The FDA's Looming Decision on MDMA-Assisted Therapy: Experts Weigh In

As the mental health community eagerly awaits the FDA's decision on MDMA-assisted therapy for PTSD, expected around August 11th, the landscape is rife with both anticipation and apprehension. This groundbreaking approach combines the psychoactive compound MDMA with psychotherapy, offering new hope for those struggling with treatment-resistant PTSD. However, it also brings its own set of challenges and considerations.

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Carlene MacMillan, M.D., Chief Medical Officer at Osmind, recently hosted a panel of experts on the Psychiatry Tomorrow podcast to explore the complexities surrounding this landmark decision. The conversation brought together Owen Muir, M.D., an interventional psychiatrist and author of the Frontier Psychiatrists newsletter, Boris Heifets, M.D, PhD., an associate professor of anesthesiology at Stanford, and Andrew Penn, RN, MS, NP and clinical professor at UCSF School of Nursing.

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In this deep dive on MDMA-AT and the FDA, we'll explore:

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• The current landscape of clinical enthusiasm and regulatory caution

• Key challenges facing MDMA-assisted therapy approval

• Regulatory considerations and potential requirements

• The unique aspects of combining MDMA with psychotherapy

• Expert insights on the future of psychedelic medicine

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The Current Landscape: Enthusiasm Meets Caution

Recent survey results from an Osmind’s clinical community reveal a striking contrast in the mental health community. At the time we recorded this Psychiatry Tomorrow episode, our survey found the following:

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• While nearly 60 percent of clinicians would approve MDMA assisted therapy if they were at the FDA, only 28 percent believe the FDA will actually grant approval in August.

• If approved, 42 percent of our respondents said they would offer MDMA assisted therapy as soon as possible, while others expressed concerns about safety, protocol, and the readiness of our healthcare system to support this new modality.

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This disparity highlights the complex nature of this decision, balancing clinical enthusiasm with regulatory caution.
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• One respondent called MDMA and other psychedelics, “miracle workers in the field of mental health.”

• Another cautioned about the need for “a more transparent discussion about the obvious financial incentives."

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Providing further insight into the regulatory landscape, Dr. L. Alison McInnes, M.D., M.S., VP of Scientific Affairs at Osmind, recently spoke with Husseini Manji, M.D., F.R.C.P.C, who was instrumental in bringing intranasal esketamine through the FDA approval process. When asked about Lykos' situation, Dr. Manji empathized with the challenges of bringing a novel intervention past regulatory scrutiny. He noted that with MDMA-assisted therapy, there is both a novel drug and a novel therapy, stating, "A lot could go wrong." However, he remained optimistic that MDMA-assisted therapy would eventually be approved and didn't believe other psychedelic sponsors should be discouraged.

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Even with strong clinical potential, significant challenges remain. Let's explore some of the key hurdles facing MDMA-assisted therapy's path to approval.
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Key Challenges and Regulatory Hurdles Facing MDMA-AT

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Functional Unblinding in Clinical Trials

The nature of MDMA's effects presents a significant challenge in maintaining true blinding in clinical trials. Andrew Penn points out, "Functional unblinding is not unique to psychedelics. It makes for good New Yorker comics, but it's not a unique problem." He elaborates with a vivid example: "Take just psychostimulants for ADHD. Do you know you're on a psychostimulant? Hell yeah, you know, compared to a placebo."

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This reality extends beyond trials into clinical practice. Penn explains, "Once this gets out in the world, all clinical work is open label. Everything we do in our offices with patients is open label. I know what you're getting, you know what you're getting. Does that create expectancy biases? Absolutely."

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Interestingly, Penn suggests these biases aren't necessarily negative in practice: "A smart clinician knows how to amplify those. The placebo effect is your biggest ally in clinical practice, but your enemy in trials." This leads him to a provocative conclusion: "I really wish the clinical trial model was more representative of what we actually do in clinical work."

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Dr. Owen Muir illustrates the ethical limitations of blinding with a striking analogy: "We couldn't ethically run a randomized control trial for parachutes and sham parachutes. That trial would be stopped early because the sham parachute group would immediately die."

