PMID- 33972795
OWN - NLM
STAT- MEDLINE
DCOM- 20210819
LR  - 20230131
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 27
IP  - 6
DP  - 2021 Jun
TI  - MDMA-assisted therapy for severe PTSD: a randomized, double-blind, 
      placebo-controlled phase 3 study.
PG  - 1025-1033
LID - 10.1038/s41591-021-01336-3 [doi]
AB  - 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.
FAU - Mitchell, Jennifer M
AU  - Mitchell JM
AUID- ORCID: 0000-0002-7567-8129
AD  - Department of Neurology, University of California San Francisco, San Francisco, 
      CA, USA. jennifer.mitchell@ucsf.edu.
AD  - Department of Psychiatry and Behavioral Sciences, University of California San 
      Francisco, San Francisco, CA, USA. jennifer.mitchell@ucsf.edu.
FAU - Bogenschutz, Michael
AU  - Bogenschutz M
AD  - Department of Psychiatry, New York University Grossman School of Medicine, New 
      York, NY, USA.
FAU - Lilienstein, Alia
AU  - Lilienstein A
AD  - Multidisciplinary Association for Psychedelic Studies (MAPS), San Jose, CA, USA.
FAU - Harrison, Charlotte
AU  - Harrison C
AD  - MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA.
FAU - Kleiman, Sarah
AU  - Kleiman S
AD  - Kleiman Consulting and Psychological Services, Sayreville, NJ, USA.
FAU - Parker-Guilbert, Kelly
AU  - Parker-Guilbert K
AD  - KPG Psychological Services LLC, Brunswick, ME, USA.
FAU - Ot'alora G, Marcela
AU  - Ot'alora G M
AUID- ORCID: 0000-0001-6174-7317
AD  - Aguazul-Bluewater Inc., Boulder, CO, USA.
AD  - MDMA Therapy Training Program, MAPS Public Benefit Corporation, San Jose, CA, 
      USA.
FAU - Garas, Wael
AU  - Garas W
AD  - Aguazul-Bluewater Inc., Boulder, CO, USA.
FAU - Paleos, Casey
AU  - Paleos C
AD  - Nautilus Sanctuary, New York, NY, USA.
FAU - Gorman, Ingmar
AU  - Gorman I
AUID- ORCID: 0000-0003-4674-2969
AD  - Fluence, Woodstock, NY, USA.
FAU - Nicholas, Christopher
AU  - Nicholas C
AD  - Department of Family Medicine and Community Health, University of Wisconsin 
      School of Medicine and Public Health, Madison, WI, USA.
FAU - Mithoefer, Michael
AU  - Mithoefer M
AD  - MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA.
AD  - MDMA Therapy Training Program, MAPS Public Benefit Corporation, San Jose, CA, 
      USA.
AD  - Medical University of South Carolina, Charleston, SC, USA.
FAU - Carlin, Shannon
AU  - Carlin S
AD  - MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA.
AD  - MDMA Therapy Training Program, MAPS Public Benefit Corporation, San Jose, CA, 
      USA.
FAU - Poulter, Bruce
AU  - Poulter B
AUID- ORCID: 0000-0002-0489-2806
AD  - Aguazul-Bluewater Inc., Boulder, CO, USA.
AD  - MDMA Therapy Training Program, MAPS Public Benefit Corporation, San Jose, CA, 
      USA.
FAU - Mithoefer, Ann
AU  - Mithoefer A
AD  - MDMA Therapy Training Program, MAPS Public Benefit Corporation, San Jose, CA, 
      USA.
FAU - Quevedo, Sylvestre
AU  - Quevedo S
AD  - Department of Psychiatry and Behavioral Sciences, University of California San 
      Francisco, San Francisco, CA, USA.
AD  - San Francisco Insight and Integration Center, San Francisco, CA, USA.
FAU - Wells, Gregory
AU  - Wells G
AUID- ORCID: 0000-0003-0902-5282
AD  - San Francisco Insight and Integration Center, San Francisco, CA, USA.
FAU - Klaire, Sukhpreet S
AU  - Klaire SS
AD  - British Columbia Centre on Substance Use, Vancouver, British Columbia, Canada.
FAU - van der Kolk, Bessel
AU  - van der Kolk B
AD  - Boston University School of Medicine, Boston, MA, USA.
