In an open‑label Phase IIa trial (n-12), a single 10 mg intranasal dose of 5‑MeO‑DMT (BPL‑003) given alongside a 10‑week relapse‑prevention CBT programme was acceptable in safety and tolerability in people with moderate–severe alcohol use disorder. Over 12 weeks, participants showed large improvements in drinking (mean abstinent days rose from 33.2% to 80.8% and heavy drinking days fell from 56.2% to 13.2%), providing preliminary evidence of efficacy and supporting larger controlled trials.
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Garcia-Romeu, A., Davis, A. K., Fire Erowid et al. · Journal of Psychopharmacology (2019)
Background and Aims
Psychedelic drugs may help treat alcohol use disorder (AUD). This study evaluated BPL‐003, a novel intranasal powder formulation of 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT) benzoate salt, in people with moderate–severe AUD enrolled in a standard of care, 10‐week programme of relapse‐prevention oriented Cognitive Behavioural Therapy (CBT).
Design
Open‐label, phase 2a, single‐dose, clinical trial with 12‐week follow‐up (Day 84 endpoint) with a target of 12 participants.
Setting
Two clinics in England between 29 March 2023 and 2 July 2024.
Participants
Thirteen participants were enrolled. Most were male (n = 10; 76.9%), of White‐UK origin (n = 12; 92.3%), with a mean age of 49.3 years. Twelve participants completed the study (efficacy analysis set). Intervention Participants received a single intranasal dose of 10 mg BPL‐003 in a controlled environment with psychological support. Participants received three pre‐dose preparation sessions and three post‐dose integration sessions before CBT.
Measurements
Primary endpoints were safety and tolerability (by physical examination, laboratory evaluations, cardiac telemetry and treatment emergent adverse events [TEAEs]). Exploratory endpoints included Timeline Follow‐Back recording of alcohol use (abstinent days, units per day/week, heavy drinking days [HDDs; defined according to the UK government definition of binge drinking: ≥7 units per day women, ≥9 units per day men]) to Week 12 follow‐up (study endpoint); craving, alcohol‐related problems; and patient‐ and clinician‐reported measures of well‐being and health‐related quality of life (HRQoL).
Findings
Over 12 weeks, 41 TEAEs (all mild or moderate in severity) were reported by 11 of 12 (84.6%) participants (no TEAE‐related withdrawals). The most common TEAEs were study drug administration site pain (four participants; 30.8%); transient elevations in blood pressure after drug administration (four participants; 30.8%); and flashbacks (reactivations), nightmares, and nausea (two participants; 15.4%). At Week 12, the mean (standard deviation [SD]) percentage of abstinent days increased from 33.2% (22.8) at baseline to 80.8% (28.2) and HDDs reduced from 56.2% (SD 26.4) at baseline to 13.2% (SD 21.8). Six of 12 participants (50%) were continuously abstinent, three (25%) had meaningful reductions in alcohol consumption, and three (25%) had no change or a limited change in their drinking patterns. Overall, measures of the negative consequences of alcohol, craving, well‐being and HRQoL indicated improvement.
Conclusions
A first phase 2a clinical trial of 5‐methoxy‐N,N‐dimethyltryptamine (BPL‐003 10 mg) in the context of a 10‐week programme of CBT demonstrated acceptable safety and tolerability and provided preliminary evidence of efficacy for reducing alcohol craving and consumption. These findings support progression to larger, controlled trials of BPL‐003 for the treatment of alcohol use disorder.
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.