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For clinicians, the message is clear: while striving for blinding in clinical trials is important, it's crucial to consider how subjective effects and the therapeutic relationship shape outcomes in both research and practice. Perception and belief can be as impactful as the substance itself.

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MDMA-AT Risk Evaluation and Mitigation Strategy (REMS)

Existing REMS programs for drugs like Clozapine and Spravato offer insights into what an MDMA-AT REMS might entail. Dr. Owen Muir cites Clozapine as an example of "a drug for treatment-resistant conditions with extraordinary FDA requirements, acknowledged to be very dangerous and came to market with mandatory monitoring." Similarly, Dr. Carlene MacMillan highlights the Spravato REMS: "It's very strict about the two hours of monitoring. If you let patients go early or make a documentation mistake, you'll get a call within 24 hours from the REMS people."

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For MDMA-AT, Dr. Boris Heifets predicts an even more comprehensive approach: "It would be a registry, documenting every use. They're going to mandate the credentialing of therapists, monitoring for a certain length of time, with explicit adverse events of special interest being suicidality. Maybe videotape the sessions."

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The experts envision an MDMA-AT REMS that would involve comprehensive monitoring of vital signs, dissociation, sedation, and detailed discharge plans. For clinicians considering this potential new treatment, prepare for increased scrutiny and documentation. However, tools like Osmind are already addressing these challenges. For instance, Osmind integrates Spravato REMS documentation into its psychiatry EHR, significantly reducing the administrative burden on clinicians. Similar solutions could be developed for MDMA-assisted therapy, streamlining the process while ensuring compliance with strict safety protocols.

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Safety Monitoring and Long-Term Follow-Up

Dr. Heifets emphasizes the critical need for extended observation: "Long term follow up would have answered so many questions, in terms of efficacy. No matter what is happening in that therapy room, if you have good long-term outcomes without continued use of the drug... that could have addressed a lot of things." This sentiment is echoed in the industry, with Dr. MacMillan noting, "Compass has long term follow up built in their COM 360 trial, and I think that makes a ton of sense."

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Dr. Muir outlines the extensive checks required even for established treatments like Spravato: "You're getting pulse, you're getting blood pressure. You're getting, was there dissociation? Was there sedation? When did it resolve? After how many minutes? What were the vitals at baseline? What were they 40 minutes later? What were they before discharge?" He argues that for MDMA, which affects a broader population including those with potential cardiac issues, such rigorous monitoring is not just bureaucratic overkill but a clinical necessity.

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In the brave new world of psychedelic-assisted therapy, safety isn't just about the immediate session, but about understanding the long-term impact on patients' lives. For clinicians looking to enter this field, prepare for a marathon, not a sprint, when it comes to patient care and data collection.

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Provider Qualifications and Training

The question of who will be qualified to guide patients through these experiences is crucial. Dr. Heifets points out, "Who's trained to give, who's the best psychotherapist? It's often just not people with MDs. So you have to open the gates a little bit to let other practitioners in with experience."

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This opens up a Pandora's box of credentialing questions. As Heifets notes, "The people coming through Center for Integrative Sciences (CIS); does that count as an appropriate credential? Is there a practice board that they answer to?" It's a reminder that in this new frontier, traditional medical qualifications may not be the only benchmark.

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Andrew Penn makes a compelling case for nurses’ involvement: "I'm co-founder of Open Nurses, which is intended to advocate for the role of nursing in this because, you know, nurses sit with people in altered states of consciousness all the time." Plus, it’s economically viable:"There's 5 million of us in the US so you could siphon off 1% and have a ready-made workforce of 50,000 people, which we're going to need in order to do this."

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However, Penn also underscores the unique challenges of MDMA-assisted therapy: "MDMA-AT may require a tremendous amount of discernment, especially when people are vulnerable, especially maybe if somebody starts having sexualized feelings towards the therapist." It's a stark reminder that this isn't just about medical knowledge, but about navigating complex emotional terrains.

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The takeaway? As the field of psychedelic-assisted therapy evolves, so too must our understanding of what qualifies someone to practice it. From MDs to nurses to specialized therapists, the future workforce may be as diverse as the experiences they're guiding.

