High hopes for the regulation of psychedelic medicines have been challenged after an FDA advisory panel voted against approving MDMA-assisted therapy for post-traumatic stress disorder (PTSD). The decision has cast a spotlight on the credibility of the research and the safety of participants involved in the trials.
Credibility of Data Questioned
The New Drug Application (NDA) for midomafetamine (MDMA), submitted by Lykos Therapeutics, included data from two Phase 3 multi-site, randomized, placebo-controlled trials that met their objectives. Lykos stated that its clinical development program was designed in consultation with the FDA to ensure the generalizability and interpretability of results, demonstrating rapid and clinically meaningful improvement in patients’ PTSD symptoms.
However, the FDA advisors voted 9-2 against the effectiveness of MDMA in treating PTSD and 10-1 against the benefits outweighing the risks. The panel cited concerns about data credibility and research practices, also addressed in an Institute for Clinical and Economic Review (ICER) report, which highlighted substantial concerns about the validity of the results.
Issues with Blinding and Bias
One major issue was the blinding of the study, with most patients correctly identifying that they had been given MDMA. Additionally, strong prior beliefs about the benefits of the treatment among both participants and therapists raised concerns about bias. Matthew Johnson PhD, a scientist at Sheppard Pratt, noted that the treatment may be held to a higher standard, despite the common approval of easily identifiable drugs in clinical trials for conditions like sleep and anxiety.
Other issues included a lack of diversity in the trials and a failure to provide data on adverse effects, such as the potential for abuse. Concerns were raised that therapists discouraged reports of substantial harms, treating psychedelics more like a religious movement than pharmaceutical products. A Phase 3 trial participant, Sarah McNamee, reported feeling pressured to view worsening symptoms as evidence of healing and to believe her responses could jeopardize legalization.
Concerns of a 'Therapy Cult'
Evidence presented to the panel raised serious concerns about the conduct of Lykos and its therapy model. The ICER report included public reports of sexual boundaries being severely crossed with at least one patient in a Phase I MAPS trial. A citizen petition cited allegations of entrapment, sexual abuse, and coercive control connected to the organizational culture and psycho-spiritual beliefs encoded in the MAPS/Lykos protocol.
Neşe Devenot PhD, a lecturer at Johns Hopkins University, referred to Lykos’ research practices as a “therapy cult,” citing a wide range of exploitations and abuses. Lykos responded that it follows all industry regulatory requirements and that MAPS is a separate non-profit entity. The company stated that sites were trained to report adverse events per the protocol and that participants were free to discontinue from the studies at any time, with any reports of misconduct investigated and reported to health authorities.
Whistleblower Allegations
Russell Hausfeld, a journalist at Psymposia, reported that whistleblowers and former employees expressed concerns about the company’s conduct, including a sloppy approach to data and a situation in which anyone in the company could access and potentially edit trial results. Lykos maintains that its studies were conducted under guidelines for good clinical practices (GCP), monitored by an independent Data Monitoring Committee, and that clinical site personnel did not have access to the blinded endpoint database.
Patient Safety and Ethical Concerns
Concerns around the safety of patients in vulnerable states during psychedelic trials were echoed by others in the field. The ICER report highlighted the risk of therapists taking advantage of patients due to MDMA breaking down barriers and heightening suggestibility. Reports have surfaced regarding loose boundaries and a training manual that encouraged physical touch. Lykos stated that therapeutic touch was described to provide guidance on appropriate conduct and that independent mental health professionals reviewed video recordings to assess therapist adherence.
Matthew Johnson spoke of an “ego problem” in the field, where the meaningful experiences of patients could lead doctors to act more like cult leaders. He noted that the belief that psychedelics are for the “future of humanity” could lead to sweeping issues under the rug to avoid giving ammunition to critics. Johnson emphasized the need to see the good, the bad, and the ugly for successful therapy approval, acknowledging that there is always a risk-benefit ratio.
Future of Psychedelic Medicine
The FDA will make a final decision on MDMA-assisted therapy in August. While regulators are not bound by the panel’s guidance, it is unlikely they will go against it. Lykos remains optimistic and will work with the FDA on the responsible integration of MDMA-assisted therapy into the healthcare system.
Russell Hausfeld hopes this will be a “learning moment” for the industry, leading to less attachment to “movement-oriented language” and more scrutiny of the motives behind the research. Johnson believes future investigators may invest in more robust trials with measures such as REMS (Risk Evaluation and Mitigation Strategies), training programs, and state boards to minimize potential concerns.
The VA plans to conduct and fund further studies on MDMA and other psychedelic compounds under stringent protocols to evaluate efficacy and safety, aiming to deliver maximum benefit to veterans while minimizing risks.
