The FDA Panel has raised multiple critical concerns regarding Lykos Therapeutics’ MDMA-assisted therapy trials for treating PTSD, offering valuable lessons for future clinical research. These concerns span various aspects of the trials, including bias due to functional unblinding, significant safety risks, ethical misconduct, the psychotherapy component, and the durability of the treatment’s effects. This comprehensive examination highlights the concerns brought up during the panel.
FDA Panel Raises Concerns Over Bias in MDMA-Assisted Therapy Trials
The FDA Panel expressed significant concerns about functional unblinding and expectation bias in Lykos Therapeutics’ MDMA-assisted therapy trials for PTSD. Functional unblinding occurs when the drug’s effects are so apparent that participants and investigators can easily determine who receives the active drug versus a placebo. MDMA’s pronounced psychoactive effects, such as heightened emotional states and empathy, make it challenging to maintain the blind in a double-blind study. This leads to expectation bias, where participants’ and investigators’ beliefs about the treatment influence outcomes, potentially exaggerating the drug’s perceived benefits.
The FDA panel recommended including an active comparator with noticeable psychoactive effects to help maintain blinding, but Lykos Therapeutics did not implement this. Consequently, the trials remained vulnerable to bias, complicating the interpretation of results. The panel highlighted that this issue makes it difficult to separate the true therapeutic effects of MDMA from placebo effects driven by expectations. This methodological flaw highlights the need for robust strategies to mitigate functional unblinding and expectation bias in trials involving psychoactive substances, raising questions about the reliability of the efficacy data and posing a hurdle in the approval process for MDMA-assisted therapy for PTSD.
Panel Highlights Safety Concerns in MDMA-Assisted Therapy Trials
The panel raised several significant safety concerns regarding MDMA. One major issue was the insufficient data to fully assess cardiovascular risks, such as the potential for QT interval prolongation, which can lead to serious cardiac arrhythmias. Additionally, increased blood pressure and heart rate observed in participants raised concerns about other cardiac issues. MDMA stimulates the sympathetic nervous system, leading to elevated heart rate and blood pressure, which is risky for individuals with preexisting cardiovascular conditions. The panel recommended further studies to characterize the cardiovascular safety profile of MDMA better.
The panel also identified an incomplete assessment of hepatotoxicity, or liver damage, as a critical safety issue. Given the liver’s role in metabolizing MDMA, there is a potential risk for liver toxicity, which can lead to serious health complications. Additional investigations, including post-marketing studies, were deemed necessary to monitor and understand these potential effects. Moreover, the panel highlighted concerns about MDMA’s abuse potential due to its psychoactive effects, such as euphoria and enhanced emotional connectivity. The trials did not systematically collect data on abuse-related adverse events, which is crucial for understanding MDMA’s central nervous system effects and potential for misuse. The panel stressed the need for systematic data collection on abuse-related outcomes to accurately assess and mitigate these risks.
Ethical Misconduct in MDMA-Assisted Therapy Trials
The panel and speakers raised significant concerns about patient safety and ethical violations in Lykos’s clinical framework for PTSD treatment in the trial. Reports by study participants of boundary violations by therapists, including inappropriate physical contact and emotional intimacy, breached professional ethical standards and undermined patient trust. For example, therapists in the trial engaged in overly affectionate behaviors or made suggestive comments, creating a potentially harmful environment for patients. These issues are especially concerning given MDMA’s effects, which can heighten emotional openness and reduce inhibitions, making patients more vulnerable to inappropriate advances.
The panel emphasized that if such boundary violations are not addressed, they could become widespread, harming numerous patients and damaging the credibility of the treatment. Rigorous training and clear guidelines for therapists are essential, along with strict oversight and regular audits to ensure patients’ rights. Ethical breaches could impact trial validity, as patients who felt violated might report less improvement or deterioration in their PTSD symptoms, skewing study data. Addressing these issues is crucial for the potential approval and safe implementation of MDMA-assisted therapy for PTSD in clinical settings.
Panel Raises Concerns Over Psychotherapy Component in MDMA-Assisted Therapy Trials
The panel highlighted significant concerns about the psychotherapy assessment component of MDMA-assisted therapy. The primary issue was the lack of standardization and consistency with established clinical practice guidelines, raising questions about the validity and reproducibility of the treatment protocol. In the trials, the psychotherapy was tailored to each patient, deviating from structured therapies like prolonged exposure, cognitive processing therapy, and EMDR, which are widely accepted and rigorously tested for PTSD. While potentially beneficial, this individualized approach could lead to inconsistencies in treatment delivery and outcomes.
Moreover, the manualized therapy used in the MDMA sessions included elements from various therapeutic approaches but lacked direct comparisons to these established methods. Without studies comparing this manualized therapy to other psychotherapies or MDMA alone, it’s difficult to determine the psychotherapy’s contribution to the treatment effect. All study arms included psychotherapy, complicating the isolation of MDMA’s specific benefits. While the MDMA group showed significant PTSD symptom improvements, the placebo group also benefited, suggesting that psychotherapy alone had therapeutic value. The panel stressed the need for standardized protocols in future trials to ensure the treatment’s validity and reproducibility across clinical settings.
Panel Questions Durability of MDMA-Assisted Therapy for PTSD
The panel raised significant concerns about the durability of MDMA-assisted therapy’s effects. One primary issue was the high dropout rate, with about 25% of participants not completing follow-up assessments, which casts doubt on long-term efficacy data. Additionally, the use of non-study drugs by participants between the main study and follow-up assessments further muddled results. Some participants might have started using other therapeutic drugs, like antidepressants, influencing their PTSD symptoms independently of the MDMA treatment and complicating the attribution of observed benefits solely to MDMA.
The panel also noted timing discrepancies between the main study’s completion and follow-up visits. In one of the phase 3 studies, participants had a longer interval between their last treatment session and the follow-up assessment due to the study being completed and unblinded earlier, impacting long-term data consistency. For instance, a participant might report significant symptom relief after MDMA-assisted therapy but could have started using another psychotropic medication, confounding the assessment of MDMA’s durability. Conversely, if participants with adverse effects or minimal benefits dropped out, the data might predominantly reflect positive outcomes, skewing results. These issues highlight the need for rigorous follow-up studies to determine if the benefits of MDMA-assisted therapy are sustained over time and truly attributable to the treatment.
Summary
The FDA Panel’s comprehensive review of Lykos Therapeutics’ MDMA-assisted therapy trials emphasizes significant challenges that must be addressed before MDMA can be considered a viable treatment for PTSD. Although the FDA may approve Lykos’s MDMA-assisted therapy, the concerns brought up during the panel provide important lessons for the future of clinical research involving psychoactive substances. From biases in trial design to safety concerns and ethical violations, the issues highlight the need for stringent oversight and methodical approaches. Ensuring standardized psychotherapy protocols, ethical compliance, and thorough long-term efficacy assessments is crucial. Addressing these concerns is essential for the potential approval and safe implementation of MDMA-assisted therapy, aiming to provide a reliable and effective treatment option for PTSD patients in clinical settings.
Moe Alsumidaie is Chief Editor of The Clinical Trial Vanguard. Moe holds decades of experience in the clinical trials industry. Moe also serves as Head of Research at CliniBiz and Chief Data Scientist at Annex Clinical Corporation.