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Will the FDA approve MDMA-AT? The answer may be contingent on Post-Approval Monitoring and Phase IV trials

"The FDA, their incentives are not to let something out in the wild that's going to kill people and they're going to get egg on their face." - Dr. Owen Muir

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The FDA's decision on MDMA-assisted therapy is likely to be just the beginning of a long regulatory journey.

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Dr. Boris Heifets, while optimistic, predicts approval "with a very restrictive REMS, and it's going to be contingent on phase four studies." He cites a precedent: "A breast cancer drug was approved about 15 years ago contingent on phase four trials being positive. The phase four studies were actually designed like phase three... and then the FDA withdrew approval a year later or a couple years later after the trials came back."

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This approach allows the FDA to balance public pressure for approval with safety concerns. As Heifets notes, "There's tremendous public and political pressure to approve. We've seen the FDA do things under similar circumstances with esketamine and Aduhelm."

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However, Dr. Andrew Penn offers a more cautious view: "I'm leaning towards expecting a no or a very restrictive contingent yes." He points out that the FDA might "require Lykos to go back and do additional phase three studies," which could create financial challenges for the organization.

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The complexity of MDMA-assisted therapy, particularly its therapy component, adds another layer of uncertainty. Penn explains, "Having that embedded in the New Drug Application (NDA) creates some real problems... some of the questions that were asked really pointed to some of the complexities of trying to regulate that. And that makes me less optimistic at this point. It's also possible that August 11th could come and go and they don't give an answer; they can just kick it down the road."

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Looking Ahead: The Future of Psychedelic Medicine

Dr. Heifets offers a provocative prediction: "This will be, at best, a Pyrrhic victory for MAPS, and in 10 years, no one is going to be using MDMA;they're going to be using the derivatives that all jumped in as soon as MDMA was available."

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This suggests that while MDMA-assisted therapy may be groundbreaking, it could also be just the beginning of a new era in psychedelic medicine. The approval of MDMA-AT could open the door for the development of next-generation compounds with improved safety profiles and more targeted effects.

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However, the experts emphasize that the future of psychedelic medicine isn't just about new compounds. It's also about refining our approach to research and treatment. There's a growing recognition of the need for more nuanced, personalized approaches to mental health treatment.

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Conclusion: A Pivotal Moment in Mental Health Treatment

As the FDA's decision looms, Dr. MacMillan summed up the situation: "I'm hoping after August 11th, we can all take as Andrew says a deep, meaningful sigh and figure out a path forward here because I think we all want to see patients get helped and see these breakthrough treatments get safely and reasonably accessibly deployed."

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Whatever the outcome, this decision marks a pivotal moment in the field of mental health treatment. It has the potential to open new doors for research and treatment, not just for MDMA, but for a whole new class of psychedelic medicines.

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Subscribe to the "Psychiatry Tomorrow" newsletter and podcast for the latest updates on this groundbreaking development in mental health treatment.

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Timestamped shownotes:

‍[00:00:00] Introduction and disclosures from panelists

[00:05:00] Discussion begins on FDA's upcoming decision on MDMA-assisted therapy

[00:11:00] Dr. Boris Heifets predicts approval with restrictive REMS and phase four studies

[00:13:00] Andrew Penn expresses cautious pessimism about approval

[00:16:00] Dr. Owen Muir discusses potential FDA responses and historical context

[00:20:00] Conversation on adverse events reporting and data integrity concerns

[00:22:00] Discussion on the challenge of coding adverse events in MDMA trials

[00:27:00] Exploration of FDA's motivations and industry implications

[00:31:00] Panelists speculate on potential REMS requirements for MDMA-assisted therapy

[00:34:00] Debate on the necessity of extensive safety monitoring for MDMA

[00:38:00] Comparison to existing REMS programs like Clozapine and Spravato

[00:42:00] Discussion on provider qualifications and training for MDMA-assisted therapy

[00:47:00] Andrew Penn advocates for nurses' involvement in psychedelic therapies

[00:50:00] Conversation on functional unblinding and placebo effects in clinical trials

[00:53:00] Dr. Owen Muir discusses alternative trial designs for psychedelic research

[00:57:00] Concluding thoughts and hopes for the future of MDMA-assisted therapy