Randomized, Double-blind, Active Placebo-Controlled Pilot Study of MDMA-assisted Psychotherapy in People With Chronic PTSD

Study Overview
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Brief Summary
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This Phase 2 pilot study assessed 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 MDMA, followed 1.5 to 2.5 hours later by a supplemental half-dose of 62.5 mg of MDMA. The remaining eight subjects enrolled in Stage 1 of the study and received either an active placebo dose (low dose of 25 mg MDMA, with a supplemental dose of 12.5 mg MDMA) or a fully active dose of MDMA (125 mg, with a supplemental dose of 62.5 mg MDMA) during two experimental psychotherapy session, each lasting six to eight hours and scheduled three to five weeks apart. 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]. 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 MDMA on the same schedule as Stage 1.

Detailed Description
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Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that can develop after a person experiences a traumatic event, such as sexual assault, war, or any other life-threatening event. PTSD is a worldwide health problem that severely reduces a person's quality of life and is associated with high rates of psychiatric and medical comorbidity, disability, suffering, and suicide. At least a third of PTSD patients fail to respond to established PTSD psychotherapies. A wider array of effective treatments for PTSD are needed. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy may be a potential treatment option for PTSD. MDMA is a monoamine releaser that affects serotonin, norepinephrine, and dopamine. MDMA is capable of inducing unique psychopharmacological effects such as decreased feelings of fear, increased feelings of wellbeing, increased sociability and extroversion, increased interpersonal trust, and an alert state of consciousness. In the U.S., MDMA was used as an adjunct to psychotherapy by a considerable number of psychiatrists and therapists before it was placed in Schedule I in 1985 as a result of non-medical use. 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 MDMA, followed by a supplemental half-dose of 62.5 mg of MDMA 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 MDMA with a supplemental half-dose of 12.5 mg MDMA) or a fully active dose (125 mg MDMA with a supplemental half-dose of 62.5 mg MDMA) during two experimental psychotherapy session, each lasting six to eight hours and scheduled three to five weeks apart. Subjects remained with their male/female co-therapist team for the entirety of the study. 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 where subjects processed and connected their thoughts and feelings about the experience. 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 MDMA (125 mg and 62.5 mg supplemental) on the same schedule as Stage 1.

Official Title
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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)

Conditions
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Posttraumatic Stress Disorder (PTSD)

Intervention / Treatment
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* Drug: Active Placebo Dose MDMA (25 mg)
* Drug: Full Dose MDMA (125 mg)
* Drug: Open Label Full Dose MDMA (125 mg)
* Behavioral: Psychotherapy


Participation Criteria
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Eligibility Criteria
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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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 End of Stage 1 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. | End of Stage 1 to End of Stage 2 | 
| 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 Score From End of Stage 1 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. | End of Stage 1 to End of Stage 2 | 
| 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 End of Stage 1 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. | End of Stage 1 to End of Stage 2 | 
| 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 End of Stage 1 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. | End of Stage 1 to End of Stage 2 | 
| 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 End of Stage 1 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. | End of Stage 1 to End of Stage 2 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDMA, Posttraumatic stress disorder, PTSD, Israel, psychotherapy