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

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ClinicalTrials.gov Identifier: NCT01689740
Recruitment Status : Completed
First Posted : September 21, 2012
Results First Posted : October 30, 2020
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
Multidisciplinary Association for Psychedelic Studies

Brief Summary:
This Phase 2 pilot study assessed the safety and efficacy of MDMA-assisted psychotherapy in 10 people with chronic, treatment-resistant posttraumatic stress disorder (PTSD), comparing the effects of low and full dose MDMA as an adjunct to psychotherapy. The first two subjects were enrolled in the open label full dose lead-in with 125 mg of MDMA, followed 1.5 to 2.5 hours later by a supplemental half-dose of 62.5 mg of MDMA. The remaining eight subjects enrolled in Stage 1 of the study and received either an active placebo dose (low dose of 25 mg MDMA, with a supplemental dose of 12.5 mg MDMA) or a fully active dose of MDMA (125 mg, with a supplemental dose of 62.5 mg MDMA) during two experimental psychotherapy session, each lasting six to eight hours and scheduled three to five weeks apart. The extent of PTSD symptoms was assessed at baseline and two months after the second experimental session using the Clinician Administered PTSD Scale (CAPS) [Blake et al., 1995]. Subjects who enrolled in Stage 1 and received the active placebo had the opportunity to enroll in Stage 2 of the study and complete open-label experimental sessions with the fully active dose of MDMA on the same schedule as Stage 1.

Condition or disease Intervention/treatment Phase
Posttraumatic Stress Disorder (PTSD) Drug: Active Placebo Dose MDMA (25 mg) Drug: Full Dose MDMA (125 mg) Drug: Open Label Full Dose MDMA (125 mg) 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 randomized, double-blind, active placebo-controlled Phase 2 pilot study investigated the safety and efficacy of MDMA-assisted psychotherapy in 10 people with chronic, treatment-resistant posttraumatic stress disorder (PTSD), comparing the effects of low and full dose MDMA as an adjunct to psychotherapy. The first two subjects were enrolled in the open label full dose lead-in with 125 mg of MDMA, followed by a supplemental half-dose of 62.5 mg of MDMA after 1.5 to 2.5 hours. The remaining eight subjects enrolled in Stage 1 of the study and received either an active placebo dose (low dose of 25 mg MDMA with a supplemental half-dose of 12.5 mg MDMA) or a fully active dose (125 mg MDMA with a supplemental half-dose of 62.5 mg MDMA) during two experimental psychotherapy session, each lasting six to eight hours and scheduled three to five weeks apart.

Subjects remained with their male/female co-therapist team for the entirety of the study. Upon enrollment, subjects met with their therapist team for three preparatory sessions. After each MDMA-assisted psychotherapy session, subjects met with their therapist team for integrative psychotherapy sessions where subjects processed and connected their thoughts and feelings about the experience.

The extent of PTSD symptoms was assessed at baseline and two months after the second experimental session using the Clinician Administered PTSD Scale (CAPS) (Blake et al., 1995). Safety measures, vital signs, and a measurement of psychological distress was assessed during all experimental sessions. Blood pressure and heart rate were assessed periodically during each experimental session.

Subjects who enrolled in Stage 1 and received the active placebo had the opportunity to enroll in Stage 2 of the study and complete open-label experimental sessions with the fully active dose of MDMA (125 mg and 62.5 mg supplemental) on the same schedule as Stage 1.

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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 : March 1, 2013
Actual Primary Completion Date : July 2017
Actual Study Completion Date : September 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lead in: 125 mg MDMA (Open Label)
Participants receive open-label MDMA with an initial dose of 125 mg, possibly followed by a supplemental dose of 62.5 mg, during two psychotherapy sessions scheduled 3-5 weeks apart.
Drug: Open Label Full Dose MDMA (125 mg)
Initial dose of 125 mg MDMA administered orally at the start of each of two psychotherapy sessions, possibly followed by a supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Other Name: 3,4-methylenedioxymethamphetamine

Behavioral: Psychotherapy
Non-directive psychotherapy will be conducted throughout the study.
Other Name: Manualized MDMA-assisted psychotherapy

Placebo Comparator: Active placebo dose MDMA (25 mg)
Participants receive initial dose of 25 mg MDMA, possibly followed by a supplemental dose of 12.5 mg, during two psychotherapy sessions scheduled 3-5 weeks apart.
Drug: Active Placebo Dose MDMA (25 mg)
Initial dose of 25 mg MDMA administered orally at the start of each of two psychotherapy sessions, possibly followed by a supplemental dose of 12.5 mg MDMA 1.5 to 2.5 hours later.
Other Name: 3,4-methylenedioxymethamphetamine

Behavioral: Psychotherapy
Non-directive psychotherapy will be conducted throughout the study.
Other Name: Manualized MDMA-assisted psychotherapy

Experimental: Full dose MDMA (125 mg)
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: Full Dose MDMA (125 mg)
Initial dose of 125 mg MDMA administered orally at the start of each of two psychotherapy sessions, possibly followed by a supplemental dose of 62.5 mg MDMA 1.5 to 2.5 hours later.
Other Name: 3,4-methylenedioxymethamphetamine

Behavioral: Psychotherapy
Non-directive psychotherapy will be conducted throughout the study.
Other Name: Manualized MDMA-assisted psychotherapy




Primary Outcome Measures :
  1. Change in Clinical Administered PTSD Scale (CAPS-IV) Total Score From Baseline to End of Stage 1 [ Time Frame: Baseline to 1-Month Post Experimental Session 2 (End of Stage 1) ]
    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. 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 in Clinical Administered PTSD Scale (CAPS-IV) Total Score From End of Stage 1 to End of Stage 2 [ Time Frame: End of Stage 1 to End of Stage 2 ]
    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. 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. Change in Clinical Administered PTSD Scale (CAPS-IV) Total Score From Baseline to Long-Term Follow-Up [ Time Frame: Baseline to 12 months post-final 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. 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 Beck Depression Inventory (BDI-II) Total Scores From Baseline to End of Stage 1 [ Time Frame: Baseline to 1-Month Post Experimental Session 2 (End of Stage 1) ]
    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 BDI-II is scored by summing the ratings for the 21 items. Each item is rated on a 4-point scale ranging from 0 to 3. The maximum total score is 63.