This was an open-label, phase 2a, proof-of-concept, two-centre clinical trial (). The CBT intervention, adapted for the trial, was developed by J.M., L.M., G.S., F.S. and M.K. and aligned with UK national clinical recommendations. The study was performed in accordance with the Declaration of
The study population consisted of adults (≥18-64 years) with moderate [4-5 criteria on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)] or severe AUD (≥6 criteria on DSM-5), a wish to receive CBT and a voluntarily stated goal to abstain or reduce harmful drinking. Participants were recruited to the study from each service or by community advertisement. The main inclusion criteria were: ≥4 heavy drinking days (HDDs) defined according to the UK government's definition of binge drinking [i.e. ≥7 standard units (≥56 g of ethanol) per day for women and ≥9 units (≥72 g of ethanol) per day for men in the 28 days before screening; for a 175 mL (13% alcohol by volume) glass of wine or one pint of 4% beer, a woman consuming ≥3 and a man consuming ≥4 of either drink on a single occasion would reach the threshold for this HDD criterion]and abstinence from alcohol for at least 24 hours before study drug administration. At the start of the study, eligibility for screening required completion of any medically supervised alcohol withdrawal management and ≥10 HDDs in the 28 days before screening, but this was amended to ≥4 HDDs to facilitate recruitment. The main exclusion criteria were: any medical condition that could risk harm of temporary blood pressure or heart rate elevations; regular or dependent use of non-medical drugs (excluding caffeine and nicotine); use of psychedelic compounds in the past 6 months; current suicidal ideation with intent; more than 14 days since last HDD; ≥1 HDD within 3 days before study drug administration; and a positive alcohol breath test before dosing (all inclusion and exclusion criteria in Table).
All participants completed a medical history and received a physical examination with an electrocardiogram (ECG). Clinical assessments included liver function tests, complete blood count, blood chemistry and coagulation and a urine drug test. A serum pregnancy test was completed for female participants. Psychiatric history was assessed using medical records and the Mini-International Neuropsychiatric Interview (MINI). The 10-item Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar)assessed alcohol withdrawal symptoms, with higher scores representing more severe symptoms. Suicide risk assessment was conducted via Columbia-Suicide Severity Rating Scale (C-SSRS).
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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.
Psychological support was provided before, during and after study drug administration, in accordance with established safety practices for psychedelic research. Tablelists all study assessments.
Over approximately 2 weeks before dosing, participants were invited to attend three approximately 90-minute sessions of pre-dose support, facilitated by two licensed psychological therapists, one with knowledge of and experience with delivering psychedelic therapy, the other with experience of treating AUD. The aim of the sessions was to familiarise the participant with the study drug and the setting for the dosing procedure; to discuss the participant's drinking history and goals; to practice guided breathing and visualisation exercises to be used to aid relaxation; to determine the participant's wishes regarding therapeutic touch; to manage expectations about the treatment; and to establish therapeutic alliance between the participant and therapists.
On arrival for the dosing session, participants completed a negative breath alcohol test and a single-item visual analogue scale (VAS) for desire for alcohol. During the dosing session, the same two psychological therapists were present in the room to provide nondirective support and reassurance (if requested by the participant), in a manner agreed and practiced during preparation. Reassurance was provided through verbal or non-verbal methods, including breathing with the participant or therapeutic touch (therapist's hand on the participant's forearm, with the participant uppermost so they could remove). At the time of dosing, participants were in a semi-supine position on a hospital bed. If the participant was in danger of falling, therapeutic touch (hand on the participant's shoulder) was applied to guide them back to bed. Readiness for discharge was assessed every 30 minutes, starting 90 minutes after dosing. If the VAS desire for alcohol score was at a greater level than the level recorded at admission, a 'talk down' procedure was conducted with the research team and the VAS was repeated until it was at a level that was lower or not greater. Participants were discharged into the care of a responsible adult to accompany them home.
During the approximately 2 weeks after dosing, participants were invited to attend three 60-minute sessions of integration support. During these sessions, the participant was encouraged to reflect on their experience and integrate any insights from the dosing session to their present circumstances.
Participants were subsequently invited to attend 10 × 60-minute weekly sessions of individual CBT with the AUD therapist. These sessions were guided by a collaborative psychological formulation of AUD, leveraged any insights from the dosing session and included self-monitoring, cognitive restructuring and behavioural experiments (targeting AUD-related beliefs, emotions and behaviours).
