Many people have interpreted as a setback the “no” vote by an advisory committee to the Food and Drug Administration on Lykos Therapeutics’ new drug application for MDMA-assisted psychotherapy for post-traumatic stress disorder. We believe it is an opportunity to build upon Lykos’ success and rally support for better-funded, well-controlled clinical trials to determine the safety and efficacy of a promising PTSD treatment.
Upon reviewing the FDA’s and Lykos’ briefing documents, the Psychopharmacologic Drugs Advisory Committee deemed the study data insufficient to approve the application, and it determined that the company’s risk evaluation and mitigation strategy did not fully address potential harms of this therapy.
The committee’s concerns about study design and data limitations are not uncommon in clinical trials, especially those on psychedelics. However, Lykos’ reliance on philanthropy and donations may have limited its capacity to ensure the rigor needed to meet the agency’s evidentiary standards, particularly in neglecting to properly investigate and quantify the specific contributions of the psychotherapy component. These issues raise the possibility that better study planning and coordination, enabled by more extensive funding, may have mitigated these challenges.
The potential of MDMA-assisted psychotherapy for PTSD treatment
As the FDA noted in its briefing documents, PTSD is a condition affecting an estimated 13 million Americans that may arise following intensely distressing life events, such as threats of death, severe injury, or sexual violence. Besides intrusive memories, hyperarousal, and avoidant behavior, persons with PTSD have a higher risk of suicidal ideation and behavior. Although 60% respond to FDA-approved medications such as sertraline and paroxetine, only 20% to 30% achieve remission, underscoring a vast unmet need for effective PTSD treatments, particularly for those most likely to experience trauma (e.g., combat veterans, women, racial, sexual, and gender minorities).
First synthesized in the early 1900s, MDMA gained notoriety as the 1980s street drug ecstasy before being banned as a Schedule I substance. It resurfaced in the 1990s when clinical researchers noted its capacity to facilitate profound empathy and compassion toward self and others, making it a promising adjunct to psychotherapy. Of relevance to PTSD and other avoidance-based disorders is MDMA’s capacity to diminish fear responses and facilitate lasting shifts from avoidance to acceptance behaviors.
By reducing the aversiveness of unpleasant thoughts and emotions, MDMA enables greater tolerance of traumatic memories and enhances empathetic acceptance.
Understanding the MDMA trials and the committee’s decision
Lykos submitted data from two Phase 3 clinical trials, known as MAPP1 and MAPP2, which compared the effects of MDMA-assisted psychotherapy for severe and at least moderate PTSD versus inactive placebo plus psychotherapy. Treatment for each participant, provided over four months, consisted of preparatory sessions, an eight-hour medication session, and integrative therapy. Endpoints measured changes in symptoms and functional impairment at 18 weeks.
Both studies reported significant improvement with MDMA-assisted psychotherapy and limited evidence of adverse events.
After careful deliberation, the Psychopharmacologic Drugs Advisory Committee endorsed several concerns raised in the FDA’s briefing documents:
First, committee members were concerned that many participants guessed correctly their assignment to the MDMA-assisted and placebo conditions, which may have affected patient-reported outcomes. No additional analyses were reported to examine this possibility.
Second, the committee pointed out missing lab tests and underreported drug reactions like euphoria and elation, which are essential for assessing side effects and abuse potential.
Third, the panelists shared FDA’s concerns that there were insufficient safeguards to protect patients from coercion, misconduct, and injury following improper discharge after MDMA dosing sessions.
Fourth, the committee concluded that the proposed strategies to mitigate potential harms needed more provisions for therapist training and potential misconduct, external monitoring, on-site medical supervision, and ways for patients to report issues.
A need for improved clinical trials infrastructure
The MAPP1 and MAPP2 data exhibit many common shortcomings of clinical trials on psychedelics that make it challenging to be sure that the findings reflect unbiased estimates of the underlying phenomena, namely that MDMA-assisted psychotherapy for PTSD, as implemented by Lykos Therapeutics, is safe and effective.
Given the methodological noise, the reported findings suggest a promising signal that is hard to decipher. While acknowledging the challenges raised by these studies, the committee’s “no” vote does not discourage research on MDMA-assisted psychotherapy for PTSD. Rather, in line with the National Academies of Sciences, Engineering, and Medicine’s recommendations, it suggests the need for public sector collaboration and investment to support more rigorous clinical trials to advance knowledge and translate findings into new tools for mental health.
Two examples of such public investment are noteworthy. First, the National Institutes of Health’s HIV Clinical Trials Networks models how to support high-quality clinical research worldwide, with coordinated leadership and operations, laboratory, and statistical and data management centers collaborating with advocates, government, academia, industry, and nongovernmental organizations. These networks develop and test novel HIV treatments and cure strategies with state-of-the-science protocol development, research design, and data safety and monitoring.
A second example is the U.S. Department of Veterans Affairs’ National Center for PTSD, which seeks to improve clinical care for military veterans through interdisciplinary research on stress-related disorders. Recently, the VA issued its first request for applications since the 1960s to study psychedelic compounds for treating PTSD and depression. This initiative aligns with extant NIH efforts to establish a psychedelic science and medicine interest group, co-sponsor workshops, and a $7.3 million portfolio of predominantly preclinical psychedelic studies. Although the VA’s investments primarily benefit veterans, they highlight the potential for federal investment in clinical trials to identify safe and effective PTSD treatments.
A call to action
The Psychopharmacologic Drugs Advisory Committee’s vote on Lykos Therapeutics’ new drug application is a call to action for advocates, academics, political leaders, funding agencies, foundations, and the scientific community. Public investment is driven by affected communities advocating for their needs and resources to address morbidity and mortality risks. In the 1990s, HIV advocates in the U.S. drastically increased federal and state investment in HIV science, shortened NIH funding cycles, and accelerated access to experimental drugs, bringing control of the global pandemic within reach. Advocates for those with PTSD should follow their lead in pushing for the rapid development of safe and effective new therapies for a persistent threat to well-being.
The time is right. There is a receptive audience in Washington, D.C., for public investment in psychedelic-assisted psychotherapy: the bipartisan Congressional Psychedelics Advancing Clinical Treatments (PACT) Caucus, led by Reps. Lou Correa (D-Calif.) and Jack Bergman (R-Mich.), which aims to fund research on the safety, efficacy, and durability of these treatments to address the national mental health crisis. In the footsteps of Australia and the Netherlands, the U.S. must redouble its efforts to fund more rigorous clinical trials to determine the safety and efficacy of a promising PTSD treatment for those who stand to benefit from it.
Andrew D. Forsyth, Ph.D., is an independent consultant and former NIH program officer based in Berkeley, Calif. Mallory O. Johnson, Ph.D., is a professor of medicine and nursing at the University of California, San Francisco. Jae M. Sevelius, Ph.D., is a professor of medical psychology in the Department of Psychiatry at New York Presbyterian/Columbia University Irving Medical Center.