Hypertensive Crisis Linked to Psilocybin Mushroom Use in Patient Taking MAOI and Amphetamine

A new case report highlights what may be the first documented hypertensive emergency resulting from a combination of psilocybin mushrooms, tranylcypromine and extended-release dextroamphetamine-amphetamine.

Published in The Journal of Clinical Psychopharmacology, the report urges clinicians to proactively counsel patients about the potential dangers of mixing monoamine oxidase inhibitors (MAOIs) with naturally occurring psychedelics.

An unexpected interaction

The case describes a 42-year-old man with treatment-resistant major depressive disorder who developed severe hypertension and chest pain shortly after ingesting 1 gram of Psilocybe cubensis (“Golden Teacher”) mushrooms. At the time, he was taking tranylcypromine 20 mg twice daily and extended-release dextroamphetamine-amphetamine 20 mg daily, among other medications.

Within 30 minutes of mushroom ingestion, the patient experienced chest pain radiating to the jaw, heart palpitations and a pounding headache, says lead author Brian Barnett, MD, a psychiatrist in the Center for Adult Behavioral Health at Cleveland Clinic Lutheran Hospital.

The patient’s blood pressure reached 230s/100s mm Hg, prompting an emergency medical evaluation. An electrocardiogram showed ST elevation consistent with myocardial infarction; however, subsequent cardiac catheterization revealed normal coronary arteries and ventricular function. His blood pressure normalized following treatment with lorazepam, nitroglycerin and aspirin, and he was discharged the next day without residual deficits.

Although psilocybin remains investigational and is not FDA-approved for psychiatric indications, Dr. Barnett notes that patients are increasingly using psychedelic compounds to self-treat depression and other mental health conditions. This trend, combined with a resurgence of MAOI prescribing in treatment-resistant depression, raises new safety challenges.

“Our concern is that clinicians will increasingly encounter patients who are experimenting with psychedelics while on prescription medications,” he explains. “Because formal interaction studies are nearly nonexistent, both patients and prescribers may underestimate the risks.”

Contributing factors

Dr. Barnett and his coauthors propose that the hypertensive emergency in this case stemmed not from psilocybin itself but from phenylethylamine (PEA) — a trace compound with amphetamine-like activity recently identified in Psilocybe cubensis.

“PEA is an indirect sympathomimetic,” he says. “When combined with an MAOI like tranylcypromine, which prevents its breakdown, and a stimulant such as dextroamphetamine, the cumulative pressor effect can be profound.”

Dr. Barnett, codirector of Cleveland Clinic’s Psychiatric Treatment-Resistance Program, emphasizes that the patient’s medication profile and timing likely played key roles in the crisis.

“Tranylcypromine’s irreversible MAOI activity, combined with dextroamphetamine’s noradrenergic properties, likely set the stage,” he says. “The addition of phenylethylamine from the mushrooms acted as a final trigger.”

Notably, the patient had previously taken a higher dose (3 g) of an unknown psilocybin mushroom species while prescribed phenelzine and nortriptyline, without incident. The difference, Dr. Barnett suggests, might reflect the specific pharmacologic profile of tranylcypromine, which has stronger sympathomimetic effects than phenelzine, as well as the absence of nortriptyline, which may blunt pressor responses to catecholamines.

Clinical and safety implications

While classic psychedelics such as LSD, dimethyltryptamine and synthetic psilocybin have demonstrated relatively stable hemodynamic profiles — even when combined acutely with MAOIs in historical studies — natural psilocybin mushrooms are chemically heterogeneous. In addition to psilocybin and psilocin, they contain multiple alkaloids, including baeocystin, norbaeocystin and PEA, whose pharmacologic properties are not well understood.

“This case highlights the unpredictability of plant- and fungus-derived substances,” Dr. Barnett adds. “Even small compositional differences can have significant physiologic effects when combined with prescription drugs. In an uncontrolled environment, ‘natural’ does not mean ‘safe.’”

Guidance for clinicians

Dr. Barnett urges psychiatrists and primary care providers to explicitly warn patients taking MAOIs — particularly tranylcypromine — about the risks of ingesting psilocybin mushrooms. He notes that co-prescribed stimulants, such as amphetamine-based medications for ADHD, may further amplify the danger.

He also emphasizes the importance of maintaining an open dialogue with patients about psychedelic use. “Most patients won’t volunteer that they’re using psychedelics unless clinicians ask directly and without judgment,” he notes. “Creating that space can prevent potentially life-threatening outcomes.”

As psychedelic-assisted therapy research expands, psychiatrists will need updated training to manage and counsel patients appropriately, Dr. Barnett adds. He and his colleagues cite surveys showing that clinicians identify drug-interaction education as one of the most desired areas of continuing education regarding psychedelics.

“This case provides a glimpse into the evolving clinical landscape in which our patients have more access to powerful psychoactive substances than ever before,” he says. “We need to be prepared to guide them safely.”