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

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)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01793610

Enrollment

Registered

2013-02-15

Start date

2013-05-13

Completion date

2017-02-01

Last updated

2025-06-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Posttraumatic Stress Disorder

Keywords

MDMA, Posttraumatic stress disorder, sleep, Depression, Safety

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.

Interventions

DRUGActive Dose 2 (100 mg) MDMA HCl

An initial dose of full-dose 100 mg midomafetamine HCl 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).

DRUGComparator Dose (40mg) MDMA HCl

An initial comparator-dose of 40 mg midomafetamine HCl 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).

DRUGActive Dose 1 (125 mg) MDMA HCl

An initial dose of full-dose 125 mg midomafetamine HCl 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).

BEHAVIORALPsychotherapy

Non-directive manualized therapy

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 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 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
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.

Countries

United States

Participant flow

Recruitment details

Candidates were recruited via Internet advertisements and referrals from mental health professionals.

Participants by arm

Arm	Count
Active Dose 1 MDMA (125 mg) and Psychotherapy 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.	12
Active Dose 2 MDMA (100 mg) and Psychotherapy 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.	9
Comparator-dose MDMA (40 mg) and Psychotherapy 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.	6
Total	27

Baseline characteristics

Characteristic	Comparator-dose MDMA (40 mg) and Psychotherapy	Total	Active Dose 1 MDMA (125 mg) and Psychotherapy	Active Dose 2 MDMA (100 mg) and Psychotherapy
Age, Continuous	40 years STANDARD_DEVIATION 11.71	42.4 years STANDARD_DEVIATION 12.93	45.7 years STANDARD_DEVIATION 15.53	39.6 years STANDARD_DEVIATION 9.8
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	1 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants	26 Participants	12 Participants	8 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized American Indian Or Alaska Native	1 Participants	1 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Other	0 Participants	1 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized White	5 Participants	25 Participants	11 Participants	9 Participants
Sex: Female, Male Female	5 Participants	19 Participants	8 Participants	6 Participants
Sex: Female, Male Male	1 Participants	8 Participants	4 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk
deaths Total, all-cause mortality	0 / 13	0 / 9	0 / 6	0 / 12	0 / 9	0 / 5	0 / 11	0 / 9	0 / 5	0 / 13	0 / 9	0 / 6
other Total, other adverse events	8 / 13	6 / 9	1 / 6	5 / 12	3 / 9	3 / 5	2 / 11	1 / 9	1 / 5	0 / 13	0 / 9	5 / 6
serious Total, serious adverse events	0 / 13	1 / 9	0 / 6	0 / 12	1 / 9	0 / 5	0 / 11	1 / 9	0 / 5	0 / 13	0 / 9	0 / 6

Outcome results

Primary

Change in Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) Total Severity Score From Baseline to One 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.