Randomized, Double-blind, Controlled of MDMA-assisted Psychotherapy in 12 Subjects With PTSD

A Randomized, Double-Blind, Controlled Phase 2 Pilot Study of Manualized 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy in 12 Subjects With Treatment-Resistant Posttraumatic Stress Disorder (PTSD) - Canada

This small ("pilot") study is designed to provide information on whether the combination of psychotherapy with the drug MDMA is safe and helpful for people with post traumatic stress disorder (PTSD). The researchers will use the results of this study to design more studies of this treatment. The study compares a comparator (placebo) and a full dose. For each session, there will be an initial dose possibly followed 1.5 to 2.5 hours later by a dose half the size of the initial dose. The study will measure symptoms of PTSD, depression, general psychological well-being, sleep quality, feelings that the self or world is unreal (dissociation), potentially positive effects of surviving traumatic events and cognitive function (thinking, memory and attention). People experiencing pain or tinnitus (ringing in the ears) will record their symptoms throughout the study. Seven people will be randomly (by chance) assigned to receive full-dose MDMA and five will be randomly assigned to receive a comparator. There will be three preparatory psychotherapy sessions before the first experimental session, and subjects will have supportive or "integrative" sessions after each MDMA-assisted psychotherapy session. Subjects will meet with a male and female psychotherapist for all experimental sessions and for sessions before and after each experimental session. Subjects who received comparator can enroll in Stage 2, where they will have three open-label MDMA-assisted psychotherapy sessions, meaning everyone will know they are receiving an active dose of MDMA. Subjects receiving full dose in Stage 1 will have a third experimental session.. Symptoms of PTSD and other symptoms will be measured again at least 12 months after each subject has started the study.

Post traumatic stress disorder (PTSD) is a debilitating disorder that can develop after people experience a traumatic event, such as a rape, car accident or other life threatening event. PTSD is a worldwide health problem. PTSD is treated with psychotherapy or drugs, but these treatments do not help everyone. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy might be a potential treatment for PTSD. MDMA is the active ingredient in ecstasy. Before it was made illegal, some psychotherapists combined MDMA with psychotherapy to help treat people with psychological problems, including PTSD. This is a Phase 2 randomized, dose comparison, double-blind study to assess safety and efficacy of manualized MDMA-assisted psychotherapy in treating chronic, treatment-resistant PTSD. Seven subjects will be randomized to receive full dose MDMA (full dose condition) and five subjects will receive a comparator (comparator condition), with an optional supplemental half-dose available 1.5 to 2.5 hours after the initial dose. Global Clinician-Administered PTSD Scale (CAPS) score one month after two sessions of MDMA-assisted psychotherapy is the primary outcome measure. MDMA or comparator will be administered in two blinded experimental sessions lasting up to eight hours and scheduled three to five weeks apart. The will last up to one and a half years, including approximately three to five months of psychotherapy, and a long-term follow up visit scheduled a year after the final experimental session. Study subjects will have a medical and psychiatric examination to assess eligibility for enrollment. Once in the study, they will see the same male and female psychotherapist for the entire study. The subject will learn more about MDMA-assisted psychotherapy and the investigators will learn more about the subject during three preparatory sessions occurring before the first experimental session. During experimental sessions, subjects will receive an initial dose of either full dose MDMA or placebo along with psychotherapy, and one and a half to two and a half hours later, the subject may have a supplemental half the size of the initial dose. Vital signs and psychological distress will be measured throughout the experimental session. There will be three integrative psychotherapy sessions after each experimental session, including one occurring the day after an experimental session. Subjects will express, understand and connect any of their thoughts or feelings about PTSD symptoms and their causes, and they will discuss their experience during experimental sessions with the therapists. Subjects will learn the dose of MDMA they received one month after the second MDMA-assisted psychotherapy session. Subjects who received full dose will complete Stage 1, with a third open-label session, and subjects who received comparator dose MDMA will go on to Stage 2, an open label period of the study that is nearly identical to stage 1, but with one instead of three preparatory sessions and one of two active doses of MDMA used in all three experimental sessions. Symptoms of PTSD, depression, dissociation, general psychological well-being, sleep quality and potential positive effects of experiencing traumatic events will be measured in all subjects at baseline, one month after the second experimental session and 12 months after their final experimental session, and any subjects reporting pain or tinnitus at the start of the study will record these symptoms throughout the study.Subjects who received the full dose and go on to the third experimental session will complete questionnaires and measures of PTSD and other symptoms two months after the third experimental session. Subjects who received comparator dose MDMA will be tested one month after their second Stage 2 experimental session and two months after the third experimental session. Measures of cognitive function will be given to subjects in Stage two months after their third experimental session, and to Stage 2 subjects two months after their third Stage 2 session. People will also complete measures of their experience of the experimental session soon after each experimental session. At least 12 months after their final Stage 1 or Stage 2 session, measures of PTSD symptoms, other symptoms, sleep quality, general well-being and and post traumatic growth will be assessed again, and subjects will complete a questionnaire on the benefits and harms of study participation and other life events and views related to study participation. This study will compare the effects of MDMA-assisted psychotherapy with comparator versus full dose MDMA, and it will also assess the duration of any changes in symptoms a year after MDMA-assisted psychotherapy.

Participants will receive full-dose MDMA (125 mg) with therapy during each of two experimental sessions.

Placebo administered in two experimental sessions; may take part in Stage 2 upon learning condition assignment

Participants receive full-dose MDMA during two experimental sessions; after learning their condition assignment, participants will receive a third full-dose session.

Clinician-administered and scored assessment of PTSD symptoms via structured interview, including global symptom severity, dichotomous diagnostic score and subscale scores. The Clinician-Administered PTSD Scale for DSM-4 (CAPS-4) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-4. It contains symptom subscales, a CAPS-4 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.

Baseline to Primary Endpoint (Primary Endpoint was approximately 18 weeks after Baseline and 1 month after the 2nd experimental session)

Inclusion Criteria: Diagnosed with PTSD, duration of six months or longer Have a CAPS score showing moderate to severe PTSD symptoms; Have had 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; 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; Willing to follow restrictions and guidelines concerning consumption of food, beverages, and nicotine the night before and just prior to each experimental session; Willing to remain overnight at the study site; Agree to have transportation other than driving themselves home or to where they are staying after the integrative session on the day after the MDMA session; 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; Must provide a contact in the event of a participant becoming suicidal; Are proficient in speaking and reading English; Agree to have all clinic visit sessions recorded to audio and video Agree not to participate in any other interventional clinical trials during the duration of this study. 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

Jerome L, Feduccia AA, Wang JB, Hamilton S, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R. Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology (Berl). 2020 Aug;237(8):2485-2497. doi: 10.1007/s00213-020-05548-2. Epub 2020 Jun 4.

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.

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.