PTSD is a debilitating psychiatric disorder arising after a traumatic life event. The condition is a public health issue. There are recognized psychotherapeutic and pharmacologic treatments for PTSD, but a wider array of treatments is needed. Methylenedioxymethamphetamine (MDMA) has shown promise in Phase 2 research studies as a psychotherapeutic adjunct for people with PTSD. In the context of psychotherapy, MDMA has been noted to reduce defenses and fear of emotional injury while enhancing communication and capacity for introspection. Cognitive-behavioral conjoint therapy (CBCT) for PTSD is a three-phase, 15-session, manualized treatment engaging an individual with PTSD and a "concerned significant other" in addressing PTSD symptoms, and relationship issues together. During the course of CBCT, pairs are provided with information about PTSD and the therapy rationale, address relationship issues and a key PTSD symptom and consider the meaning of the traumatic event. MDMA-assisted psychotherapy is a manualized treatment developed to use the effects of MDMA to enhance and strengthen the therapeutic process, and it includes preparatory and integrative sessions that occur prior to and after up to three sessions of MDMA-assisted psychotherapy.

This study will combine methods described in the Treatment Manual for conducting MDMA-assisted psychotherapy with methods from the CBCT for PTSD manual. A combined treatment of MDMA-assisted psychotherapy and CBCT may be especially useful for treating PTSD because MDMA can attenuate the fear arising in response to perceived threat to one's emotional integrity and decrease defensiveness without blocking access to memories or preventing a deep and genuine experience of emotion. Elimination of these conditioned fear responses can lead to more open and comfortable communication about past traumatic events and greater access to information about them. Participants are expected to be able to experience and express fear, anger, and grief, and to be able to engage in the CBCT sessions with less likelihood of feeling overwhelmed by these emotions. As a result, MDMA-assisted psychotherapy with CBCT may enable the participants to develop a wider behavioral and emotional repertoire with which to communicate with each other and respond to anxiogenic stimuli.

This is a Phase 1/2 open-label study in 10 dyads (pairs) that include a participant who has been diagnosed with PTSD for at least 6 months (PTSD+ participant) and a concerned significant other participant (i.e., intimate or non-intimate person) who does not have a current diagnosis of PTSD (CSO participant). The overall objective of this study is to explore the safety and estimate the effect size of MDMA-assisted psychotherapy in conjunction with CBCT (MDMA+CBCT) on PTSD symptoms in participants with PTSD and, to examine relationship functioning in both participants. Dyads in this study will be enrolled in a course of CBCT that will also include two sessions of MDMA-assisted psychotherapy. Eligible and enrolled participants will undergo a 1-month course of psychotherapy as a dyad that includes CBCT for PTSD integrated with MDMA-assisted psychotherapy.

Prior to the first session with MDMA and CBCT, participants will undergo an introductory psychotherapy session via telemedicine (videoconference) followed by a five-hour CBCT visit at the study site. After each MDMA+CBCT session, the pair will have integrative sessions that include an on-site integrative session on the day following MDMA+CBCT and further integrative and CBCT sessions conducted via videoconference.

During the first experimental (MDMA+CBCT) session, both members of the pair will receive 75 mg MDMA with the option of receiving a second dose of 37.5 approximately an hour and a half later. During the second session, subjects may receive either 100 or 75 mg, with the decision concerning dose made by the researchers. An optional dose half the size of the initial dose may be offered approximately an hour and a half later. The doses used in this study have been investigated by researchers conducting trials in healthy human volunteers and people with PTSD. Vital signs (blood pressure, heart rate and body temperature) will be periodically measured during the session, and the pair will complete simple measures of state interpersonal closeness and degree of distress. They will have an overnight stay at the study site, followed by the first post-session integrative session on the day after the experimental session. The researchers will contact the PTSD+ and CSO daily for a week after each MDMA+CBCT session, with contact possible through telephone or teleconference line. Integrative sessions will occur over teleconference (telemedicine) line. Integrative psychotherapy held over videoconference falls after the on-site integrative session.

Thirteen days after the first experimental session, the dyad meet with the investigators at the study site to complete measures of PTSD symptoms, symptoms of other conditions, emotion perception and regulation, sleep quality, facets of interpersonal relationships and psychological function. The course of combined CBCT and MDMA-assisted psychotherapy will continue until approximately two and a half weeks after the second MDMA+CBCT session, when the primary endpoint assessment will occur. The dyad will be assessed at the three month and six month follow up visits.

Dyads will participate in an introductory session, CBCT sessions, two day-long MDMA+CBCT sessions, and five integrative sessions after each MDMA+ CBCT session. PTSD symptoms, growth from trauma experience, sleep quality, symptoms of depression, other psychological symptoms or difficulties, emotion regulation, emotion perception, relationship factors, and facets of life function will be measured two weeks after the first MDMA-assisted session and five weeks, three months and six months after the second and final MDMA-assisted session. Assessment five weeks after the second experimental (MDMA-assisted) session will be the study primary endpoint. The Clinician Administered PTSD Scale - 5 (CAPS-5) will be the primary outcome measure, with drops in CAPS-5 Global Severity score expected from baseline to primary endpoint. There will be follow up assessments three and six months after the second MDMA+CBCT session. Safety data collected will include vital signs during each MDMA+CBCT session, suicidal ideation and behavior assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Adverse events will be collected throughout the course of the study.