5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) for alcohol use disorder: An open-label, phase 2, proof-of-concept, clinical trial

Harmful alcohol consumption and alcohol use disorder (AUD) remain major global public health problems with high morbidity and comorbidity, and available pharmacotherapies and psychotherapies have limited uptake and modest effectiveness. Previous research on classical psychedelics (psilocybin, LSD, ayahuasca) suggests potential benefit for AUD but is limited by methodological weaknesses, long acute drug effects (typically 4–12 hours) and dated studies. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent tryptamine psychedelic that produces intense but very short-lived subjective effects (typically 15–20 minutes when inhaled), making it an attractive candidate for clinical investigation. Marsden and colleagues report a first-in-patient Phase IIa, open-label, proof-of-concept trial evaluating BPL-003, a benzoate salt formulation of 5-MeO-DMT delivered as a 10 mg intranasal powder, given once alongside a 10-week manualised relapse-prevention cognitive behavioural therapy (CBT) programme. The study aimed primarily to assess safety and tolerability and secondarily to gather exploratory clinical outcomes (alcohol consumption, craving, biomarkers, quality of life and measures of the acute psychedelic experience) over a 12-week follow-up period to inform whether randomised controlled trials are warranted.

Design: The study was an open-label, Phase IIa, single-dose, two-centre clinical trial conducted in England. It combined a one-time intranasal administration of 10 mg BPL-003 with a standard-of-care, relapse-prevention oriented CBT programme delivered over 10 weeks. The trial followed participants for 12 weeks post-dose (Day 84 endpoint). Participants and screening: Adults aged 18–64 years with moderate or severe AUD (DSM-5 criteria; severe defined as ≥6 criteria) and a stated goal to abstain or reduce harmful drinking were eligible. Initial inclusion required ≥10 heavy drinking days (HDDs) in the prior 28 days but this was amended to ≥4 HDDs to aid recruitment. HDD was defined using the UK government binge-drinking definition (≥7 units/day for women; ≥9 units/day for men). Key exclusions included medical conditions increasing risk from transient blood pressure or heart rate elevations, recent psychedelic use within 6 months, regular non-medical drug dependence (excluding nicotine/caffeine), current suicidal intent, recent HDDs very close to dosing, and a positive breath alcohol test prior to dosing. Screening included medical history, physical examination, ECG, laboratory tests, urine drug screen, pregnancy test where applicable, psychiatric assessment using the MINI, CIWA-Ar for withdrawal, and C-SSRS for suicide risk. Psychological support and interventions: Participants received three ~90-minute pre-dose preparation sessions delivered by two licensed therapists (one with psychedelic therapy experience and one specialising in AUD), a single supervised dosing session (semi-supine position, continuous therapist support, readiness-for-discharge checks beginning 90 minutes post-dose), three ~60-minute integration sessions in the two weeks after dosing, and then 10 weekly 60-minute individual CBT sessions (days 21–84) adapted for AUD. Therapists used nondirective support during dosing and allowed agreed therapeutic touch. Dosing: A single intranasal 10 mg dose of BPL-003 was administered in a controlled setting using a dry powder intranasal device. Participants were required to be abstinent for at least 24 hours before dosing and to have completed medically supervised withdrawal where relevant. Outcomes and assessments: The primary endpoints were safety and tolerability assessed by physical exams, labs, vital signs, cardiac telemetry and treatment-emergent adverse events (TEAEs), coded with MedDRA and rated for severity and relatedness. Exploratory endpoints included alcohol consumption measured by Timeline Follow-Back (TLFB) (abstinent days, units per day/week, days to first drink, heavy drinking days), alcohol biomarkers (carbohydrate-deficient transferrin, CDT; urine ethyl glucuronide, EtG), craving (ACQ-SF-R and single-item visual analogue scale), alcohol-related problems (Short Inventory of Problems, SIP), mood (MADRS), global impressions (PGIC, CGI-S), health-related quality of life (EQ-5D-5L and EQ-VAS), treatment expectancy (SETS), and acute subjective psychedelic experience (MEQ-30 and Ego Dissolution Inventory, EDI). Sample size and analysis: The target was 12 participants, consistent with pilot psychedelic trials, intended to detect common safety events rather than to provide hypothesis testing; no formal power calculation was performed. The safety analysis set comprised participants who received the drug with post-dose pharmacokinetic data; the efficacy analysis set required at least one efficacy measure post-dose. Descriptive statistics (means, SDs) were produced using SAS v9.4. No null-hypothesis inferential testing was reported; participant-level daily alcohol use was visualised with a heatmap.

