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

• ClinicalTrials.gov Identifier: NCT01689740
• Recruitment Status: Completed
• First Posted: September 21, 2012
• Last Update Posted: August 21, 2018
• Sponsor: Multidisciplinary Association for Psychedelic Studies
• Information provided by (Responsible Party): Multidisciplinary Association for Psychedelic Studies

Study Description

Brief Summary:

This study will examine symptoms of posttraumatic stress disorder (PTSD) in people before and after psychotherapy with 25 mg followed two hours later by 12.5 mg or 125 mg followed two hours later by 62.5 mg methylenedioxymethamphetamine (MDMA) in order to see if this treatment is safe and can help reduce PTSD symptoms. Participants will be randomly assigned to one of the two doses of MDMA given in two sessions scheduled three to five weeks apart. They will prepare for the sessions before the first one and they will work with psychotherapists in conventional (non-drug assisted) psychotherapy afterwards. Symptoms of PTSD and depression, sleep quality and general psychological health will be measured at the start of the study and 2 and 12 months after the second session.

Condition or disease	Intervention/treatment	Phase
Posttraumatic Stress Disorder (PTSD)	Drug: Active placebo dose MDMA; Drug: Full dose MDMA; Drug: 125 mg MDMA (open label); Behavioral: Psychotherapy	Phase 2

Detailed Description:

Posttraumatic stress disorder (PTSD) is a debilitating disorder that develops after people undergo a traumatic event, such as a rape, car accident or other life-threatening event. PTSD is a worldwide health problem. Psychotherapy or drugs are used to treat PTSD, but there is an interest in developing other treatment options. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy is one potential treatment. MDMA is known as the active ingredient in "ecstasy." It was used along with psychotherapy to treat people in the past, and a study suggests that MDMA-assisted psychotherapy might help people with PTSD.

This Phase 2 research study will investigate the safety and efficacy of MDMA-assisted psychotherapy in 10 people with chronic, treatment-resistant posttraumatic stress disorder (PTSD). After open-label lead-in in two subjects there will be a randomized, double-blind arm comparing 125 vs. 25 mg MDMA in eight participants, and an open-label arm for participants who received active placebo.

In this study, five people will be randomly assigned to receive the full dose of 125 and 62.5 mg MDMA and three will be randomized to receive the active placebo dose of 25 and 125. mg MDMA. MDMA will be administered during two six to eight hour long experimental sessions scheduled three to five weeks apart. Study subjects will have a medical and psychiatric examination and a measure of their PTSD symptoms to make sure they meet the criteria to be in the study. Subjects must be in good physical health. They will also complete questionnaires about their PTSD symptoms, symptoms of depression and sleep quality. These tests will be given by a researcher who will not be present during any of the therapy sessions. This same researcher will give the subject the same tests or measures two months after the second experimental session and 12 months after a final experimental session.

Once enrolled, subjects will have three preparatory sessions with a team of two therapists, one male and one female. The same team of therapists will work with them throughout the entire study. The subject will learn more about MDMA-assisted psychotherapy and the therapists will learn more about the subject's goals, hopes and fears. Starting from the second preparatory session, subjects will answer questions on thoughts about hurting or killing themselves; these questions will be asked during face to face contact this and on two of the contact days, which may occur over the telephone. Subjects will have to stop taking their psychiatric medication before they have their first experimental session, with exact times dependent upon the specific medications involved.

Both therapists will be present for each experimental session. During experimental sessions, subjects will be encouraged to confront trauma-related thoughts, feelings and memories. Blood pressure, heart rate (pulse) and body temperature will be measured regularly, and the researchers will periodically ask the subject to rate his or her degree of distress. Subjects will stay overnight at the clinic and have their first integrative session, where they will examine what happened during their experimental session. They will have two more integrative sessions until they have their next experimental session. Subjects will fill out a questionnaire on their PTSD symptoms on every third integrative session. Two months after the second experimental session, subjects will answer questions or complete questionnaires about PTSD symptoms, symptoms of depression and sleep quality, and one of the researchers will assess their general psychological function.

Subjects and the therapists, but not the person measuring symptoms, will find out if the subject had the active placebo or full dose of MDMA at this time, and if the subject had the active placebo, they can start the second arm of the study. What happens during this arm is very similar to the arm except that the subject and therapists will know the subject is getting a full dose of MDMA.

Twelve months after the subject's final follow-up visit (two months after their final experimental session), PTSD symptoms, symptoms of depression and sleep quality will be assessed again, and subjects will complete an additional questionnaire about their experiences during and after the study.

