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.

Background:Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms.Aims:This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams.Methods:Twenty-eight people with chronic posttraumatic stress disorder were randomized in a double-blind dose response comparison of two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA administered during eight-hour psychotherapy sessions. Change in the Clinician-Administered PTSD Scale total scores one month after two sessions of MDMA served as the primary outcome. Active dose groups had one additional open-label session; the low dose group crossed over for three open-label active dose sessions. A 12-month follow-up assessment occurred after the final MDMA session.Results:In the intent-to-treat set, the active groups had the largest reduction in Clinician-Administered PTSD Scale total scores at the primary endpoint, with mean (standard deviation) changes of −26.3 (29.5) for 125 mg, −24.4 (24.2) for 100 mg, and −11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set (p=0.03). Posttraumatic stress disorder symptoms remained lower than baseline at 12-month follow-up (p<0.001) with 76% (n=25) not meeting posttraumatic stress disorder criteria. There were no drug-related serious adverse events, and the treatment was well-tolerated.Conclusions:Our findings support previous investigations of MDMA-assisted psychotherapy as an innovative, efficacious treatment for posttraumatic stress disorder.

Background: Posttraumatic stress disorder (PTSD) is a debilitating mental health condition associated with serious adverse health outcomes and functional impairment. Previous MDMA–assisted therapy (MDMA-AT) studies have shown promising results in single site studies. Two open-label studies tested this modality in multisite clinical trials to assess the feasibility of scaling this manualized therapy across 14 North American sites. Method: Cotherapist dyads were trained in the manualized MDMA-AT protocol and administered three experimental sessions 3 to 5 weeks apart among participants with severe PTSD. Cotherapist dyads were provided clinical supervision and evaluated for protocol adherence by centralized raters. Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) assessed change in symptoms severity. Results: Adherence rating scores were high across cotherapist dyads ( M = 95.08%, SD = 3.70%) and sites ( M = 95.23%, SD = 2.20%). CAPS-5 scores decreased following 3 MDMA-AT sessions at 18 weeks post baseline (Δ M = −29.99, Δ SD = 13.45, p < .0001, n = 37, Cohen’s d = 2.2, confidence interval [1.97, 2.47]). MDMA was well tolerated. Conclusions: These findings corroborate previous results that MDMA-AT can achieve significant improvements in PTSD symptom severity and demonstrate scalability of manualized therapy across clinic sites in the United States and Canada.

TSD is a common and debilitating condition with immeasurable social and economic costs that affects the lives of hundreds of millions of people annually. There are a number of environmental and biological risk factors that contribute to the development and maintenance of PTSD 1 , and poor PTSD treatment outcomes are associated with several comorbid conditions that include childhood trauma 2 , alcohol and substance use disorders 3 , depression 4 , suicidal ideation 5 and dissociation 6 .It is therefore imperative to identify a therapeutic that is beneficial in those individuals with the comorbidities that typically confer treatment resistance.The selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are Food and Drug Administration (FDA)-approved first-line therapeutics for the treatment of PTSD. However, an estimated 40-60% of patients do not respond to these compounds 7 . Likewise, although evidenced-based trauma-focused