PMID- 29728331 OWN - NLM STAT- MEDLINE DCOM- 20190813 LR - 20190813 IS - 2215-0374 (Electronic) IS - 2215-0366 (Linking) VI - 5 IP - 6 DP - 2018 Jun TI - 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. PG - 486-497 LID - S2215-0366(18)30135-4 [pii] LID - 10.1016/S2215-0366(18)30135-4 [doi] AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is prevalent in military personnel and first responders, many of whom do not respond to currently available treatments. This study aimed to assess the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treating chronic PTSD in this population. METHODS: We did a randomised, double-blind, dose-response, phase 2 trial at an outpatient psychiatric clinic in the USA. We included service personnel who were 18 years or older, with chronic PTSD duration of 6 months or more, and who had a Clinician-Administered PTSD Scale (CAPS-IV) total score of 50 or greater. Using a web-based randomisation system, we randomly assigned participants (1:1:2) to three different dose groups of MDMA plus psychotherapy: 30 mg (active control), 75 mg, or 125 mg. We masked investigators, independent outcome raters, and participants until after the primary endpoint. MDMA was administered orally in two 8-h sessions with concomitant manualised psychotherapy. The primary outcome was mean change in CAPS-IV total score from baseline to 1 month after the second experimental session. Participants in the 30 mg and 75 mg groups subsequently underwent three 100-125 mg MDMA-assisted psychotherapy sessions in an open-label crossover, and all participants were assessed 12 months after the last MDMA session. Safety was monitored through adverse events, spontaneously reported expected reactions, vital signs, and suicidal ideation and behaviour. This study is registered with ClinicalTrials.gov, number NCT01211405. FINDINGS: Between Nov 10, 2010, and Jan 29, 2015, 26 veterans and first responders met eligibility criteria and were randomly assigned to receive 30 mg (n=7), 75 mg (n=7), or 125 mg (n=12) of MDMA plus psychotherapy. At the primary endpoint, the 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity (mean change CAPS-IV total scores of -58.3 [SD 9.8] and -44.3 [28.7]; p=0.001) than the 30 mg group (-11.4 [12.7]). Compared with the 30 mg group, Cohen's d effect sizes were large: 2.8 (95% CI 1.19-4.39) for the 75 mg group and 1.1 (0.04-2.08) for the 125 mg group. In the open-label crossover with full-dose MDMA (100-125 mg), PTSD symptom severity significantly decreased in the group that had previously received 30 mg (p=0.01), whereas no further significant decreases were observed in the group that previously achieved a large response after 75 mg doses in the blinded segment (p=0.81). PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA (mean CAPS-IV total score of 38.8 [SD 28.1] vs 87.1 [16.1]; p<0.0001). 85 adverse events were reported by 20 participants. Of these adverse events, four (5%) were serious: three were deemed unrelated and one possibly related to study drug treatment. INTERPRETATION: Active doses (75 mg and 125 mg) of MDMA with adjunctive psychotherapy in a controlled setting were effective and well tolerated in reducing PTSD symptoms in veterans and first responders. FUNDING: Multidisciplinary Association for Psychedelic Studies. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Mithoefer, Michael C AU - Mithoefer MC AD - Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA. FAU - Mithoefer, Ann T AU - Mithoefer AT AD - Private Practice Office, Mount Pleasant, SC, USA. FAU - Feduccia, Allison A AU - Feduccia AA AD - MAPS Public Benefit Corporation, Santa Cruz, CA, USA. Electronic address: alli@mapsbcorp.com. FAU - Jerome, Lisa AU - Jerome L AD - MAPS Public Benefit Corporation, Santa Cruz, CA, USA. FAU - Wagner, Mark AU - Wagner M AD - Department of Neurology, Medical University of South Carolina, Charleston, SC, USA. FAU - Wymer, Joy AU - Wymer J AD - Department of Neurology, Medical University of South Carolina, Charleston, SC, USA. FAU - Holland, Julie AU - Holland J AD - Private Practice Office, New York, NY, USA. FAU - Hamilton, Scott AU - Hamilton S AD - Stanford School of Medicine, Stanford Stroke Center, Palo Alto, CA, USA. FAU - Yazar-Klosinski, Berra AU - Yazar-Klosinski B AD - Multidisciplinary Association for Psychedelic Studies, Santa Cruz, CA, USA. FAU - Emerson, Amy AU - Emerson A AD - MAPS Public Benefit Corporation, Santa Cruz, CA, USA. FAU - Doblin, Rick AU - Doblin R AD - Multidisciplinary Association for Psychedelic Studies, Santa Cruz, CA, USA. LA - eng SI - ClinicalTrials.gov/NCT01211405 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20180501 PL - England TA - Lancet Psychiatry JT - The lancet. Psychiatry JID - 101638123 RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) MH - Adult MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Firefighters/psychology/*statistics & numerical data MH - Humans MH - N-Methyl-3,4-methylenedioxyamphetamine/*therapeutic use MH - Police/psychology MH - Psychiatric Status Rating Scales/statistics & numerical data MH - Psychotherapy/*methods MH - Stress Disorders, Post-Traumatic/drug therapy/*therapy MH - Treatment Outcome MH - Veterans/psychology/*statistics & numerical data MH - Young Adult EDAT- 2018/05/08 06:00 MHDA- 2019/08/14 06:00 CRDT- 2018/05/06 06:00 PHST- 2018/01/11 00:00 [received] PHST- 2018/03/23 00:00 [revised] PHST- 2018/03/24 00:00 [accepted] PHST- 2018/05/08 06:00 [pubmed] PHST- 2019/08/14 06:00 [medline] PHST- 2018/05/06 06:00 [entrez] AID - S2215-0366(18)30135-4 [pii] AID - 10.1016/S2215-0366(18)30135-4 [doi] PST - ppublish SO - Lancet Psychiatry. 2018 Jun;5(6):486-497. doi: 10.1016/S2215-0366(18)30135-4. Epub 2018 May 1.