MDMA-Assisted Psychotherapy in People With Posttraumatic Stress Disorder

• ClinicalTrials.gov Identifier: NCT00090064
• Recruitment Status: Completed
• First Posted: August 25, 2004
• Results First Posted: October 25, 2021
• Last Update Posted: November 26, 2021
• Sponsor: Multidisciplinary Association for Psychedelic Studies
• Information provided by (Responsible Party): Multidisciplinary Association for Psychedelic Studies

Tracking Information

• First Submitted Date: August 24, 2004
• First Posted Date: August 25, 2004
• Results First Submitted Date: August 25, 2021
• Results First Posted Date: October 25, 2021
• Last Update Posted Date: November 26, 2021
• Study Start Date: March 2004
• Actual Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 22, 2021)

• Baseline Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) [ Time Frame: Less than 4 weeks before first experimental session ]
  The CAPS-IV is a structured clinical interview designed to assess the symptoms and severity of PTSD. The CAPS-IV provides a means to evaluate the frequency and intensity dimensions of each symptom, the impact of symptoms on the patient's social and occupational functioning, the overall severity of the symptom complex, global improvement since baseline, and the validity of the ratings obtained. Total severity scores range from 0 to 136, with higher scores indicating greater severity of PTSD symptoms.
• Primary Endpoint Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) [ Time Frame: 2 months after second experimental session ]
  The CAPS-IV is a structured clinical interview designed to assess the symptoms and severity of PTSD. The CAPS-IV provides a means to evaluate the frequency and intensity dimensions of each symptom, the impact of symptoms on the patient's social and occupational functioning, the overall severity of the symptom complex, global improvement since baseline, and the validity of the ratings obtained. Total severity scores range from 0 to 136, with higher scores indicating greater severity of PTSD symptoms.
• Change in Clinician-Administered PTSD Scale (CAPS-IV) From Baseline to 2-month Follow-up [ Time Frame: Baseline to 2 months post second experimental session ]
  The Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-IV. The total severity score is a sum of symptom frequency and intensity scores for the subscales B (re-experiencing), C (avoidance) and D (hypervigilance) and ranges from 0 to 136, with higher scores indicating greater severity of PTSD symptoms.

• Original Primary Outcome Measures (submitted: June 23, 2005): Improvement in PTSD symptoms, measured by CAPS score

Current Secondary Outcome Measures (submitted: October 22, 2021)

• Baseline Impact of Events Scale Revised (IES-R) [ Time Frame: Baseline (less than 4 weeks before first experimental session) ]
  The Impact of Events Scale Revised (IES-R) is a 22-item self-report measure (for DSM-IV) designed to measure the extent to which a given stressful life event produces subjective distress. Each item corresponds directly to 14 of the 17 DSM-IV symptoms of PTSD and is rated on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely") for the extent to which the item was true for the participant during the past seven days. The IES-R yields a total score ranging from 0 to 88 with higher scores indicated greater distress.
• Primary Endpoint Impact of Events Scale Revised (IES-R) [ Time Frame: 2 months after second experimental session ]
  The Impact of Events Scale Revised (IES-R) is a 22-item self-report measure (for DSM-IV) designed to measure the extent to which a given stressful life event produces subjective distress. Each item corresponds directly to 14 of the 17 DSM-IV symptoms of PTSD and is rated on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely") for the extent to which the item was true for the participant during the past seven days. The IES-R yields a total score ranging from 0 to 88 with higher scores indicated greater distress.
• Change in Impact of Events Scale Revised (IES-R) From Baseline to 2-month Follow-up [ Time Frame: Baseline to 2 months post second experimental session ]
  The Impact of Events Scale Revised (IES-R) is a 22-item self-report measure (for DSM-IV) designed to measure the extent to which a given stressful life event produces subjective distress. Each item corresponds directly to 14 of the 17 DSM-IV symptoms of PTSD and is rated on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely") for the extent to which the item was true for the participant during the past seven days. The IES-R yields a total score ranging from 0 to 88 with higher scores indicated greater distress.

