MDMA-Assisted Therapy for PTSD Awaits FDA Decision

MAPS Public Benefit Corporation (MAPS PBC) announced on December 12 the submission of the New Drug Application (NDA) to the U.S. Food & Drug Administration (FDA) for MDMA-Assisted Therapy for PTSD—marking the first NDA submission for any psychedelic-assisted therapy.¹

PTSD affects about 13 million Americans a year, yet not many effective treatments exist for the mental health condition. In the 1960s and 1970s, mental health providers used MDMA to improve patient’s ability to process emotions and experiences, but in 1885, the Drug Enforcement Administration banned the drug from being used for medical use.

It wasn’t until the 2000s when investigators began studying the safety and efficacy of MDMA-assisted therapy for treating PTSD.

MDMA (3, 4 – Methylenedioxy-methamphetamine) is an entactogen, a type of psychoactive drug which produces “emotional communion, oneness, relatedness, emotional openness,” according to a MAPS PBC press release. MDMA-assisted therapy combines MDMA with psychotherapy and other supportive services.

Investigators at MAPS PBC studied MDMA-assisted therapy for > 30 years. The NDA submission to the FDA included 2 randomized, double-blind, placebo-controlled phase 3 trials (MAPP1 and MAPP2). The team evaluated the efficacy and safety of MDMA-assisted therapy versus placebo with therapy in participants with moderate or severe PTSD.

The first trial was a pivotal trial, and the second trial was a replication trial. Together, the trials took about 7 years to conduct. People participated in the trial for about 4 months, going through the screening and enrollment period. The study included 3 treatment cycles, consisting of preparatory therapy, a full treatment day, and weekly integration sessions for 3 weeks.

The 2 submitted trials both met their primary and secondary endpoints. The primary endpoint was change from baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and the secondary endpoint was improvement in functional impairment linked with PTSD, measured by the change from baseline in the Sheehan Disability Scale. The investigators did not observe serious adverse events in either study.

In an interview with HCPLive, Jennifer Mitchell, PhD, lead investigator of the MAPS PBC studies, professor of neurology and psychiatry and behavioral sciences at University of California, San Francisco, and associate chief of staff for research and development at the San Francisco VA Medical and Centers, shared what MDMA-treatment means for people with PTSD.

“Well, I’m cautiously optimistic that it could be a true game changer,” Mitchell said. “We do not have great therapies right now for PTSD.”

Currently, the FDA only approved 2 pharmacotherapies, both serotonin reuptake inhibitors (SSRIs) that could be used to treat PTSD: sertraline (Zoloft) and paroxetine (Paxil). Yet, as Mitchell pointed out, the drugs were not developed to specifically treat PTSD—they were designed to treat depression.

“The other is that [with] the two-gold standard psychological therapies that we use for PTSD treatment, namely prolonged exposure therapy and cognitive behavior therapy, it’s very hard to get people to complete a full course of treatment, if they have PTSD,” Mitchell said. “And in those that do, they’re often lingering symptoms. So, I think we could do better.”

Lingering symptoms include dissociation nightmares, trouble engaging, difficulty functioning at work, at home, and at school, and they struggle connecting with family members and friends.

“So, you can image that, over time, it’s actually quite debilitating,” Mitchell said.

In the submitted pivotal trials, 68% of participants administered MDMA-assisted therapy lost their diagnosis of PTSD by the end of the trial.² MDMA provides psychopharmacological effects, such as reduced feelings of fear and defensiveness, increasing feelings of wellbeing, increased sociability, and extroversion, increased interpersonal trust, and an alert state of consciousness.³

A benefit of MDMA-assisted therapy is that the treatment allows people to revisit trauma that doesn’t instantly cause them to disengage to dissociate. Treatment that leads participants to disengage or dissociate can stand as a barrier to improvement.

“If you have somebody that has severe PTSD, and you have them in a therapeutic setting, for example, and you are asking them to recall a horrible event that happened when they were on a tour in Afghanistan, it’s very hard for them to share that with you,” Mitchell said. “And that when they were experiencing MDMA assisted therapy, they found that it was easier to share that subject material and to do it in a way that also involves sort of an eye of self-compassion.”

Mitchell said many people with trauma face shame, regret, embarrassment, and those negative emotions hinder healing. Furthermore, another barrier to improvement is the lack of diversity in the trials. Mitchell and her colleagues wanted to have a diverse participant population, but it is difficult for people in marginalized communities to make time for clinical trials in their schedule.

“I think what we generally found is that if somebody that was quite privileged and affluent was being recruited into the study, and we asked them if they could modify their schedule for a period of four months to accommodate all the study visits, they almost undoubtedly said, of course, but that if we ask somebody from a more marginalized place, can you redesign your schedule for the next four months to accommodate this level? And they would often come back with things like I can’t miss work, and I don’t have a car, and I have to provide childcare, eldercare, et cetera. Can you help me?”

Except, MAPS did not have the funds to help these individuals accommodate their schedules. However, a sponsor allowed them to allocate the funds to help these marginalized communities participate in the study for the replication trial.

Mitchell highlighted the comforting environment where MDMA-assisted therapy was administrated and how that could play a role on the treatment’s success.

“If you’ve seen pictures of these treatment rooms, they look a lot like really comfortable living rooms—they have squishy sofas, and pillows, and blankets, and the lighting is all really nice and low,” Mitchell said. “And there’s a wonderful musical soundtrack, and they’re often wrapped in a warm blanket, and they have eye shades. And we don’t yet know what this therapy would look like if taken out of that context. I think that that’s important for people to recognize, because recently, we’ve heard in the headlines about many people that have decided on their own to self-medicate with these drugs in very different contexts, and without the type of emotional and medical and psychological support that they get from being in a phase trial.”

The investigators did not observe any serious adverse events, but Mitchell pointed out that if people start to take this drug in other contexts, this might not necessarily be the case.

While not everyone responds to psychedelic assisted therapy—and Mitchell believes more research is needed to determine who is and isn’t a responder to the treatment type—the MDMA-assisted therapy offers a new paradigm in the approach for PTSD treatment.

“It’s also potentially an episodic treatment that may have rapid and very meaningful benefits for patients,” Steve Levine, MD, of Patient Access & Medical Affairs COMPASS Pathways, told HCPLive. “At least that’s what’s been demonstrated in their phase three studies with impressive durability of that response.”

The FDA has 60 days from December 12 to deceive whether they will accept the NDA application for MDMA-assisted therapy to treat PTSD. From there, they can make a decision to approve the application in 6 months or 10 months.

“This is an exciting point to know that that new drug application is in,” Mitchell said, “and I think we’re all waiting anxiously to hear what the FDA might have to say.”

References

1. ^{MAPS PBC Announces Submission of New Drug Application to the FDA for MDMA-Assisted Therapy for PTSD. PR Newswire. December 12, 2023.https://www.prnewswire.com/news-releases/maps-pbc-announces-submission-of-new-drug-application-to-the-fda-for-mdma-assisted-therapy-for-ptsd-302011980.html. Accessed December 21, 2023.}
2. ^{Hoffman, Matt. MDMA-Assisted Psychotherapy Improves PTSD Symptoms in Veterans, First Responders. HCPLive. May 3, 2018. https://www.hcplive.com/view/mdma-assisted-psychotherapy-improves-ptsd-symptoms-in-veterans-first-responders. Accessed December 21, 2023.}
3. ^{MDMA-Assisted Therapy for PTSD. https://maps.org/mdma/ptsd/. Accessed December 21, 2023.}