Mast cell activation syndrome (MCAS) has recently garnered attention due to mast cells’ role in COVID-19 and long COVID. Mast cells are a normal type of immune cell distributed throughout our bodies, including within the bone marrow, blood vessels, respiratory tract, and skin. Mast cells release chemical mediators to coordinate protection against infection or promote wound healing. They may also release histamine, which results in an allergic reaction. The 65 million individuals with long COVID show symptoms strikingly similar to those of MCAS, adding intrigue to this complex and mysterious condition.

Despite growing attention, the actual prevalence and other aspects of MCAS remain controversial, highlighting the challenges in understanding and recognizing this often misunderstood condition. Some sources believe it is rare, with one type of mast cell activation disease affecting 1 in 10,000. Other sources say its prevalence is unknown. Contrastingly, some leaders in the field believe it could affect up to 17 percent of the global population.

MCAS falls under the spectrum of mast cell activation disease (MCAD), which also includes rare systemic mastocytosis (SM) and its subtypes. Both MCAS and SM involve abnormal mast cell activity but differ in their underlying mechanisms.

Systemic Mastocytosis (SM)

In SM, there is an abnormal increase in mast cells within various tissues, diagnosed via a bone marrow sample. SM can be benign or malignant, such as in the rare mast cell leukemia subtype.

MCAS

In MCAS, there is an excessive release of mast cell mediators. MCAS has the following different types:

• Primary (clonal): In this type, most people have an abnormally high number of mast cells in their skin or body. To diagnose this type, a specific genetic change in mast cells (KIT D816V mutation) and specific proteins on the surface of mast cells are checked.
• Secondary: In this type, mast cell activation is not due to an abnormal number of mast cells but happens in response to a specific trigger or an underlying issue like a food allergy or reaction to a drug or insect sting.
• Mixed: In mixed MCAS, a person shows signs of both primary and secondary MCAS.
• Hereditary alpha tryptasemia (HαT):  People with this condition have extra copies of a gene that makes tryptase, an enzyme produced in the mast cells. This results in higher tryptase levels in the blood, even when the body is not having a reaction.
• Idiopathic (non-clonal): In this type, the number of mast cells is normal, but the cells are overly responsive for an unknown reason. It induces allergy-like symptoms, even when there is no underlying allergy.

Ruling out SM is an essential step before determining the type of MCAS. Understanding the type is crucial for accurate diagnosis and treatment. This guide focuses on MCAS, particularly the primary and idiopathic types.

In addition, depending on your history and physical exam, your health care provider should explore alternative diagnoses like histamine intolerance and chemical sensitivity, which can mimic some of the symptoms seen in MCAS.

The symptoms of MCAS vary greatly among individuals and can fluctuate. Moreover, they are not exclusive to MCAS and often occur in numerous other conditions, creating diagnostic challenges and debate among medical professionals regarding which symptoms should be considered diagnostic criteria.

The symptoms list proposed by Valent et al. includes the following symptoms categorized by bodily systems:

• Skin: redness, itching, hives, swelling.
• Respiratory: shortness of breath, throat swelling, wheezing, airway constriction, anaphylaxis.
• Naso-ocular: stuffy nose, itchy nose, hoarseness, red eyes, increased mucus production.
• Gastrointestinal: nausea, abdominal pain and cramps, diarrhea, excess stomach acid.
• Cardiovascular: low blood pressure, rapid heartbeat, near fainting or fainting.
• General: fever, chills.
• Neuropsychiatric: headache.

Some professionals believe this list is too restrictive and will result in underdiagnosis, so they include other symptoms in their criteria. Some experts expand on the above, adding neurological, psychiatric, musculoskeletal, and general symptoms like fatigue and weakness. Others include symptoms not only related to the skin and eyes but also to the mouth, kidneys, sex organs, hormones, blood, and more.

In a study of 413 MCAS patients, the following physical signs occurred with greater than 28 percent frequency, and symptoms occurred in at least 49 percent of patients. All are listed in order of frequency.

