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

• Sponsor: Multidisciplinary Association for Psychedelic Studies (Other)
• Overall Status: Completed
• CT.gov ID: NCT01793610
• Collaborator: (none)
• Enrollment: 29
• Location: 1
• Arms: 3
• Duration (Months): 52
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that can develop after a traumatic life experience that severely reduces quality of life. This Phase 2 pilot study examined the safety and efficacy of MDMA-assisted psychotherapy in 23 subjects with chronic, treatment-resistant posttraumatic stress disorder (PTSD). This study is part of a global series of Phase 2 pilot clinical trials. This randomized, double-blind, dose response study assessed two active doses of MDMA, 100 mg and 125 mg, to a comparator dose of MDMA (40 mg) during psychotherapy sessions. The initial dose 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 in two experimental sessions lasting up to eight hours and scheduled three to five weeks apart. Subjects were prepared for MDMA-assisted psychotherapy prior to the first session in three preparatory sessions, and worked with the same pair of therapists throughout the study. After each MDMA-assisted psychotherapy session, subjects had three integrative sessions with their therapist team to process and understand their experience.

This study assessed the change in symptoms of PTSD, as measured by the Clinical Administered PTSD Scale (CAPS) [Blake et al., 1995], as well as symptoms of depression, as measured by the Beck Depression Inventory II (BDI-II) [Beck, A.T. and R.A, 1984; Beck, A.T., et al., 1996] from baseline enrollment to one month after the second MDMA-assisted psychotherapy session (primary endpoint).

Participants who received the comparator dose of MDMA (40 mg) were given the option to enroll in Stage 2, where they underwent three open-label MDMA-assisted psychotherapy sessions with an active dose of MDMA. People who received either of the active doses of MDMA in Stage 1 had a third MDMA-assisted psychotherapy session with another active dose of MDMA.

Condition or Disease	Intervention/Treatment	Phase
Posttraumatic Stress Disorder	Drug: Comparative-dose (40mg) MDMA; Drug: Active Dose 2 (100 mg) MDMA; Drug: Active Dose 1 (125 mg) MDMA; Behavioral: Psychotherapy	Phase 2

Detailed Description

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 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 is part of a global series of Phase 2 pilot clinical trials. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Dose Response Phase 2 Pilot Study of Manualized MDMA-Assisted Psychotherapy in Subjects With Chronic, Treatment-Resistant Posttraumatic Stress Disorder (PTSD)
• Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Feb 1, 2017
• Actual Study Completion Date: Feb 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Comparator-dose (40 mg) MDMA and Psychotherapy Participants receive an initial dose of comparator-dose MDMA (40 mg) during each of the two experimental sessions.	Drug: Comparative-dose (40mg) MDMA; An initial comparator-dose of 40 mg MDMA orally given at the start of two separate psychotherapy sessions scheduled 3 to 5 weeks apart, with the initial dose possibly followed 1.5 to 2.5 hours later by a supplemental dose half the size of the initial dose (20 mg MDMA).; Other Names: 3,4-methylenedioxymethamphetamine ; Behavioral: Psychotherapy; Psychotherapy conducted throughout experimental sessions.; Other Names: Manualized MDMA-assisted psychotherapy
Experimental: Active Dose 2 (100 mg) MDMA and Psychotherapy Participants receive an initial dose of Active Dose 2 MDMA (100 mg) during each of the two experimental sessions.	Drug: Active Dose 2 (100 mg) MDMA; An initial dose of full-dose 100 mg MDMA orally given at the start of two separate psychotherapy sessions scheduled 3 to 5 weeks apart, with the initial dose possibly followed 1.5 to 2.5 hours later by a supplemental dose half the size of the initial dose (50 mg MDMA).; Other Names: 3,4-methylenedioxymethamphetamine ; Behavioral: Psychotherapy; Psychotherapy conducted throughout experimental sessions.; Other Names: Manualized MDMA-assisted psychotherapy
Experimental: Active Dose 1 (125 mg) MDMA and Psychotherapy Participants receive an initial dose of Active Dose 1 MDMA (125 mg) during each of two experimental sessions.	Drug: Active Dose 1 (125 mg) MDMA; An initial dose of full-dose 125 mg MDMA orally given at the start of two separate psychotherapy sessions scheduled 3 to 5 weeks apart, with the initial dose possibly followed 1.5 to 2.5 hours later by a supplemental dose half the size of the initial dose (62.5 mg MDMA).; Other Names: 3,4-methylenedioxymethamphetamine ; Behavioral: Psychotherapy; Psychotherapy conducted throughout experimental sessions.; Other Names: Manualized MDMA-assisted psychotherapy

Outcome Measures

Primary Outcome Measures

1. Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) Total Severity Score at Baseline (ITT) [Baseline Enrollment]

   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.

2. Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) Total Severity Score at One Month Post 2nd Experimental Session (ITT) [One month after 2nd experimental session (approximately 3 months post enrollment)]

   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.

3. Change in Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) Total Severity Score From Baseline to One Month Post 2nd Experimental Session (ITT) [Baseline Enrollment to 1-Month Post 2nd 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. 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

1. Beck Depression Inventory II (BDI-II) at Baseline (ITT) [Baseline Enrollment]

   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.

2. Beck Depression Inventory II (BDI-II) at One Month Post 2nd Experimental Session (ITT) [One month after 2nd experimental session (approximately 3 months post enrollment)]

   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.

3. Change in Beck Depression Inventory II (BDI-II) From Baseline to One Month Post 2nd Experimental Session (ITT) [Baseline Enrollment to 1-Month Post 2nd 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 scores range from 0 to 63, with higher score indicating greater severity of depressive symptoms.

4. Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to One Month Post 2nd Experimental Session (ITT) [Baseline Enrollment to 1-Month Post 2nd 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Offices of Marcela d'Otalora	Boulder	Colorado	United States	80304

Sponsors and Collaborators

• Multidisciplinary Association for Psychedelic Studies

Investigators

• Principal Investigator: Marcela d'Otalora, MA, LPC, Private Practice

Study Documents (Full-Text)

• Study Protocol - Aug 15, 2014
• Statistical Analysis Plan - Feb 26, 2016
• Informed Consent Form - Jul 18, 2016

More Information

Publications

• Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess. 1996 Dec;67(3):588-97.
• Beck AT, Steer RA. Internal consistencies of the original and revised Beck Depression Inventory. J Clin Psychol. 1984 Nov;40(6):1365-7.
• 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. Review.

• Responsible Party: Multidisciplinary Association for Psychedelic Studies
• ClinicalTrials.gov Identifier: NCT01793610
• Other Study ID Numbers: MP-12
• First Posted: Feb 15, 2013
• Last Update Posted: Jul 11, 2022
• Last Verified: Jun 1, 2022

• Keywords provided by Multidisciplinary Association for Psychedelic Studies: MDMA; Posttraumatic stress disorder; sleep; Depression; Safety
• Additional relevant MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; N-Methyl-3,4-methylenedioxyamphetamine

Study Results

Participant Flow

Recruitment Details	Candidates were recruited via Internet advertisements and referrals from mental health professionals. Potential participants were men and women 18 years or older. Inclusion criteria required PTSD for at least six months. The study was conducted at an outpatient clinic in Boulder, Colorado between October 2012 and February 2017.
Pre-assignment Detail	One participant was excluded for not meeting eligibility criteria after enrollment prior to randomization.

Arm/Group Title	Comparator-dose MDMA (40 mg) and Psychotherapy	Active Dose 2 MDMA (100 mg) and Psychotherapy	Active Dose 1 MDMA (125 mg) and Psychotherapy
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Period Title: Overall Study
STARTED	6	9	13
COMPLETED	5	9	12
NOT COMPLETED	1	0	1

Baseline Characteristics

Arm/Group Title	Comparator-dose MDMA (40 mg) and Psychotherapy	Active Dose 2 MDMA (100 mg) and Psychotherapy	Active Dose 1 MDMA (125 mg) and Psychotherapy	Total
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.	Total of all reporting groups
Overall Participants	6	9	13	28
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	6 100%	9 100%	12 92.3%	27 96.4%
>=65 years	0 0%	0 0%	1 7.7%	1 3.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40 (11.7)	39.6 (9.8)	44.6 (15.4)	42 (12.9)
Sex: Female, Male (Count of Participants)
Female	5 83.3%	6 66.7%	8 61.5%	19 67.9%
Male	1 16.7%	3 33.3%	5 38.5%	9 32.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 11.1%	0 0%	1 3.6%
Not Hispanic or Latino	6 100%	8 88.9%	13 100%	27 96.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) Total Severity Score at Baseline (ITT)
Description	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.
Time Frame	Baseline Enrollment

Outcome Measure Data

Analysis Population Description

Intent-to-Treat set (ITT)

Arm/Group Title	Comparator-dose MDMA (40 mg) and Psychotherapy	Active Dose 2 MDMA (100 mg) and Psychotherapy	Active Dose 1 MDMA (125 mg) and Psychotherapy
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Measure Participants	6	9	13
Mean (Standard Deviation) [score on a scale]	84.8 (8.04)	94.4 (20.17)	93.5 (20.05)

