Randomized, Double-blind, Placebo-Controlled Pilot Study of MDMA-assisted Therapy for PTSD

A Randomized, Double-Blind, Active Placebo-Controlled Phase 2 Pilot Study of MDMA-assisted Psychotherapy in People With Chronic, Treatment-Resistant Posttraumatic Stress Disorder (PTSD)

The goal of this clinical trial is to learn if MDMA-assisted therapy is safe and effective in people with chronic, treatment-resistant PTSD.

The main question it aims to answer is: Is there a reduction in PTSD symptoms in people given a low dose of MDMA with therapy versus a high dose of MDMA with therapy?

Researchers will compare two sessions of MDMA-assisted therapy with either 25 mg of MDMA HCl or 125 mg of MDMA HCl in Stage 1.

Participants will undergo preparatory therapy sessions without any study drug, followed by two sessions of MDMA-assisted therapy, each followed by integrative therapy sessions without study drug. Participants who received 25 mg during Stage 1 will be given the option to enroll in Stage 2 and complete two additional open-label MDMA-assisted therapy sessions with the full dose of 125 mg MDMA.

Study Overview

• Status: Completed
• Conditions: Posttraumatic Stress Disorder (PTSD)
• Intervention / Treatment: Behavioral: Psychotherapy; Drug: Open-Label Full Dose MDMA-assisted therapy (125 mg); Drug: Active Placebo Dose MDMA-assisted therapy (25 mg); Drug: Full Dose MDMA-assisted therapy (125 mg)

Detailed Description

This randomized, double-blind, active placebo-controlled Phase 2 pilot study investigated the safety and efficacy of MDMA-assisted psychotherapy in 10 people with chronic, treatment-resistant posttraumatic stress disorder (PTSD), comparing the effects of low and full dose MDMA as an adjunct to psychotherapy. The first two subjects were enrolled in the open label full dose lead-in with 125 mg of midomafetamine HCl, followed by a supplemental half-dose of 62.5 mg after 1.5 to 2.5 hours. The remaining eight subjects enrolled in Stage 1 of the study and received either an active placebo dose (low dose of 25 mg midomafetamine HCl with a supplemental half-dose of 12.5 mg) or a fully active dose (125 mg midomafetamine HCl with a supplemental half-dose of 62.5 mg) during two experimental psychotherapy session, each lasting six to eight hours and scheduled three to five weeks apart.

Upon enrollment, subjects met with their therapist team for three preparatory sessions. After each MDMA-assisted psychotherapy session, subjects met with their therapist team for integrative psychotherapy sessions.

The extent of PTSD symptoms was assessed at baseline and two months after the second experimental session using the Clinician Administered PTSD Scale (CAPS) (Blake et al., 1995). Safety measures, vital signs, and a measurement of psychological distress was assessed during all experimental sessions. Blood pressure and heart rate were assessed periodically during each experimental session.

Subjects who enrolled in Stage 1 and received the active placebo had the opportunity to enroll in Stage 2 of the study and complete open-label experimental sessions with the fully active dose of midomafetamine HCl (125 mg and 62.5 mg supplemental) on the same schedule as Stage 1.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• Israel
  • Be'er Ya'aqov, Israel, 70350
    • Beer Yaakov Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Diagnosed with chronic PTSD with a duration of 6 months or longer.
• Have a CAPS score showing moderate to severe symptoms.
• Had at least one unsuccessful attempt at treatment for PTSD, either with talk therapy or with drugs, or stopped treatment because of inability to tolerate psychotherapy or drug therapy.
• Are at least 18 years old.
• 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.
• Agree that, one week before the MDMA session, will refrain from taking all below unless with prior approval of research team: herbal supplements, nonprescription medications (with the exception of nonsteroidal anti-inflammatory drugs or acetaminophen, any prescription medications, with the exception of birth control pills, thyroid hormone, or other medications;
• Are willing to follow restrictions and guidelines concerning consumption of food, beverages. and nicotine the night before and just prior to each experimental session.
• Are willing to remain overnight at the study site.
• 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.
• Agree not to participate in any other clinical trial for the duration of this clinical trial, including the follow-up period.
• Are proficient in speaking and reading Hebrew.
• Agree to have all psychotherapy sessions recorded to audio/video.

Exclusion Criteria:

• Are pregnant or nursing, or if they can have children and are not practicing an effective means of birth control.
• Weigh less than 48 kg.
• Are abusing illegal drugs.
• Have used "Ecstasy" (material represented as containing MDMA) more than five times or at least once within 6 months of the MDMA session.
• 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.

