Mast Cell Activation Syndrome (MCAS): A Neuroimmune Perspective (2025 Update)

Mast Cell Activation Syndrome (MCAS) has become an important—though still evolving—diagnostic category within allergy, immunology, and neuroimmune medicine. Many patients experience years of multi-system symptoms without a clear explanation, and clinicians often struggle to integrate the immune, autonomic, and stress-related components involved. This page summarizes the current state of knowledge in 2025, grounded in peer-reviewed literature while acknowledging areas where research is rapidly developing.

1. How MCAS Is Defined Today

Although terminology varies between clinicians and research centers, most recent publications distinguish MCAS from other mast-cell disorders by emphasizing recurrent episodes of mast-cell mediator release without evidence of a clonal mast-cell population. MCAS is one subset of the broader category of mast cell activation disorders (MCADs), which also includes:

• clonal disorders such as systemic mastocytosis or monoclonal MCAS,

• secondary mast-cell activation driven by IgE allergy, autoimmune disease, infection, or other triggers,

• idiopathic MCAS, where no clear trigger is found.

A 2024 review in The Journal of Allergy and Clinical Immunology notes that MCAS has been used inconsistently in medical practice. Some patients with clear, recurrent anaphylactoid episodes remain undiagnosed, while others receive the label despite lacking objective evidence. For this reason, major organizations such as the AAAAI and ECNM continue to emphasize three core diagnostic criteria:

1. Recurrent, multi-system symptoms typical of mast-cell mediator release (for example, flushing, hives, abdominal pain, diarrhea, headaches, tachycardia, or sudden drops in blood pressure).

2. Objective evidence of mast-cell activation, such as a rise in serum tryptase during an episode or elevated urinary prostaglandins, leukotrienes, or histamine metabolites.

3. Clinical response to medications that block or dampen mast-cell activity (antihistamines, cromolyn, leukotriene antagonists).

This framework is now widely accepted, even by groups expressing concern about the overuse of the MCAS label. A 2024 JACI: In Practice “dilemma paper” reinforces the importance of adhering to these criteria, both to avoid missed diagnoses and to prevent mislabeling patients whose symptoms arise from other causes.

MCAS is also increasingly viewed as a spectrum rather than a singular entity. Guidance from Mast Cell Action (2024) emphasizes that some individuals experience unmistakable mast-cell–driven episodes without neatly fitting the formal criteria; others sit at a border where immune, autonomic, and environmental factors overlap.

2. What Mast Cells Actually Do—and Why They Matter in MCAS

Mast cells are highly specialized immune cells located at the body’s environmental interfaces: the skin, the respiratory and gastrointestinal mucosa, the dura and meninges surrounding the brain, and the perivascular and perineural tissues that regulate blood flow and nerve signaling. Their job is to sense danger—whether infection, allergen exposure, physical injury, or stress—and mobilize rapid responses.

When activated, mast cells release a complex range of inflammatory mediators. Some are pre-stored and released almost instantly (histamine, tryptase, chymase, TNF-α), while others are produced on demand (prostaglandin D₂, leukotrienes, interleukins). These mediators affect:

• vascular tone and blood flow,

• permeability of blood vessels and mucosal barriers,

• smooth muscle contraction,

• nerve sensitivity and pain signaling,

• immune-cell recruitment.

Notably, the non-histamine mediators—prostaglandins, leukotrienes, and cytokines—are now recognized as major contributors to symptoms such as flushing, dysautonomia-like episodes, visceral pain, and cognitive effects. This has helped explain why antihistamines alone often provide only partial relief.

Mast cells are activated through far more varied pathways than classic IgE-driven allergy. They can respond to complement fragments, pattern-recognition receptors (TLRs), neuropeptides like Substance P and CGRP, corticotropin-releasing hormone (CRH), temperature changes, mechanical pressure, infections, and hormonal shifts. This broad reactivity is one reason symptoms can feel unpredictable and difficult to trace to a single allergen.

