When Medications Make You Worse: A Closer Look at MCAS and Mental Health

Some people are told they’re too sensitive. Too anxious. Too much. Especially when every medication seems to make things worse. Especially when they keep returning to the doctor, or the ER, and no one has clear answers.

But what if the issue isn’t just in your mind? What if your body is sounding the alarm?

There’s a condition called Mast Cell Activation Syndrome (MCAS). It can be difficult to diagnose, but it’s gaining recognition among clinicians who work with complex chronic illness. MCAS occurs when mast cells—an important part of the immune system—release chemicals like histamine inappropriately, causing widespread effects throughout the body, including the nervous system.

Unfortunately, MCAS is frequently missed by psychiatrists and other medical professionals, especially when symptoms are subtle, overlap with mental health diagnoses, or shift from day to day. As a result, many patients are misdiagnosed or not taken seriously, delaying appropriate care.

MCAS can contribute to psychiatric symptoms such as anxiety, panic, insomnia, brain fog, and mood swings. For some people, especially women, symptoms also include nausea, flushing, dizziness, and extreme sensitivity to medications or environmental triggers. These symptoms may be intermittent and difficult to capture with standard testing, which I'll talk more about.

And there’s more: mast cells don’t just operate in the body—they also live in the brain.

Emerging research shows that brain-resident mast cells play a critical role in the body's stress response and neuroinflammatory signaling. After trauma, concussion, or even chronic psychological stress, these cells can become hyperactive, contributing to PTSD, brain fog, emotional dysregulation, and even changes in how the blood-brain barrier functions. This is especially important in people with a history of traumatic brain injury (TBI), repetitive stress, or persistent post-viral symptoms.

These factors may help explain why some people experience neurologic sensitivity—a sort of inflamed alert system that amplifies both physical and psychiatric symptoms.

MCAS Often Overlaps With Other Conditions

It’s important to note that MCAS frequently co-occurs with other complex chronic conditions, including:

Postural Orthostatic Tachycardia Syndrome (POTS)
Ehlers-Danlos Syndrome (EDS)
Small fiber neuropathy
Chronic Fatigue Syndrome (ME/CFS)
Autoimmune disorders
Tickborne or mold-related illnesses

These overlapping syndromes can complicate the diagnostic picture—and they often show up in people who are dismissed, told "it’s just anxiety," or encouraged to push through without deeper evaluation.

Clinically, I often seen mast cell activation symptoms start to show up during periods of hormone changes in women such as peri-menopause and sometimes occurs on a monthly basis, in the days leading up to menstruation.

What This Can Look Like

Panic or anxiety that feels physiological, not situational
Nausea, GI issues, or flushing with no clear cause
Lightheadedness, brain fog, or a wired-but-tired feeling
Difficulty tolerating medications, supplements, or foods
Diagnoses that don’t seem to fit the whole picture

Getting Evaluated

MCAS can be challenging to detect through labs. Some testing is available—tryptase, chromogranin A, plasma histamine, prostaglandin D2, and urinary methylhistamine—but levels often fluctuate and may only spike briefly during episodes. Samples typically need to be kept chilled and processed promptly. Insurance may cover some of these labs.

More often than not, MCAS is a clinical diagnosis, based on history, symptom pattern, and how you respond to trial treatments. Working with a knowledgeable provider is key. They’ll take a careful timeline of your symptoms and look for patterns across multiple systems (gut, nervous system, skin, etc.).

Approaches to Support

Treatment is individualized, but may include:

Antihistamines (H1 and H2 blockers), such as hydroxyzine, which may also support anxiety
Mast cell stabilizers: cromolyn sodium, low dose naltrexone, quercetin, luteolin, ketotifen (there are others)
A low-histamine diet
Avoiding known triggers: mold, heat, infections, stress, specific foods
Compounded or dye-free medications, since fillers can trigger flares
Starting psychiatric medications at micro-doses, with close monitoring

And because mast cells interface closely with the nervous system, many people benefit from approaches that calm the limbic system and regulate the body’s stress response:

Vagus nerve toning (humming, cold exposure, breathwork, vagus nerve stimulation devices)
Limbic system retraining programs (e.g., DNRS, Gupta)
Hypnotherapy or guided meditation
Trauma-informed somatic practices

Resources to Explore

Mast Cell Action (UK-based but informative): mastcellaction.org
The Mast Cell Disease Society: tmsforacure.org
Dysautonomia International: dysautonomiainternational.org
Books by Dr. Neil Nathan, including Toxic and The Sensitive Patient’s Guide to Healing

How to Share With Your Doctor

If your provider hasn’t heard of MCAS, it can help to bring a short article, note how your symptoms cluster across systems, and explain what makes them worse or better. Keeping a brief journal of flares, triggers, and responses can go a long way.

You might say something like:

“I’ve been learning about mast cell activation, and some of the symptoms match what I’ve been experiencing—especially the sensitivity to meds and how quickly things change. Could we explore that possibility?”

Approaching the conversation with curiosity rather than confrontation often opens more doors. MCAS isn’t rare—but it is often unrecognized. With the right approach, healing is possible.

For Clinicians: Implications for Psychiatric Practice

MCAS is not just a physical condition—it’s a neuropsychiatric masquerader. Recognizing it can transform how we understand “sensitive” patients.

Clinical pearls:

Extreme medication sensitivity, especially with mood stabilizers, SSRIs, or antipsychotics, may reflect neuroinflammatory mast cell activation—not personality pathology.
Trauma or mild TBI can disrupt the blood-brain barrier and prime mast cells in the brain—leading to neuroimmune dysregulation and psychiatric instability.
Consider MCAS in patients with:
- Complex symptom clusters (GI + neuro + dermatologic + psych)
- Atypical presentations or paradoxical drug responses
- Chronic illness histories (e.g., Lyme, mold, POTS, EDS, ME/CFS)

Suggested clinical strategies:

Start medications at a much lower dose with titration
Use preservative-free or compounded meds when available
Consider adding H1/H2 blockers or cromolyn prior to psychotropic trials
Collaborate with integrative or allergy-informed colleagues
Don’t underestimate the power of nervous system regulation as an adjunct to MCAS care

When we reframe “medication intolerance” as a neuroimmune signal—not a character flaw—we create space for more compassionate, effective care.

References

Afrin, L. B., Molderings, G. J., & Weinstock, L. B. (2016). Presentation, diagnosis, and management of mast cell activation syndrome. Current Treatment Options in Allergy, 3(4), 453–464. https://doi.org/10.1007/s40521-016-0087-5

Theoharides, T. C., & Kalogeromitros, D. (2006). The critical role of mast cells in allergy and inflammation. Annals of the New York Academy of Sciences, 1088, 78–99. https://doi.org/10.1196/annals.1366.062

Weinstock, L. B., Molderings, G. J., & Afrin, L. B. (2023). Mast cell activation disease and the psychiatry interface. Cureus, 15(8), e66323. https://doi.org/10.7759/cureus.66323

Silver, R., & Brostoff, J. (2023). Mast cells and the mind: A possible link between immune dysregulation and psychiatric disorders. Medical Hypotheses, 174, 111030. https://doi.org/10.1016/j.mehy.2023.111030

Kempuraj, D., Selvakumar, G. P., Thangavel, R., Ahmed, M. E., & Zaheer, S. (2017). Mast cell activation in brain injury, stress, and PTSD. Frontiers in Neuroscience, 11, 703. https://doi.org/10.3389/fnins.2017.00703