Original Secondary Outcome Measures (submitted: June 23, 2005)

• Improvement in PTSD symptoms as assessed through other measures
• No impairment in tests of attention, memory or problem-solving

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: MDMA-Assisted Psychotherapy in People With Posttraumatic Stress Disorder
• Official Title: Phase II Clinical Trial Testing the Safety and Efficacy of 3,4-Methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy in Subjects With Chronic Posttraumatic Stress Disorder
• Brief Summary: This randomized, double-blind placebo-controlled study assessed the safety and effectiveness of MDMA-assisted therapy among people with chronic, treatment-resistant PTSD, including veterans. The study enrolled 23 participants. Participants were assigned to receive either therapy with a single divided dose of MDMA or lactose placebo during two blinded experimental sessions spaced three to five weeks apart during Stage 1 of the study. During these experimental sessions, participants received an initial dose of 125 mg of MDMA followed by a supplemental dose of 62.5 mg of MDMA, or they received initial and supplemental doses of inactive placebo.

Detailed Description

Posttraumatic stress disorder (PTSD) occurs in response to a traumatic event or events. It is most likely to occur following an event involving perceived personal threat, such as rape or physical assault. PTSD is clearly a public health problem that causes a great deal of suffering and accounts for a significant portion of health care costs.

MDMA is a substance possessing unique effects that make it well suited to intensive psychotherapy. MDMA has been hypothesized to represent a new class of drugs, called entactogens, that produce feelings of closeness to others, empathy, well being, and insightfulness. Anecdotal reports of therapy conducted before MDMA was placed on Schedule I suggest that MDMA-assisted psychotherapy may benefit people with PTSD.

This randomized, double-blind placebo-controlled study assessed the safety and effectiveness of MDMA-assisted therapy among people with chronic, treatment-resistant PTSD, including veterans. The study enrolled 23 participants. Participants were assigned to receive either therapy with a single divided dose of MDMA or lactose placebo during two blinded experimental sessions spaced three to five weeks apart during Stage 1 of the study. During these experimental sessions, participants received an initial dose of 125 mg of MDMA followed by a supplemental dose of 62.5 mg of MDMA, or they received initial and supplemental doses of inactive placebo. Psychotherapists and independent raters were blinded to participants' treatment conditions. This treatment period also consisted of preparatory sessions and several non-drug therapy sessions to facilitate integration of material arising during experimental sessions.

During Stage 2 of the study, the blind was broken and participants assigned to receive MDMA in Stage 1 underwent a third open-label experimental session of MDMA-assisted therapy. Participants assigned placebo during Stage 1 who chose to enroll in Stage 2 underwent three open-label sessions of MDMA-assisted therapy. Outcome measures were administered two months after the second MDMA or placebo session in Stage 1 and four to six weeks after the second MDMA session in Stage 2. A final data-collection session took place at two months after the third experimental session.

The primary objective of the study was to measure change in PTSD symptoms via CAPS-IV across the study in participants receiving the placebo vs. full dose of MDMA-assisted psychotherapy.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Posttraumatic Stress Disorder

Intervention

• Drug: 3,4-methylenedioxymethamphetamine
  125 mg MDMA followed by a supplemental half-dose of 62.5 mg MDMA
  Other Name: MDMA
• Drug: Lactose placebo pill
  125 mg placebo followed by a supplemental half-dose of 62.5 mg placebo
  Other Name: Placebo
• Behavioral: Therapy
  Non-directive therapy provided by a team of two co-therapists

Study Arms

• Experimental: MDMA-assisted therapy
  Participants will receive an initial dose of 125 mg MDMA orally followed 2 to 2.5 hours later by a second dose of 62.5 mg MDMA during two 8-hour long blinded therapy sessions.
  Interventions:

