In August 2024, the U.S. Food and Drug Administration (FDA) dealt a significant blow to the psychedelic therapy movement by rejecting the approval of MDMA, commonly known as ecstasy, for the treatment of post-traumatic stress disorder (PTSD). Lykos Therapeutics had sought approval for a midomafetamine variant of MDMA in combination with psychological interventions, but the FDA’s independent advisory panel, the Psychopharmacologic Drugs Advisory Committee, voted overwhelmingly against it, citing concerns over safety, efficacy, and study integrity. This decision has left many in the medical and mental health fields wondering about the future of psychedelic-assisted therapies, particularly for substances like psilocybin.
Why did the FDA deny the MDMA application?
Lykos Therapeutics’ application for MDMA-assisted therapy was rejected in a 9-2 vote by the FDA’s Psychopharmacologic Drugs Advisory Committee. The committee’s decision was primarily based on concerns over the integrity of the clinical trials and the safety risks posed by MDMA. According to reports, the data from two double-blind, placebo-controlled Phase 3 studies raised doubts about the drug’s efficacy in treating PTSD. Committee members voiced concerns over the potential for abuse, insufficient safeguards to prevent misuse, and the reliability of the psychological follow-up sessions that were integral to the treatment plan.
One major issue highlighted was the difficulty in maintaining a true double-blind study due to the drug’s pronounced psychoactive effects. Approximately 90% of those assigned to the MDMA group correctly identified that they were receiving the drug, compared to 75% in the placebo group, significantly reducing the reliability of the study results. Additionally, allegations of bias and misconduct in the trials, which the FDA is still investigating, further undermined the committee’s confidence in the data.
The FDA’s briefing documents also raised concerns about potential adverse effects, such as increased blood pressure and the risk of misuse. “It seems like there are so many problems with the data,” said Melissa Barone, a psychologist with the VA Maryland Health Care System. “Each one alone might be OK, but when you pile them up on top of each other…” These safety concerns, combined with methodological issues, made the committee hesitant to approve the treatment.
Barriers to FDA approval for psychedelics like psilocybin
Psychedelics like psilocybin face several significant barriers on their road to FDA approval, many of which mirror the challenges faced by MDMA. One of the primary hurdles is the classification of these substances under the Controlled Substances Act.
As Colin Beatty, CEO of Column Health, explained, “Psychedelics are classified as Schedule I substances, meaning they’re considered to have no accepted medical use and a high potential for abuse. This classification not only adds stigma but also makes the approval process difficult by imposing strict research regulations.” For psilocybin to gain approval, extensive, multi-phase clinical trials are required to demonstrate both safety and efficacy, but conducting such trials is challenging due to regulatory constraints and the complex psychoactive effects of these substances.
Another challenge is the difficulty of conducting traditional double-blind, placebo-controlled studies with psychedelics. Like MDMA, psilocybin produces profound psychoactive effects that can make it obvious to participants and researchers alike who are receiving the active drug versus a placebo. This “functional unblinding” can introduce bias and affect the reliability of study results. Dr. Maria Knobel, Medical Director of Medical Cert UK, emphasized the need for innovative trial designs, such as active placebos, to maintain the integrity of future clinical trials.
Additionally, there is still limited long-term data on the safety and efficacy of psychedelics. While early studies have shown promise, more research is needed to understand the potential risks and benefits of repeated use and to identify which patient populations are most likely to benefit.
Impact of the MDMA decision on future psychedelic approvals
The FDA’s rejection of MDMA for PTSD treatment could have far-reaching implications for other psychedelics, including psilocybin. The decision signals the FDA’s high level of scrutiny when it comes to psychedelic therapies, particularly regarding issues of safety, trial design, and data integrity. As Dr. Michael Louwer, MD at Reset Medical and Wellness Center, explained, “The recent rejection of MDMA for PTSD treatment highlights the importance of high-quality, evidence-based testing. With further research, psychedelic medicines can have a very beneficial impact on the mental health community.”
Future clinical trials for psilocybin and other psychedelics will likely face increased pressure to address the concerns raised during the MDMA review. These trials will need to demonstrate not only that the drugs are effective but also that they can be safely administered in a controlled medical setting. Researchers will also need to develop more sophisticated methods for ensuring that trials remain blinded and unbiased, potentially by using active placebos that mimic some of the physical effects of the drug without inducing psychoactive experiences.
Beatty believes that, despite the setback with MDMA, psilocybin may have a better chance of gaining approval, particularly if it is integrated into a well-regulated medical model. “There is a better, safer, faster opportunity for approval of psychedelic pharmacotherapies leveraging psilocybin both at the federal and state levels,” he said. “A medical model of care delivery for mental health diagnoses done in concert with stringent, data-driven, multidisciplinary standards and guidelines for administering these substances will be critical to a successful legalization process.”
Potential consequences for patients and the healthcare system
The failure to approve psychedelic therapies like MDMA and psilocybin could have serious consequences for patients and the healthcare system. Many individuals suffering from treatment-resistant conditions, such as PTSD, depression, and anxiety, may continue to struggle without access to potentially life-changing therapies. As Beatty noted, “Patients with treatment-resistant conditions, such as PTSD, depression, and anxiety, may continue to suffer without access to potentially life-changing therapies.”
Existing treatments for these conditions, including selective serotonin reuptake inhibitors (SSRIs) and psychotherapy, are often inadequate for many patients, leaving them with few options. Psychedelics have shown promise in early studies, offering hope where other treatments have failed. Without FDA approval, however, patients may be forced to seek out unregulated or underground treatments, which could increase the risk of misuse and adverse effects.
For the healthcare system, the failure to approve psychedelics could mean missing out on innovative treatments that have the potential to improve patient outcomes and reduce long-term healthcare costs. Psychedelic therapies, if proven effective, could offer a new approach to treating mental health disorders that are currently placing a significant burden on the healthcare system.
Outlook for future clinical trials and FDA approval
The outlook for future clinical trials of psychedelics remains cautiously optimistic, despite the setback with MDMA. Researchers and advocates believe that with further research, innovative trial designs, and regulatory reform, psychedelics like psilocybin could eventually gain FDA approval. As Dr. Knobel suggested, “Future trials need to develop and adhere to detailed, standardized protocols for the therapeutic component. This includes training therapists to follow specific guidelines and documenting the therapeutic process meticulously to ensure consistency and replicability.”
One potential path forward is the reclassification of psychedelics from Schedule I substances, which would remove some of the regulatory barriers currently hindering research. Additionally, large-scale, multi-phase clinical trials are needed to provide robust evidence of safety and efficacy. Policy reforms that prioritize value-based care models, where the focus is on patient outcomes and cost-effective care, could also strengthen the case for approval.
In the meantime, the rejection of MDMA highlights the importance of transparency and objectivity in the approval process. While the path to FDA approval for psychedelics is likely to be long and complex, many believe that these substances hold great promise for addressing the ongoing mental health crisis.
