Exploring Entactogens With Hiroe Imai Hu, DO, and James W. Murrough, MD, PhD

In this episode of “Psychopharm Today,” host Jenessa Johnston, PhD, and guests James Murrough, MD, PhD, of the Icahn School of Medicine at Mount Sinai, and Hiroe Hu, DO, a clinical research fellow in the National Institute of Mental Health's (NIMH) Experimental Therapeutics and Pathophysiology Branch, discuss the case for entactogens in mood and anxiety disorders. The conversation explores entactogenic therapeutics as a potential new frontier for these conditions.

Murrough and Hu framed entactogens as suited to social anxiety, loneliness, and social anhedonia—features that cut across diagnoses rather than sitting neatly within depression or posttraumatic stress disorder (PTSD). Hu described a patient with treatment-resistant depression and social anxiety disorder who wanted connection but could not act on it; she said she wished she could offer EMP-01 or R-MDMA to lower his psychological defenses and restore social drive as a buffer against relapse. Murrough said the field's broader goal is matching specific mechanisms to specific treatments rather than treating all antidepressants as interchangeable.

The pair discussed neuroplasticity "windows" opened by different compounds—a concept tied to Nardou et al's 2019 Nature paper on MDMA reopening a critical period for social reward learning. Ketamine's window is short but fast-acting, useful in suicidal crises; longer-acting compounds like LSD or ibogaine may suit substance use disorder, with ibogaine showing the most prolonged plasticity effect despite safety concerns limiting its development. They stressed pairing each drug's window with well-timed psychotherapy.

On terminology, Hu explained "entactogen" (Latin for "touch within") is often confused with "empathogen"; one framework describes MDMA as a "connectogen" combining both effects, since classification is currently based on subjective experience rather than chemistry. Murrough noted that turning attention inward, as these drugs do, doesn't appear to worsen hypervigilance in PTSD and anxiety—instead facilitating reframing and self-forgiveness.

On the FDA's August 2024 Complete Response Letter for MDMA-assisted therapy, both said the rejection surprised many given strong Nature Medicine phase 3 results, and that FDA's concerns centered on trial methodology and how to label the psychotherapy component—not core safety or efficacy. Murrough expects significant movement in entactogens and psychedelics over the next 12 to 36 months.

Hu favors transdiagnostic trials built around dimensional features like social anhedonia; Murrough was more cautious, citing regulatory and reviewer inertia toward DSM categories, predicting incremental change instead. Both flagged unresolved questions about how therapy-intensive protocols will fit routine psychiatric practice.