The primary aim of the study was to assess the safety [assessed by medical risk and evidenced by physical examination, clinical laboratory evaluations, vital signs and cardiac telemetry during dosing and adverse events (AEs)] of a single intranasal dose of the study drug and evaluate the negative impact of any side effects (tolerability). AEs were reported throughout the study and were coded using the Medical Dictionary for Regulatory Activities (MedDRA), rated for severity and judged for likely relationship to study drug. An AE that emerged during treatment (having been absent before treatment), or worsened after treatment, was defined as a treatment-emergent AE (TEAE).
Alcohol use. The field-standard, Timeline Follow-Back (TLFB) structured interview procedure was administered at baseline (covering the 12 weeks preceding enrolment) and at each follow-up visit to yield a day-to-day record to the day 84 study endpoint. TLFB data yielded the following summative measures: number of drinking days; number of abstinent days; longest continuous number of abstinent (days); number of days to first drink after dosing; number of days after dosing to first HDD; number and percentage of HDDs; units per week; units per day; and maximum number of units consumed on any one day. Biomarkers. Carbohydrate-deficient transferrin (CDT) and urine ethyl glucuronide (EtG)-biomarkers of chronic and acute alcohol consumption, respectively-were assessed at screening and on days -3, 28 and 84 (CDT) and days 1, 28, 56 and 84 (EtG). Alcohol craving and alcohol-related problems. Alcohol craving was assessed using the Alcohol Craving Questionnaire Short Form Revised (ACQ-SF-R) and a single-item VAS. The ACQ-SF-R is a 12-item scale of compulsivity, expectancy, purposefulness and emotionality-related aspects of craving in the current context. Each item is rated on a 7-point scale ranging from 'strongly disagree' to 'strongly agree', with higher scores indicating higher alcohol cravings. The VAS was a rating of desire to drink alcohol now, recorded by marking a position on a 100 mm line (0 mm, 'no desire at all'; 100 mm, 'extremely high desire'). The 15-item Short Inventory of Problems (SIP) was used to measure consequences of alcohol use, with higher scores indicating more problems relating to alcohol use. Well-being and health-related quality of life. Well-being was assessed via the participant-rated Patient Global Impression of Change (PGIC) and the investigator-rated Clinical Global Impression of Severity (CGIS). The PGIC is a 7-item scale that rates total improvement reported by the participant (1, 'very much improved'; 7, 'very much worse'), regardless of whether the improvement is because of drug treatment. The CGIS is a 7-point scale of disease severity based on observed and reported symptoms, behaviour and function. Changes in mood were evaluated using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS), with higher scores indicating more severe depression. Participants' self-reported health-related quality of life (HRQoL) was measured using the 5-level EuroQol-5 Dimension (EQ-5D-5L). The EQ-5D assesses mobility, self-care, usual activities, pain/ discomfort and anxiety/depression. The instrument also contains an EQ-VAS, where the participant selects a number between 1 and 100 to describe the current condition of their health, with 100 being the best imaginable. Treatment expectations and psychedelic experience. Participant expectancy before initiating treatment was assessed via the Stanford Expectations of Treatment Scale (SETS), a 6-item scale of positive and negative expectancies for study interventions. The Mystical Experience Questionnaire (MEQ-30)and the Ego Dissolution Inventory (EDI)were administered post dose to evaluate these aspects of the acute subjective experiences. The MEQ-30 includes 30 mystical, positive mood, transcendence of time and space and ineffability experiences, and it requires participants to rate the degree to which they experience each one on a 6-point scale. The EDI comprises eight statements that participants rate using a VAS (0, 'no, not more than usually'; 100, 'yes, entirely or completely'). Higher scores on the MEQ-30 and EDI indicate more extreme experiences.
