Open Label Multi-Site Study of Safety and Effects of MDMA-assisted Therapy for Treatment of PTSD

• Sponsor: Multidisciplinary Association for Psychedelic Studies (Other)
• Overall Status: Completed
• CT.gov ID: NCT03282123
• Collaborator: (none)
• Enrollment: 38
• Locations: 12
• Arm: 1
• Actual Duration (Months): 20
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This multi-site, open-label, Phase 2, lead-in study assesses the safety and effect of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy in participants diagnosed with at least severe posttraumatic stress disorder (PTSD). Therapy teams that have been identified and trained to work on the sponsor's planned Phase 3 studies will treat at least one open-label participant in this study.

This study will compare the effects of three open-label manualized Experimental Sessions of therapy assisted by flexible doses of MDMA. Initial doses per Experimental Session include 80 mg or 120 mg of MDMA compounded with lactose, followed 1.5 to 2 hours later by a supplemental half-dose (40 mg or 60 mg). Total amounts of MDMA to be administered per Experimental Session range from 80 mg to 180 mg. This ~12-week Treatment Period is preceded by three Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by three Integrative Sessions of non-drug psychotherapy. The Primary Outcome measure is the change in Clinician Administered PTSD Scale for DSM 5 (CAPS-5) total severity scores from Baseline to Primary Endpoint (Visit 19).

Condition or Disease	Intervention/Treatment	Phase
PTSD	Drug: MDMA; Behavioral: Therapy	Phase 2

Detailed Description

PTSD is a serious debilitating disorder that negatively impacts a person's daily life. PTSD is a stress-related psychiatric condition that may occur following a traumatic event such as war, disaster, sexual abuse, violence, terrorism, and accidents. PTSD negatively impacts a person's daily life, resulting in relationship difficulties, difficulty in finding and maintaining a job, reduced cognitive and psychosocial functioning, substance abuse, high-cost healthcare use, and increased depression and suicide risk. Available PTSD treatments, including medications and therapy, effectively treat only a fraction of people who try them for adequate dose and duration. People with PTSD can be treated with psychotherapies and pharmacotherapies. In the past decade, there has been a growing amount of research into medications and other methods that may augment the effectiveness of psychotherapy for PTSD

3,4-methylenedioxymethamphetamine is a drug that releases serotonin, norepinephrine and dopamine in the brain and indirectly increases levels of the neurohormones oxytocin, arginine vasopressin and cortisol. The combined neurobiological effects of MDMA increase compassion, reduce defenses and fear of emotional injury, and enhance communication and introspection. MDMA produces anxiolytic and prosocial effects, which counteract avoidance and hyperarousal in the context of therapy. A combined treatment of MDMA and therapy may be especially useful for treating PTSD.

This multi-site, open-label, Phase 2, lead-in study assesses the safety and effect of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy in participants diagnosed with at least severe posttraumatic stress disorder (PTSD). Therapy teams that have been identified and trained to work on the sponsor's planned Phase 3 studies will treat at least one open-label participant in this study.

This study will compare the effects of three open-label manualized Experimental Sessions of psychotherapy assisted by flexible doses of MDMA. Initial doses per Experimental Session include 80 mg or 120 mg of MDMA compounded with lactose, followed 1.5 to 2 hours later by a supplemental half-dose (40 mg or 60 mg). Total amounts of MDMA to be administered per Experimental Session range from 80 mg to 180 mg. This ~12-week Treatment Period is preceded by three Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by three Integrative Sessions of non-drug psychotherapy. The Primary Outcome measure is the change in Clinician Administered PTSD Scale for DSM 5 (CAPS-5) from Baseline to Primary Endpoint (Visit 19).

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Three sessions of MDMA-assisted therapy with flexible dose of MDMA (80 to 120 mg with optional supplemental half-dose)Three sessions of MDMA-assisted therapy with flexible dose of MDMA (80 to 120 mg with optional supplemental half-dose)
• Masking: None (Open Label)
• Masking Description: This study will be open label
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Site Phase 2 Study of the Safety and Effect of Manualized MDMA-Assisted Therapy for the Treatment of Severe Posttraumatic Stress Disorder
• Actual Study Start Date: Dec 8, 2017
• Actual Primary Completion Date: Aug 10, 2019
• Actual Study Completion Date: Aug 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MDMA-assisted therapy Three sessions of MDMA-assisted therapy with flexible dose of MDMA from 80 to 120 mg and optional supplemental dose half that of initial dose 1.5 to 2 hours later	Drug: MDMA; 80 to 120 mg MDMA; Other Names: 3,4-methylenedioxymethamphetamine ; Behavioral: Therapy; Non-directive therapy conducted during MDMA-assisted therapy session

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Visit 19 in CAPS-5 Total Severity Scores [Baseline to 18 weeks post-enrollment]

   The Clinician-Administered PTSD Scale for DSM-V (CAPS-5) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-5. 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. Change From Baseline to Visit 19 in Adapted SDS Total Score [Baseline to 18 weeks post-enrollment]

