3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial

Brazil has high levels of interpersonal violence and a substantial burden of trauma-related disorders. Population surveys in major metropolitan areas indicate that more than 80% of people have experienced traumatic events in their lifetime, with rape or sexual molestation reported in 1.3–4.9% of respondents; an estimated 5% met criteria for PTSD in the previous year and 10% at some point in their lives. Existing psychological and pharmacological treatments provide insufficient response for a considerable proportion of patients with PTSD, motivating investigation of alternative approaches. Against this background, Jardim and colleagues sought to test 3,4-methylenedioxymethamphetamine-assisted psychotherapy (MDMA-AP) in a Brazilian clinical sample. MDMA-AP had received a ‘‘breakthrough therapy’’ designation by the US Food and Drug Administration after Phase II trials abroad and was entering Phase III evaluation; the study therefore aimed to implement the established MAPS protocol in Brazil to assess feasibility, safety, and signals of clinical efficacy in people with chronic, severe PTSD, particularly where sexual abuse is a common trauma type.

The investigators implemented an open-label Phase II-style intervention following the Multidisciplinary Association for Psychedelic Studies (MAPS) manual and prior Phase II studies. The treatment sequence comprised three preparatory psychotherapy sessions, then three monthly cycles each containing a single MDMA-assisted psychotherapy session followed by three integrative psychotherapy sessions. Preparatory and integrative sessions lasted about 90 minutes; each MDMA-AP session lasted approximately eight hours. Dosing began at 75 mg for the first MDMA session, with the second and third sessions given as either 75 mg or 125 mg per joint decision of participant, physician and therapist; a supplemental dose equal to 50% of the initial dose was offered 90–120 minutes after dosing. All therapists and the physician completed MAPS training before study start. Participants were recruited via social media, press, medical referrals and word of mouth. Key inclusion criteria reported included: a DSM-IV diagnosis of PTSD confirmed with the Structured Clinical Interview for DSM-IV and the Clinician-Administered PTSD Scale for DSM-IV (CAPS-4) for at least six months, a CAPS-4 score at or around 60 or higher, age 18 or older, and at least one prior treatment failure. Major exclusion criteria included pregnancy or non-use of contraception, primary psychotic disorder, type I bipolar disorder, significant cardiac or hepatic disease, uncontrolled hypertension, recent problematic illicit drug use, current drug abuse or dependence (except nicotine or caffeine), serious suicide risk, inability to consent, and other medical/psychiatric contraindications. The extracted text reports a detailed list of behavioural restrictions around alcohol, nicotine, caffeine and driving for peri-session safety. The primary outcome was CAPS-4 score at baseline and two months after the final MDMA-AP session. Secondary outcomes included the PTSD Checklist—Civilian Version (PCL-C), Post-Traumatic Growth Inventory (PTGI), Columbia–Suicide Severity Rating Scale, Beck Depression Inventory-II (BDI-II), Dissociative Experiences Scale-II, Pittsburgh Sleep Quality Index, Global Assessment of Functioning (GAF), and subjective measures such as the Mystical Experience Questionnaire and Subjective Units of Distress Scale. Change scores from baseline to two months post-treatment were calculated and interpreted using standard instrument cut-offs. Effect size for the primary outcome was estimated using Rosenthal's r, calculated in Stata v.12. Ethical and regulatory approvals were obtained from the National Research Ethics Commission (CONEP) and the Brazilian Clinical Trials Registry; national controlled-substance authorisation and import/export permits were secured. MDMA was manufactured by Dr David Nichols and supplied by MAPS.

Of 60 volunteers who expressed interest, 24 underwent screening. Nine met diagnostic criteria for PTSD, but five were excluded due to comorbidities or other exclusion criteria; four met all inclusion criteria but one withdrew before enrolment because of an untreated infection. Three participants (one male, two female) were therefore enrolled and completed the protocol. All three were survivors of sexual abuse (two during childhood, one as an adult); ages were 45, 35 and 41. One participant was Afro-Brazilian and two were Caucasian. All participants chose to receive the supplemental dose in every MDMA-AP session, yielding total doses of 112.5 mg in the first session and 187.5 mg in the second and third sessions. Physiological and subjective changes in emotion, cognition, blood pressure, heart rate and temperature were observed (details referenced to a supplementary table in the source). No serious adverse events occurred. Across the study there were 54 adverse events recorded during the nine preparatory sessions, 20 during the nine MDMA sessions, and 73 during the 27 integrative sessions. Somatic pain was the most frequently reported event during preparatory (seven occurrences) and MDMA sessions (four occurrences); anguish was most frequently reported during integrative sessions (16 occurrences). No hyperthermia cases were reported. Large reductions in CAPS-4 scores were observed for all three participants at the primary endpoint (two months after the final MDMA session). Baseline CAPS-4 scores of 90, 78, and 72 fell to 61, 27, and 8, representing decreases of 29 (32%), 51 (65%), and 64 (89) points respectively. Statistical reporting for the group change yielded z = 1.604, Rosenthal's r = 0.924 and p = 0.108. Secondary measures showed improvement in PTSD symptoms on the PCL-C, substantial increases in post-traumatic growth on the PTGI (reported as approximately 5-fold and 7-fold increases for two patients and a 2.5-fold increase for the third), and marked reductions in depressive symptoms on the BDI-II: one patient moved from severe to mild depression, and two patients moved from severe to minimal, with two final BDI-II scores reported as 10 and 2. GAF scores improved from serious impairment at baseline to moderate, mild and slight impairment across the three participants. Changes in dissociation (Dissociative Experiences Scale-II) and sleep quality (Pittsburgh Sleep Quality Index) were minimal.

Jardim and colleagues report that all three participants, each with severe PTSD resulting from sexual abuse, showed clinically meaningful improvement after MDMA-assisted psychotherapy, with one small, one moderate and one large reduction in CAPS-4 score. The reported effect size (r = 0.92) is large, but the authors caution that the small sample size and open-label design limit inferential strength and susceptibility to placebo or caregiver effects. Safety outcomes were acceptable in this small sample: no serious adverse events, no hyperthermia, and adverse events described as tolerable and short-lived. The authors situate their findings alongside prior Phase II MDMA-AP trials and two recent meta-analyses that reported large effects for MDMA-AP; they note that the present results are broadly consistent with those earlier studies but emphasise the sample size limitation. They argue that these preliminary outcomes justify further research in Brazil given the high prevalence of trauma and the unmet treatment need. Additional implications highlighted include the novelty of conducting controlled psychedelic-assisted psychotherapy research in Brazil and the potential for future Phase III data to inform regulatory approval. Limitations acknowledged by the investigators include the very small sample, open-label design, and therefore limited ability to attribute change definitively to the intervention rather than expectancy or non-specific therapeutic effects. The authors recommend larger, controlled trials in Brazil to establish efficacy, safety and generalisability.