After MDMA’s FDA Approval Setback, Science Must Lead the Way

The United States Food and Drug Administration (FDA) rejected Lykos Therapeutics’ new drug application (NDA) for midomafetamine, which is intended to treat post-traumatic stress disorder (PTSD) when used in combination with psychotherapy, last week.

Lykos Therapeutics – a commercial spinout of The Multidisciplinary Association for Psychedelic Studies, or MAPS – is now required to conduct an additional Phase 3 trial to further evaluate the safety and efficacy of midomafetamine (MDMA).

The company declared the decision “deeply disappointing,” and said it would request a meeting with the FDA to ask for reconsideration, perhaps unaware that further blows were yet to be dealt; the journal Psychopharmacology retracted three papers about MDMA-assisted psychotherapy trial data the next day, citing “protocol violations amounting to unethical conduct.” Several authors on these studies are associated with MAPS/Lykos. Later that week, Lykos announced a reorganization of its structure that would reduce its workforce by ~75%.   

The events of the last few weeks have left many wondering how the FDA’s decision might stall the progression of psychedelics research, which has been gaining momentum since the 1990s.

In an interview with Technology Networks, Dr. Sergio Pérez Rosal explains why, in his opinion, “hope is not lost” and the therapeutic potential of these compounds could still be unlocked. However, Pérez Rosal, a medical doctor specialized in anesthesia, intensive care and emergency medicine, and co-founder of the OVID Clinics, emphasizes that what happens next must be firmly rooted in science.    

Molly Coddington (MC): What are your general thoughts regarding the emerging applications of psychedelic compounds to treat neurological disorders?

Sergio Pérez Rosal (SPR): The resurgence of interest in psychedelic research marks a significant turning point in the treatment and psychiatric disorders. This revival, often referred to as the "psychedelic renaissance," comes after decades of stagnation largely due to the regulatory environment established during the Nixon administration's "War on Drugs." In the 1970s, psychedelics were classified as Schedule I substances – denoting high abuse potential, no accepted medical use, and a lack of safety data – leading to a significant reduction in research activity.

In recent years, advancements in research methodology, ethical standards and neuroscientific tools have reignited interest in the potential of psychedelic compounds, particularly serotonergic or "classic" psychedelics, like psilocybin and LSD. These compounds have shown promise in treating a variety of psychiatric disorders, including major depressive disorder, end-of-life anxiety and PTSD. Beyond their therapeutic potential, psychedelics have contributed to a deeper understanding of brain function and consciousness.

The term "psychedelic," derived from the Greek words "psyche" (mind) and "delos" (manifesting), reflects the ability of these substances to reveal the mind's inner workings. In a therapeutic context, with proper preparation and integration, these altered states of consciousness can lead to significant personal insights and psychological healing.

Proponents of this approach refer to it as a paradigm shift in psychiatry – moving from a substitution-based model, where symptoms are managed through ongoing medication, to a transformation-based model, or "transformative psychiatry," where the focus is on achieving long-lasting change. While the exact mechanisms by which psychedelics produce long-lasting symptom remission remain under investigation, the results of ongoing trials offer hope to patients and their families, particularly in areas like PTSD where treatment options have been very limited.

MC: What are your thoughts on the quality of the trial data Lykos presented to the FDA ahead of its decision, which was ultimately a “no” vote?

SPR: The concerns raised by the FDA’s consulting panel, as well as those outlined in the citizen petition, highlight significant issues in the trials conducted by Lykos Therapeutics (formerly MAPS).

The combination of a pharmaceutical agent with psychotherapy as a hybrid intervention presents unique challenges that require a rigorous and methodologically sound approach to ensure the validity of the results. The FDA’s mandate typically involves evaluating drugs, not drug-psychotherapy combinations, making it crucial to thoroughly assess the novel aspects of such interventions.

One key critique centers on the hypothesized mechanism of action termed “inner healing intelligence.” This concept, likened to the body’s natural healing processes (e.g., a cut healing on its own), suggests that the therapy facilitates a form of self-healing.

However, as an anesthesiologist and emergency medicine expert, I can attest that in cases of severe trauma – such as in car accidents – intervention is necessary before any healing can occur. This analogy falls short when applied to psychological trauma, where the need for external guidance and support is often critical.

In my view, the “inner healing intelligence” analogy serves two key purposes, and it is not to be taken literally. First, it is designed to empower participants by reinforcing the belief that they possess the inherent capacity to overcome trauma. This perspective can be highly motivating, encouraging individuals to actively engage in their healing process with the confidence that they already have the necessary tools within themselves. Second, the analogy aims to address and balance the power dynamics within the therapeutic relationship. By emphasizing that the therapist’s role is to “assist” rather than to heal, it reminds both the therapist and the patient that the primary work of healing comes from within the patient. This approach fosters a more collaborative and patient-centered therapeutic environment, where the therapist supports rather than directs the healing process.

Furthermore, the references to spiritual dimensions in the therapy protocols present challenges for their integration into a scientific framework, raising concerns about the interpretability and replicability of the findings.

MC: Blinding is essential in clinical trials – can you explain why it was a problem in this trial and others?

SPR: Blinding is another significant issue in psychedelic research, including the trials conducted by Lykos. The altered states of consciousness induced by psychedelics make it nearly impossible to maintain a true double-blind setup, which is considered the gold standard in clinical research. In a double-blind study, neither the participants nor the researchers know who receives the active substance and who receives a placebo. This is crucial to minimize expectation bias, placebo effects and potential manipulation or underreporting of adverse events. The inability to maintain proper blinding in these trials raises substantial concerns about the validity of the data, as highlighted by the citizen petition.

