the patient almost failed to mention) that tipped me off as a likely culprit of this wide array of symptoms: Mast Cell Activation Syndrome.

I’ve written in the past about the differences between allergies, sensitivities, and intolerances. Well, here’s one more curve ball to throw at you regarding another exaggerated immune response that can be brought on by food, infections, mold, chemicals, and even stress which often have very similar symptoms.

Mast Cell Activation Syndrome

Mast cells are the white blood cells directly responsible for monitoring the innate immune system; the lead detector of viruses, bacteria, parasites, toxins, allergens, wounds and trauma. When a person comes in contact with a perceived threat, be it a problematic food, mold, virus (etc.) the body acts by releasing histamine and several other chemical mediators such as interleukins, prostaglandins, cytokines, and chemokines which are stored in the cytoplasm of mast cells (and basophils). These chemicals are intended to start the immune process of addressing potential threats to our body, which is why we often experience symptoms such as watery eyes, sneezing, itching, GI issues, and inflammation as the body attempts to protect itself from what it perceives as invaders.

While mast cells are located throughout the body, they are abundant in areas that interact with the outside world, such as the skin and gut. Mast Cell Activation Syndrome (MCAS) is a mast cell disorder characterized by over production or over activation of mast cells. In most cases, over activation of mast cells tends to result in mast cells are releasing their chemical contents faster than the body can maintain a healthy immune and inflammatory balance.

Potential triggers of mast cell activation can include: stress, sudden temperature changes, exercise, foods, drugs (opioids, NSAIDS, antibiotics), heavy metal toxicity, odors/perfumes, mold, insect bites, infections (viral, bacterial, or fungal) and even sunlight! (8) Being a newly recognized condition (officially identified in 2007) there is A LOT to learn on this topic. So far, numerous conditions have been associated with MCAS including:

  • Allergies
  • Asthma
  • Autoimmune diseases
  • Celiac Disease
  • Chemical Sensitivities
  • Chronic Fatigue Syndrome
  • Endometriosis
  • Eosinophilic Esophagitis
  • Fibromyalgia
  • Food Allergies
  • Gastroesephageal Reflux Disease
  • Interstitial Cystitis
  • Irritable Bowel Syndrome
  • Migraine Headaches
  • Mood Disorders
  • Postural Orthostatic Tachycardia Syndrome (POTS)

Histamine Intolerance

Now, let’s take a minute to understand the term histamine intolerance, a seemingly closely related condition (and often confused as MCAS). As previously mentioned, histamines are released as part of the innate immune system when mast cells are activated. Those struggling with symptoms of an exaggerated histamine response, are often diagnosed with a “Histamine Intolerance”. The name itself is actually misleading, as symptoms are not necessarily caused by an intolerance or sensitivity to histamine but rather an overproduction or overconsumption of the chemical or even the inability for the body to effectively degrade histamines. In a healthy body, histamines are broken down by the N-methyltransferase (HMT) enzyme (in the nervous system) or diamine oxidase enzyme (DAO) in the gut. When a person lacks the HMT or DAO enzymes they are unable to manage and break down histamines and symptoms develop. So, in the case of a true histamine intolerance, the body is not necessarily having an exaggerated immune response or overproduction of mast cells as with MCAS.

Histamine Intolerance can develop as a result of:

Genetic Predisposition: Lacking the genes needed for producing the HMT and DAO enzymes or poor methylation due to MTHFR mutations

Poor gut health: causing a decrease in the production and efficiency of the DAO enzyme

Diet: Consuming a diet which contains more histamine than the body can degrade

Foods linked to histamine intolerance can be placed into three categories: High Histamine Foods, Histamine-Releasing Foods (also known as Liberators) and Diamine Oxidase Blockers. In a nutshell, the high histamine foods actually contain histamines and the other foods either promote a release of more histamine in the body or block DAO function.