   The Sheehan Disability Scale (SDS) is a clinician-rated assessment of functional impairment that was adapted for the purposes of this study to limit missing item-level data as per the FDA requirements and included use of the three-item mean as the total score and imputation of work-related impairment. The SDS is a 3-item scale measuring the severity of disability in the domains of work, family life/home responsibilities and social/leisure activities, with each item scored on a ten-point Likert scale from 0 ('not at all impaired') to 10 ('very severely impaired'). The SDS total score was the mean of the 3 item responses. The SDS total score ranged from 0 to 10, with higher scores indicating greater functional impairment.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Are at least 18 years old

• Are fluent in speaking and reading the predominantly used or recognized language of the study site

• Agree to have study visits recorded, including Experimental Sessions, Independent Rater assessments, and non-drug psychotherapy sessions

• Must provide a contact (relative, spouse, close friend or other caregiver) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal or unreachable.

Must agree to inform the investigators within 48 hours of any medical conditions and procedures

• If of childbearing potential, must have a negative pregnancy test at study entry and prior to each Experimental Session, and must agree to use adequate birth control through 10 days after the last Experimental Session.

• Must not participate in any other interventional clinical trials during the duration of the study,

• Must be willing to remain overnight at the study site after each Experimental Session and be driven home after, and commit to medication dosing, therapy, and study procedures

• Meet DSM-5 Criteria for Severe PTSD

Exclusion Criteria:

• Are not able to give adequate informed consent

• Have uncontrolled hypertension

• Have a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds [ms] corrected by Bazett's formula)

• Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

• Have evidence or history of significant medical disorders

• Have symptomatic liver disease

• Have history of hyponatremia or hyperthermia

• Weigh less than 48 kilograms (kg)

• Are pregnant or nursing, or are of childbearing potential and are not practicing an effective means of birth control.

• Are abusing illegal drugs

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New School Research LLC	North Hollywood	California	United States	91601
2	San Francisco Insight and Integration Center	San Francisco	California	United States	94114
3	University of California San Francisco	San Francisco	California	United States	94122
4	Aguazul-Blue Water Inc.	Boulder	Colorado	United States	80302
5	Wholeness Center	Fort Collins	Colorado	United States	80525
6	University of Connecticut	Farmington	Connecticut	United States	06030
7	Ray Worthy Psychiatry LLC	New Orleans	Louisiana	United States	70123
8	Trauma Research Foundation	Brookline	Massachusetts	United States	02446
9	New York University	New York	New York	United States	10016
10	Affective Care	New York	New York	United States	10024
11	Zen Therapeutic Solutions, LLC	Mount Pleasant	South Carolina	United States	29464
12	University of Wisconsin at Madison	Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• Multidisciplinary Association for Psychedelic Studies

Investigators

• Study Director: Michael C Mithoefer, MD, MAPS Public Benefit Corp.

Study Documents (Full-Text)

• Study Protocol - Jan 3, 2018
• Statistical Analysis Plan - Sep 3, 2019
• Informed Consent Form - Jun 27, 2017

More Information

Publications

None provided.

• Responsible Party: Multidisciplinary Association for Psychedelic Studies
• ClinicalTrials.gov Identifier: NCT03282123
• Other Study ID Numbers: MP-16
• First Posted: Sep 13, 2017
• Last Update Posted: Jul 11, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Multidisciplinary Association for Psychedelic Studies: MDMA; methylenedioxymethamphetamine; therapy
• Additional relevant MeSH terms: N-Methyl-3,4-methylenedioxyamphetamine

Study Results

Participant Flow

Recruitment Details	Subjects were recruited through print and internet advertisements, referrals from other psychiatrists, psychotherapists, or physicians, and by word of mouth. The sponsor monitored demographics on an ongoing basis and encouraged diversity in enrollment by communicating with sites

Arm/Group Title	MDMA-assisted Psychotherapy
Arm/Group Description	Three sessions of MDMA-assisted psychotherapy with flexible dose of MDMA from 80 to 120 mg and optional supplemental dose half that of initial dose 1.5 to 2 hours later MDMA: 80 to 120 mg MDMA Psychotherapy: Non-directive psychotherapy conducted during MDMA-assisted psychotherapy session
Period Title: Overall Study
STARTED	38
COMPLETED	33
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	MDMA-assisted Psychotherapy
Arm/Group Description	Three sessions of MDMA-assisted psychotherapy with flexible dose of MDMA from 80 to 120 mg and optional supplemental dose half that of initial dose 1.5 to 2 hours later MDMA: 80 to 120 mg MDMA Psychotherapy: Non-directive psychotherapy conducted during MDMA-assisted psychotherapy session
Overall Participants	33
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.4 (11.1)
Sex: Female, Male (Count of Participants)
Female	20 60.6%
Male	13 39.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3%
Not Hispanic or Latino	32 97%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 3%
Asian	5 15.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3%
White	24 72.7%
More than one race	2 6.1%
Unknown or Not Reported	0 0%
Baseline CAPS-5 Total Severity Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	45.3 (6.9)
Baseline Adapted SDS Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.3 (1.5)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Visit 19 in CAPS-5 Total Severity Scores
Description	The Clinician-Administered PTSD Scale for DSM-V (CAPS-5) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-5. 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 to 18 weeks post-enrollment