Signs Observed Upon Physical Exam

• Raised marks on the skin when stroked or scratched.
• Tired look.
• Chronically ill look.
• Edema (swelling).
• Obesity.
• Rash.
• High blood pressure.
• Abdominal pain or tenderness.
• Fast heart rate.
• Aching look.

Symptoms

• Fatigue.
• Fibromyalgia-type pain.
• Fainting or near fainting.
• Headache.
• Itching.
• “Pins and needles” sensation.
• Nausea and/or vomiting.
• Chills.
• Swelling that moves.
• Eye irritation.
• Shortness of breath.
• Acid reflux/GERD.
• Cognitive dysfunction/brain fog.

These diagnostic challenges and disagreements have a significant impact on patients, with delays in obtaining a correct diagnosis and resulting in prolonged physical and emotional distress. Research has shown that patients may wait decades, on average 30 years, before receiving an accurate diagnosis, with potential misdiagnosis and inappropriate treatments along the way.

MCAS arises from the abnormal and repetitive activation of mast cells, particularly in tissues that interface with the external environment, such as the skin, lungs, and digestive tract. When triggered, these cells release chemical mediators that can cause inflammation and a wide range of symptoms across multiple systems.

Some research has suggested that vitamin D deficiency may contribute to mast cell activation and that vitamin D is required to stabilize mast cells, but a causal relationship has not been established. While the exact cause of MCAS may not be fully understood, various triggers are known to set off symptoms in those affected.

When mast cells encounter a trigger, they interpret it as a threat and launch an immune response. MCAS involves the release of excess chemical mediators, including proteases, histamine, prostaglandins, leukotrienes, heparin, and numerous cytokines and chemokines.

These chemical mediators are released into the surrounding tissue and bloodstream, which can have widespread effects on the body. Here’s how they impact different systems:

• Blood vessels: Blood vessels dilate, leading to increased blood flow and fluid leakage, contributing to symptoms like hives and swelling.
• Nerve endings: Mediators can stimulate nerve endings, leading to symptoms such as itching and pain.
• Respiratory: They can cause airway constriction and increased mucus production, contributing to symptoms like coughing and wheezing.
• Gastrointestinal: Increased fluid secretion, smooth muscle contraction, and changes in intestinal permeability can contribute to symptoms like diarrhea, cramping, and nausea.
• Cardiovascular: Mediator release can result in low or high blood pressure and a rapid heart rate.

The release of these mediators can impact almost every part of the body, resulting in temporary allergic symptoms in multiple organ systems.

Triggers

Triggers (that which mast cells perceive as a threat) vary among individuals. Common ones include:

• Foods and food additives.
• Fragrances.
• Stress.
• Exercise.
• Medications.
• Temperature changes.
• Heat or cold.
• Rubbing or pressure.
• Emotional/mood swings.
• Sleep deprivation.

In addition to these triggers, peer-reviewed sources have also linked activation to the following:

• Estrogen.
• Mold toxicity and mycotoxins.
• Electromagnetic field (EMF) exposure in cell cultures.
• Alcohol.
• Radiocontrast media/dye.
• Insect bites.
• Infections (especially Lyme disease, Bartonella, and COVID-19).
• Toxicants such as volatile organic compounds (VOCs), pesticides, and herbicides, including glyphosate.
• Chemical or heavy metal exposure.

Identifying and avoiding these triggers is essential for managing MCAS and improving the quality of life for individuals affected by this condition. By recognizing and avoiding triggers, patients can actively manage their condition and improve their quality of life.

