MDMA-Assisted Psychotherapy Found Superior to Placebo in Phase 3 Trial

By Nick Zagorski

A lively and engaging session at APA’s online 2021 Annual Meeting on the past, present, and future of psychedelics was punctuated with promising new results from the first phase 3 clinical trial testing MDMA-assisted psychotherapy for the treatment of posttraumatic stress disorder (PTSD).

The trial, which included 90 adults with chronic PTSD across 15 clinical sites, found that participants who received three supportive psychotherapy sessions after taking MDMA (3,4-methylenedioxymethamphetamine) had nearly double the reduction in the severity of their PTSD symptoms compared with participants who received psychotherapy plus placebo.

Overall scores on the clinician-administered PTSD Scale for DSM-5 (CAPS-5) dropped by almost 25 points in the MDMA group after 18 weeks compared with 14 points in the placebo group. These differences translated to an effect size of 0.9, suggesting a large and meaningful difference for MDMA-assisted therapy (scores above 0.7 are considered substantial). As a comparison, the antidepressants approved for the treatment of PTSD—sertraline and paroxetine—produced effect sizes between 0.3 and 0.5 in clinical studies.

MDMA was also well tolerated, with muscle tightness and decreased appetite being the most common side effects. Importantly, MDMA was not associated with any increases in suicidal ideation or any indication of potential for abuse.

In 1985, the federal government placed an emergency ban on MDMA and classified it as a Schedule I drug, defined as a substance with no currently accepted medical use. In 2017, the Food and Drug Administration (FDA) granted Breakthrough Therapy designation to MDMA-assisted psychotherapy for the treatment of PTSD, which paved the way for this clinical trial.

This study was led by Michael Mithoefer, M.D., the senior medical director for medical affairs, training, and supervision for the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS), which supported this study.

In his discussion, Mithoefer was extremely encouraged by the robust findings, given that the participants had severe symptoms, comorbid depression, and high suicidal ideation. He noted that a second phase 3 trial of MDMA-assisted psychotherapy involving 100 additional patients is under way in Europe and the United States. If all goes well, he hopes MAPS can submit a new drug application with the FDA by the end of 2022.

Mithoefer also stressed that he and his team managed to train 80 new therapists in the process of MDMA-assisted psychotherapy using a manual he wrote. Psychedelic psychotherapy sessions can last up to eight hours, and the treatment regimen also includes multiple sessions before and after the MDMA session so patients can prepare for and integrate their psychedelic experience. “This shows that MDMA-assisted psychotherapy is scalable,” he said.

Mithoefer also noted that patients with the dissociative subtype of PTSD (having elevated feelings that oneself or the world around them is not real) seemed to respond the best, which aligns with the idea that psychedelics help people look inward and find their authentic self. This finding is clinically relevant as dissociative PTSD is considered harder to treat than other subtypes. ■