Similarly to other pilot trials of psychedelics, a target of 12 participants was judged sufficient to detect common drug-induced safety events in this patient population and, therefore, address the aims of the study. There was no statistical power calculation given the exploratory nature of the study and no null-hypothesis statistical testing. The safety analysis set was defined as those participants who received the study drug and for whom a post-dose pharmacokinetics measure was available. The efficacy analysis set was defined as the safety analysis set where there was also at least one efficacy measure available. SAS Version 9.4was used to obtain descriptive statistics with SD for means. Participant-level daily use of alcohol to day 84 follow-up was visualised by a heatmap.
Between 29 March 2023 and 2 July 2024, 22 potentially eligible participants were identified, of which nine were excluded before screening, most commonly because of failure to meet the inclusion/ exclusion requirements of the study (Figure). Thirteen participants were enrolled and included in the safety analysis set. All met the criteria for severe AUD at baseline. Most participants were male [n = 10 (76.9%)] and white [n = 12 (92.3%)], and mean age was 49.3 years (range = 27-62 years) (Table). Of the 13 participants enrolled, one participant withdrew from the study after a suspected malfunction of the intranasal spray device, and they declined to participate in postdose efficacy assessments. Twelve participants were, therefore, included in the efficacy analysis set. Eleven of the 12 participants attended all scheduled CBT sessions.
During BPL-003 dosing, transient increases in systolic blood pressure occurred, peaking at approximately 10 minutes and returning to the a Initially the study protocol eligibility criteria required at least 10 HDDs in the 28 days before screening; however, it was established that participants who met this inclusion criteria generally had exclusionary criteria related to their physical health. Therefore, the protocol was amended to require at least four HDDs in the 28 days before screening. Eleven (84.6%) of 13 participants in the safety analysis set reported at least one TEAE (Table), with a total of 41 TEAEs reported (22 mild; 19 moderate). One participant (7.7%) experienced mild suicidal ideation, which was judged unrelated to the study drug. No participants were withdrawn from the study because of TEAEs. A summary of TEAEs by system organ class and preferred term is shown in Table, and details of drug-related TEAEs are provided in Table. Most TEAEs occurred on the day of dosing, and participants recovered from the effects of the study drug within a short time frame. The most frequently occurring drug-related AEs were drug administration site pain in four (30.8%) participants, transient elevations in blood pressure in four (30.8%) participants, nightmares in two (15.4%) participants and vomiting in two (15.4%) participants (Table). Of the four participants who experienced administration site pain, nasal pain began within 30 minutes of dosing and lasted 40 to 195 minutes. Two (15.4%) participants reported re-experiencing certain elements of the drug-induced state after the drug effects had worn off (reactivations). These experiences were coded as flashback AEs. On waking during two nights in the week following dosing, one participant described seeing lights and experiencing non-distressing, fleeting physical sensations, which they associated with BPL-003. The other participant reported a single event 22 days after dosing, in which they felt they could see inside their body while in the bath. The event T A B L E 1 Baseline characteristics (safety analysis set). lasted approximately 2 minutes and resolved completely. Both participants were aware of their surroundings during the reactivation events.