While more research is needed to fully understand the risk factors associated with developing MCAS, certain trends have emerged from existing studies. Here are the factors currently implicated:

• Sex: MCAS is more frequently diagnosed in females, with studies reporting as high as 80 percent. This imbalance may be due to female hormones, but it is unclear if it is truly biological or if more women seek care for MCAS symptoms.
• Ethnicity: Research indicates that MCAS diagnosis is more frequent in individuals of European descent. However, this could be because more cases have been reported in this group.
• Age: MCAS can affect people of all ages, with symptoms typically starting between 10 and 18 years of age but not being diagnosed until around 49 years of age.
• Family history: MCAS seems to run in families. A study of people with MCAD, 60 percent of whom had MCAS, found that 74 percent of them had a close family member with the condition. Additionally, 67 percent of the affected family members were female. This indicates a potential genetic link to MCAS, but further research is needed to understand the specific genetic factors involved.
• Comorbidities: Individuals with other mast cell disorders, such as mastocytosis or HαT, may have an increased risk of developing MCAS. This suggests a possible genetic predisposition or shared underlying mechanisms among mast cell-related conditions. However, more research is needed to validate this hypothesis. Additionally, the relationship with other comorbidities is not yet fully understood, and it has been hypothesized that mast cell activation underlies the development of these comorbidities rather than the other way around.
• Exposure to triggers: Exposure to various triggers, as mentioned earlier, can play a role in the development or exacerbation of MCAS.

Diagnosis typically requires symptoms in two or more systems, adding to the complexity of this condition.

Two groups, Consensus 1 and Consensus 2, have put forward different sets of criteria, leading to ongoing debate and uncertainty within the medical field about which criteria should be used to diagnose MCAS effectively.

In 2010, a group referring to themselves as “faculty members“ came together to create diagnostic criteria for all mast cell disorders. Dubbing themselves the ”consensus” (referred to here as Consensus 1), they proposed diagnostic criteria that have evolved slightly over the years. A diagnosis requires meeting all three of the following:

1. Typical clinical symptoms: Patients should have recurring symptoms that involve two or more organ systems.
2. Laboratory evidence: An increase in serum tryptase levels or other mast cell mediators is necessary for diagnosis. Serum tryptase is considered the “gold standard“ for demonstrating mast cell activity. An increase of 20 percent + 2 during an episode is required, which means measuring tryptase levels when the patient is not experiencing symptoms and again when they are within four hours.
3. Response to treatment: A clear response to medications targeting mast cell-derived mediators, such as antihistamines or mast cell stabilizing agents.

Critics, a larger group known as Afrin et al., have expressed concerns about these criteria. They labeled themselves “Consensus 2,” highlighting the lack of true consensus in this field. Their main criticisms include:

• The Consensus 1 criteria are considered too restrictive, potentially leading to underdiagnosis by reducing the number of considered symptoms.
• Not everyone worldwide has access to recommended laboratory tests.
• The criteria require treating patients before confirming the diagnosis instead of letting the diagnosis guide treatment.
• The 20 percent + 2 formula for serum tryptase lacks validation from large studies, is not suitable for everyone, and should not be the sole laboratory criterion.
• The criteria specify limited treatment options without specifying the number of drugs, dosages, or duration required to establish a therapeutic response.

The Consensus 2 proposals differ by including a broader range of symptoms caused by mast cell mediators, allowing more mediators to be measured as diagnostic evidence, and acknowledging the challenge of finding effective treatments for hypersensitive individuals.

Consensus 2 acknowledges that their criteria may lead to overdiagnosis but considers the consequences of underdiagnosis, including occasional mortality, to be more severe. They recommend diagnosing MCAS using criteria that provide quicker access to treatment and advocate for global collaboration among academics and health care practitioners to prioritize human needs over scientific debate.

The potential complications of MCAS can encompass a range of physical and mental health issues, including:

• Anaphylaxis: Severe, life-threatening allergic reactions can occur suddenly and affect the whole body.
• Inability to take medications: Due to heightened sensitivity and unpredictable reactions, people with MCAS may face challenges tolerating certain medications, including anesthetics and contrast dyes used in medical procedures.
• Partial or complete disability: The chronic and unpredictable nature of MCAS symptoms can significantly impact daily functioning, potentially leading to partial or total disability in some cases.
• Reduced quality of life: Excessive mediators can cause a wide range of symptoms, including pain, inflammation, swelling, low blood pressure, and gastrointestinal symptoms that can be debilitating and affect overall quality of life.
• Depression and anxiety: Research indicates that individuals with suspected idiopathic MCAS commonly experience depression and anxiety disorders.

An estimated 16 percent of people with MCAS experience depression, and 12 percent have anxiety. The connection with MCAS is complex, but these numbers emphasize that MCAS might influence not only physical health but also mental well-being.

MCAS can potentially affect the balance of gut microbes and lead to increased intestinal permeability (often called “leaky gut”). In turn, these factors are connected to conditions like irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and even pain, stress, depression, and anxiety.

A review of the research found that people with conditions like diarrhea-predominant IBS (IBS-D) and IBD may have more mast cells and higher levels of mediators in their gut. The resulting inflammation and its effects have been linked to the following:

• Depression.
• Anxiety.
• Imbalance in gut microbes.
• Leaky gut.
• Gut motility issues.

Furthermore, the challenges of obtaining a correct diagnosis and treatment lead to situational stress. This can be frustrating and emotionally distressing, potentially contributing to feelings of helplessness, frustration, depression, and anxiety.

While the research is limited and has primarily been conducted in animal models, it is clear that mast cell activation in the gut is connected to gut health and mental well-being. Understanding this connection is essential to providing comprehensive care for individuals with MCAS, addressing both their physical and emotional needs.

To effectively treat MCAS, it’s crucial first to reduce or eliminate exposure to known triggers.

Here are the main types of treatments used to target mast cell activation, with the first three being the most prescribed:

1. H1 blockers: These are antihistamines that block histamine’s effects on the body. They are often used to treat allergic reactions. Examples include sedating diphenhydramine (Benadryl) and nonsedating options like cetirizine (Zyrtec), loratadine (Claritin), and fexofenadine (Allegra).
2. H2 blockers: These antihistamines work by reducing stomach acid production, which can help with gastrointestinal symptoms. Examples include cimetidine, ranitidine (Zantac), famotidine (Pepcid), and nizatidine.
3. Mast cell stabilizers: Stabilizers prevent mast cells from releasing their inflammatory substances. Examples include cromolyn sodium (nasal spray available without a prescription), nedocromil sodium, which requires a prescription, and ketotifen, which may need to be custom-compounded.
4. Anti-leukotrienes: These drugs, typically used for asthma, work by reducing the production of a specific inflammatory mediator called leukotriene, helping to open airways. Examples are montelukast and zileuton.

In addition to the above, for primary MCAS, treatment may incorporate tyrosine kinase inhibitors, such as midostaurin or avapritinib, to inhibit the activity of the mutated KIT protein. Since secondary MCAS is linked to other conditions or triggers, such as infections, autoimmune diseases, or environmental factors, treatment should address the underlying cause or triggers.

Depending on your symptoms and their severity, your health care provider may recommend additional medications. For instance, severe allergic reactions might require self-administered epinephrine. If your symptoms don’t respond well to standard treatments, other medications like prednisone, cyclosporine, low-dose methotrexate, or azathioprine might be considered.

Stress and trauma can activate mast cells, increasing mediator release and inflammation. The psychological toll of living with a chronic, misunderstood condition is significant. Incorporating stress reduction and a positive mindset into the management of MCAS can be beneficial for reducing activation and inflammation and improving overall well-being.

Some functional and integrative practitioners include steps in their therapy to address the overreactive stress response and resulting structural changes in the brain, which can keep the brain and body in an overactive state of fight, flight, or freeze. These steps include vagus nerve stimulation to calm the nervous system and decrease mast cell activation. However, while these techniques are in practice, there is limited scientific research specifically addressing their effectiveness in the context of MCAS.

The interconnectedness of the mind and body underscores the importance of a holistic approach integrating emotional, physical, and spiritual well-being for optimal management of MCAS.

Natural supplements and lifestyle choices can improve the quality of life for those with MCAS. Natural supplements may provide alternatives to antihistamines and mast cell stabilizers for those sensitive to drugs. Below are some natural approaches that have been found to be helpful. Practitioners use many more natural supplements and herbs, but these are just a few with evidence. Always talk to your health care provider before starting new supplements.

