First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder

Alcohol use disorder (AUD) is common and heterogenous, and many patients present with comorbid psychological trauma, depression, social anxiety and social exclusion. Current pharmacological treatments (for example acamprosate, naltrexone, nalmefene, disulfiram) and psychosocial programmes have limited effectiveness for some patients, and there is growing interest in therapeutic approaches that improve engagement with psychotherapy and interrupt automatic responses to stress and craving. Earlier research on 3,4-methylenedioxymethamphetamine (MDMA) has shown that it elevates mood, increases sociability and reduces amygdala reactivity to negative memories; these properties have motivated clinical trials of MDMA-assisted psychotherapy in PTSD and suggest potential applicability to addictions, but MDMA has not previously been evaluated experimentally for AUD. Sessa and colleagues report the Bristol Imperial MDMA in Alcoholism (BIMA) study, an open-label, within-subjects, proof-of-concept investigation designed primarily to assess safety and tolerability of MDMA-assisted psychotherapy delivered after successful alcohol detoxification. The study also collected preliminary outcome data on drinking behaviour, mental well-being, psychosocial functioning and quality of life up to nine months post-detoxification to inform future controlled trials.

This was an open-label, non-randomised safety and tolerability feasibility study conducted under regulatory approval (Imperial College London sponsorship, favourable REC opinion, MHRA oversight). Fourteen participants aged 18–65 years with a primary DSM-defined diagnosis of AUD who had completed a community alcohol detoxification were enrolled from a local substance misuse service. Key inclusion criteria included informed consent, successful detoxification and the ability to identify a supportive contact; exclusions included primary psychotic disorder, bipolar I, serious suicide risk, relevant cardiac or neurological disease, regular recent MDMA/ecstasy use, dependence on other illicit drugs, and contraindicated concomitant medications. Females of childbearing potential and male participants with partners of childbearing potential were required to use effective contraception for at least six days after dosing. Participants received an eight-week recovery-based therapy course comprising 10 psychotherapy sessions. Two of these sessions (weeks 3 and 6) were extended six- to eight-hour MDMA-assisted psychotherapy sessions. On each dosing day an initial oral dose of 125 mg MDMA was administered, followed two hours later by a 62.5 mg booster dose to prolong the experience. Non-dosing sessions were approximately one hour and employed motivational interviewing and 'third-wave' cognitive-behavioural approaches. Participants remained overnight after each MDMA session with medically trained staff present; integration psychotherapy occurred the morning after dosing and daily telephone contact continued for six days to assess mood, suicidal risk (C-SSRS) and sleep (Leeds Sleep Evaluation Questionnaire). Follow-up visits to collect outcome measures occurred at three, six and nine months from baseline. Primary outcomes were feasibility metrics: number completing the eight-week course, number accepting the second booster dose on drug-assisted days, and adverse events. Secondary outcomes included changes in alcohol consumption (units per week at three, six and nine months), mental well-being and psychosocial/functioning measures. Physiological monitoring during MDMA sessions recorded blood pressure, heart rate and temperature at baseline, half-hourly up to two hours and hourly thereafter for at least six hours. Subjective Units of Distress (SUDS), hourly self- and observer-rated drug-effect scores and Profile of Mood States (seven-day post-session) were also collected. Data were recorded on paper CRFs, digitised, and analysed descriptively using GraphPad Prism and Excel; no formal hypothesis testing was performed given the open-label design.