  • Drug: 3,4-methylenedioxymethamphetamine
  • Behavioral: Therapy
• Placebo Comparator: Placebo with therapy
  Participants will receive an initial dose of 125 mg placebo orally followed 2 to 2.5 hours later by a second dose of 62.5 mg placebo during two 8-hour long blinded therapy sessions.
  Interventions:

  • Drug: Lactose placebo pill
  • Behavioral: Therapy

Publications *

• Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol. 2011 Apr;25(4):439-52. doi: 10.1177/0269881110378371. Epub 2010 Jul 19. Erratum in: J Psychopharmacol. 2011 Jun;25(6):852.
• Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Martin SF, Yazar-Klosinski B, Michel Y, Brewerton TD, Doblin R. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol. 2013 Jan;27(1):28-39. doi: 10.1177/0269881112456611. Epub 2012 Nov 20.
• Jerome L, Feduccia AA, Wang JB, Hamilton S, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R. Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology (Berl). 2020 Aug;237(8):2485-2497. doi: 10.1007/s00213-020-05548-2. Epub 2020 Jun 4.
• Feduccia AA, Jerome L, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R. Breakthrough for Trauma Treatment: Safety and Efficacy of MDMA-Assisted Psychotherapy Compared to Paroxetine and Sertraline. Front Psychiatry. 2019 Sep 12;10:650. doi: 10.3389/fpsyt.2019.00650. eCollection 2019. Review.
• Mithoefer MC, Feduccia AA, Jerome L, Mithoefer A, Wagner M, Walsh Z, Hamilton S, Yazar-Klosinski B, Emerson A, Doblin R. MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology (Berl). 2019 Sep;236(9):2735-2745. doi: 10.1007/s00213-019-05249-5. Epub 2019 May 7.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 22, 2014): 23
• Original Enrollment (submitted: June 23, 2005): 20
• Actual Study Completion Date: September 2010
• Actual Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Be diagnosed with chronic PTSD, duration of 5 years or longer resulting from traumatic experience during military service or a victim of crime;

• Have a CAPS score showing moderate to severe PTSD symptoms;

  1. Have had at least one unsuccessful attempt at treatment for PTSD either with talk therapy or with drugs, or discontinuing treatment because of inability to tolerate psychotherapy or drug therapy.
  2. Are at least 18 years old;
• Must be generally healthy;
• Must sign a medical release for the investigators to communicate directly with their therapist and doctors;
• Are willing to refrain from taking any psychiatric medications during the study period;
• Willing to follow restrictions and guidelines concerning consumption of food, beverages, and nicotine the night before and just prior to each experimental session;
• Willing to remain overnight at the study site;
• Agree to have transportation other than driving themselves home or to where they are staying after the integrative session on the day after the MDMA session;
• are willing to be contacted via telephone for all necessary telephone contacts;
• Must have a negative pregnancy test if able to bear children, and agree to use an effective form of birth control;
• must provide a contact in the event of a participant becoming suicidal;
• Are proficient in speaking and reading English;
• agree to have all clinic visit sessions recorded to audio and video
• Agree not to participate in any other interventional clinical trials during the duration of this study.

Exclusion Criteria:

• Are pregnant or nursing, or if a woman who can have children, those who are not practicing an effective means of birth control;
• Weigh less than 50 kg;
• Are abusing illegal drugs;
• Are unable to give adequate informed consent;
• Upon review of past and current drugs/medication must not be on or have taken a medication that is exclusionary.
• Upon review of medical or psychiatric history must not have any current or past diagnosis that would be considered a risk to participation in the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00090064
• Other Study ID Numbers: MP1
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Multidisciplinary Association for Psychedelic Studies
• Original Responsible Party: Not Provided
• Current Study Sponsor: Multidisciplinary Association for Psychedelic Studies
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Michael Mithoefer, MD; Private Practice

• PRS Account: Multidisciplinary Association for Psychedelic Studies
• Verification Date: November 2021