Natural Supplements

• Quercetin is a flavonoid with anti-inflammatory, antioxidant properties, and mast cell-inhibitory actions. It has been found in human cell culture studies to be more effective than cromolyn in blocking cytokine release.
• Perilla seed extract has been shown to reduce histamine and decrease pro-inflammatory cytokines in animal studies.
• Luteolin is a flavonoid that exhibits anti-inflammatory and antioxidant effects. It may help stabilize mast cells and inhibit the release of histamine and other inflammatory mediators.
• Pycnogenol is reported to have anti-inflammatory and antioxidant properties and the ability to inhibit histamine release as well or better than cromolyn in animal cell studies.
• Stinging nettles (Urtica dioica): In herbal medicine, one animal study showed objective effectiveness with demonstrated effects as an anti-inflammatory and antihistamine.
• Curcumin is found in turmeric and has anti-inflammatory effects and reduced inflammatory mediator release from mast cells in animal models.
• Chinese skullcap (Baicalein) is a flavonoid with anti-inflammatory and antioxidant properties that was shown to inhibit the release of inflammatory mediators in one human cell culture study.
• Diamine oxidase (DAO) is an enzyme that breaks down histamine in the gut. Supplementation with DAO enzymes may reduce histamine-related symptoms.
• Resveratrol: Found in red grapes, it has anti-inflammatory and antioxidant effects. One human cell culture study showed it inhibited mass cell mediator release.
• Probiotics: Certain probiotic strains can modulate the immune response, reduce inflammation, stabilize mast cells, or increase DAO activity. Some are high-histamine, and some are low-histamine. The effects are strain-specific, and the wrong strain could cause problems. Some companies do not disclose their strains. It is best to work with a professional to obtain a quality probiotic of the right strain and avoid inactive ingredients that could be a trigger.
• Isatis tinctoria: Traditionally used in Chinese medicine for its anti-inflammatory properties, this plant reduced the number of mast cells and the release of inflammatory mediators from mast cells in an animal study.
• Fisetin is a flavonoid found in various fruits and vegetables and has been studied for its anti-inflammatory and antioxidant effects. A human cell culture study found it to suppress the activation of mast cells.
• Vitamin D: As previously mentioned, vitamin D is required to stabilize mast cells.

Lifestyle Factors

• Journaling: Keeping a journal to track symptoms and potential triggers can help identify patterns and manage the condition more effectively.
• Diet: Adopting an anti-inflammatory diet, such as a low-histamine or specific carbohydrate diet (SCD), may help reduce symptom severity. Any exclusionary diet can result in malnutrition, including inadequate vitamins and minerals, and should be done under the supervision of a medical or nutrition professional.
• Moderate exercise: Incorporating moderate exercise helps manage stress and supports overall well-being.
• Stress reduction: Mind-body practices like meditation, yoga, acupressure, acupuncture, and limbic system retraining can help alleviate symptoms.
• Restful sleep: Promote adequate sleep by establishing a healthy sleep routine and calming environment.
• Adequate hydration: Drink half your body weight in ounces of water—up to 1 gallon—daily to stay hydrated and support your body’s natural healing processes. For example, if you weigh 120 pounds, drink 60 ounces of water.

Preventing MCAS can be tough because it’s complex, especially when you don’t know all the specific things that trigger it. If you have primary or HαT, you might not be able to stop it entirely, but you can still reduce the symptoms. Think of mast cell activation as a symptom and ask, “What’s causing it, and how can we make it better?” Here are some things you can do to help prevent or manage MCAS:

• Identify and avoid triggers.
• Minimize your toxic load, starting with clean air, water, and food.
• Consider replacing old dental work done with amalgam fillings to avoid mercury and getting regular exams to prevent hidden infections.
• Minimize EMF exposure and time on devices.
• Consider mold/mycotoxin testing for your environment and home.
• Address any underlying chronic infections that can trigger or exacerbate MCAS symptoms.
• Address any unresolved trauma to reduce stress-related health risks.