MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

Abstract

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

Psychedelic perceptions: mental health service user attitudes to psilocybin therapy

“…Conversely, there is accumulating clinical data indicating a transdiagnostic antidepressant [ 3 , 5 , 6 ], anxiolytic [ 11 , 76 ], and anti-addictive [ 8 – 10 ] therapeutic action of higher doses of psilocybin administered in the context of psychological support. Results from ongoing phase 2 RCTs [ 77 , 78 ] will determine whether psilocybin therapy will progress to phase 3 trials and likely follow esketamine/ketamine and MDMA therapy for PTSD [ 79 ] into the psychiatric clinic.…”

Psilocybin and MDMA for the treatment of trauma-related psychopathology

“…The selfreport BDI scale, the outcome measure used in these trials, is not a blinded outcome measure thus expectancy effects are more likely to have contributed to findings. A recent, phase 3 RCT investigating MDMA therapy for PTSD by the same group demonstrated MDMA therapy was effective in reducing depressive mood symptoms (as measured by the BDI-II) (Mitchell et al, 2021).…”

“…In 2017, MDMA was granted this designation for its use in psychotherapy for the treatment of PTSD. As of September 2020, The Multidisciplinary Association for Psychedelic Studies (MAPS) have completed one of two planned phase 3 randomized, double-blind, placebo-controlled, multi-site clinical trials to assess the safety and efficacy of MDMA-assisted psychotherapy in participants with PTSD (Mitchell et al, 2021;Multidisciplinary Association for Psychedelic Research, 2020). Psilocybin therapy has been designated in the same 'breakthrough' category for both the treatment of MDD and TRD (COMPASS Pathways, 2018;Feduccia et al, 2019;Nichols, 2020).…”

Psychotherapy-supported MDMA treatment for PTSD

“…The first Phase III randomized controlled trial of 3,4-methyl enedioxy methamphetamine (MDMA) supported the efficacy of this drug for the treatment of posttraumatic stress disorder (PTSD). 1 This 18-week study (MDMA n = 46, Placebo n = 44) involved three drug administration sessions combined with a supportive psychotherapy. From a baseline PTSD severity score of approximately 44 on the Clinician Administered PTSD Scale for DSM5, MDMA produced a 24.4-point (55.5%) reduction in PTSD severity, which was significantly greater than that seen with placebo (13.9 points, 31.5% reduction).…”