3. The Neuroimmune Interface: Mast Cells and the Autonomic Nervous System

Among the most significant developments in the last decade is the recognition that mast cells and the autonomic nervous system (ANS) are deeply intertwined. Mast cells sit in close apposition to sympathetic, parasympathetic, and sensory nerves. They express receptors for neurotransmitters and neuropeptides, and their mediators—especially histamine, prostaglandins, and cytokines—modify nerve excitability and vascular dynamics.

Recent reviews in Cell and Frontiers describe mast cells as integral components of the somatosensory and neuroimmune systems, not simply immune sentinels. They influence:

• pain sensitivity,

• vascular tone and perfusion,

• thermoregulation,

• gut motility and visceral sensitivity,

• the brain’s immune environment.

Emerging work using neuroimmune organoids—co-cultures of human iPSC-derived mast cells, neurons, microglia, and endothelial cells—demonstrates that mast-cell activation changes neural firing and that neural signals can trigger mast-cell degranulation. These models are being used to study autonomic dysfunction, neuropathic pain, and stress-mediated inflammation.

Clinically, this dovetails with the frequently observed triad of hypermobile Ehlers–Danlos syndrome (hEDS), POTS/dysautonomia, and MCAS-like presentations. Although high-quality studies remain limited, multiple reviews note a plausible shared biology involving connective-tissue laxity, vascular instability, and overly reactive mast cells. The GI literature echoes this: a 2025 AGA update on disorders of gut–brain interaction specifically addresses the overlap between hEDS, POTS, and mast-cell–mediated GI symptoms.

The ANS–mast cell connection does not replace classical immunology, but it adds explanatory power for patients whose symptoms span vascular, neurologic, and GI domains in complex and recurrent ways.

4. Stress, Trauma, and Mast-Cell Reactivity

Psychological stress is not a superficial contributor—it has a direct biochemical impact on mast cells. Stress activates the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system, which increases circulating catecholamines and CRH. Mast cells both release and respond to CRH, and CRH can directly provoke degranulation.

Research in Annals of Allergy, Asthma & Immunology and Frontiers in Cellular Neuroscience links stress-induced mast-cell activation to:

• worsening of atopic and allergic disease,

• visceral hypersensitivity and IBS-like symptoms,

• flares of certain pain syndromes,

• changes in blood–brain barrier permeability.

There is not yet a large prospective study connecting early trauma specifically with MCAS as defined by strict consensus criteria. However, the stress → autonomic shift → mast-cell reactivity pathway is well established biologically. Many patients describe flares during periods of emotional strain, not because symptoms are psychological “in origin,” but because stress physiology amplifies mast-cell sensitivity at a molecular level.

5. How MCAS Presents Clinically

MCAS tends to follow characteristic episodic patterns. Symptoms may include:

• flushing or sudden warmth,

• itching, hives, or swelling,

• abdominal cramping, nausea, or diarrhea,

• headaches, pressure, or “brain fog,”

• tachycardia or near-syncope,

• sensitivity to temperature changes, odors, or foods,

• in some cases, full anaphylactoid events.

Because mast cells are distributed widely, symptoms often span multiple systems. This multisystem pattern is one reason the condition can be misdiagnosed as functional GI disease, panic disorder, POTS, or chronic fatigue before a unifying explanation is found.

A careful evaluation typically includes mediator testing (tryptase or urinary markers), screening for clonal disease, and assessment for related conditions such as hEDS, IgE allergies, or dysautonomia.

Treatment commonly begins with H1 and H2 antihistamines and may add leukotriene blockers, cromolyn, ketotifen, aspirin (in prostaglandin-driven flushing), and targeted therapy in clonal disease. Many patients benefit from layered regimens, as no single pathway drives all symptoms.

6. How This Maps to Traditional Chinese Medicine

Traditional Chinese Medicine (TCM) offers an elegant systems-level framework that aligns surprisingly well with current neuroimmune science. Many MCAS-like presentations track onto classical patterns involving the Liver, Spleen, Lung, and Kidney systems, each describing not only organ function but the body’s broader regulatory networks.