The study will compare PTSD symptoms before and after MDMA-assisted psychotherapy with a full dose and therapy with an active placebo dose of MDMA.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: October 2013
• Actual Primary Completion Date: July 2017
• Actual Study Completion Date: September 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Lead in: 125 mg MDMA (Open Label) and psychotherapy; Open label: 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: 125 mg MDMA (open label); Initial dose of MDMA administered orally at the start of each of two psychotherapy sessions, supplement administered 1.5 go 2.5 hours later.; Behavioral: Psychotherapy; Psychotherapy provided throughout course of main study
Placebo Comparator: Active placebo dose MDMA and psychotherapy; Participants receive initial doses of 25 mg MDMA during each of two experimental sessions.	Drug: Active placebo dose MDMA; Initial dose of 25 mg MDMA administered orally at the start of each of two separate psychotherapy sessions scheduled three to five weeks apart possibly followed by a supplemental dose of 12.5 mg MDMA 1.5 to 2.5 hours later.; Behavioral: Psychotherapy; Psychotherapy provided throughout course of main study
Experimental: Full dose MDMA and psychotherapy; Participant will receive full dose MDMA (125 mg NDMA( during two separate psychotherapy sessions.	Drug: Full dose MDMA; Initial dose of 125 mg MDMA administered orally at the start of each of two psychotherapy sessions scheduled three to five weeks apart. In each case, it may be followed 1.5 to 2.5 hours later with 62.5 mg MDMA.; Behavioral: Psychotherapy; Psychotherapy provided throughout course of main study

Outcome Measures

Primary Outcome Measures :

1. Clinician Administered PTSD Scale (CAPS) [ Time Frame: 14-19 weeks post enrollment) ]
   Clinician-administered and scored assessment of PTSD symptoms via structured interview, including global symptom severity, dichotomous diagnostic score and subscales
2. Clinician Administered PTSD Scale (CAPS) [ Time Frame: 0 weeks post-enrollment ]
   Clinician-administered and scored assessment of PTSD symptoms via structured interview, including global symptom severity, dichotomous diagnostic score and subscales

Secondary Outcome Measures :