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
Experimental: Lead in: 125 mg MDMA-assisted therapy (Open-Label); Participants receive open-label MDMA with an initial dose of 125 mg midomafetamine HCl, possibly followed by a supplemental dose of 62.5 mg, during two psychotherapy sessions scheduled 3-5 weeks apart.	Behavioral: Psychotherapy; Non-directive psychotherapy will be conducted throughout the study.; Other Names: Manualized MDMA-assisted psychotherapy; Drug: Open-Label Full Dose MDMA-assisted therapy (125 mg); Initial dose of 125 mg midomafetamine HCl administered orally at the start of each of two psychotherapy sessions, possibly followed by a supplemental dose of 62.5 mg 1.5 to 2.5 hours later.; Other Names: MDMA; 3,4-methylenedioxymethamphetamine; midomafetamine; midomafetamine HCl
Placebo Comparator: Active placebo dose MDMA-assisted therapy (25 mg); Participants receive initial dose of 25 mg midomafetamine HCl, possibly followed by a supplemental dose of 12.5 mg, during two psychotherapy sessions scheduled 3-5 weeks apart.	Behavioral: Psychotherapy; Non-directive psychotherapy will be conducted throughout the study.; Other Names: Manualized MDMA-assisted psychotherapy; Drug: Active Placebo Dose MDMA-assisted therapy (25 mg); Initial dose of 25 mg midomafetamine HCl administered orally at the start of each of two psychotherapy sessions, possibly followed by a supplemental dose of 12.5 mg 1.5 to 2.5 hours later.; Other Names: MDMA; 3,4-methylenedioxymethamphetamine; midomafetamine; midomafetamine HCl
Experimental: Full dose MDMA-assisted therapy (125 mg); Participants receive initial dose of 125 mg midomafetamine HCl, possibly followed by a supplemental dose of 62.5 mg, during two psychotherapy sessions scheduled 3-5 weeks apart.	Behavioral: Psychotherapy; Non-directive psychotherapy will be conducted throughout the study.; Other Names: Manualized MDMA-assisted psychotherapy; Drug: Full Dose MDMA-assisted therapy (125 mg); Initial dose of 125 mg midomafetamine HCl administered orally at the start of each of two psychotherapy sessions, possibly followed by a supplemental dose of 62.5 mg 1.5 to 2.5 hours later.; Other Names: MDMA; 3,4-methylenedioxymethamphetamine; midomafetamine; midomafetamine HCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Clinical Administered PTSD Scale (CAPS-IV) Total Score From Baseline to End of Stage 1	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 1-Month Post Experimental Session 2 (End of Stage 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Clinical Administered PTSD Scale (CAPS-IV) Total Score From Baseline to Long-Term Follow-Up	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 12 months post-final experimental session
Change in Beck Depression Inventory (BDI-II) Total Scores From Baseline to End of Stage 1	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 1-Month Post Experimental Session 2 (End of Stage 1)
Change in Beck Depression Inventory (BDI-II) Total Scores From Baseline to Long-Term Follow-Up	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 12 month post-final experimental session
Change in Global Assessment of Functioning (GAF) Scale From Baseline to End of Stage 1	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 1-Month Post 2nd Experimental Session (End of Stage 1)
Change in Global Assessment of Functioning (GAF) Scale From Baseline to Long-Term Follow-Up	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 12 months post-final experimental session
Change in Posttraumatic Stress Diagnostic Scale (PDS) Symptom Severity Score From Baseline to End of Stage 1	The Posttraumatic Stress Diagnostic Scale (PDS) is a 49-item self-report instrument designed to aid in the diagnosis of PTSD. Responses to 17 symptom items are made on a 4 point scale ranging from 0 (not at all) to 3 (five or more times per week). The symptom items are summed to calculate the symptom severity score which ranges from 0 to 51, with higher scores indicating more severe PTSD symptoms.	Baseline to 1-Month Post 2nd Experimental Session (End of Stage 1)
Change in Posttraumatic Stress Diagnostic Scale (PDS) Symptom Severity Score From Baseline to Long-Term Follow-Up	The Posttraumatic Stress Diagnostic Scale (PDS) is a 49-item self-report instrument designed to aid in the diagnosis of PTSD. Responses to 17 symptom items are made on a 4 point scale ranging from 0 (not at all) to 3 (five or more times per week). The symptom items are summed to calculate the symptom severity score which ranges from 0 to 51, with higher scores indicating more severe PTSD symptoms.	Baseline to 12 months post-final experimental session
Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to End of Stage 1	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 1-Month Post 2nd Experimental Session (End of Stage 1)
Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to Long-Term Follow-Up	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 12 months post-final experimental session
Change in Clinical Administered PTSD Scale (CAPS-IV) Total Score From Baseline to End of Stage 2	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 End of Stage 2
Change in Beck Depression Inventory (BDI-II) Total Score From Baseline to End of Stage 2	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 End of Stage 2
Change in Global Assessment of Functioning (GAF) Scale From Baseline to End of Stage 2	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 End of Stage 2
Change in Posttraumatic Stress Diagnostic Scale (PDS) Symptom Severity Score From Baseline to End of Stage 2	The Posttraumatic Stress Diagnostic Scale (PDS) is a 49-item self-report instrument designed to aid in the diagnosis of PTSD. Responses to 17 symptom items are made on a 4 point scale ranging from 0 (not at all) to 3 (five or more times per week). The symptom items are summed to calculate the symptom severity score which ranges from 0 to 51, with higher scores indicating more severe PTSD symptoms.	Baseline to End of Stage 2
Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to End of Stage 2	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 End of Stage 2

Collaborators and Investigators

• Sponsor: Lykos Therapeutics
• Investigators: Principal Investigator: Moshe Kotler, Beer Yaakov Hospital

Publications and helpful links

General Publications

• Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, Keane TM. The development of a Clinician-Administered PTSD Scale. J Trauma Stress. 1995 Jan;8(1):75-90. doi: 10.1007/BF02105408.
• 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): January 17, 2013
• Primary Completion (Actual): April 7, 2016
• Study Completion (Actual): July 16, 2017

Study Registration Dates

• First Submitted: September 7, 2012
• First Submitted That Met QC Criteria: September 17, 2012
• First Posted (Estimated): September 21, 2012

Study Record Updates

• Last Update Posted (Actual): June 6, 2025
• Last Update Submitted That Met QC Criteria: May 23, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: PTSD; MDMA; psychotherapy; Posttraumatic stress disorder; Israel; midomafetamine
• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Mental Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Membrane Transport Modulators; Psychotropic Drugs; Adrenergic Agents; Neurotransmitter Uptake Inhibitors; Adrenergic Uptake Inhibitors; Serotonin Agents; Hallucinogens; N-Methyl-3,4-methylenedioxyamphetamine
• Other Study ID Numbers: MP-9