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	MDMA-assisted Therapy
Arm/Group Description	Three sessions of MDMA-assisted therapy with flexible dose of MDMA from 80 to 120 mg and optional supplemental dose half that of initial dose 1.5 to 2 hours later MDMA: 80 to 120 mg MDMA Psychotherapy: Non-directive therapy conducted during MDMA-assisted therapy session
Measure Participants	33
Mean (Standard Deviation) [score on a scale]	-30.5 (14.14)

2. Secondary Outcome

Title	Change From Baseline to Visit 19 in Adapted SDS Total Score
Description	The Sheehan Disability Scale (SDS) is a clinician-rated assessment of functional impairment that was adapted for the purposes of this study to limit missing item-level data as per the FDA requirements and included use of the three-item mean as the total score and imputation of work-related impairment. The SDS is a 3-item scale measuring the severity of disability in the domains of work, family life/home responsibilities and social/leisure activities, with each item scored on a ten-point Likert scale from 0 ('not at all impaired') to 10 ('very severely impaired'). The SDS total score was the mean of the 3 item responses. The SDS total score ranged from 0 to 10, with higher scores indicating greater functional impairment.
Time Frame	Baseline to 18 weeks post-enrollment

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	MDMA-assisted Psychotherapy
Arm/Group Description	Three sessions of MDMA-assisted therapy with flexible dose of MDMA from 80 to 120 mg and optional supplemental dose half that of initial dose 1.5 to 2 hours later MDMA: 80 to 120 mg MDMA Psychotherapy: Non-directive therapy conducted during MDMA-assisted therapy session
Measure Participants	33
Mean (Standard Deviation) [score on a scale]	-5.0 (2.26)

Adverse Events

Time Frame	All adverse events from enrollment to end of study (approximately 5 months)
Arm/Group Title	MDMA-assisted Psychotherapy
Arm/Group Description	Three sessions of MDMA-assisted psychotherapy with flexible dose of MDMA from 80 to 120 mg and optional supplemental dose half that of initial dose 1.5 to 2 hours later MDMA: 80 to 120 mg MDMA Psychotherapy: Non-directive psychotherapy conducted during MDMA-assisted psychotherapy session
All Cause Mortality
	MDMA-assisted Psychotherapy
	Affected / at Risk (%)	# Events
Total	0/38 (0%)
Serious Adverse Events
	MDMA-assisted Psychotherapy
	Affected / at Risk (%)	# Events
Total	1/38 (2.6%)
Psychiatric disorders
Suicide attempt	1/38 (2.6%)	1
Other (Not Including Serious) Adverse Events
	MDMA-assisted Psychotherapy
	Affected / at Risk (%)	# Events
Total	38/38 (100%)
Cardiac disorders
Palpitations	3/38 (7.9%)
Eye disorders
Vision Blurred	2/38 (5.3%)
Vision Impairment	3/38 (7.9%)
Gastrointestinal disorders
Abdominal Discomfort	5/38 (13.2%)
Nausea	11/38 (28.9%)
Dry Mouth	3/38 (7.9%)
General disorders
Fatigue	8/38 (21.1%)
Temperature Intolerance	2/38 (5.3%)
Chest Discomfort	2/38 (5.3%)
Pain	2/38 (5.3%)
Infections and infestations
Upper respiratory tract infection	3/38 (7.9%)
Viral upper respiratory tract infection	2/38 (5.3%)
Injury, poisoning and procedural complications
Contusion	3/38 (7.9%)
Metabolism and nutrition disorders
Decreased Appetite	5/38 (13.2%)
Musculoskeletal and connective tissue disorders
Pain in Jaw	4/38 (10.5%)
Myalgia	3/38 (7.9%)
Muscle Tightness	18/38 (47.4%)
Back Pain	3/38 (7.9%)
Neck Pain	3/38 (7.9%)
Musculoskeletal pain	2/38 (5.3%)
Musculoskeletal stiffness	2/38 (5.3%)
Nervous system disorders
Nystagmus	8/38 (21.1%)
Headache	23/38 (60.5%)
Dizziness	5/38 (13.2%)
Paraesthesia	3/38 (7.9%)
Dysgeusia	2/38 (5.3%)
Psychiatric disorders
Anxiety	14/38 (36.8%)
Insomnia	14/38 (36.8%)
Restlessness	3/38 (7.9%)
Panic Reaction	2/38 (5.3%)
Flashback	3/38 (7.9%)
Bruxism	3/38 (7.9%)
Suicidal Ideation	10/38 (26.3%)
Depression	2/38 (5.3%)
Emotional disorder	2/38 (5.3%)
Illusion	2/38 (5.3%)
Nightmare	2/38 (5.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/38 (5.3%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	4/38 (10.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.