1. Clinician-Administered PTSD Scale [ Time Frame: 24 to 35 weeks post-enrollment ]
   Clinician administered and scored assessment of PTSD symptoms
2. Clinician-Administered PTSD Scale [ Time Frame: Up to 64 weeks post-enrollment ]
   Clinician administered and scored assessment of PTSD symptoms
3. Beck Depression Inventory - II [ Time Frame: 14-19 weeks post-enrollment ]
   Established self-report measure of symptoms of depression
4. Beck Depression Inventory - II [ Time Frame: 0 weeks post-enrollment ]
   Established self-report measure of symptoms of depression
5. Beck Depression Inventory - II [ Time Frame: 24 to 35 weeks post-enrollment ]
   Established self-report measure of symptoms of depression
6. Beck Depression Inventory - II [ Time Frame: Up to 64 weeks post-enrollment ]
   Established self-report measure of symptoms of depression
7. Global Assessment of Functioning (GAF) [ Time Frame: 14-19 weeks post-enrollment ]
   Clinician-scored assessment of general psychological well-being, range 1-100
8. Global Assessment of Functioning (GAF) [ Time Frame: 0 week post-enrollment ]
   Clinician-scored assessment of general psychological well-being, range 1-100
9. Global Assessment of Functioning (GAF) [ Time Frame: 24 to 35 weeks post-enrollment ]
   Clinician-scored assessment of general psychological well-being, range 1-100
10. Global Assessment of Functioning (GAF) [ Time Frame: Up to 64 weeks post-enrollment ]
    Clinician-scored assessment of general psychological well-being, range 1-100
11. Pittsburgh Sleep Quality Index [ Time Frame: 0 weeks post-enrollment ]
    Assesses self-reported sleep quality
12. Pittsburgh Sleep Quality Index [ Time Frame: 14-19 weeks post-enrollment ]
    Assesses self-reported sleep quality
13. Pittsburgh Sleep Quality Index [ Time Frame: Up to 64 weeks post-enrollment ]
    Assesses self-reported sleep quality
14. Posttraumatic Diagnostic Scale (PDS) [ Time Frame: 0 weeks post-enrollment ]
    Self-report measure of PTSD symptoms and diagnosis
15. Posttraumatic Diagnostic Scale (PDS) [ Time Frame: 5-8 weeks post-enrollment ]
    Self-report measure of PTSD symptoms and diagnosis
16. Posttraumatic Diagnostic Scale (PDS) [ Time Frame: 8-13 weeks post-enrollment ]
    Self-report measure of PTSD symptoms and diagnosis
17. Posttraumatic Diagnostic Scale (PDS) [ Time Frame: 14-19 weeks post-enrollment ]
    Self-report measure of PTSD symptoms and diagnosis
18. Posttraumatic Diagnostic Scale (PDS) [ Time Frame: Up to 64 weeks post-enrollment ]
    Self-report measure of PTSD symptoms and diagnosis
19. Peak Systolic blood pressure [ Time Frame: 3-6 weeks post-enrollment: collected from measurements made every 30 min for 6-8 hours ]
    Systolic blood pressure will be periodically measured, and pre-drug, peak and endpoint values will be recorded
20. Peak Systolic blood pressure [ Time Frame: 6-11 weeks post-enrollment: collected from measurements made every 30 min for 6-8 hours ]
    Systolic blood pressure will be periodically measured, and pre-drug, peak and endpoint values will be recorded
21. Peak diastolic blood pressure [ Time Frame: 3-6 weeks post-enrollment: from measurements taken every 30 min for 6-8 hours ]
    Blood pressure will be periodically measured throughout the first experimental session
22. Peak diastolic blood pressure [ Time Frame: 6-11 weeks post-enrollment: from measurements taken every 30 min for 6-8 hours ]
    Blood pressure will be periodically measured throughout the first experimental session
23. Peak heart rate (HR) [ Time Frame: 3-6 weeks post enrollment; from measurements taken every 30 minutes for 6-8 hours ]
    Heart rate will be assessed by measuring pulse
24. Peak heart rate (HR) [ Time Frame: 6-11 weeks post-enrollment: from measurements taken every 30 minutes for 6-8 hours ]
    Heart rate will be assessed by measuring pulse
25. Peak body temperature [ Time Frame: 3-6 weeks post-enrollment; from measurements taken every 60-90 min throughout session ]
    Body temperature will be measured
26. Peak body temperature [ Time Frame: 6-11 weeks post-enrollment; from measurements taken every 60-90 min throughout session ]
    Body temperature will be measured
27. Peak subjective units of distress (SUD) [ Time Frame: 3-6 weeks post-enrollment; from measurements taken every 60-90 min throughout session ]
    Degree of psychological (subjective) distress will be assessed by asking participant to choose a number between 1 and 7
28. Peak subjective units of distress (SUD) [ Time Frame: 6-11 weeks post-enrollment; from measurements taken every 60-90 min throughout session ]
    Degree of psychological (subjective) distress will be assessed by asking participant to choose a number between 1 and 7
29. End-point systolic blood pressure [ Time Frame: 3-6 weeks post-enrollment; last measurement ]
    Blood pressure will be measured up up to 6 h postdrug or until drug effects wane
30. End-point systolic blood pressure [ Time Frame: 6-11 weeks post-enrollment; last measurement ]
    Blood pressure will be measured up up to 6 h postdrug or until drug effects wane
31. End-point diastolic blood pressure [ Time Frame: 3-6 weeks post-enrollment; last measurement ]
    Blood pressure will be measured up up to 6 h postdrug or until drug effects wane
32. End-point diastolic blood pressure [ Time Frame: 6-11 weeks post-enrollment; last measurement ]
    Blood pressure will be measured up up to 6 h postdrug or until drug effects wane
33. End-point heart rate (HR) [ Time Frame: 3-6 weeks post-enrollment; last measurement ]
    Heart rate will be measured by measuring pulse up up to 6 h postdrug or until drug effects wane
34. End-point heart rate (HR) [ Time Frame: 6-11 weeks post-enrollment; last measurement ]
    Heart rate will be measured by measuring pulse up up to 6 h postdrug or until drug effects wane
35. End-point body temperature [ Time Frame: 3-6 weeks post-enrollment; last measurement ]
    Body temperature will be measured up up to 6 h postdrug or until drug effects wane
36. End-point body temperature [ Time Frame: 6-11 weeks post-enrollment; last measurement ]
    Body temperature will be measured up to 6 h postdrug or until drug effects wane
37. End-point Subjective Units of Distress (SUD) [ Time Frame: 3-6 weeks post-enrollment; last measurement ]
    Psychological (subjective) distress will be measured up up to 6 h postdrug or until drug effects wane
38. End-point Subjective Units of Distress (SUD) [ Time Frame: 6-11 weeks post-enrollment; last measurement ]
    Psychological (subjective) distress will be measured up up to 6 h postdrug or until drug effects wane
39. Pre-drug systolic blood pressure [ Time Frame: 3-6 weeks post-enrollment; first measurement taken prior to drug administration ]
    Blood pressure will be measured at start of experimental session and thereafter every 30 min
40. Pre-drug systolic blood pressure [ Time Frame: 6-11 weeks post-enrollment; first measurement taken prior to drug administration ]
    Blood pressure will be measured at start of experimental session and thereafter every 30 min
41. Pre-drug diastolic blood pressure [ Time Frame: 3-6 weeks post-enrollment; first measurement taken prior to drug administration ]
    Blood pressure will be measured at start of experimental session and thereafter every 30 min
42. Pre-drug diastolic blood pressure [ Time Frame: 6-11 weeks post-enrollment; first measurement taken prior to drug administration ]
    Blood pressure will be measured at start of experimental session and thereafter every 30 min
43. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 0 weeks post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
44. Pre-drug heart rate [ Time Frame: 3-6 weeks post-enrollment: collected prior to drug administration ]
    Heart rate will be measured via pulse at start of experimental session and thereafter every 30 min
45. Pre-drug heart rate [ Time Frame: 6-11 weeks post-enrollment; first measurement taken prior to drug administration ]
    Heart rate will be measured via pulse at start of experimental session and thereafter every 30 min
46. Pre-drug body temperature [ Time Frame: 3-6 weeks post-enrollment; first measurement taken prior to drug administration ]
    Body temperature will be measured at the start of the experimental session and every 60 to 90 minutes afterwards
47. Pre-drug body temperature [ Time Frame: 6-11 weeks post-enrollment; first measurement taken prior to drug administration ]
    Body temperature will be measured at the start of the experimental session and every 60 to 90 minutes afterwards
48. Pre-drug Subjective Units of Distress (SUD) [ Time Frame: 3-6 weeks post-enrollment; last measurement ]
    Psychological (subjective) distress will be measured at the start of the study and for every 60 to 90 minutes afterwards
49. Pre-drug Subjective Units of Distress (SUD) [ Time Frame: 6-11 weeks post-enrollment; last measurement ]
    Psychological (subjective) distress will be measured at the start of the study and for every 60 to 90 minutes afterwards
50. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 2 weeks post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
51. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 3-6 weeks post-enrollment (session start/approx. 6 hours postdrug) ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
52. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 6-11 weeks post-enrollment (session start/approx. 6 hours postdrug) ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
53. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: Up to 64 weeks post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
54. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 3 weeks +1 day to 6 weeks + 1 day post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
55. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 6 weeks +1 day to 11 weeks + 1 day post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
56. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 4-7 weeks post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
57. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 5-8 weeks post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
58. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 7-12 weeks post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
59. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 8-13 weeks post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
60. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 3 weeks +3 and 8 days to 6 weeks +3 and 8 days post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
61. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 6 weeks +3 and 8 days to 11 weeks +3 and 8 days post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses
62. Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: 14-19 weeks post-enrollment ]
    A clinician-administered and scored measure of suicidal ideation and behavior, consisting of a series of questions and adaptive to subject's responses

