MDMA Therapy for Mental Health Conditions: Do the Benefits Outweigh the Risks?

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On August 9, 2024, the FDA announced that it had sent a Complete Response Letter (CRL) to Lykos Therapeutics regarding its New Drug Application (NDA) for midomafetamine capsules (MDMA) for the treatment of post-traumatic stress disorder (PTSD). Citing the need for more data, the agency felt that the NDA didn’t prove that the drug could safely treat patients with PTSD.¹

Despite the setback, experts in MDMA therapy remain positive that the drug will eventually be approved. In an interview with Pharm Exec, Fran Brown, SVP, drug development science, Certara, spoke about the FDA’s CRL for midomafetamine and what Lykos is doing to make sure this doesn’t happen again.

“When I reviewed the FDA documents to support the advisory committee hearing, there were five or six major concerns that were coming up around the program,” said Brown. “What the FDA felt that they couldn’t do at the end of the review was to make a good judgement call on the treatment as a whole. Among those concerns were questions about whether the efficacy was properly demonstrated and that there were significant gaps when it came to safety.”

Brown stressed that there were also issues with the clinical trials for midomafetamine capsules.

“There’s an issue of functional unblinding,” she continued. “Because of the nature of MDMA itself, over 90% of the patients that participated in active studies could tell if they were on a placebo or active treatment. With psychoactive therapy and diseases that sit within the [central nervous system], that person’s knowledge to affect behavior is huge. So, for these indications more than any other, having well-blinded placebo-controlled studies is a big part of unbiased efficacy.

“The FDA was also concerned with the fact that they had not properly looked at the duration of effect. They did have an extension study, but it was started long after the first phase of the study finished, so a lot of patients rolling over from that study already knew what therapy they were on, and they were well past the six-month targeting point that the company had set.”

On June 23, 2023, the FDA drafted guidelines for researchers investigating the use of psychedelic drugs for the potential treatment of medical conditions, including psychiatric or substance use disorders. As part of the guidelines, all research must provide sufficient chemistry, manufacturing, and control information to ensure proper identification, quality, purity, and strength of the investigational drug substance and drug product during all phases of clinical trials. Additionally, there were recommendations on non-binding, assessments for abuse potential, and recommendations on clinical pharmacology.^2,3

“Psychedelic drugs show initial promise as potential treatments for mood, anxiety and substance use disorders. However, these are still investigational products. Sponsors evaluating the therapeutic potential of these drugs should consider their unique characteristics when designing clinical studies,” said Tiffany Farchione, MD, director, division of psychiatry, FDA Center for Drug Evaluation and Research, in a press release. “By publishing this draft guidance, the FDA hopes to outline the challenges inherent in designing psychedelic drug development programs and provide information on how to address these challenges. The goal is to help researchers design studies that will yield interpretable results that will be capable of supporting future drug applications.”²

A 2015 study published in the National Library of Medicine (NLM) suggested that psychedelic medicine often requires relatively time-limited interventions, which may make them economically viable compared to long-term pharmacotherapeutic treatments currently available. Additionally, the study suggested that few, if any, serious adverse events are associated with the use of psychedelics in controlled settings, indicating a favorable safety profile when compared to illicit use.

Further, the authors of the study wrote that as evidence accumulates regarding the therapeutic value of psychedelics, there may be a need for policymakers to be open to new treatment approaches, including updating drug control scheduling classifications to reflect the scientific evidence about the relative risks and harms of psychedelics when used in supervised clinical settings, as opposed to uncontrolled recreational use.⁴

“I think that regulatory authorities are open to discussions about how you could do things slightly different in order to be able to make an assessment of risk/benefit,” explained Brown. “What that will look like, I don’t know. But I do know it’s going to take that collaboration to find a path where you can have a more robust answer about risk/benefit.”

The NLM study also mentioned a number of risks associated with psychedelic therapy. First, there is a risk of precipitating psychotic breaks in individuals with a personal or family history of psychotic disorders or a predisposition to such disorders. While uncommon, patients who are treated with psychedelic therapy can experience hallucinogen persisting perception disorder (HPPD), also known as flashbacks. Despite being rare, the effects of HPPD can be severe.⁴

Despite the potential risks, Carl Marci, MD, chief clinical officer, managing director, mental health and neuroscience, OM1, said that there are ways that investigators can ensure that these treatments are both safe and effective.

“This is why we have the FDA,” said Marci. “This is why we have an FDA process. There’s a lot of controversy surrounding it. I think that some of the reports that came out over clinicians being overly enthusiastic about the benefits of this treatment are a bit much, because this therapy is still relatively new. At the end of the day, I think we should all applaud the FDA for doing its job and not rushing what could be a very exciting treatment that the market hasn’t seen before.”

In an interview with Penn Medicine News, Emily Hartwell, PhD, assistant professor, psychiatry, Hospital of the University of Pennsylvania, explained the importance of creating proper guidelines before considering factors such as dosing, scheduling, and therapy.⁵

“That is a piece that can be left out of these conversations,” Hartwell told Penn Medicine News. “Typically, what we see in trials is that people that react the best take the drug in combination with therapy, such as how some patients take selective serotonin reuptake inhibitors in combination with psychotherapy for treating depression.”

Hartwell also stressed the need for combination therapy with psychotherapy, similar to traditional antidepressant treatments, and affordability for widespread accessibility.⁵ Marci also expressed his belief that this combination will be vital to the success of MDMA therapy.

“I think it’s critical,” he explained. “On the one hand, it’s very hard to study. Once these drugs get approved over time, researchers will begin what we call dismantling studies, where we take little pieces of psychotherapy and then try to study them individually. Let’s say the drug gets approved and it has a rich protocol.

“You can imagine researchers saying, ‘What if we don’t do the after, or what if we don’t do the before, or some other kind of combination?’ One of the things that I think about too is the costs and the insurance reimbursements. There’s the costs of therapists and medication. That’s going to cost money, but it’ll be okay if we get results on the back end. But I think that ultimately, understanding the psychotherapy part of this treatment is going to be very important for its long-term success.”

References

1. Lykos Therapeutics Announces Complete Response Letter for Midomafetamine Capsules for PTSD. Lykos. August 9, 2024. Accessed October 21, 2024. https://news.lykospbc.com/2024-08-09-Lykos-Therapeutics-Announces-Complete-Response-Letter-for-Midomafetamine-Capsules-for-PTSD

2. FDA Issues First Draft Guidance on Clinical Trials with Psychedelic Drugs. FDA. June 23, 2023. Accessed October 21, 2024. https://www.fda.gov/news-events/press-announcements/fda-issues-first-draft-guidance-clinical-trials-psychedelic-drugs

3. Psychedelic Drugs: Considerations for Clinical Investigations. FDA. Accessed October 21, 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/psychedelic-drugs-considerations-clinical-investigations

4. Psychedelic medicine: a re-emerging therapeutic paradigm. NIH. October 6, 2015. Accessed October 21, 2024. https://pmc.ncbi.nlm.nih.gov/articles/PMC4592297/

5. Charting a new frontier with psychedelic drugs. Penn Medicine News. June 26, 2024. Accessed October 21, 2024. https://www.pennmedicine.org/news/news-blog/2024/june/charting-a-new-frontier-with-psychedelic-drugs