A Critical Step Forward: A Clinician’s Thoughts on MDMA-Assisted Therapy

CLINICAL CONVERSATIONS

The US Food and Drug Administration (FDA) Advisory Committee Meeting will meet on June 4, 2024, to review investigational MDMA-assisted therapy (MDMA-AT) for posttraumatic stress disorder (PTSD). In advance of this meeting, we spoke to Kelley O'Donnell, MD, PhD, a lead educator and clinical consultant in the Lykos Therapeutics MDMA Therapist Education Program to get a clinician’s perspective on this potential treatment.

PT: Investigational MDMA-AT for PTSD could be the first new PTSD treatment in 25 years, as well as the first MDMA-AT and psychedelic-assisted therapy. If approved, how will MDMA change the future treatment of PTSD?

Kelley O’Donnell, MD, PhD: The approval of MDMA-AT could be a breakthrough for patients who suffer from PTSD—even those who have not benefited from prior medications or psychotherapy. It is not uncommon for patients with PTSD to struggle to trust themselves and others, and avoidance of traumatic memories is a hallmark symptom of PTSD. Both of those factors can make it difficult for many patients to participate in conventional psychotherapy for PTSD, and drop-out rates are high.

The pharmacological effects of MDMA often increase the patient’s sense of trust in the health care, and often reduce the anxiety and avoidance associated with traumatic memories and intense emotions. That allows them to engage in the psychotherapy more fully, processing their experiences with a greater sense of self-efficacy and a greater ability to take advantage of the therapist’s support. Some of these benefits last even after the MDMA has worn off, with patients continuing to process insights and experiences even in the drug-free therapy sessions that follow. The whole therapeutic framework of MDMA-AT that was used in the phase 3 trials encourages expression, rather than suppression, of a patient’s experience, which is the opposite of what medications do.

PT: What other potential indications might MDMA-assisted therapy be used for?

O’Donnell: MDMA is currently being studied in conjunction with psychotherapy for several indications, including obsessive-compulsive disorder, eating disorders, social anxiety, and alcohol use disorder.

PT: You have been involved in psychedelic research since 2015. In your experience, how have psychedelics changed over the past few years? What has been the most exciting part of your research?

O’Donnell: There has been a reduced stigma around psychedelic research since then, with an increasing amount of interest, a large influx of funding, and a significant amount of hype. (Unfortunately, the hype has sometimes led participants, clinicians, and the public to have unrealistic expectations about what kinds of drug experiences a person might have, with some people idealizing or fetishizing the psychedelic substance while minimizing or disregarding the potential role of the psychotherapy.) As a therapist, it is a profound experience to be able, in a short period of time, to engage with participants at a level of depth that might take much longer to get to in conventional psychotherapy, if it happens at all.

The most rewarding part of the work has been to see the deep shifts that sometimes emerge out of intense experiences—not simply a change in symptoms or behavior, but in a patient’s sense of self, with an attendant increase in self-awareness, self-compassion, and self-efficacy. But these shifts are not necessarily immediate, and they tend to require significant attention and reinforcement in the drug-free psychotherapy sessions that follow the dosing sessions. This is why it is so important to combat the hype and manage expectations at the outset.

PT: What are the most important takeaways from the MAPP1 and MAPP2 studies?

O’Donnell: MDMA-assisted therapy may be a breakthrough for patients with PTSD, providing symptom relief and functional improvement even for patients who have not benefited from other PTSD treatments.

PT: Critics have claimed the study results are biased because it is not possible to truly blind the active treatment. What can you tell readers to make them feel more comfortable with how the studies were conducted and their results?

O’Donnell: Functional unblinding is a real problem in all psychedelic research, but we cannot let that be a barrier to FDA approval. Instead, we must take measures to reduce its effects to the extent possible. MAPP1 and MAPP2 did this in a rigorous way, using a clinician-administered primary outcome measure (the CAPS-5), administered by an independent rater who had no other contact with the participant and did not discuss the case with the study therapists. The participants were specifically instructed not to tell the independent raters what they thought they had received, and the raters were trained to look for any under- or overreporting of symptoms, to mitigate possible expectancy effects.

PT: What do you wish all clinicians knew about psychedelics?

O’Donnell: Psychedelics are not a panacea, and they are not without risks—including physiologic, psychological, and interpersonal. I would suggest that clinicians familiarize themselves with those risks, so they can take a harm-reduction approach with patients who might be interested in seeking out psychedelic experiences outside the regulated setting.

PT: What advice would you give to a clinician who is reluctant to treat patients with psychedelics?

O’Donnell: It is reasonable for clinicians to conduct a careful risk-benefit analysis for any treatment, particularly one that lacks FDA approval. Besides ketamine, which is sometimes used in a psychedelic model of treatment, there are no FDA-approved psychedelic substances. I would not encourage any clinician to recommend something illegal to their patients. I would urge them to familiarize themselves with the potential risks of illicit use, and adopt a harm-reduction approach with any patients who come to them to discuss an interest in taking psychedelics in an unregulated setting. If MDMA-AT and other psychedelic treatments are approved by the FDA, I would urge clinicians to look past any hype or stigma and practice evidence-based care, familiarize themselves with the safety and efficacy data that led to approval, and stay on top of the literature, so they can support their patients in making informed decisions about their health.

PT: In your opinion, why should clinicians be excited about the upcoming FDA Advisory Committee Meeting to review investigational MDMA-assisted therapy for PTSD?

O’Donnell: The meeting will provide an opportunity to review the clinical outcomes from the phase 3 trials, to learn more about how the FDA is thinking about MDMA-AT, and to think about what structural elements will need to be in place in order to optimize the benefit-risk ratio moving forward. Whatever happens at the meeting, it is a critical step forward in bringing this breakthrough treatment to the patients who need it most.

PT: Thank you!

Dr O’Donnell is board-certified psychiatrist, research assistant professor of Psychiatry at the NYU School of Medicine/Director of Clinical Training at the NYU Center for Psychedelic Medicine, and lead educator and clinical consultant in the Lykos Therapeutics MDMA Therapist Education Program.