Participants and retention: Between 29 March 2023 and 2 July 2024, 22 potentially eligible individuals were identified; 13 were enrolled and formed the safety analysis set. All 13 met criteria for severe AUD at baseline. The sample was predominantly male (10/13; 76.9%), white-UK (12/13; 92.3%), with a mean age of 49.3 years (range 27–62). One participant withdrew after a suspected device malfunction and declined post-dose efficacy assessments; 12 participants constituted the efficacy analysis set. Eleven of 12 participants attended all scheduled CBT sessions. Safety and tolerability: Across the safety set (n = 13), 41 treatment-emergent adverse events (TEAEs) were reported in 11 participants (84.6%). Of these TEAEs, 22 were coded as mild and 19 as moderate. There were no serious adverse events and no TEAE-related withdrawals. One participant experienced mild suicidal ideation which investigators judged unrelated to the study drug. Most TEAEs occurred on the day of dosing and resolved within a short timeframe. The most frequent drug-related TEAEs were administration-site pain (4/13; 30.8%), transient increases in blood pressure (4/13; 30.8%), nightmares (2/13; 15.4%) and vomiting (2/13; 15.4%). Nasal pain in those reporting administration-site pain began within 30 minutes and lasted between 40 and 195 minutes. Two participants (15.4%) reported re-experiencing elements of the drug-induced state after acute effects had ended (coded as flashback/reactivation events): one had brief non-distressing sensations on waking in the week after dosing, and the other reported a single 2-minute event 22 days after dosing; both were aware of surroundings during these events. During dosing, transient systolic blood pressure increases peaked at approximately 10 minutes and returned thereafter. Alcohol consumption and biomarkers: TLFB measures showed reductions across follow-up. By Day 84, six of 12 participants (50%) were continuously abstinent over the 12-week follow-up, three participants (25%) had meaningful reductions in alcohol consumption, and three participants (25%) had no or limited change in drinking. Mean (SD) percentage of abstinent days increased from 33.2% at baseline to 80.8% (28.2) at week 12. The extracted text reports that mean (SD) percentage of heavy drinking days (HDDs) decreased from 56.2% (26.4) at baseline to an unclear value reported as ".2% (21.8)" at week 12; the follow-up value is not clearly reported in the extracted text. Alcohol biomarker data were broadly consistent with self-report: all six abstinent participants had CDT ≤0.8% on day 84, and participants who reported drinking had CDT ≥0.8% on day 84. Abstinent participants had EtG <60 μg/L at all post-dose assessments; among the remaining drinkers, the mean EtG on day 84 was reported as 42553.8 μg/L, and two participants had higher EtG at day 84 than at screening, mirroring increased drinking toward study end. Craving, mood and quality of life: Overall, baseline craving and withdrawal intensity were reported as mild and minimal, respectively. A single dose of 10 mg BPL-003 plus CBT was associated with reductions in self-reported alcohol craving and consumption over follow-up. On the EQ-5D-5L participants rated HRQoL as relatively high at baseline for mobility, self-care, usual activities and pain/discomfort, with about one third reporting slight or moderate anxiety/depression; EQ-5D domain scores did not change markedly over the study, but mean EQ-VAS rose numerically from 72.2 mm at baseline to 77.3 mm at day 84. Treatment expectations and acute psychedelic experience: Participants generally held positive treatment expectations predose, although the extracted text does not clearly report the numerical SETS positive-expectancy mean. The mean (SD) EDI score reported was 51.0 (24.2). One third of participants met criteria for a mystical experience on the MEQ-30 post dose; reductions in alcohol use were observed both in participants who did and did not report mystical experiences.

The authors interpret the findings as preliminary evidence that a single 10 mg intranasal dose of BPL-003 (5-MeO-DMT) administered with psychological support and followed by CBT was well tolerated and associated with sustained reductions in alcohol use over 12 weeks in a subset of participants. All reported TEAEs were mild or moderate, consistent with prior Phase I data, and there were no serious adverse events or drug-related withdrawals. Administration-site pain and transient blood pressure elevations were the most common drug-related events; blood pressure changes were short-lived and participants were generally ready for discharge about two hours after dosing. Reactivations (flashbacks) occurred in two participants (15.4%) and were described as brief and non-distressing; the authors note such events are recognised with 5-MeO-DMT and may sometimes be experienced positively. Regarding efficacy signals, the authors highlight three responder groups: continuous abstinence (6/12), meaningful reductions (3/12) and little or no change (3/12). Biomarkers (CDT, EtG) broadly corroborated self-reported TLFB data. While a third of participants had a mystical experience on the MEQ-30, reductions in drinking were also observed in those without mystical experiences, implying that therapeutic change may occur via multiple mechanisms (for example, enhanced psychological flexibility, mindfulness, neuroplasticity or anti-inflammatory effects), not solely via mystical-type experiences. The authors acknowledge important limitations: small sample size, a predominance of white male participants limiting generalisability, absence of a blinded or CBT-only control group (making it difficult to separate drug effects from psychotherapy and expectancy), and the single-dose design which does not address multi-dose safety or optimal dosing for long-term abstinence. They conclude that larger, randomised, controlled, and more representative trials are needed to establish efficacy and dosing strategies for BPL-003 in AUD.