Thirty-six people attended screening and 14 participants (8 male, 6 female; mean age 48 years; all white British) were enrolled. Employment status varied (four employed, nine unemployed, one retired). Participants reported early onset of alcohol use (mean age first use 13) and moderate-to-severe AUD symptom severity on screening measures. All 14 had successfully completed detoxification at baseline per the CIWA scale. Twelve participants received both MDMA sessions; one participant received only the first session and declined the second after relapsing to heavy drinking for reasons stated to be unrelated to the study, and one participant omitted a booster dose during a session because she had missed her antihypertensive medication. In total 26 MDMA-assisted psychotherapy sessions were delivered. Physiological monitoring showed the expected mild, transient rises in blood pressure, heart rate and temperature; with the exception of one participant whose blood pressure reached 183/118 mmHg at two hours (attributed to missed antihypertensive medication), parameters remained within normal limits and no medical interventions were required. That participant omitted the two-hour booster dose that day and later completed a second uneventful MDMA session after taking her antihypertensive medication. No sustained abnormal physiological disturbances, symptomatic events related to vital signs, or other medical interventions were reported during MDMA sessions. Subjective distress (SUDS) tended to be mildly elevated pre-dose and decreased during sessions as MDMA effects emerged. Self-rated and observer-rated drug-effect scores increased over the first two hours, rose further after the booster at t = 2 hours, then plateaued and declined, returning to baseline by the end of the session day; no significant disagreement was found between participant and observer ratings. Participants did not report significant neurocognitive impairments in the weeks and months following treatment. Regarding alcohol use, the cohort reported an average of 130.6 units per week in the month before detoxification and no alcohol at the point of detox. At nine months post-detoxification, the group mean had risen to 18.7 units per week. At that nine-month endpoint, 11 of 14 participants were drinking fewer than 14 units per week, including nine who were totally abstinent, while three had relapsed to more than 14 units per week. Seven-day post-session Profile of Mood States scores showed no evidence of a post-dose 'come-down'; average mood scores indicated sustained positive mood for seven days after each MDMA session. Brief mood and anxiety measures (PHQ-9, GAD-7) demonstrated an initial reduction after screening and baseline, a transient rise at three months, a further reduction at six months and a moderate rise again at nine months. Suicidality assessments (C-SSRS) identified no participants with current suicidal ideation, intent, plans or self-harm during the study. No unexpected adverse events were observed, no psychotic symptoms occurred, and participants reported no desire to use illicit ecstasy/MDMA after the clinical sessions. The authors note additional collected measures (sleep, compassion/empathy scales, quality of life) will be reported separately.

The investigators interpret these findings as preliminary evidence that MDMA-assisted psychotherapy can be delivered safely and is generally well tolerated in a post-detoxification AUD population. They propose that MDMA's prosocial and empathogenic effects may enhance psychotherapeutic engagement, increase self-awareness and reduce denial of harmful drinking, and that these mechanisms could be particularly relevant for patients with histories of psychological trauma. The discussion situates MDMA relative to classic psychedelics (LSD, psilocybin), noting that while psychedelic experiences with strong mystical content have been associated with durable benefit in substance use interventions, not all patients tolerate those experiences; MDMA may offer an alternative with fewer perceptual disturbances and greater acceptability for some patients. Authors compare the BIMA cohort informally with a prior observational 'Outcomes' study conducted by the same team, cautioning that the studies are not comparable statistically because of non-randomisation; nonetheless, they highlight that only 21% of BIMA participants exceeded 14 units per week at nine months compared with 75% in the observational sample. Key limitations acknowledged by the study team include the small sample size, the open-label non-placebo-controlled design mandated by regulators for a first-time clinical application in this population, and the reliance primarily on self-reported alcohol use despite some objective checks (breath alcohol tests, medical note reviews, Gamma-GT testing). The authors note that additional objective monitoring (for example, wearable alcohol sensors) was considered but judged overly intrusive given that efficacy was not the primary outcome. Finally, the investigators recommend advancing to a placebo-controlled randomised controlled trial in which therapist contact is matched between conditions, to permit attribution of any between-group differences to MDMA itself rather than differential psychological support.

The study team concludes that MDMA-assisted psychotherapy can be administered safely and is well tolerated in patients with AUD following detoxification, with no unexpected adverse events observed in this small sample. They suggest the intervention has potential to intensify psychotherapeutic processes by reducing avoidance of distressing material and increasing empathy for self and others, and they recommend a placebo-controlled randomised trial with equivalent therapist contact as the logical next step to test efficacy.