Study Comparing Three Doses of MDMA Along With Therapy in Veterans With Posttraumatic Stress Disorder

Randomized, Triple-Blind, Phase 2 Pilot Study Comparing 3 Different Doses of MDMA in Conjunction With Manualized Therapy in 24 Veterans, Firefighters and Police Officers With Chronic Posttraumatic Stress Disorder (PTSD)

This study is designed to provide information on whether therapy ("talk therapy") combined with the drug MDMA is safe and helpful for subjects with posttraumatic stress disorder (PTSD). The study will compare the effects of a low, a medium and a full dose of MDMA on symptoms of PTSD in 24 veterans, firefighters or police officers. MDMA dose will be assigned at random, and the investigators and the subject will not know the dose given. The researchers will also investigate depression symptoms. The researchers believe that the full dose of MDMA will produce a greater reduction in PTSD symptoms than the two lower doses.

Study Overview

• Status: Completed
• Conditions: Posttraumatic Stress Disorder
• Intervention / Treatment: Drug: Low dose MDMA; Behavioral: Therapy; Drug: Medium dose MDMA; Drug: Full dose MDMA

Detailed Description

Posttraumatic stress disorder (PTSD) is a debilitating mental disorder, that can develop after service in the armed forces. Therapy performed along with MDMA is an innovative form of therapy for PTSD. This study will follow on the findings of an initial pilot study in a sample largely made up of people whose PTSD did not develop from serving in the military. This study will investigate whether MDMA-assisted therapy is safe and efficacious in a sample of veterans and whether maintaining an effective double-blind can be better addressed by performing a dose comparison study.

This study is a randomized, double-blind, dose comparison study with an open-label cross-over segment that will assess the safety and efficacy of MDMA-assisted therapy in veterans with chronic PTSD. Twelve of 24 participants will receive the full dose of 125 mg, six will receive 75 mg and six will receive 30 mg (active placebo dose). An independent rater blind to condition will assess symptoms of PTSD and depression, general quality of life and posttraumatic growth prior to any therapy sessions one month after the second experimental session.

After undergoing three 90-minute non-drug introductory therapy sessions with a male/female co-therapist team, study participants will undergo two eight-hour long experimental sessions scheduled three to five weeks apart, during which they will randomly receive either 30, 75 or 125 mg MDMA on both occasions, followed by a supplemental dose of half the initial dose. Participants will undergo integrative therapy in between each experimental session, including on the day after each session. Vital signs and psychological distress will be measured throughout each experimental session, and suicidality will be assessed throughout the course of the study. Spontaneously reported side effects will be collected on the day of each experimental session, and for six days afterward. PTSD symptoms, symptoms of depression, general psychological function, posttraumatic growth and quality of sleep will be assessed one month after the second experimental session, and the blind will be broken.

Participants who received 125 mg MDMA will continue to have a third experimental session, and they will be assessed two months after the third experimental session.

Participants who received 30 or 75 mg MDMA may take part in an open-label crossover segment that will follow nearly identical procedures, except that there will only be one introductory session prior to the first experimental session. There will be three experimental sessions. Symptoms of PTSD, depression and posttraumatic growth will be assessed at the start of the study. They will also be assessed one month after the second and two months after the third experimental session.

All participants will be assessed 12 months after their final experimental session. PTSD and depression symptoms and posttraumatic growth will be assessed, and participants will complete a questionnaire concerning the costs and benefits of being in the study.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Mount Pleasant, South Carolina, United States, 29464-4345
      • Offices of Michael Mithoefer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Be diagnosed with chronic PTSD, duration of 6 months or longer resulting from traumatic experience during military service;
• Have a CAPS score showing moderate to severe PTSD symptoms;
• 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.
• 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:

5.3.2 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 48 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 s

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low dose MDMA; Participants will receive 30 mg MDMA during each of two blinded experimental sessions.	Drug: Low dose MDMA; 30 mg MDMA administered p.o. once at start of an experimental session. Upon mutual agreement, this may be followed by a supplemental dose of 15 mg MDMA 1.5 to 2 hours later; Other Names: MDMA; 3,4-methylenedioxymethamphetamine; midomafetamine; Behavioral: Therapy; Non-directive therapy during each session
Active Comparator: Medium dose MDMA; Participants will receive 75 mg MDMA on each of two blinded experimental sessions	Behavioral: Therapy; Non-directive therapy during each session; Drug: Medium dose MDMA; 75 mg MDMA administered p.o. once at start of an experimental session. Upon mutual agreement, this may be followed by a supplemental dose of 37.5 mg MDMA 1.5 to 2 hours later; Other Names: MDMA; 3,4-methylenedioxymethamphetamine; midomafetamine
Experimental: Full dose MDMA; Participants will receive 125 mg MDMA during each of two blinded experimental sessions, followed by a third open label session.	Behavioral: Therapy; Non-directive therapy during each session; Drug: Full dose MDMA; 125 mg MDMA administered p.o. once at start of an experimental session. Upon mutual agreement, this may be followed by a supplemental dose of 62.5 mg MDMA 1.5 to 2 hours later; Other Names: MDMA; 3,4-methylenedioxymethamphetamine; midomafetamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Clinician-Administered PTSD Scale (CAPS-IV) Total Score	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.	Baseline
Change in Clinician-Administered PTSD Scale (CAPS-IV) From Baseline to Primary Endpoint	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.	Baseline to one month after second experimental session
Stage 1 Primary Endpoint Clinician-Administered PTSD Scale (CAPS-IV) Total Score	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.	One month after second experimental session