2. Primary Outcome

Title	Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) Total Severity Score at One Month Post 2nd Experimental Session (ITT)
Description	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.
Time Frame	One month after 2nd experimental session (approximately 3 months post enrollment)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat set (ITT)

Arm/Group Title	Comparator-dose MDMA (40 mg) and Psychotherapy	Active Dose 2 MDMA (100 mg) and Psychotherapy	Active Dose 1 MDMA (125 mg) and Psychotherapy
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Measure Participants	6	9	13
Mean (Standard Deviation) [score on a scale]	73.3 (24.49)	70.0 (28.19)	64.3 (33.59)

3. Primary Outcome

Title	Change in Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) Total Severity Score From Baseline to One Month Post 2nd Experimental Session (ITT)
Description	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.
Time Frame	Baseline Enrollment to 1-Month Post 2nd Experimental Session

Outcome Measure Data

Analysis Population Description

Intent-to-Treat set (ITT)

Arm/Group Title	Comparator-dose (40 mg) MDMA and Psychotherapy	Active Dose 2 (100 mg) MDMA and Psychotherapy	Active Dose 1 (125 mg) MDMA and Psychotherapy
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Measure Participants	6	9	13
Mean (Standard Deviation) [score on a scale]	-11.5 (21.21)	-24.4 (24.22)	-26.3 (29.52)

4. Secondary Outcome

Title	Beck Depression Inventory II (BDI-II) at Baseline (ITT)
Description	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.
Time Frame	Baseline Enrollment

Outcome Measure Data

Analysis Population Description

Intent-to-Treat set (ITT)

Arm/Group Title	Comparator-dose MDMA (40 mg) and Psychotherapy	Active Dose 2 MDMA (100 mg) and Psychotherapy	Active Dose 1 MDMA (125 mg) and Psychotherapy
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Measure Participants	6	9	13
Mean (Standard Deviation) [score on a scale]	23.8 (6.24)	28.2 (13.62)	29.3 (11.74)

5. Secondary Outcome

Title	Beck Depression Inventory II (BDI-II) at One Month Post 2nd Experimental Session (ITT)
Description	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.
Time Frame	One month after 2nd experimental session (approximately 3 months post enrollment)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat set (ITT)

Arm/Group Title	Comparator-dose MDMA (40 mg) and Psychotherapy	Active Dose 2 MDMA (100 mg) and Psychotherapy	Active Dose 1 MDMA (125 mg) and Psychotherapy
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Measure Participants	6	9	13
Mean (Standard Deviation) [score on a scale]	12.3 (6.31)	18.3 (16.23)	17.3 (16.72)

6. Secondary Outcome

Title	Change in Beck Depression Inventory II (BDI-II) From Baseline to One Month Post 2nd Experimental Session (ITT)
Description	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.
Time Frame	Baseline Enrollment to 1-Month Post 2nd Experimental Session

Outcome Measure Data

Analysis Population Description

Intent-to-Treat set (ITT)

Arm/Group Title	Comparator-dose (40 mg) MDMA and Psychotherapy	Active Dose 2 (100 mg) MDMA and Psychotherapy	Active Dose 1 (125 mg) MDMA and Psychotherapy
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Measure Participants	6	9	13
Mean (Standard Deviation) [score on a scale]	-11.5 (7.79)	-9.9 (13.26)	-11.0 (13.68)

7. Secondary Outcome

Title	Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to One Month Post 2nd Experimental Session (ITT)
Description	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.
Time Frame	Baseline Enrollment to 1-Month Post 2nd Experimental Session

Outcome Measure Data

Analysis Population Description

Intent-to-Treat set (ITT)

Arm/Group Title	Comparator-dose (40 mg) MDMA and Psychotherapy	Active Dose 2 (100 mg) MDMA and Psychotherapy	Active Dose 1 (125 mg) MDMA and Psychotherapy
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.	Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Measure Participants	6	9	13
Mean (Standard Deviation) [score on a scale]	-0.83 (2.48)	-3.56 (6.19)	-1.92 (4.91)

