The Rise, Fall (and Future?) of MDMA-Assisted Therapy

MDMA-assisted therapy went through the wringer this past year. What seemed to be leading up to a monumental breakthrough in psychiatry resulted instead in a setback for integrating psychedelics into the treatment paradigm for mental disorders.

Midomafetamine capsules (3,4 -Methylenedioxy-methamphetamine) alongside psychotherapy held promise in improving PTSD symptoms, such as self-awareness, emotional regulation, and interpersonal dynamics.1 The US Food and Drug Administration (FDA) expressed interest in MDMA-assisted therapy for PTSD, granting Lykos Therapeutics’ New Drug Application (NDA) priority review and assigning the application a Prescription Drug User Fee Act target date of August 11, 2024.

Not only would the approval of MDMA-assisted therapy have shifted the mental health treatment paradigm, but the approval would have broken the over 20-year dry period of new PTSD drugs. Patients with PTSD have limited treatment options and trauma-focused psychotherapy, the first-line treatment, only provides modest improvement in quality of life. The medications for PTSD—sertraline and paroxetine—do not work well for many patients, leaving people aching for more PTSD treatment options.

The Beginning: Before the FDA Decision

On December 12, 2023, months before the FDA decision, Lykos Therapeutics—then MAPS PBC—announced their NDA submission to the FDA for MDMA-assisted therapy to treat PTSD.2

Lykos Therapeutics studied MDMA-assisted therapy for > 30 years. The NDA package included 2 randomized, double-blind, placebo-controlled phase 3 trials called MAPP1 and MAPP2 which evaluated the efficacy and safety of MDMA-assisted therapy versus placebo therapy in participants with moderate to severe PTSD.

Combined, these studies took 7 years to conduct. The study included 3 treatment cycles: preparatory therapy, a full treatment day, and weekly integration sessions for 3 weeks.

MAPP1 and MAPP2 met their primary endpoint of change from baseline in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and their secondary endpoint of functional impairment linked with PTSD, measured by the change from baseline in the Sheehan Disability Scale. The studies reported no serious adverse events.

With the FDA accepting the first NDA for psychedelic-assisted therapy, excitement spread among not only psychiatrists, psychologists, and people suffering from PTSD but also from people outside the medical sphere, such as in religious settings.

“I think people in those camps were also excited about it because it would have marked the first step by the federal government towards increasing access to psychedelic adjacent substances,” Brett Gelbord, JD, an attorney at Dykema and founding member of the Psychedelic Bar Association, told HCPLive.

The initial enthusiasm surrounding MDMA's potential shifted to skepticism after the FDA’s Psychopharmacologic Advisory Committee (PDAC) voted 2-9 against supporting the effectiveness of MDMA in the treatment of PTSD during their meeting on June 4, 2024.3 The committee also voted 1-10 to reject the benefits of MDMA. During the meeting, the FDA cited concerns related to safety, cardiovascular risks, and functional unblinding. An ICER report detailed some allegations of misreported adverse events.

The Uphill Battle for MDMA-Assisted Therapy

Veterans arranged last-made efforts to sway the FDA into approving MDMA-assisted therapy. US Veterans gathered at Lafayette Park to display an art installation of a large army boot cutout surrounded by 17 pairs of real army boots.4 Veterans put together this display to bring attention to the urgent PTSD and suicide crisis ahead of the FDA’s decision on MDMA-assisted therapy.

On July 10, 2024, the attention of MDMA-assisted therapy reached the steps of the Capitol, with the gathering of veterans, bipartisan lawmakers, and PTSD experts. The week of the FDA decision on August 4, 2024, 61 members of the House, 19 senators, and > 700 veterans and first responders sent letters of support to President Biden and FDA Commissioner Califf.5

The Downfall of MDMA-Assisted Therapy

Even with this bipartisan support, the FDA’s stance on MDMA-assisted therapy remained intact. Five days later on August 9, 2024, the FDA issued a Complete Response Letter (CRL) for MDMA-assisted therapy.6

Although the PDAC vote foreshadowed this decision, the decision left many people disappointed, including MDMA-assisted therapy trial participant Cristina Pearse, founder of the Protea Foundation.7

“I am so disappointed because it's clear to me that this is something that can absolutely address complex trauma and trauma in general in a way that any existing medications can't touch,” Pearse said.

SSRIs were harmful to Pearse, making her suicidal. Pearse liked how MDMA allows for neurological repair before addressing the trauma.

“To me, this was such a massive disappointment because the amount of people that need this now who are in a life-and-death sort of equation, this is going to cost lives, and I think it is really important for us to keep in mind that this delay is denying people who are really grappling with suicidality,” Pearse said. “This is a really impactful delay.”

Hans Eriksson, MD, PhD, chief medical officer at HMNC Brain Health, said many drugs create difficulty for functioning arm blinding but are not scrutinized as much as MDMA-assisted therapy. For instance, many psychiatric drugs are sedating, leading people to get sleepy, but the FDA does not give these drugs as much attention.

“I think [this is] because the psychedelics are a bit spectacular and a bit controversial,” Eriksson said. “More light has been directed onto this topic than for some other therapy areas.”

The FDA’s decision may be a setback in the integration of psychedelics into the treatment paradigm, but that does not mean this is over for the future of MDMA-assisted therapy. The CRL instructed Lykos Therapeutics to conduct another phase 3 trial before submitting MDMA-assisted therapy for PTSD again.8

“I don't think that they've signaled that they're closing the door on the issue, but I do think that they're going to be taking a really close look at anything that kind of falls under the larger umbrella of psychedelic medicine,” Gelbord said.

Psychedelics Hurdles

Psychedelics pose legal concerns due to their Schedule 1 status. As of now, psychedelics are only legal in Oregon and Colorado, but both have different laws in terms of psychedelic facilitation. For instance, a regular licensed psychologist or a therapist who has a therapy practice cannot also provide psychological assisted therapy on top of their regular services.

“You can only wear one hat or the other under the Oregon framework,” Gelbord said.

Conversely, Colorado does not have any laws preventing a licensed therapist from getting their psychedelic facilitator’s license. Colorado’s rules are still being finalized, so this could potentially change.

The End for Now: Hope on the Horizon

2024 may have transitioned from high hopes for MDMA-assisted therapy to a sense of disillusionment. However, the horizon for psychedelic advancements in psychiatry still looks bright—and the future for MDMA-assisted therapy.

Investigators are currently studying other psychedelics, such as psilocybin. Emma Wille, MS, a healthcare analyst at Citeline, pointed out one of Compass Pathways’ phase 3 trials has included multiple drug arms: a couple of groups that are dosed sub-therapeutically, a placebo group, and a therapeutic level group.

“The idea is that people will be able to tell whether or not they got psilocybin, but presumably the results of the psilocybin are not going to be completely dependent on whether or not they can tell that they got the drug,” Wille said.

She believed it was good that the FDA rejected MDMA-assisted therapy in its current application, despite its high potential. Already, there was so much publicity surrounding MDMA-assisted therapy, especially concerning the questioned drug’s safety.

“If the FDA had approved [the] MDMA application in the state that it was in, they would have lost a lot of public trust, and that is the key to being able to implement new technologies like psychedelics,” Wille said.

Wille said it would be a good idea if Lykos Therapeutics implemented the sub-therapeutic drug arm, like Compass Pathways, to remove the issue of functional unblinding. Mind Med also did a similar thing for their trials on LSD for anxiety, studying 4 different doses of LSD and the placebo group. Although 90% of participants reported knowing they received LSD, their anxiety scores were still dependent on the dose.

As Wille had said, psychedelic-assisted therapy is not new and has been used for centuries among indigenous people. MDMA-assisted therapy may have been the first psychedelic to reach the FDA, but as experts believe, it will not be the last. This setback may have left people disappointed, but it is not yet over for psychedelic-assisted therapy

“The years up till now has been, to some extent, a preamble to where we are right now,” Eriksson said.

He continued by saying how many companies are studying psychedelics for mental health. Most of the research has been animal data and smaller exploratory phase 2 studies. Recently, we have moved into a period where larger pivotal trials on psychedelics are coming out.

“I see 2025 as the beginning of the harvest time for the psychedelic space,” Eriksson added.

References:

1. Derman, C. MDMA-Assisted Therapy for PTSD Is Backed by Positive Data. HCPLive. April 4, 2024. https://www.hcplive.com/view/mdma-assisted-therapy-for-ptsd-is-backed-by-positive-data. Accessed December 19, 2024.
2. Derman, C. MDMA-Assisted Therapy for PTSD Awaits FDA Decision. HCPLive. December 21, 2023. https://www.hcplive.com/view/mdma-assisted-therapy-for-ptsd-awaits-fda-decision. Accessed December 19, 2024.
3. Kunzmann, K. FDA Psychopharmacologic Advisory Committee Votes Against Supporting Effectiveness of MDMA for PTSD. HCPLive. June 4, 2024. https://www.hcplive.com/view/live-updates-fda-psychopharmacologic-advisory-committee-meeting-mdma-ptsd. Accessed December 19, 2024.
4. Murillo, M. Why are there 17 pairs of Army boots lined up outside the White House? The answer has to do with PTSD — and psychedelic drugs. wtopnews.com. July 26, 2024. https://wtop.com/dc/2024/07/a-dc-art-installation-is-a-call-for-more-treatments-for-veterans-suffering-from-ptsd/. Accessed December 19, 2024.
5. Letter to President Biden from VSOs and Veterans. August 4, 2024. https://drive.google.com/file/d/1AEAsV4RZ0PiWBnZVv42Y6-nNZeHHBRwY/view. Accessed December 19, 2024
6. Derman, C. FDA Rejects Application for MDMA-Assisted Therapy in PTSD, Calls for Additional Trial. HCPLive. August 9, 2024. https://www.hcplive.com/view/fda-rejects-application-for-mdma-assisted-therapy-in-ptsd-calls-for-additional-trial. Accessed December 19, 2024.
7. Derman, C. MDMA-Assisted Therapy Trial Participant Reacts to FDA’s Decision on Lykos’ NDA. HCPLive. August 12, 2024. https://www.hcplive.com/view/mdma-assisted-therapy-trial-participant-reacts-to-fda-s-decision-on-lykos-nda. Accessed December 19, 2024.
8. Derman, C. Crisis Point: Psychiatry at a Crossroad Following FDA Decision on MDMA-Assisted Therapy. HCPLive. August 16, 2024. https://www.hcplive.com/view/crisis-point-psychiatry-at-a-crossroad-following-fda-decision-on-mdma-assisted-therapy. Accessed December 19, 2024.