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Global Assessment of Function (GAF) From Baseline to Primary Endpoint	The Global Assessment of Functioning (GAF) Scale is a numeric scale ranging from 0 through 100 that is used by mental health clinicians and physicians to subjectively rate the social, occupational, and psychological functioning of adults. Higher scores indicate better functioning.	Baseline to one month after second experimental session
Change in Posttraumatic Growth Inventory (PTGI) From Baseline to Primary Endpoint	The Posttraumatic Growth Inventory (PTGI) is a 21-item self-report measure of perceived growth or benefits occurring after a traumatic event. It contains five subscales; relationship to others, new possibilities, personal strength, spiritual change, and appreciation of life. Questions are answered on a scale from 0 (I did not experience this change) to 5 (I experienced this change to a great degree). Items are added to calculate the total PTGI score which ranges from 0 to 105, with higher scores indicative of greater growth.	Baseline to one month after second experimental session
Change in Beck Depression Inventory (BDI-II) From Baseline to Primary Endpoint	Validated self-report measure of symptoms of depression. The BDI-II total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe depressive symptoms. The BDI-II is scored by summing the ratings for the 21 items. Each item is rated on a 4-point scale ranging from 0 to 3. The maximum total score is 63.	Baseline to one month after second experimental session
Change in Dissociative Experience Scale (DES-II) From Baseline to Primary Endpoint	The DES-II is a 28-item self-report measure of dissociation, defined as a lack of normal integration of an individual's thoughts, feelings, or experiences into the stream of consciousness or memory. Respondents indicate how often the specific experience happens to them, from "never" (0% of the time) to "always" (100%). The scale is scored by treating percentages as single digits and summing to produce a total score, ranging from 0 to 100. The higher the score, the more dissociative symptoms.	Baseline to one month after second experimental session
Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to Primary Endpoint	The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances. It is comprised of 18 items that yield seven component scores. Component scores are summed to create a total score. Total scores range from 0 (better) to 21 (worse), with higher scores indicating poor sleep quality.	Baseline to one month after second experimental session
Change in Neuroticism-Extroversion-Openness Personality Inventory-Revised (NEO-PI-R) From Baseline to Primary Endpoint	The NEO-PI-R is a 240-item self-report assessment that defines personality structure according to a five-factor model. Items related to neuroticism, extraversion, openness, agreeableness, and conscientiousness are rated on a five-point scale from strongly disagree to strongly agree. T-scores range from 20 to 80 with a mean score of 50. Higher scores in each domain indicating stronger facets of those personality factors. The NEO-PI-R is a measure of personality traits, not psychopathology symptoms.	Baseline to one month after second experimental session

Collaborators and Investigators

• Sponsor: Lykos Therapeutics
• Investigators: Principal Investigator: Michael C Mithoefer, MD, Private Practice

Publications and helpful links

General Publications

• Mithoefer MC, Mithoefer AT, Feduccia AA, Jerome L, Wagner M, Wymer J, Holland J, Hamilton S, Yazar-Klosinski B, Emerson A, Doblin R. 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. Lancet Psychiatry. 2018 Jun;5(6):486-497. doi: 10.1016/S2215-0366(18)30135-4. Epub 2018 May 1.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 10, 2010
• Primary Completion (Actual): June 4, 2015
• Study Completion (Actual): August 2, 2016

Study Registration Dates

• First Submitted: August 6, 2010
• First Submitted That Met QC Criteria: September 28, 2010
• First Posted (Estimated): September 29, 2010

Study Record Updates

• Last Update Posted (Estimated): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Veterans; MDMA; Therapy; Posttraumatic Stress Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Trauma and Stressor Related Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Hallucinogens; Adrenergic Uptake Inhibitors; N-Methyl-3,4-methylenedioxyamphetamine
• Other Study ID Numbers: MP-8

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share de-identified outcome data appearing in any published reports upon request. IPD may include de-identified baseline, demographic and outcome measure data. To ensure participant privacy, it will never include PHI. Please contact the central trial contact for details about data sharing and data available.
• IPD Sharing Time Frame: Data and study-related documents will be available following primary publication of outcomes.
• IPD Sharing Access Criteria: Interested persons should correspond with the central contact for the study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP