The recent FDA rejection of Lykos’ leading psychedelic candidate, an MDMA based therapeutic designed for treating PTSD, has sparked significant concern and introspection within the psychedelic research community. This decision underscores the complexities involved in bringing novel therapies to market, especially those as unconventional as psychedelics. The rejection also highlights the critical need for more robust clinical trial designs and greater collaboration with regulatory agencies.
 
This editorial will explore the implications of this rejection, the lessons learned, and the path forward for psychedelic therapies in addressing unmet medical needs.

Real-World Consequences of Delay

The delay has real-world consequences, and I have seen first-hand the transformative impact properly controlled psychedelic therapy can have – providing a lasting cure in many cases. In our case, my husband, despite well intentioned use and professional guidance, became addicted to Adderall some years ago and like many others entered a spiral of addictive behavior. In our search for a solution, we found that psychedelics, with their ability to promote neuroplasticity, offered our only genuine hope for relearning good behaviors. We had heard positive outcomes for others using Ibogaine therapy when overseen by a psychiatrist.
 
Sadly, this breakthrough therapy is not available in the US, and we were forced to make the long, arduous trip to the Bahamas to access this life-saving medicine. My husband was besieged by severe withdrawals during our journey, and we were fortunate to have made it. He’s one of the lucky ones.
 
However, once the therapy was underway (under the care of an experienced physician), at a specialized Ibogaine Retreat – it’s no exaggeration to say the results were instant and truly transformative. To bring this story full circle to the recent news, this is not something that many veterans awaiting a Lykos approval can access. I implore the industry to continue to work vigilantly to improve trial design alongside the FDA.
 
The FDA’s decision to withhold approval for MDMA, requiring another phase 3 trial, has meant that we are still trying to find the right way forward for psychedelic research. My hope is that this is only a delay and a final teething problem as we navigate the complexities.

Reasons for the FDA’s Decision

At the heart of this decision were a few perceived critical flaws in the trial design and execution that led to the failure of the drug to prove clinical safety and efficacy. The phase 3 trials conducted by Lykos were notably small, involving only around 100 participants each. Given the registrational nature of these trials, the limited sample size was a significant concern. Smaller trials are statistically less powerful, increasing the risk that the findings may not be generalizable to the broader population. This is particularly problematic in the context of a treatment as controversial and complex as MDMA for PTSD.
 
Moreover, the trial design itself had some issues in the FDA’s view, notably the choice to use placebo groups rather than a low-dose MDMA comparator arm. Placebo groups in psychedelic trials are well known to be particularly challenging due to the potential for functional unblinding, where participants and researchers can guess who is receiving the active treatment based on the drug’s noticeable psychoactive effects. This unblinding can introduce bias and compromise the integrity of the trial’s results. So, the absence of an active comparator arm was perhaps, with hindsight, a missed opportunity to more rigorously evaluate MDMA’s therapeutic efficacy.
 
Expectancy bias further complicates psychedelic trials. This bias occurs when participants’ expectations about the treatment influence their outcomes, and it is particularly problematic in psychedelic studies, where the drug’s profound effects can easily sway perceptions of its efficacy. Many participants in these trials are already believers in the potential benefits of psychedelics, which can lead to an overestimation of the drug’s effects. Combating this bias requires meticulous trial design, including the use of active comparators and sophisticated blinding techniques to ensure objective results.
 
The FDA also raised concerns about the lack of comprehensive safety data in the Lykos trial, particularly regarding cardiac and liver functions. Given that MDMA is a Schedule I compound with inherent risks, the absence of thorough safety evaluations heightened concerns about its broader application. In the regulator’s view, these trials did not sufficiently address these safety issues, especially in vulnerable populations, which was a critical factor in the FDA’s decision to require further trials. These are important lessons for the industry to learn, and addressing these concerns is crucial for transforming the potential of psychedelic research into approved and successful therapies.