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosed with chronic PTSD with a duration of 6 months or longer;
• Have a CAPS score showing moderate to severe symptoms
• at least one unsuccessful attempt at treatment for PTSD either with talk therapy or with drugs, or stopping 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;
• 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 a woman who can have children, those who 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

Contacts and Locations

Locations

Israel

Beer Yaakov Hospital

Be'er Ya'aqov, Israel, 70350

Sponsors and Collaborators

Multidisciplinary Association for Psychedelic Studies

Investigators

• Principal Investigator: Moshe Kotler; Beer Yaakov Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Feduccia AA, Jerome L, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R. Breakthrough for Trauma Treatment: Safety and Efficacy of MDMA-Assisted Psychotherapy Compared to Paroxetine and Sertraline. Front Psychiatry. 2019 Sep 12;10:650. doi: 10.3389/fpsyt.2019.00650. eCollection 2019. Review.

Mithoefer MC, Feduccia AA, Jerome L, Mithoefer A, Wagner M, Walsh Z, Hamilton S, Yazar-Klosinski B, Emerson A, Doblin R. MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology (Berl). 2019 Sep;236(9):2735-2745. doi: 10.1007/s00213-019-05249-5. Epub 2019 May 7.

• Responsible Party: Multidisciplinary Association for Psychedelic Studies
• ClinicalTrials.gov Identifier: NCT01689740
• Other Study ID Numbers: MP-9
• First Posted: September 21, 2012
• Last Update Posted: August 21, 2018
• Last Verified: August 2018

Keywords provided by Multidisciplinary Association for Psychedelic Studies:

MDMA; Posttraumatic stress disorder; PTSD; Israel; psychotherapy

Additional relevant MeSH terms:

Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Trauma and Stressor Related Disorders; Mental Disorders; N-Methyl-3,4-methylenedioxyamphetamine; Hallucinogens; Physiological Effects of Drugs; Psychotropic Drugs; Serotonin Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adrenergic Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Adrenergic Agents