Another serious concern relates to the vulnerability of participants undergoing MDMA-assisted therapy. Reports of therapists exploiting this vulnerability underscore the need for stringent ethical standards, comprehensive training and close supervision in these therapeutic settings. While this issue touches on ethical considerations that extend beyond the FDA’s purview, it underscores the complexity of evaluating such interventions and the necessity of safeguarding participant welfare.

Given the known challenges of treating patients with substances that induce profound alterations in consciousness, the stigma surrounding “illegal substances” and the novelty of combining pharmacological and psychotherapeutic approaches, Lykos’ trials could have benefited from more meticulous protocols designed to minimize bias and ensure data integrity.

While it is easy to criticize, it is essential to propose constructive solutions. One approach could involve developing alternative methodologies tailored specifically to psychedelic research, thereby upholding rigorous scientific standards.

It is also important to acknowledge that the field of psychopharmacological research, particularly psychedelic research, is severely underfunded. The legal status and societal stigma surrounding these substances further exacerbate these challenges. However, these obstacles should not be used to justify deviations from good scientific practice. As scientists, we must remain critical of our findings and committed to the highest standards of research integrity, ensuring that clinical trials pave the way for safe and effective novel therapies.

MC: Lykos’ MDMA-based therapy for PTSD incorporates a psychotherapy element. A concern raised here is the issue of standardizing that therapy for all patients. Do you have any ideas on how this could be achieved?

SPR: The psychotherapy component of MDMA-assisted therapy is a critical and complex element that presents unique challenges for standardization. Some argue that the psychedelic experience itself is merely a side effect of the treatment and there are ongoing efforts to develop non-psychedelic psychedelics. However, in my view, it is the synergy between the neuropharmacological effects of MDMA and the subjective experience it induces that can lead to profound, life-changing outcomes. The combination of these elements is what makes this form of therapy distinct and potentially transformative.

There is still ongoing debate within the field regarding the exact role and importance of psychotherapy in this context. To standardize this element, we must start by ensuring that therapists and doctors are equipped with a solid theoretical foundation and practical experience, delivered through a competency-based training curriculum. This curriculum should be integrative, eclectic and specifically adapted to the unique demands of psychedelic-assisted therapy (PAT). Supervision during training is crucial, as no single program can prepare practitioners for every challenge they might encounter.

Learning from those with extensive experience in this field, particularly those who have worked with these substances over many years, is essential and should not be overlooked in the development of standardized practices.

The field of psychedelic science is inherently interdisciplinary, bringing together neuroscience, pharmacology, psychology, philosophy, ethics and even theological studies. Despite the complexities involved, the experience gained through clinical studies, such as those conducted by MAPS, has significantly advanced our understanding of how to work effectively with these substances. These studies have helped to develop frameworks that address some of the most critical issues in psychedelic therapy.

One promising approach to standardizing the psychotherapy element is the model proposed by Rochester and colleagues in 2022. It outlines a dual-tier approach to practitioner credentialing, which includes a primary facilitator with a mental health professional license and a secondary facilitator with a minimum of a bachelor’s degree, working under the primary facilitator’s supervision. This structure aligns with current best practices but remains adaptable as the field evolves and as ongoing research explores alternative methodologies.

The Rochester model emphasizes core competencies that are essential for safely and effectively facilitating psychedelic sessions. These include cultural sensitivity, legal and ethical considerations and a deep understanding of both Western and traditional approaches to psychedelic therapy. It also highlights the importance of supervised personal experience with psychedelics as a critical component of therapist training, ensuring that facilitators are not only theoretically knowledgeable but also personally attuned to the altered states of consciousness they will help their patients navigate.

Additionally, this model respects the contributions of Indigenous knowledge and practices by acknowledging that elders and ordained clergy from recognized entheogen traditions possess internal credentialing and do not require additional qualifications. This respect for traditional practices is crucial as we develop regulatory standards and seek to integrate this ancient wisdom into modern therapeutic frameworks.

MC: What’s next for psychedelic therapies, in your opinion?

SPR: As we navigate the approval process for novel therapeutic approaches like MDMA-assisted therapy, it is crucial that our decisions remain firmly grounded in science.

The history of psychedelic substances offers a poignant lesson: the criminalization of these compounds was driven by political motives rather than scientific evidence, and we must be careful not to repeat such mistakes.

While the urgency to find effective treatments for those suffering from severe conditions like PTSD is undeniable, we cannot allow political or lobbying pressures to influence the rigorous standards that should guide the approval of new therapies.

Science must lead the way in ensuring that these interventions are both safe and effective. This means thoroughly addressing the concerns raised by experts and critics, adhering to the highest standards of research methodology, and making decisions based on solid evidence rather than expediency. It is only by maintaining this commitment to scientific integrity that we can truly unlock the potential of these therapies and offer genuine hope to those in need, without compromising safety or efficacy.

Dr. Sergio Pérez Rosal is a medical doctor specialized in anesthesia, intensive care and emergency medicine. He holds an MSc in neuroscience and psychology from Kings College London and is training in cognitive behavioral psychotherapy. He is the co-founder of the OVID Clinics, the first psychedelic medicine clinic in Germany.