Understanding MCAS in ME/CFS, Long COVID, and Fibromyalgia: A Guide for Patients

Mast Cell Activation Syndrome (MCAS) is increasingly recognised as a common coexisting condition in individuals with chronic illnesses such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), long COVID, and fibromyalgia. These syndromes, which share symptoms like fatigue, cognitive dysfunction, pain, and hypersensitivity to various stimuli, often overlap with MCAS, creating a complex clinical picture that can be difficult to untangle.

What is MCAS?

MCAS is a condition in which mast cells — a type of white blood cell that plays a critical role in allergic responses and immune regulation — become overactive and release chemical mediators (like histamine, tryptase, prostaglandins, and leukotrienes) inappropriately or excessively. Unlike traditional allergies, MCAS reactions are not always triggered by known allergens, making it a diagnostic challenge.

Symptoms of MCAS are wide-ranging and can include:

• Flushing, hives, or itching

• Gastrointestinal distress (nausea, diarrhoea, abdominal pain)

• Brain fog and fatigue

• Headaches and dizziness

• Heart palpitations or low blood pressure

• Sensitivities to smells, chemicals, or foods

• Anaphylactoid reactions (without a known allergen)

  
  

In people with ME/CFS, long COVID, or fibromyalgia, these symptoms can mimic or worsen the underlying condition, making diagnosis and treatment especially important.

The Link Between MCAS and Chronic Illnesses

Emerging research suggests that immune dysregulation may be a common thread between MCAS, ME/CFS, long COVID, and fibromyalgia (1). In these conditions, the immune system appears to be persistently activated or dysfunctional, possibly due to infections, environmental triggers, or genetic predisposition. Mast cells, being key immune regulators, may become hyperresponsive — contributing to systemic inflammation and a worsening of symptoms like fatigue, pain, cognitive dysfunction, and hypersensitivities.

Some studies have proposed that mast cell dysfunction may underlie or exacerbate post-exertional malaise (PEM) in ME/CFS and long COVID by amplifying inflammatory responses to even minor physical or cognitive exertion (2). Similarly, the widespread pain and sensory sensitivities in fibromyalgia may be partly due to mast cell activity in the skin, gut, and nervous system (3) (4).

MCAS vs. Histamine Intolerance: How to Tell the Difference

While MCAS and histamine intolerance (HIT) often present with overlapping symptoms — such as flushing, headaches, GI issues, and reactions to high-histamine foods — there are important distinctions:

Feature	MCAS	Histamine Intolerance
Mechanism	Overactivation of mast cells	Impaired breakdown of histamine
Triggers	Wide variety: foods, stress, heat, chemicals, exercise, infections	Primarily high-histamine foods
Onset	Can be spontaneous or delayed	Typically occurs within hours of eating
Mediators involved	Histamine + many others (e.g., prostaglandins, leukotrienes)	Mostly histamine
Testing	Elevated tryptase, histamine, prostaglandin D2 (variable)	Low diamine oxidase (DAO) activity
Response to treatment	May require antihistamines, mast cell stabilisers, anti-leukotrienes	Often improved with low-histamine diet and DAO supplements

In practice, some patients may have both conditions, and symptoms often improve with overlapping strategies like dietary changes and antihistamines. (See our blog post on histamine intolerance)

Strategies to Alleviate MCAS Symptoms

If you suspect MCAS — especially in the context of ME/CFS, long COVID, or fibromyalgia — here are several steps that may help reduce symptom burden:

1. Identify and Avoid Triggers

Common triggers include:

• High-histamine foods (e.g., aged cheese, alcohol, fermented foods)

• Heat or cold exposure

• Stress (physical or emotional)

• Strong odours or chemicals

• Infections or exercise

  
  

Keeping a symptom and food diary can help uncover patterns.

2. Dietary Modifications

• Follow a low-histamine diet: eliminate aged, fermented, and processed foods; favour freshly cooked meals.

• Consider a low FODMAP or low salicylate approach if additional intolerances are suspected.

  
  

3. Pharmacologic Support

Always work with a knowledgeable healthcare provider, but common treatment options include:

• H1 antihistamines (e.g., cetirizine, loratadine)

• H2 antihistamines (e.g., famotidine)

• Mast cell stabilizers (e.g., cromolyn sodium, quercetin)

• Leukotriene inhibitors (e.g., montelukast)

• DAO supplements (if histamine intolerance is suspected)

  
  

Start low and go slow — MCAS patients often have increased drug sensitivity.

4. Environmental Control

• Use HEPA filters to reduce allergens.

• Avoid synthetic fragrances and cleaning products with harsh chemicals.

• Wear natural fibres and avoid tight clothing if you experience skin sensitivities.

  
  

5. Supplements and Nutraceuticals

Certain supplements may help stabilise mast cells or reduce inflammation:

• Quercetin: a natural mast cell stabilizer and antihistamine

• Vitamin C: supports DAO activity and histamine metabolism

• Magnesium: may help reduce neurological symptoms

• Omega-3 fatty acids: anti-inflammatory properties

  
  

Again, introduce one at a time to assess tolerance.

6. Address Comorbidities

Conditions like dysautonomia, POTS, small intestinal bacterial overgrowth (SIBO), or Ehlers-Danlos syndrome are frequently seen in people with MCAS and ME/CFS or long COVID. A holistic approach is often necessary.

Final Thoughts

For those with ME/CFS, long COVID, or fibromyalgia, MCAS can be a hidden driver of symptom flares, food intolerances, and hypersensitivities. While diagnosis is not always straightforward, recognising the signs and implementing practical strategies can bring meaningful relief. Advocacy, self-education, and collaboration with informed healthcare professionals are key.