Dose-Response Study of MDMA-assisted Psychotherapy in People With PTSD

Phase 2

Completed

Conditions: Posttraumatic Stress Disorder

Interventions: Drug: Comparator Dose (40mg) MDMA HCl
Drug: Active Dose 2 (100 mg) MDMA HCl
Drug: Active Dose 1 (125 mg) MDMA HCl
Behavioral: Psychotherapy

Registration Number: NCT01793610

Lead Sponsor: Lykos Therapeutics

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

The main questions it aims to answer are:

* Does MDMA-assisted therapy reduce PTSD symptoms?

* Is there a difference in PTSD symptoms between the 40 mg, 100 mg, and 125 mg groups?

Researchers will compare two active doses (100 mg and 125 mg) of MDMA-assisted therapy versus a comparator dose of 40 mg MDMA-assisted therapy to determine if there is a reduction in PTSD symptoms.

Participants will undergo three non-drug preparatory sessions, three MDMA-assisted therapy sessions and three non-drug integrative therapy sessions after each MDMA-assisted therapy session.

Detailed Description: This Phase 2 pilot study is a randomized, double-blind, dose response study to examine the safety and efficacy of MDMA-assisted psychotherapy in 23 subjects with chronic, treatment-resistant PTSD of at least six months duration. This study assessed two active doses of MDMA, active dose 1 (100 mg) and active dose 2 (125 mg), to a comparator dose of MDMA (40 mg) during psychotherapy sessions. The initial dose of MDMA was followed 1.5 to 2.5 hours later by an optional supplemental dose of MDMA that was half the size of the first dose. MDMA was administered orally in two experimental sessions lasting up to eight hours and scheduled three to five weeks apart.

Subjects were prepared for MDMA-assisted psychotherapy in three preparatory sessions prior to the first experimental session, and worked with the same pair of therapists throughout the study. After each experimental session, three integrative sessions were scheduled with the subject, including one integrative session the morning after the experimental session. During integrative sessions, subjects processed and connected their thoughts and feelings about the experience with their therapist team.

Subjects who received the comparator dose (40 mg) were given the option to enroll in Stage 2, where they underwent three open-label MDMA-assisted psychotherapy sessions. 100 mg of MDMA was administered in the first session and therapists determined whether to increase to 125 mg of MDMA for the second and third experimental sessions. People who received 125 mg of MDMA during the first two experimental sessions received the same dose during an open-label third experimental session. People who received 100 mg of MDMA during the first two sessions were able to choose, in consultation with their therapist, to either continue to receive 100 mg in a third session or to increase their dose to 125 mg.

A blinded independent rater (IR) assessed the severity of PTSD symptoms at baseline, one month after the second experimental session (the primary endpoint), two months after the third open-label experimental session, and at equivalent points in Stage 2.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 29

Inclusion Criteria

Diagnosed with chronic PTSD for six months or longer.
Have a CAPS score showing moderate to severe PTSD symptoms.
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.
Are willing to refrain from taking any psychiatric medications during the study period.
Willing to follow restrictions and guidelines concerning consumption of food, beverages or nicotine the night before and just prior to each MDMA session.
Willing to remain overnight at the study site.
Are willing to be driven home after experimental sessions either by a driver they arrange, a taxi, or study personnel.
Are willing to be contacted via telephone by study personnel.
If of child-bearing age, must have a negative pregnancy and agree to use an effective form of birth control.
Must provide a personal contact who is willing to be reached in case of emergency.
Agree to let the investigators know within 48 hours of any planned medical interventions.
Are proficient in reading and speaking English.
Agree to have all psychotherapy sessions recorded.
Agree not to participate in any other interventional clinical trials during the course of the study.