Adverse Events

Time Frame	All AEs from baseline to long-term Follow-up (approximately 1 year, 2 months)
Arm/Group Title	Comparator-dose MDMA (40 mg) and Psychotherapy (Stage 1)		Active Dose 2 MDMA (100 mg) and Psychotherapy (Stage 1)		Active Dose 1 MDMA (125 mg) and Psychotherapy (Stage 1)		Active Dose 1 and Active Dose 2 (100mg or 125mg) and Psychotherapy (Stage 2)
Arm/Group Description	Participants receive an initial dose of 40 mg of MDMA orally, with an optional supplemental dose of 20 mg MDMA 1.5 to 2.5 hours later.		Participants receive an initial dose of 100 mg of MDMA orally, with an optional supplemental dose of 50 mg MDMA 1.5 to 2.5 hours later.		Participants receive an initial dose of 125 mg of MDMA orally, with an optional supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.		Subjects who receive the comparator dose will be offered the option to continue to the open-label Stage 2. In the first session, active dose 2 will be administered and the therapists will choose one of the two active doses of MDMA for the second and third experimental sessions, with an optional supplemental half dose at each of three experimental sessions at time points equivalent to those in Stage 1.
All Cause Mortality
	Comparator-dose MDMA (40 mg) and Psychotherapy (Stage 1)		Active Dose 2 MDMA (100 mg) and Psychotherapy (Stage 1)		Active Dose 1 MDMA (125 mg) and Psychotherapy (Stage 1)		Active Dose 1 and Active Dose 2 (100mg or 125mg) and Psychotherapy (Stage 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/9 (0%)		0/13 (0%)		0/5 (0%)
Serious Adverse Events
	Comparator-dose MDMA (40 mg) and Psychotherapy (Stage 1)		Active Dose 2 MDMA (100 mg) and Psychotherapy (Stage 1)		Active Dose 1 MDMA (125 mg) and Psychotherapy (Stage 1)		Active Dose 1 and Active Dose 2 (100mg or 125mg) and Psychotherapy (Stage 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		2/9 (22.2%)		1/13 (7.7%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Lower limb fracture	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ruptured ovarian cyst	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Breast cancer	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Comparator-dose MDMA (40 mg) and Psychotherapy (Stage 1)		Active Dose 2 MDMA (100 mg) and Psychotherapy (Stage 1)		Active Dose 1 MDMA (125 mg) and Psychotherapy (Stage 1)		Active Dose 1 and Active Dose 2 (100mg or 125mg) and Psychotherapy (Stage 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)		6/9 (66.7%)		11/13 (84.6%)		4/5 (80%)
Eye disorders
Visual Impairment	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Vision blurred	0/6 (0%)		0/9 (0%)		0/13 (0%)		1/5 (20%)
Gastrointestinal disorders
Abdominal pain upper	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		0/5 (0%)
Vomiting	0/6 (0%)		0/9 (0%)		3/13 (23.1%)		0/5 (0%)
General disorders
Fatigue	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		0/5 (0%)
Headache	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Pain	1/6 (16.7%)		0/9 (0%)		0/13 (0%)		0/5 (0%)
Pyrexia	1/6 (16.7%)		2/9 (22.2%)		0/13 (0%)		0/5 (0%)
Malaise	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Feeling abnormal	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		0/5 (0%)
Injury, poisoning and procedural complications
Accidental overdose	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Incorrect dose administered	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Skeletal injury	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Concussion	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		0/5 (0%)
Post concussion syndrome	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		0/5 (0%)
Road traffic accident	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		0/5 (0%)
Metabolism and nutrition disorders
Nausea	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		0/5 (0%)
Muscle tightness	0/6 (0%)		0/9 (0%)		2/13 (15.4%)		0/5 (0%)
Muscle twitching	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		0/5 (0%)
Myalgia	0/6 (0%)		0/9 (0%)		2/13 (15.4%)		0/5 (0%)
Back pain	0/6 (0%)		0/9 (0%)		0/13 (0%)		1/5 (20%)
Nervous system disorders
Migraine	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Psychiatric disorders
Anxiety	0/6 (0%)		4/9 (44.4%)		5/13 (38.5%)		1/5 (20%)
Depressed mood	0/6 (0%)		2/9 (22.2%)		2/13 (15.4%)		0/5 (0%)
Irritability	0/6 (0%)		2/9 (22.2%)		1/13 (7.7%)		0/5 (0%)
Obsessive rumination	0/6 (0%)		1/9 (11.1%)		2/13 (15.4%)		0/5 (0%)
Restlessness	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Panic attack	0/6 (0%)		0/9 (0%)		2/13 (15.4%)		0/5 (0%)
Suicidal ideation	0/6 (0%)		0/9 (0%)		1/13 (7.7%)		2/5 (40%)
Reproductive system and breast disorders
Ovarian cyst	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)
Vascular disorders
Deep vein thrombosis	0/6 (0%)		1/9 (11.1%)		0/13 (0%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.