High histamine foods include:

  • Fermented beverages (beer, wine and champagne)
  • Fermented foods: sauerkraut, vinegar, soy sauce, yogurt, kefir, kombucha
  • Vinegar containing foods: mayonnaise, pickled vegetables
  • Cured Meats: hot dogs, sausages, bacon, salami, pepperoni, lunch meats
  • Soured foods: sour cream, sour milk, sourdough breads
  • Dried fruits
  • Aged cheeses
  • Some nuts/legumes including walnuts, cashews, peanuts and chickpeas
  • Most citrus fruits
  • Certain vegetables/fruits: avocados, eggplant, spinach and tomatoes
  • Certain fresh fish and smoked fish: mackerel, mahi-mahi, tuna, anchovies, sardines
  • Chocolate and cocoa products

Histamine-Releasing foods include alcohol, bananas, chocolate, cows milk, nuts, papaya, pineapple, shellfish, strawberries, and tomatoes. DAO-Blocking foods include alcohol, energy drinks, black tea, mate tea and green tea.

In addition, specific probiotics have been shown to either produce additional histamine in the gut, or degrade histamine levels. Histamine producing strains include: lactobacillus bulgaricus, Lactobacillus casei, S. thermophiles and Lactobacillus delbrueckii.

Histamine degrading strains of probiotics include: bifidobacteriaum infantis and Bifidobacterium longum 5, lactobacillus gasseri, lactobacillus rhamnosus 6, Lactobacillus plantarum, Bifidobacterium brevem, Lactobacillus salivarius, Bifidobacterium lactis and Bifidobacterium Bifidum.

Now here is where the water gets murky- It is important to understand that what might appear to be a Histamine Intolerance could actually be a Mast Cell disorder (and vice versa). Some practitioners actually believe that these disorders are one and the same, however I believe that while they are similar and often mistaken for one another (as they share the same symptoms, often caused by the abundance of histamine released in both conditions), they are in fact two separate conditions.

Typically, Histamine Intolerance can be treated by decreasing the amount of histamines coming into the body (dietary changes) as well as increasing the enzymes needed to degrade the histamines via supplementation of DAO and natural anti-histamines including quercetin, stinging nettle, vitamin C and bromelain. Taking steps to heal the gut is also essential. Relief of symptoms with dietary changes and supplementation tends to be a relatively effective method treatment of histamine intolerance. Those looking for additional answers may also move forward with genetic testing assessing one’s possession of specific genetic markers that might decrease ones production of histamine degrading enzymes DAO and HNMT (23andMe is a great tool for this; the A0C1/ABP1 gene produces DAO and HNMT gene makes HNMT). Addressing an underlying MTHFR genetic mutation can also be very beneficial for assuring proper methylation, another factor worth considering.

Meanwhile, MCAS can be a much deeper, more complicated condition to treat. Generally speaking, I’ve found that if a patient doesn’t respond to dietary and supplement changes, they are likely dealing with a Mast Cell issue NOT histamine intolerance and likely have a deeper underlying cause. In cases of MCAS syndrome, we must first address the trigger(s) in order to stop the release of histamines and other symptoms.

As mentioned, symptoms of MCAS and histamine intolerance are generally very similar and include:

  • Itching of the skin, eyes, ears, and nose
  • Hives
  • Swelling, typically in the face, mouth and sometimes the throat
  • Drop in blood pressure or (in severe cases) increased blood pressure
  • Increased pulse rate, “heart racing”
  • Racing heart and/or symptoms resembling anxiety or panic attack
  • Chest pain
  • Headaches
  • Nasal congestion, runny nose, seasonal allergies
  • Conjunctivitis (irritated, watery, reddened eyes)
  • Fatigue, confusion, irritability
  • Insomnia
  • Digestive upset, especially heartburn, “indigestion”, and reflux
  • Irregular menstrual cycle
  • Nausea and/or vomiting

Criteria for Mast Cell Activation Syndrome (all 3 must be present)

  1. Episodic (sporadic) multisystem symptoms as listed above
  2. Appropriate response of symptoms to treatment targeting mast cell activation
  3. Lab testing resulting in increased serum tryptase, plasma histamine, or other validated markers of mast cell activation via blood or urine compared to the during a symptomatic period and compared with the patient’s baseline values (9)

While there are several different factors associated with MCAS, I recommend working with a specialist in this area or a Functional Medicine practitioner to look at ALL of the potential underlying drivers and for the appropriate work up. Potential triggers such as mold exposure, chronic Lyme Disease, biotoxins, and other chemical irritants are important to address first. Reducing stress, improving sleep, and focusing on gut health are going to make for a strong foundation before moving forward.

Specific Lab Testing for MCAS

When performing lab work, it is best to have blood and urine testing done during flare-up as well as times of dormancy. Having a baseline when symptoms are not present will increase the likelihood of getting accurate results. In addition, I highly recommend working with a qualified practitioner to decipher the testing needed as well as the results.

