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

Phase 2

Completed

• Conditions: Posttraumatic Stress Disorder (PTSD)
• Interventions: 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); Behavioral: Psychotherapy

• Registration Number: NCT01689740
• Lead Sponsor: Lykos Therapeutics

Brief Summary

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.

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 Timeline

• Study First Submitted: 2012-09-07
• Study First Submitted QC: 2012-09-17
• Study First Posted: 2012-09-21
• Study Start: 2013-01-17
• Primary Completion: 2016-04-07
• Study Completion: 2017-07-16
• Disposition First Submitted: 2018-08-15
• Disposition First Submitted QC: 2018-08-16
• Disposition First Posted: 2018-08-21
• Results First Submitted: 2020-08-14
• Results First Submitted QC: 2020-10-02
• Results First Posted: 2020-10-30
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-04
• Last Update Posted: 2025-03-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lead in: 125 mg MDMA-assisted therapy (Open-Label)	Open-Label Full Dose MDMA-assisted therapy (125 mg)	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.
Lead in: 125 mg MDMA-assisted therapy (Open-Label)	Psychotherapy	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.
Active placebo dose MDMA-assisted therapy (25 mg)	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.
Active placebo dose MDMA-assisted therapy (25 mg)	Psychotherapy	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.
Full dose MDMA-assisted therapy (125 mg)	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.
Full dose MDMA-assisted therapy (125 mg)	Psychotherapy	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.

Primary Outcome Measures

Name	Time	Method
Change in Clinical Administered PTSD Scale (CAPS-IV) Total Score From Baseline to End of Stage 1	Baseline to 1-Month Post Experimental Session 2 (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.

Secondary Outcome Measures

Name	Time	Method
Change in Posttraumatic Stress Diagnostic Scale (PDS) Symptom Severity Score From Baseline to Long-Term Follow-Up	Baseline to 12 months post-final experimental session	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.
Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to End of Stage 1	Baseline to 1-Month Post 2nd Experimental Session (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.
Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to End of Stage 2	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.
Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to Long-Term Follow-Up	Baseline to 12 months post-final experimental session	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.
Change in Clinical Administered PTSD Scale (CAPS-IV) Total Score From Baseline to End of Stage 2	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.
Change in Clinical Administered PTSD Scale (CAPS-IV) Total Score From Baseline to Long-Term Follow-Up	Baseline to 12 months post-final 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.
Change in Beck Depression Inventory (BDI-II) Total Scores From Baseline to End of Stage 1	Baseline to 1-Month Post Experimental Session 2 (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.
Change in Beck Depression Inventory (BDI-II) Total Score From Baseline to End of Stage 2	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.
Change in Beck Depression Inventory (BDI-II) Total Scores From Baseline to Long-Term Follow-Up	Baseline to 12 month post-final experimental session	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.
Change in Global Assessment of Functioning (GAF) Scale From Baseline to End of Stage 1	Baseline to 1-Month Post 2nd Experimental Session (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.
Change in Global Assessment of Functioning (GAF) Scale From Baseline to End of Stage 2	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.
Change in Global Assessment of Functioning (GAF) Scale From Baseline to Long-Term Follow-Up	Baseline to 12 months post-final experimental session	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.
Change in Posttraumatic Stress Diagnostic Scale (PDS) Symptom Severity Score From Baseline to End of Stage 1	Baseline to 1-Month Post 2nd Experimental Session (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.
Change in Posttraumatic Stress Diagnostic Scale (PDS) Symptom Severity Score From Baseline to End of Stage 2	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.

Trial Locations

Locations (1)

Beer Yaakov Hospital; 🇮🇱 Be'er Ya'aqov, Israel