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.

Conflict of interest statement

The authors declare the following financial competing interests: A.E., R.M., C.H., A.D.B., S.C., A.C. and J.B.W. received salary support for full-time employment with MAPS PBC for this study and other work; A.L., B.Y.-K. and R.D. received salary support for full-time employment with MAPS for this study and other work; M.M., A.M., M.O.G., B.P. and K.T. received support as contractors from MAPS PBC for training and supervision of research psychotherapists for this study and other work; S.K., K.P.-G. and S.H. received support as contractors of MAPS PBC for their contributions to this study and other work; and study investigators and researchers, J.M.M., M.B., M.O.G., W.G., C.P., I.G., C.N., B.P., S.Q., G.W., S.S.K., B.V.D.K., K.T., R.A., R.W., S.S., J.D.W., C.M., Y.G., E.H., S.A., Y.W. and R.B., received funding from MAPS PBC during the conduct of the study for this study as well as other studies. The following authors disclose receipt of personal fees or grants from companies in the field, but unrelated to the present work: M.B. (Heffter Research Institute, Turnbull Family Foundation, B. More, Mind Medicine, Fournier Family Foundation, Bill Linton, George Sarlo Foundation, RiverStyx Foundation, Dr. Bronners Family Foundation, and National Institutes of Health), C.P. (Fluence and Mindbloom), J.D.W. (Filament Ventures and Silo Pharmaceuticals), and J.M.M. and A.C. (Usona Institute). The following authors disclose non-financial relationships with organizations in the field: M.M. and A.M. serve on the Scientific Advisory Board for Awaken Life Sciences, C.P. co-founded Nautilus Sanctuary and Nautilus Psychiatric Services, S.S. serves on the advisory board for Maya Health, and I.G. serves on the Scientific Advisory Board of Journey Clinical and co-founded Fluence.

Figures

Fig. 1. Procedure timeline and study flow diagram.

a, Procedure timeline. Following the screening procedures and medication taper, participants attended a total of three preparatory sessions, three experimental sessions, nine integration sessions and four endpoint assessments (T1–4) over 18 weeks, concluding with a final study-termination visit. IR, independent rater; T, timepoint of endpoint assessment; T1, baseline; T2, after the first experimental session; T3, after the second experimental session; T4, 18 weeks after baseline. b, CONSORT diagram indicating participant numbers and disposition through the course of the trial.

Fig. 2. Measures of MDMA efficacy in the MDMA-assisted therapy group and the placebo group.

a, Change in CAPS-5 total severity score from T1 to T4 (P < 0.0001, d = 0.91, n = 89 (MDMA n = 46)), as a measure of the primary outcome. Primary analysis was completed using least square means from an MMRM model. b, Change in SDS total score from T1 to T4 (P = 0.0116, d = 0.43, n = 89 (MDMA n = 46)), as a measure of the secondary outcome. Primary analysis was completed using least square means from an MMRM model. c, Change in BDI-II score from T1 to study termination (t = −3.11, P = 0.0026, n = 81 (MDMA n = 42)), as a measure of the exploratory outcome. Data are presented as mean and s.e.m.

Fig. 3. Treatment response and remission for MDMA and placebo groups as a percentage of total participants randomized to each arm (MDMA, n = 46; placebo, n = 44).

Responders (clinically significant improvement, defined as a ≥10-point decrease on CAPS-5), loss of diagnosis (specific diagnostic measure on CAPS-5), and remission (loss of diagnosis and a total CAPS-5 score of ≤11) were tracked in both groups. Non-response is defined as a

Fig. 4. Number of participants reporting the presence of suicidal ideation as measured with the C-SSRS at each visit and separated by treatment group.

C-SSRS ideation scores range from 0 (no ideation) to 5. A C-SSRS ideation score of 4 or 5 is termed ‘serious ideation’. The number of participants endorsing any positive ideation (>0) is shown by the colored bars and noted in the table below the graph. The number of participants endorsing serious ideation is given in parentheses in the table.