FAU - Tzarfaty, Keren
AU  - Tzarfaty K
AD  - MDMA Therapy Training Program, MAPS Public Benefit Corporation, San Jose, CA, 
      USA.
FAU - Amiaz, Revital
AU  - Amiaz R
AD  - Chaim Sheba Medical Center, Tel HaShomer, Israel.
FAU - Worthy, Ray
AU  - Worthy R
AD  - Ray Worthy Psychiatry LLC, New Orleans, LA, USA.
FAU - Shannon, Scott
AU  - Shannon S
AD  - Wholeness Center, Fort Collins, CO, USA.
FAU - Woolley, Joshua D
AU  - Woolley JD
AD  - Department of Psychiatry and Behavioral Sciences, University of California San 
      Francisco, San Francisco, CA, USA.
FAU - Marta, Cole
AU  - Marta C
AD  - New School Research LLC, North Hollywood, CA, USA.
FAU - Gelfand, Yevgeniy
AU  - Gelfand Y
AD  - Zen Therapeutic Solutions, Mt Pleasant, SC, USA.
FAU - Hapke, Emma
AU  - Hapke E
AD  - University of Toronto, Toronto, Ontario, Canada.
FAU - Amar, Simon
AU  - Amar S
AD  - Dr Simon Amar Inc., Montreal, Quebec, Canada.
FAU - Wallach, Yair
AU  - Wallach Y
AD  - Be'er Ya'akov Ness Ziona Mental Health Center, Be'er Ya'akov, Israel.
FAU - Brown, Randall
AU  - Brown R
AD  - Fluence, Woodstock, NY, USA.
FAU - Hamilton, Scott
AU  - Hamilton S
AD  - Stanford School of Medicine, Stanford, CA, USA.
FAU - Wang, Julie B
AU  - Wang JB
AD  - MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA.
FAU - Coker, Allison
AU  - Coker A
AUID- ORCID: 0000-0001-5353-4653
AD  - Department of Neurology, University of California San Francisco, San Francisco, 
      CA, USA.
AD  - MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA.
FAU - Matthews, Rebecca
AU  - Matthews R
AD  - MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA.
FAU - de Boer, Alberdina
AU  - de Boer A
AD  - MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA.
FAU - Yazar-Klosinski, Berra
AU  - Yazar-Klosinski B
AD  - Multidisciplinary Association for Psychedelic Studies (MAPS), San Jose, CA, USA.
FAU - Emerson, Amy
AU  - Emerson A
AD  - MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA.
FAU - Doblin, Rick
AU  - Doblin R
AD  - Multidisciplinary Association for Psychedelic Studies (MAPS), San Jose, CA, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03537014
GR  - R25 DA037756/DA/NIDA NIH HHS/United States
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210510
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
CIN - Nat Med. 2021 Jun;27(6):950-951. PMID: 34031606
CIN - Cell Rep Med. 2021 Aug 17;2(8):100378. PMID: 34467253
CIN - Nat Med. 2021 Oct;27(10):1691-1692. PMID: 34635856
CIN - Nat Med. 2021 Oct;27(10):1689-1690. PMID: 34635857
CIN - Nat Med. 2021 Oct;27(10):1687-1688. PMID: 34635858
MH  - Adult
MH  - Combined Modality Therapy
MH  - Double-Blind Method
MH  - Drug-Related Side Effects and Adverse Reactions/*epidemiology/pathology
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*administration & dosage/adverse effects
MH  - Stress Disorders, Post-Traumatic/*drug therapy/epidemiology/pathology
MH  - Treatment Outcome
PMC - PMC8205851
COIS- 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.
EDAT- 2021/05/12 06:00
MHDA- 2021/08/20 06:00
PMCR- 2021/05/10
CRDT- 2021/05/11 06:33
PHST- 2021/02/05 00:00 [received]
PHST- 2021/04/02 00:00 [accepted]
PHST- 2021/05/12 06:00 [pubmed]
PHST- 2021/08/20 06:00 [medline]
PHST- 2021/05/11 06:33 [entrez]
PHST- 2021/05/10 00:00 [pmc-release]
AID - 10.1038/s41591-021-01336-3 [pii]
AID - 1336 [pii]
AID - 10.1038/s41591-021-01336-3 [doi]
PST - ppublish
SO  - Nat Med. 2021 Jun;27(6):1025-1033. doi: 10.1038/s41591-021-01336-3. Epub 2021 May 
      10.