Entactogens as a New Frontier for Mood and Anxiety Disorders: A Conversation With Hiroe Imai Hu, DO, and James W. Murrough, MD, PhD

“Psychopharm Today” is a video-podcast series, created collaboratively with the American Society of Clinical Psychopharmacology (ASCP), in which members converse about the latest hot topics in psychopharmacology.

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 frame entactogens as tools for social anxiety, loneliness, and social anhedonia—features they said cut across diagnostic categories rather than sitting neatly inside major depressive disorder or posttraumatic stress disorder (PTSD). Hu illustrated the point with a patient who had severe treatment-resistant depression and social anxiety disorder, was socially isolated, and showed no drive to engage even with family, despite wanting connection rather than solitude.

"I wish I could give EMP-01 or R-MDMA here to lower that psychological defense he had, and also allow him to have more drive for connecting—socially connecting with others," Hu said, describing the goal as building a protective factor against depressive relapse.

Murrough said the broader opportunity is to move psychiatry away from a diagnosis-first model, in which most antidepressants sit in a single therapeutic bucket, toward matching specific mechanisms to specific treatments.

The pair also discussed how rapid-acting and psychedelic-adjacent compounds open neuroplasticity windows of varying duration, a concept Murrough traced partly to Nardou et al's 2019 Nature paper on MDMA reopening a critical period for social reward learning.¹ Ketamine's window is comparatively short but fast-acting, making it well suited to acute suicidal crises, Hu said, while longer-acting compounds such as LSD or ibogaine may better serve chronic conditions like substance use disorder; ibogaine showed the most prolonged cellular measure of plasticity potential among compounds discussed, despite lagging in clinical development due to safety concerns. Both said the strategy is to pair a compound's window of effect with appropriately timed psychotherapy or behavioral intervention.

Hu noted that "entactogen"—from the Latin for "touch within"—is often confused with "empathogen." Entactogens promote both prosocial behavior and inward introspection, softening psychological defenses and increasing emotional openness, she said, citing EMP-01 data in social anxiety disorder and MDMA's role in trauma-focused psychotherapy for PTSD. She noted that at least one published framework describes MDMA as a "connectogen" combining both effects, and that classification currently rests on the phenomenology of a compound's subjective effects rather than its chemical structure. Both agreed field terminology, including the definition of "psychedelic" itself, remains unsettled.

Asked whether directing attention inward could aggravate disorders marked by hypervigilance, Murrough said existing data suggest the opposite: PTSD and anxiety disorders already involve hyperactive interoceptive monitoring, including in the anterior insula, with much of the distress stemming from internally generated stimuli such as intrusive memories. Entactogens, particularly paired with therapy, appear to facilitate reframing and self-forgiveness rather than reinforcing hypervigilance, he said.

The FDA issued a Complete Response Letter (CRL) for midomafetamine (MDMA) capsules for PTSD, submitted by Lykos Therapeutics, in August 2024, after two Nature Medicine phase 3 publications had reported large clinical effects and encouraging tolerability.^2,3 Murrough said the rejection surprised much of the field because the agency's concerns centered less on safety or efficacy and more on trial methodology, including blinding and standardization; Hu added that the FDA was also uncertain how to label the psychotherapy component that accompanied dosing. Murrough predicted meaningful movement in entactogens and psychedelics broadly over the next 12 to 36 months, citing MDMA-related compounds already in development.

Hu said she supports designing trials around dimensional features like social anhedonia or loneliness rather than single DSM diagnoses. Murrough was more cautious, noting that NIMH grant reviewers have pushed back on transdiagnostic study designs, questioning whether anhedonia mechanisms are shared across unipolar depression, bipolar depression, and PTSD; he said indications are more likely to evolve incrementally—for example, major depressive disorder with anxious distress—than to abandon diagnostic categories outright in the near term.

With regulatory pathways for classic entactogens still unsettled, Murrough and Hu pointed to compounds such as EMP-01—an oral, single-enantiomer R-MDMA candidate in phase 2 development for social anxiety disorder—as one route entactogenic therapeutics could reach patients in the near term.⁴ Both said how integration-heavy psychotherapy protocols will translate into routine psychiatric practice, where clinicians rarely have hours for a single patient, remains an open question the field has yet to resolve.

Dr Johnston is a postdoctoral fellow at National Institute of Mental Health.

Dr Hu is a clinical research fellow in the National Institute of Mental Health's Experimental Therapeutics and Pathophysiology Branch.

Dr Murrough is a professor of psychiatry and neuroscience, and director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai. He is also a faculty member of the Friedman Brain Institute and a primary principal investigator of the Center of Excellence in Neuropharmacology, both components of the Icahn School of Medicine.

References

1. Nardou R, Lewis EM, Rothhaas R, et al. Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature. 2019;569(7754):116-120.

2. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033.

3. Mitchell JM, Ot'alora G M, van der Kolk B, et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med. 2023;29(10):2473-2480.

4. AtaiBeckley announces positive topline results from an exploratory phase 2a trial of EMP-01 (oral R-MDMA) in social anxiety disorder. News release. Accessed August 7, 2026. https://ir.ataibeckley.com/news-releases/news-release-details/ataibeckley-announces-positive-topline-results-exploratory-phase