  4. Change in Beck Depression Inventory (BDI-II) Total Score From End of Stage 1 to End of Stage 2 [ Time Frame: End of Stage 1 to End of Stage 2 ]
    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 BDI-II is scored by summing the ratings for the 21 items. Each item is rated on a 4-point scale ranging from 0 to 3. The maximum total score is 63.

  5. Change in Beck Depression Inventory (BDI-II) Total Scores From Baseline to Long-Term Follow-Up [ Time Frame: Baseline to 12 month post-final 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 BDI-II is scored by summing the ratings for the 21 items. Each item is rated on a 4-point scale ranging from 0 to 3. The maximum total score is 63.

  6. Change in Global Assessment of Functioning (GAF) Scale From Baseline to End of Stage 1 [ Time Frame: Baseline to 1-Month Post 2nd Experimental Session (End of Stage 1) ]
    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.

  7. Change in Global Assessment of Functioning (GAF) Scale From End of Stage 1 to End of Stage 2 [ Time Frame: End of Stage 1 to End of Stage 2 ]
    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.

  8. Change in Global Assessment of Functioning (GAF) Scale From Baseline to Long-Term Follow-Up [ Time Frame: Baseline to 12 months post-final experimental session ]
    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.

  9. Change in Posttraumatic Stress Diagnostic Scale (PDS) Symptom Severity Score From Baseline to End of Stage 1 [ Time Frame: Baseline to 1-Month Post 2nd Experimental Session (End of Stage 1) ]
    The Posttraumatic Stress Diagnostic Scale (PDS) is a 49-item self-report instrument designed to aid in the diagnosis of PTSD. Responses to 17 symptom items are made on a 4 point scale ranging from 0 (not at all) to 3 (five or more times per week). The symptom items are summed to calculate the symptom severity score which ranges from 0 to 51, with higher scores indicating more severe PTSD symptoms.

  10. Change in Posttraumatic Stress Diagnostic Scale (PDS) Symptom Severity Score From End of Stage 1 to End of Stage 2 [ Time Frame: End of Stage 1 to End of Stage 2 ]
    The Posttraumatic Stress Diagnostic Scale (PDS) is a 49-item self-report instrument designed to aid in the diagnosis of PTSD. Responses to 17 symptom items are made on a 4 point scale ranging from 0 (not at all) to 3 (five or more times per week). The symptom items are summed to calculate the symptom severity score which ranges from 0 to 51, with higher scores indicating more severe PTSD symptoms.

  11. Change in Posttraumatic Stress Diagnostic Scale (PDS) Symptom Severity Score From Baseline to Long-Term Follow-Up [ Time Frame: Baseline to 12 months post-final experimental session ]
    The Posttraumatic Stress Diagnostic Scale (PDS) is a 49-item self-report instrument designed to aid in the diagnosis of PTSD. Responses to 17 symptom items are made on a 4 point scale ranging from 0 (not at all) to 3 (five or more times per week). The symptom items are summed to calculate the symptom severity score which ranges from 0 to 51, with higher scores indicating more severe PTSD symptoms.

  12. Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to End of Stage 1 [ Time Frame: Baseline to 1-Month Post 2nd Experimental Session (End of Stage 1) ]
    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.

  13. Change in Pittsburgh Sleep Quality Index (PSQI) From End of Stage 1 to End of Stage 2 [ Time Frame: End of Stage 1 to End of Stage 2 ]
    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.

  14. Change in Pittsburgh Sleep Quality Index (PSQI) From Baseline to Long-Term Follow-Up [ Time Frame: Baseline to 12 months post-final 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.



Information from the National Library of Medicine

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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.
  • Had at least one unsuccessful attempt at treatment for PTSD, either with talk therapy or with drugs, or stopped 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;
  • Are 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 they can have children and 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01689740


Locations
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Israel
Beer Yaakov Hospital
Be'er Ya'aqov, Israel, 70350
Sponsors and Collaborators
Multidisciplinary Association for Psychedelic Studies
Investigators
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Principal Investigator: Moshe Kotler Beer Yaakov Hospital
  Study Documents (Full-Text)

Documents provided by Multidisciplinary Association for Psychedelic Studies:
Study Protocol  [PDF] March 30, 2015
Statistical Analysis Plan  [PDF] May 31, 2016

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Multidisciplinary Association for Psychedelic Studies
ClinicalTrials.gov Identifier: NCT01689740    
Other Study ID Numbers: MP-9
First Posted: September 21, 2012    Key Record Dates
Results First Posted: October 30, 2020
Last Update Posted: November 17, 2020
Last Verified: August 2018
Keywords provided by Multidisciplinary Association for Psychedelic Studies:
MDMA
Posttraumatic stress disorder
PTSD
Israel
psychotherapy
Additional relevant MeSH terms:
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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