Psychedelic-Assisted Therapy: An Overview for Nonpsychiatrists

This abridged article is reprinted without references from the Cleveland Clinic Journal of Medicine (March 2025, 92 (3) 171 -180). Read the full version here.

By Brian Barnett, MD

Preliminary evidence suggests that psychedelic-assisted therapy — the enhancement of psychotherapy with psychedelics such as 3,4-methylenedioxymethamphet-amine (MDMA) and psilocybin — may be efficacious for depression, post-traumatic stress disorder, substance use disorders, and other conditions.

Therapeutic psychedelic research is advancing steadily, with psilocybin, MDMA, and lysergic acid diethylamide designated breakthrough therapies by the US Food and Drug Administration (FDA). However, in August 2024, the FDA declined to approve a New Drug Application for MDMA and asked its sponsor to conduct another phase 3 trial. Clinicians are urged to prepare for the possible return of psychedelics to medicine.

Because of the experimental nature of psychedelic-assisted therapy, internists may have little exposure to this modality. However, with possible FDA approval in the coming years and patients increasingly self-treating with psychedelics, the timing is right for clinicians to educate themselves about psychedelic-assisted therapy.

Through considerable efforts of researchers and philanthropists who believed potentially useful medicines had become unnecessary casualties of the “War on Drugs,” clinical trials exploring the therapeutic potential of psilocybin and MDMA were revived in the 2000s. Due to positive findings from these trials, numerous biotechnology companies hoping to develop psychedelics as medicines have recently emerged.

Psychiatry has also warmed to the notion of psychedelics as medicines, with 81% of psychiatrists in a 2023 national survey agreeing they show promise in treating psychiatric conditions, and over half planning to incorporate psychedelics into their practices upon FDA approval.

What are psychedelics?

Psychedelic drugs can significantly alter perception, cognition, mood, affect, social relatedness, and sense of self or meaning. They are unique in that they profoundly affect consciousness without simultaneously inducing delirium. Some of the most notable subjective effects of psychedelics are visual perceptual changes; hallucinations and pseudo-hallucinations; enhanced feelings of connectedness; and mystical experiences characterized by feelings of unity or oneness, transcendence of time and space, and deep emotional and spiritual significance. More so than other drugs, the subjective effects of psychedelics are influenced by “set and setting,” referring to one’s mindset (“set”) and the physical environment and social milieu (“setting”) of administration.

Over the past two decades, numerous studies have explored multiple psychedelic compounds for their effects on various mood, anxiety, and substance use disorders, with promising findings on efficacy and favorable safety profiles in research settings. How psychedelics might be able to treat such diverse conditions remains unclear, but multiple potential explanatory hypotheses are currently under investigation.

Neurochemically, psychedelics seem to temporarily enhance neuroplasticity — the brain’s ability to reorganize and form new neural connections — for weeks after their immediate effects have ceased. This increased neuroplasticity may promote learning and cognitive flexibility, which patients can use to develop new perspectives and facilitate lasting behavioral changes.

How it works

Psychedelic-assisted therapy arose from combining LSD and psychotherapy in the 1950s, with the eventual addition of music during sessions. Participants in psychedelic-assisted therapy clinical trials undergo preparation sessions to build therapeutic alliance with their therapists, set intentions for their psychedelic sessions, and receive psychoeducation about psychedelics.

During the treatment sessions, participants are cared for by one or two psychedelic-assisted therapy–trained therapists. Psychedelic sessions occur in a therapeutically appointed space. Inside the treatment room there typically is calming artwork, a couch or a bed on which the participant may recline, and comfortable seating for the therapists, as sessions can last 6 to 8 hours. Patients wear headphones and listen to curated music playlists. Participants are also offered eyeshades to facilitate inward focus, with periodic discussion with their therapists occurring as needed.

The subjective effects of psychedelics vary widely, though it is not unusual for participants receiving high doses to report dramatic experiences, such as being reborn or being in the presence of God. Many trial participants report that psychedelic-induced mystical experiences are among the most meaningful and spiritually significant experiences of their lives.

Vital signs are collected throughout psychedelic treatment sessions, and participants undergo medical evaluations toward the session’s end to ensure appropriateness for discharge. Once cleared, participants are released into the care of a responsible adult and instructed not to drive until the following day.

In the days to weeks after a psychedelic session, participants return for integration sessions to process their psychedelic experiences and consider how to translate resulting insights into durable behavioral change. For weeks after treatment, psychedelics appear to reopen critical periods for social learning and enhance neuroplasticity.

This provides a rationale for the potential importance of integration sessions for prolonging therapeutic efficacy, although this claim requires further investigation. The number of psychedelic sessions in a treatment course typically ranges from one to three over several weeks, depending on the protocol and condition being treated.

Expanding provider roles

If approved by the FDA, psychedelic-assisted therapy will be practiced primarily by mental health practitioners, but psychedelic-assisted therapy practitioners will likely look to internists, primary care physicians, and other physicians for guidance on the safety of psychedelics in older patients and patients with conditions that have been exclusionary in clinical trials.

Oncologists and palliative care physicians may seek to become trained in psychedelic-assisted therapy themselves due to an increasing number of studies indicating psychedelics’ potential to treat psychological distress associated with serious medical conditions.

Further, since functional disorders are frequently seen across medicine and psychedelics may treat some of them, there may be an important role for other specialists in conducting psychedelic-assisted therapy trials for these conditions and potentially delivering psychedelic-assisted therapy clinically someday. Notably, clinical trials are investigating psychedelic-assisted therapy for common pain disorders treated by internists, such as fibromyalgia, migraines, and irritable bowel syndrome.

Last word

Psychedelic-assisted therapy may be a potentially significant medical advance, offering the possibility of durable therapeutic benefits with rapid onset for some patients with PTSD and depression following only a small number of psychedelic treatments. No psychedelic is currently FDA approved, but psilocybin could possibly gain approval in less than two years. If approved, it may be the first of many psychedelics to rejoin psychiatrists’ armamentarium over the next decade. However, we have much to learn about optimizing these treatments in clinical settings and real-world patient populations.