Accounting for Challenges and Improving Safety

One of the primary lessons from this experience is the need for more robust protocols that can mitigate the issues identified by the FDA. Trial designs must account for the unique challenges posed by psychedelics, such as the problem of functional unblinding. Future studies should incorporate strategies to reduce this risk, such as using active comparators instead of placebos or employing innovative blinding techniques. Additionally, the use of AI-assisted protocol design could help set up trials quickly while avoiding future issues during regulatory review.
 
Safety concerns, particularly regarding the long-term effects of MDMA or any psychedelic compound, must also be thoroughly investigated. These compounds often have complex effects on the body, and comprehensive safety data is essential for understanding their impact. While this may slow down trial timelines, it is preferable to progress through phases quickly only to encounter issues during the FDA’s review.
 
Improving safety monitoring is not only vital for regulatory approval but also for reassuring the medical community and the public about the safety of these treatments. The rejection of MDMA is especially painful because it delays access to a potentially transformative treatment for PTSD, a condition with few effective options. PTSD is a debilitating disorder, particularly among veterans, who often suffer from treatment-resistant symptoms. MDMA has offered new hope for these individuals, and the FDA’s decision is a significant setback for those awaiting a new treatment option.
 
Beyond PTSD, psychedelics have shown promise in addressing a range of mental health conditions, including depression, anxiety, and addiction. Current treatments for these conditions are often inadequate, leading to growing interest in alternative therapies. Psychedelics, with their unique mechanisms that enhance neuroplasticity, offer the potential to treat these conditions in ways that traditional medications cannot. However, this potential can only be realized if these treatments successfully navigate the rigorous regulatory process and demonstrate both efficacy and safety.

Lessons Learned

The MDMA setback underscores the significant regulatory hurdles that psychedelic therapies must overcome. Unlike traditional pharmaceuticals, psychedelics are still navigating uncharted waters in terms of regulatory approval. Moving forward, it is crucial to engage further with the FDA. This means not only adhering to existing guidelines but also seeking early and frequent feedback to ensure that trials are designed to meet regulatory expectations. Collaboration with the FDA throughout the trial process is essential, particularly in addressing concerns that arise during the study and potentially even during the protocol design stage.
 
The design of the clinical environment itself is another important variable that sponsors and CROs should carefully evaluate. The setting in which psychedelic trials are conducted can significantly impact the results, as environmental factors can influence the therapeutic experience. Future studies must pay close attention to the physical and psychological environment in which the trials are conducted, ensuring it is conducive to the drug’s therapeutic effects.
 
From a CRO perspective, site selection is also critical to the success of these trials. A good mix of experienced sites, both academic and professional, is essential. The CRO must be vigilant in site selection to ensure that the trial is conducted by qualified and experienced teams, which can significantly impact the trial’s outcome. Last year, Emmes, a global CRO with extensive expertise in conducting clinical trials for psychedelic compounds had provided feedback to the FDA, on draft guidelines intended for sponsors of these trials. They continue to collaborate closely with the FDA to build and share knowledge on this groundbreaking therapy.

Why the Need for Approval is Urgent

One of the most concerning consequences of the delay in bringing these therapies to market is the potential for increased underground use of psychedelics. As patients grow more desperate for effective treatments, they may turn to unregulated and potentially dangerous sources. The underground market for psychedelics is fraught with risks, including the lack of standardized dosing, unverified purity, and the absence of professional oversight. The rise in underground use not only poses a danger to individuals but also threatens to undermine the progress being made in legitimate research. Accelerating the development and approval of safe, regulated treatments is urgent to provide patients with safe options and curb the growth of the underground market.
 
The psychedelic research community is at a crossroads, with the potential to revolutionize mental health treatment. However, this potential will only be realized if the industry can meet the high standards required for approval. The FDA’s rejection of MDMA is not the end of the road, but rather a challenge to do better.
 

---

Angela Hargrove, MHA, works within the psychedelic and neuroscience division at Emmes Group CRO. With over three decades of experience in addiction, mental health, and clinical research, she is a recognized thought leader in the emerging psychedelic industry