The Liver system governs the smooth flow of Qi and is deeply associated with emotional regulation, stress responses, and sudden, reactive symptoms. When constrained, it can generate “heat,” “wind,” or rapid fluctuations—patterns that resemble vasodilation, itching, migraines, or autonomic swings.

The Spleen system manages transformation and transport of fluids. When weakened by stress, irregular eating, or chronic strain, it can produce dampness or phlegm, which in modern terms parallels gut-barrier dysfunction, dysbiosis, and low-grade systemic inflammation—all factors known to amplify mast-cell activity.

The Lung system, responsible for the exterior and Wei Qi, mirrors modern descriptions of immune surveillance at the skin and mucosal surfaces. The Kidney system, associated with constitutional resilience and long-term stress physiology, offers a conceptual bridge to HPA-axis changes and chronic autonomic dysregulation.

Importantly, mast cells concentrate along nerves, vessels, fascia, and barrier layers in ways that closely match the classical descriptions of channels, collaterals, and Wei Qi circuits.

7. ALH Vials and SAAT: What Is Known and Unknown

Allergies Lifestyle & Health (ALH) produces vials used for resonance-based testing. Originally derived from 1:300 allergen dilutions, the vials now include imprinted representations of physiologic mediators relevant to inflammation. Clinicians using the method report that mast-cell–mediator panels have become particularly valuable.

Solomon Allergy Treatment/Therapy (SAAT)—developed by Nader Solomon, MD—integrates resonance testing with specific acupuncture points and semi-permanent needles. Over more than a decade, practitioners have used SAAT for IgE-mediated allergies, environmental sensitivities, alpha-gal syndrome, and now mast-cell–mediator–driven presentations.

Two published case series exist within acupuncture-professional journals: one describing post-treatment changes in IgE sensitivity testing and another addressing alpha-gal syndrome. Although these are not randomized or indexed trials, they represent the early stages of documenting clinical results.

From a biomedical perspective, SAAT remains ahead of the formal literature, but its proposed mechanisms are consistent with known effects of acupuncture on autonomic regulation, vagal pathways, inflammatory signaling, and mast-cell modulation.

8. Where Research Is Heading

The next logical steps in MCAS research, especially for patients with autonomic or trauma-related presentations, include:

• simultaneous phenotyping of mast-cell mediators, autonomic function, and stress metrics;

• small pilot trials evaluating acupuncture- or neuromodulation-based interventions with outcomes such as HRV, baroreflex sensitivity, and mediator levels;

• integration of neuroimmune organoid models to observe mast-cell/ANS interactions under controlled conditions;

• formal mapping of TCM patterns with neuroimmune biomarkers in MCAS cohorts.

These directions reflect the growing recognition that mast-cell disorders cannot be understood purely through allergy frameworks. They sit at the intersection of immune signaling, neural regulation, barrier function, and stress physiology.

9. Summary

MCAS is a real and multi-layered condition involving episodic mast-cell mediator release across multiple organ systems. Although diagnostic definitions continue to evolve, rigorous criteria are now widely accepted. Research increasingly highlights the role of the autonomic nervous system, the stress response, connective-tissue biology, and the gut–brain axis in shaping mast-cell reactivity.

For many patients, a conventional allergy-focused approach captures only part of the picture. Integrative strategies—acupuncture, neuromodulatory techniques, herbal medicine, and in select cases resonance-based protocols such as SAAT—offer additional avenues for stabilizing the underlying neuroimmune networks.

This page will be updated as new research emerges.

A warm and generous provider, Dr Villanova enjoys applying her insights and experience in allopathy, medical acupuncture, Chinese herbal medicine and Ayurveda to integrate biological, emotional, social and spiritual aspects of individual and group healing/understanding. Dr Villanova is board certified in Family Medicine and Medical Acupuncture.

When not working with patients, she conceives, writes and executes music, theatre and film productions in New York City, and is a published essayist and poet. Currently, her multimodal theater work at the nexus of neuromodulation and healing is in production in NYC and heading for Europe