Blood Tests

  • Serum Tryptase
  • Serum Chromogranin A
  • Plasma Histamine
  • Plasma Heparin (chilled)
  • Plasma Prostaglandin D2 (PGD2) (chilled)


  • N-Methylhistamine (chilled)
  • PGD2 (chilled)
  • PGF2a (chilled)

Balancing Histamines:

For those simply seeking relief from histamine-related symptoms while working to address the underlying cause of MCAS, there are a handful of supplements (also mentioned above) that have been shown to help manage histamine balance and mast cell activation in the body) These supplements include:

  • DAO Enzymes: These supplements can be very helpful for those who struggle to break down histamine (as opposed to over producing the chemical).
  • Quercetin: inhibits mast cell activation and histamine release. Found naturally in apples, dark cherries, blueberries and cruciferous veggies. For a higher potency I recommend supplement form. 10, 11
  • Selenium: Reduces mast cell activation and associated symptoms 12
  • Vitamin C (slow release) and E: Help to regulate Mast cell function. 13
  • Stinging Nettle and NAC (N-Acetyl Cysteine) are also commonly used for managing histamine-related symptoms.

*There are some natural anti-histamine products on the market that actually contain most or even all of these compounds.

As you could probably guess, I’m a little more in favor of trying the above mentioned options prior to resorting to the over-the-counter H1 Blockers (anti-histamines), H2 Blockers (acid reducers), and other mast cell stabilizers. (14)

Heal Your Gut, Reduce Stress, Reduce Toxic Exposure

While lab testing is a great way to see if one has the potential or is currently dealing with a histamine intolerance or Mast Cell Activation, and diet and supplements can be an effective method for managing symptoms, the next step in this puzzle is to determine what is causing the disruption in the first place. As mentioned, poor gut health, lifestyle factors (stress, diet, environment), heavy metal toxicity, mold exposure, and bacterial/viral infections can all potentially be pushing that immune system into overdrive, resulting in mast cells being activated. Thus, these areas should all be assessed and addressed in order to allow the body to finally heal.

Remember that patient that I’d mentioned above? She’d spent the past 5 years struggling with symptoms and battling debilitating fatigue while desperately seeking answers. The handful of doctors and specialists that this patient saw assured her that there was nothing wrong (basic lab work continued to come back normal), that this was all in her head, and they even offered her antidepressants. With my initial visit with this patient we looked at removing histamines in the diet while supplementing with a few of the supplements mentioned above to see if symptoms resolved. When little improvement was seen (basically ruling out Histamine Intolerance), we moved forward with testing for Lyme disease, heavy metal toxicity, food sensitivities and nutritional deficiencies. As I suspected (but hoped otherwise) results came back positive for chronic Lyme Disease with associated co-infections. As with all conditions and individuals, there are many pieces to this puzzle however for this particular patient, treating her underlying Lyme disease will need to be the key in resolving her symptoms of an exaggerated histamine response as well as others likely associated with the chronic infection. Watch for my next article, as I move on to the topic of Lyme Disease.


  1. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/otherendo/histamine.html
  2. Jakate S, Demeo M, John R, Tobin M, Keshavarzian A. Mastocytic enterocolitis: increased mucosal mast cells in chronic intractable diarrhea. Arch Pathol Lab Med. 2006;130:362–367.[PubMed]
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033552/#B6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033552/
  4. https://www.ncbi.nlm.nih.gov/pubmed/3132852
  5. https://www.ncbi.nlm.nih.gov/pubmed/18544899
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042653/
  7. https://www.ncbi.nlm.nih.gov/pubmed/22384111
  8. https://tmsforacure.org/symptoms/symptoms-and-triggers-of-mast-cell-activation/
  9. Frieri M, Patel R, Celestin J., Mast cell activation syndrome: a review, Curr Allergy Asthma Rep. 2013 Feb;13(1):27-32.
  10. https://www.ncbi.nlm.nih.gov/pubmed/6208910
  11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808895/
  12. https://www.ncbi.nlm.nih.gov/pubmed/23784732
  13. https://www.ncbi.nlm.nih.gov/pubmed/21244748
  14. Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin, Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options, Journal of Hematology & Oncology 2011 4:10
No Comments

Sorry, the comment form is closed at this time.