All TLFB measures were reduced over the 12-week follow-up period (Table; Figuresand). The alcohol biomarker analysis showed that all six abstinent participants had CDT levels ≤0.8% on day 84, and all participants who reported drinking during the follow-up period had CDT levels ≥0.8% on day 84. Abstinent participants had EtG < 60 μg/L at all post-dose assessments, as did one participant who reported drinking on 1 day only during the follow-up period. For the remaining five participants who reported drinking, the mean EtG on day 84 was 42553.8 μg/L. Two participants had higher EtG levels at day 84 than at screening. This was reflective of the TLFB results, which showed that both reported increased drinking toward the end of the study. Overall, during the 12-week follow-up, six of the 12 participants (50%) in the efficacy analysis set were continuously abstinent, three (25%) had meaningful reductions in alcohol consumption, and three (25%) had no change or a limited change in their drinking patterns (Figure). At week 12, the mean (SD) percentage of abstinent days increased from 33.2%at baseline to 80.8% (28.2) and the mean (SD) percentage of HDDs reduced from 56.2% (26.4) at baseline to.2% (21.8) (Table). Anxiety 1 (7.7)Depersonalisation/derealisation disorder 1 (7.7)Dissociation 1 (7.7)Fear 1 (7.7)Panic reaction 1 (7.7)Sleep disorder 1 (7.7)General disorders and administration site conditions, total no. of participants 6 (46.2) Administration site pain 4 (30.8)Administration site discomfort 1 (7.7)Administration site erythema 1 (7.7)Fatigue 1 (7.7)Investigations, total no. of participants 4 (30.8) Blood pressure increased 4 ( Nervous system disorders, total no. of participants 2 ( Paraesthesia 1 (7.7)Gastrointestinal disorders, total no. of participants 2 (15.4) Vomiting 2 (15.4)Nausea 1 (7.7)Cardiac disorders, total no. of participants 1 ( Respiratory, thoracic and mediastinal disorders, total no. of participants 1 ( Note: Participants with >1 TEAE are counted only once per system organ class and preferred term. Abbreviations: n, number of participants; TEAE, treatment-emergent adverse event. T A B L E 4 Summary of exploratory efficacy outcomes (efficacy analysis set). On the EQ-5D-5L, participants rated their HRQoL high at baseline with regard to their mobility, self-care, usual activities and levels of pain or discomfort (Table), however, approximately a third of participants said they were slightly or moderately depressed or anxious. EQ-5D-5L scores did not differ greatly during the study, although there was a numerical increase in mean (SD) score for the EQ-VAS from 72.2 mm at baseline to 77.3 mm at day 84.
Overall, participants had positive expectations of treatment; at predose (day -7), the mean (SD) SETS score for positive expectancy was). The mean total EDI score was 51.0 (SD = 24.2) (Table).
In this first proof-of-concept, open-label, phase 2a clinical study of 5-MeO-DMT administered alongside a course of CBT for AUD, a single intranasal dose of 10 mg BPL-003 was well tolerated, and there was evidence of sustained reductions in alcohol use over the 12-week follow-up period. These are encouraging findings that add to the growing body of evidence of psychedelic-assisted treatment for AUD. All TEAEs were mild or moderate and generally consistent with results reported in the phase 1 BPL-003 clinical trial in healthy volunteers. There were no serious AEs or TEAEs leading to withdrawal from treatment. Administration site pain and elevations in blood pressure were the most common drug-related AEs, and blood pressure elevations were transient and generally mild. Most AEs took place on the day of dosing, and participants recovered from the acute effects of BPL-003 within a short time frame and were assessed as ready for discharge approximately 2 hours post dose. Our findings align with the previously reported safety and tolerability outcomes during the acute experience of 5-MeO-DMT dosingand were mitigated by measures such as psychological support and a controlled environment. Reactivations (coded in MedDRA as flashbacks) to the druginduced state are a well-described phenomenon with 5-MeO-DMTand occurred in two participants (15.4%) in the present study. One participant reported a single moderate reactivation 3 weeks post dose and the other reported mild reactivations in the week after dosing. Although reactivations were categorised as AEs in this study, there is evidence to suggest they are often perceived as positive or neutral experiences that may contribute to the therapeutic benefit of the drug. The alcohol use results from the TLFB showed three distinct groups of responders. Over the 12-week study period, six participants remained completely abstinent, while three had meaningful reductions in alcohol consumption and three had no change or a limited change in drinking patterns. Alcohol biomarker data were consistent with TLFB findings, suggesting