Mast Cell Activation Syndrome (MCAS): Diagnosis and What the Research Says About Supportive Supplements

Mast Cell Activation Syndrome (MCAS): Diagnosis and What the Research Says About Supportive Supplements

Mast Cell Activation Syndrome (MCAS) is a condition in which mast cells—an important part of the immune system—become overly reactive. Because mast cells exist throughout the body, symptoms can affect multiple systems at once, making MCAS complex and sometimes difficult to diagnose.

Let’s walk through what mast cells do, how MCAS is diagnosed, and what the science says about supportive supplements.

What Are Mast Cells?

Mast cells are immune cells found in the:

• Skin
• Gut
• Lungs
• Blood vessels
• Nervous system
  

Their role is protective. When they detect a threat, they release chemical messengers such as histamine, prostaglandins, leukotrienes, and cytokines. These compounds help coordinate inflammation and healing (Molderings et al., 2011; Castells & Butterfield, 2019).

In MCAS, mast cells release these mediators too easily, too often, or in excessive amounts—sometimes without a clear trigger.

Common Symptoms of MCAS

Because mast cells are widely distributed, symptoms often involve more than one organ system at the same time.

Common symptoms include:

• Flushing, itching, or hives
• Nasal congestion or wheezing
• Abdominal pain, bloating, or diarrhea
• Headaches or brain fog
• Rapid heart rate or lightheadedness
• Fatigue
• Sensitivity to foods, smells, medications, heat, or stress

Symptoms often flare and subside and can resemble allergic reactions or even anaphylaxis.

How Is MCAS Diagnosed?

Diagnosis is not based on symptoms alone. International guidelines require all three of the following criteria (Weiler et al., 2019; Valent et al., 2024; Parente et al., 2023):

1. Recurrent Episodes Affecting Two or More Organ Systems

Symptoms must involve more than one body system at the same time—for example, skin symptoms plus digestive or cardiovascular symptoms.

2. Objective Laboratory Evidence of Mast Cell Activation

The most important test is serum tryptase, drawn within about four hours of a flare and compared to baseline.

Doctors use the “120% + 2 rule”:

Event tryptase ≥ baseline × 1.2 + 2 ng/mL.

If tryptase does not rise, supportive testing may include urine measurements of N-methylhistamine, leukotriene E4, or prostaglandin D2 metabolites.

3. Improvement With Mast-Cell–Directed Therapy

Symptom improvement with medications such as H1 antihistamines, H2 antihistamines, cromolyn, or leukotriene blockers supports the diagnosis.

If baseline tryptase is persistently elevated or other concerning features are present, additional testing for clonal mast cell disease (mastocytosis) may be recommended.

Standard Medical Treatment Comes First

First-line treatment typically includes:

• H1 and H2 antihistamines
• Mast cell stabilizers (such as cromolyn or ketotifen)

These therapies are considered foundational (Molderings et al., 2011; Castells & Butterfield, 2019).

Supplements, if used, are considered adjuncts—not replacements—for medical treatment.

A Reality Check About Supplements

Before exploring supportive nutrients, it’s important to understand:

• Most research is not specific to MCAS
• Many studies are cell-based or animal studies
• Large, dedicated MCAS trials are limited
• People with MCAS may react to fillers or additives
• Higher doses are not always better

Any supplementation plan should be individualized and ideally supervised by a clinician familiar with mast cell disorders.

Palmitoylethanolamide (PEA): A Promising Mast Cell Modulator

PEA is a naturally occurring fatty acid compound involved in regulating inflammation.

It works by:

• Activating PPAR-alpha receptors
• Modulating the endocannabinoid system
• Reducing mast cell activation

Early research identified what is sometimes called the “ALIAmide effect,” meaning PEA may calm overactive mast cells (Facci et al., 1995; Skaper et al., 2013).

Human studies relevant to mast cell activity show potential benefits in conditions such as functional dyspepsia, irritable bowel syndrome, allergic rhinitis, and mastocytosis.

Typical studied doses range from 300–600 mg daily, with some trials using up to 1200 mg short term. Higher doses do not always provide additional benefit (Gabrielsson et al., 2016).

Other Nutrients That Influence Mast Cells

Flavonoids

Certain plant compounds inhibit mast cell mediator release in laboratory and animal studies. These include:

• Quercetin
• Luteolin
• Resveratrol
• Curcumin
• EGCG (green tea extract)

Human studies most commonly use:

• Quercetin: 500–1000 mg daily
• Luteolin: 50–100 mg daily
• EGCG: 200–300 mg daily (higher doses may stress the liver)

MCAS-specific human trials remain limited.

Vitamins and Minerals

• Vitamin D: Deficiency is associated with increased mast cell activation.
• Vitamin C: Supports histamine degradation.
• Vitamin B6: May work synergistically with vitamin C.
• Magnesium and zinc: Show mast cell–stabilizing effects in experimental models.

Gut-Derived Metabolites

The gut microbiome plays a role in mast cell regulation. Short-chain fatty acids such as butyrate and propionate—produced by healthy gut bacteria—strongly inhibit mast cell activation in human models (Folkerts et al., 2020). 

This highlights the importance of gut health in mast cell regulation. Check out my Gut Health Playlist to discover more on how to restore and protect your digestive system and gut microbiome.

The Bottom Line

MCAS diagnosis requires:

• Recurrent multi-system symptoms
• Laboratory confirmation of mast cell mediator elevation during flares
• Improvement with mast-cell–targeted therapy

Standard medications remain foundational.

Research suggests certain supplements—particularly PEA—may help calm mast cell activation at a biological level. Other supportive nutrients include flavonoids, vitamin D, vitamin C with B6, magnesium, zinc, and gut-derived short-chain fatty acids.

However:

• Dedicated MCAS trials are limited
• Individual tolerance varies
• Supplements are adjunctive, not replacements
• Professional supervision is essential

Mast cell biology is complex, and personalized care matters. With appropriate testing and guidance, it is possible to better understand your symptoms and create a strategy that supports immune balance. If you would like support from a local Functional Medicine practitioner to help assess and manage MCAS, you can search the Institute for Functional Medicine practitioner database here:

Find a practitioner: https://www.ifm.org/find-a-practitioner/

This directory allows you to search by location and credentials to find a provider who aligns with your needs.