MDMA-Assisted Therapy for PTSD Is Backed by Positive Data

Bessel A. van der Kolk, MD

Credit: Trauma Research Foundation

Recent studies highlight the promising efficacy of MDMA-assisted therapy in addressing PTSD by significantly improving key aspects of self-awareness, emotional regulation, and interpersonal dynamics, suggesting a transformative potential for therapeutic interventions.¹

FDA Accepted NDA for MDMA-Assisted Therapy for PTSD

Earlier this year on February 9, 2024, Lykos Therapeutics (formerly MAPS Public Benefit Corporation) announced the US Food and Drug Administration (FDA) accepted its new drug application (NDA) for 3,4-methylenedioxymethamphetamine (MDMA) used alongside psychological intervention such as psychotherapy for individuals with PTSD.²

The FDA granted the NDA the priority review, indicating the treatment would significantly improve the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions compared to other treatments. Additionally, the FDA assigned the application a Prescription Drug User Fee Act (PDUFA) target date of August 11, 2024. If approved, it would be the first MDMA-assisted therapy and psychedelic-assisted therapy.

“I’m cautiously optimistic that it could be a true game changer,” Jennifer Mitchell, PhD, from the University of California, told HCPLive following the announcement of the NDA submission to the FDA on December 12, 2024.³ She served as lead investigator for phase 3 trials assessing MDMA-assisted therapy for PTSD. “We do not have great therapies right now for PTSD.”

Approximately 13 million Americans experience PTSD each year, and although many military veterans have PTSD, the largest cause of PTSD is not combat-related trauma but rather sexual violence, unexpected death of a loved one, life-threatening traumatic events, or interpersonal violence.²

Current PTSD treatment includes trauma-focused psychotherapy, the first-line treatment for PTSD, and the medications sertraline and paroxetine. However, psychotherapy only provided modest improvements in quality of life. As for the medications, many people do not respond to the treatment or stop the treatment. Despite the need for more treatments, the FDA has not approved any new drugs for the management of PTSD in the past 20 years.

Phase 3 Data Submitted in the NDA for MDMA-assisted therapy for PTSD

The NDA submission for MDMA-assisted therapy for PTSD included data 2 phase 3 randomized, double-blind, placebo-controlled phase 3 studies (MAPP1 and MAPP2) assessing the efficacy and safety of MDMA-assisted therapy versus placebo with therapy. MAPP1 included participants with severe PTSD, and MAPP2 had participants with moderate PTSD. Both studies met the primary endpoint as the trials demonstrated MDMA-assisted therapy reduced PTSD symptoms more effectively than therapy alone based on the Clinician-Administered PTSD Scale for DSM-5. The secondary endpoint, improvement in functional impairment associated with PTSD measured by the change from baseline in the Sheehan Disability Scale, was also met in MAPP1 and MAPP2.

Another Trial Assessing How Self-Experience Impacts MDMA-Assisted Therapy

A more recent study, led by Bessel A. van der Kolk, MD, from the Trauma Research Foundation, in Brookline, Massachusetts, evaluated how shifts in personal perception contributed to the improvement in PTSD symptoms, offering valuable insights into the efficacy of MDMA therapy.¹ Prior research showed self-capacities interfered with the successful completion of psychotherapy for PTSD, so investigators wanted to assess treatment effects on self-experience measures and whether improvements occurred independently of PTSD symptom improvements. They also wanted to see if baseline self-experience levels were linked with changes in PTSD symptoms.

All participants met DSM-5 criteria for current PTSD with symptoms lasting ≥ 6 months and a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score of ≥ 35 or greater at baseline. Many participants had past developmental trauma (84.4%) and suffered multiple traumas (87.8%). Participants were mostly women (64.6%), White (80.3%), non-Hispanic or Latino (92.7%), and college graduates (69.5%). The mean age was 41.42 years.

Ninety participants were randomized to receive either MDMA (n = 49) or placebo (n = 44) along with manualized therapy. They had 3 experimental sessions, 3 preparation, and 9 integration therapy visits.

Self-experience symptoms were measured at baseline and 2 months after the last experimental session using the 20-item Toronto Alexithymia Scale (TAS-20), the 26-item Self Compassion Scale (SCS), and the 63-item Inventory of Altered Self-Capacities (IASC).

MDMA-assisted therapy can improve the score of the Toronto Alexithymia Scale (TAS-20), the Self-Compassion Scale, as well as self-experience measures such as idealization disillusionment, abandonment concerns, identity impairment, susceptibility to influence, affect dysregulation, affect instability, affect skill deficit, and tension reduction activities—but not identity diffusion.

Investigators found MDMA had a strong effect on the measures of emotion regulation and self-experience after adjusting for potential covariates. However, after adjusting for the CAPS-5 score, only the SCS change scores were stable and statistically significant (unadjusted for CAPS-5 change, P < .001; adjusted for CAPS-5 change; P = .0076). Furthermore, the study found greater improvements in PTSD symptoms for participants who had a greater alexithymia score at baseline (-16.16; 95% CI, -28.80 to -7.52).

“Securing priority review for our investigational MDMA-assisted therapy is a significant accomplishment and underscores the urgent unmet need for new innovation in the treatment of PTSD,” said Amy Emerson, chief executive officer of Lykos Therapeutics, in a press release.² "We remain focused on working with the FDA through the review process and preparing for a controlled launch with an emphasis on quality should this potential treatment be approved."

^References

1. ^{Lykos Therapeutics Announces FDA Acceptance and Priority Review of New Drug Application for MDMA-Assisted Therapy for PTSD. Lykos Therapeutics. February 9, 2024. https://news.lykospbc.com/2024-02-09-Lykos-Therapeutics-Announces-FDA-Acceptance-and-Priority-Review-of-New-Drug-Application-for-MDMA-Assisted-Therapy-for-PTSD. Accessed April 4, 2024.}
2. ^{van der Kolk BA, Wang JB, Yehuda R, et al. Effects of MDMA-assisted therapy for PTSD on self-experience. PLoS One. 2024;19(1):e0295926. Published 2024 Jan 10. doi:10.1371/journal.pone.0295926}
3. ^{Derman, C. MDMA-Assisted Therapy for PTSD Awaits FDA Decision. HCPLive. December 21, 2024. https://www.hcplive.com/view/mdma-assisted-therapy-for-ptsd-awaits-fda-decision. Accessed April 4, 2024.}