Exclusion Criteria

Are pregnant or nursing, or if of child-bearing age and do not use an effective means of birth control.
Weigh less than 48 kg.
Meet DSM-IV criteria for substance abuse or dependence for any substance in the past 60 days.
Have used "Ecstasy" (material represented as containing MDMA) more than five times in the last ten years 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
Comparator Dose (40 mg) MDMA-assisted therapy	Comparator Dose (40mg) MDMA HCl	Participants receive an initial dose of comparator dose midomafetamine HCl (40 mg) during each of two therapy sessions.
Comparator Dose (40 mg) MDMA-assisted therapy	Psychotherapy	Participants receive an initial dose of comparator dose midomafetamine HCl (40 mg) during each of two therapy sessions.
Active Dose 2 (100 mg) MDMA-assisted therapy	Active Dose 2 (100 mg) MDMA HCl	Participants receive an initial dose of Active Dose 2 midomafetamine HCl (100 mg) during each of two therapy sessions.
Active Dose 1 (125 mg) MDMA-assisted therapy	Active Dose 1 (125 mg) MDMA HCl	Participants receive an initial dose of Active Dose 1 midomafetamine HCl (125 mg) during each of two therapy sessions.
Active Dose 2 (100 mg) MDMA-assisted therapy	Psychotherapy	Participants receive an initial dose of Active Dose 2 midomafetamine HCl (100 mg) during each of two therapy sessions.
Active Dose 1 (125 mg) MDMA-assisted therapy	Psychotherapy	Participants receive an initial dose of Active Dose 1 midomafetamine HCl (125 mg) during each of two therapy sessions.

Primary Outcome Measures

Name	Time	Method
Change in Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) Total Severity Score From Baseline to One Month Post 2nd Experimental Session	Baseline Enrollment to 1-Month Post 2nd Experimental Session (Stage 1 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. It contains symptom subscales, a CAPS-IV total severity score, and a diagnostic score. 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 PTSD Diagnostic Scale (PDS) From Baseline to One Month Post 2nd Experimental Session	Baseline Enrollment to 1-Month Post 2nd Experimental Session (Stage 1 Primary Endpoint)	The PTSD Diagnostic Scale (PSD) is self-report measure designed to follow DSM-IV criteria for assessing PTSD. It contains 49 items, with responses made on a four-point scale, ranging from 0 ("not at all") to 3 ("five or more times a week"). The PDS consists of a list of 12 potential traumatic events, 12 items addressing elements of the traumatic event, 17 symptom items, and 9 items assessing impact on areas of life function. Items addressing elements of the traumatic event and life function are answered as either present or not present (Yes or No). The 17 items are summed to create a symptom severity score, with higher scores indicating a greater number and/or intensity of PTSD symptoms. The symptom severity score ranges from 0 to 51.
Change in Beck Depression Inventory II (BDI-II) From Baseline to One Month Post 2nd Experimental Session	Baseline Enrollment to 1-Month Post 2nd Experimental Session (Stage 1 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 scores range from 0 to 63, with higher score indicating greater severity of depressive symptoms.
Change in Global Assessment of Functioning (GAF) Total Score From Baseline to One Month Post 2nd Experimental Session	Baseline Enrollment to 1-Month Post 2nd Experimental Session (Stage 1 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.
Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to One Month Post 2nd Experimental Session	Baseline Enrollment to 1-Month Post 2nd Experimental Session (Stage 1 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.
Change in Dissociative Experiences Scale (DES-II) From Baseline to One Month Post 2nd Experimental Session	Baseline Enrollment to 1-Month Post 2nd Experimental Session (Stage 1 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. The scale consists of statements describing facets of dissociation. Respondents indicate how often the specific experience happens to them, from "never" to "always." The DES-II uses the same items but with responses made on a 10 point scale from "0%" to "100%" of the time. The scale is scored by treating percentages as single digits to produce a total score with higher scores indicating greater severity. The total score ranges from 0 to 100.
Change in Posttraumatic Growth Inventory (PTGI) From Baseline to One Month Post 2nd Experimental Session	Baseline Enrollment to 1-Month Post 2nd Experimental Session (Stage 1 Primary Endpoint)	The 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. PTGI scores on a 6 point scale are: 0 - I did not experience this as a result of my crisis; 1 - I experienced this change to a very small degree as a result of my crisis; 2 - I experienced this change to a small degree as a result of my crisis; 3 - I experienced this change to a moderate degree as a result of my crisis; 4 - I experienced this change to a great degree as a result of my crisis; and 5 - I experienced this change to a very great degree as a result of my crisis. A total score is calculated by summing the responses to all 21 items, each rated on a 6-point scale, with higher scores indicating greater post-traumatic growth