that reporting of alcohol use by participants was generally accurate. Drinking, craving and withdrawal assessments showed that, overall, the intensity of cravings or urges for alcohol at baseline were mild and symptoms of alcohol withdrawal at baseline were minimal. However, a single dose of 10 mg BPL-003 in combination with CBT was associated with a reduction in alcohol craving and consumption, providing preliminary evidence of efficacy for treating adults with AUD. Generally, participants in this study had positive expectations of treatment before dosing, as assessed by SETS scores. Chronic substance use can lead to neuroadaptive changes, including impulsive behaviour and dopamine downregulation, which can further perpetuate the disorder. Psychedelic-assisted treatment may enhance learning and help people develop new coping strategies, increasing the chance of recovery. Therefore, pre-existing motivation to at least reduce alcohol use could be an important ethical factor to consider in this population. However, the sample size was too small to draw meaningful conclusions about how expectations related to changes in alcohol consumption during the follow-up period. F I G U R E 4 PGIC scores at days 28, 56 and 84 following administration of BPL-003. The PGIC is a 7-item scale that rates total improvement reported by the participant, ranging from '1 = very much improved to 7 = very much worse', regardless of whether the improvement is because of drug treatment. Throughout the study, no participants reported PGIC scores >3 ('minimally improved'). PGIC, patient global impression of change. Psychedelic experience was assessed using the MEQ-30, with a third of the study participants reporting a mystical experience, however, not all participants with mystical experiences experienced reductions in alcohol use. Although drug-occasioned mystical experiences are hypothesised to be a mediating mechanism underlying the therapeutic effects of psychedelics, in this study, reductions in alcohol use were observed in participants who did not have a mystical experience, suggesting that change also occurs through other mechanisms. Other potential 5-MeO-DMT mechanisms of action include increases in psychological flexibility, mindfulness, neuroplasticity and antiinflammation. Our findings can be considered alongside other classical psychedelics. Bogenschutz et al.carried out a small study (n = 10) followed by a randomised, placebo-controlled trial (n = 95) of psilocybin in adults with AUD in the United States (US), reporting that the treatment had a positive impact on HDDs and abstinence. In these studies, HDDs were evaluated based on the US definition, which is similar to the UK definition used in the present study. More recently, two phase 2 studies of psilocybin (25 mg) in combination with brief psychotherapy showed contrasting results. In Reiser et al., a single dose of psilocybin combined with five psychotherapy sessions was insufficient to reduce relapse rates and alcohol use in severely affected AUD patients (n = 37). However, in Jensen et al., a single dose of psilocybin was shown to be safe and effective in participants with severe AUD (n = 10), mediating significant reductions in alcohol consumption (P < 0.005). Other interventions, including the N-methyl-D-aspartate receptor antagonists ketamine and ibogaine-commonly referred to as non-classic psychedelicshave also shown promise in AUD. Grabski et al.reported that three weekly ketamine infusions were associated with significantly more days of abstinence, compared with placebo, over a 6-month period (n = 96). Although demonstrating the potential of BPL-003 for use in AUD, this study has limitations, including small sample size and a study population of predominantly white males, which is not representative of the ethnic diversity seen in the AUD population in the United Kingdom. The lack of a CBT-only control group or blinding makes it difficult to separate the effects of the drug from that of CBT. This is a potential source of bias influencing both objective and subjective outcomes. As the first clinical trial of 5 MeO-DMT in this patient population, a single-dose study design was considered appropriate for initial safety evaluation, however, further studies will be needed to investigate the safety and efficacy of multiple doses over a longer treatment period. Because of these limitations, it is not possible to infer the generalisability of the effects of BPL-003. However, over the 12-week follow-up period, the observed clinical improvements suggest that BPL-003 with psychological support and CBT may achieve clinically meaningful benefits for some people with AUD. To better determine the efficacy of BPL-003 in AUD, future trials should be suitably powered, randomised, controlled, representative of the patient population and designed to establish the optimal dosing strategy for longterm abstinence.