Single-dose psilocybin therapy for alcohol use disorder: Pharmacokinetics, feasibility, safety and efficacy in an open-label study

All ten participants completed the five-session therapy course. Pharmacokinetic analysis revealed marked between-participant variability in plasma psilocin concentrations after the single 25 mg dose: peak concentrations (Cmax) ranged approximately from 14 to 59 µg/L. Two participants were highlighted for atypical kinetics—one with a high Cmax and another with delayed absorption—yet neither showed divergent clinical outcomes. Temporal profiles of SDI closely tracked plasma psilocin concentration curves across participants, and the investigators modelled this relationship with a sigmoid Emax approach; the extraction does not report parameter estimates such as PPC50 or γ. Exploratory analyses suggested that mystical-type experiences were associated with sustained reductions in heavy drinking days, whereas plasma psilocin concentrations themselves did not appear to predict clinical improvement. Primary clinical outcomes showed statistically and clinically meaningful reductions in alcohol use over 12 weeks. Percentage heavy drinking days fell by 37.5 percentage points from baseline to week 12 (95% CI −61.1 to −13.9, p = 0.005; Cohen's d = 1.02). Drinks per day decreased by 3.4 units (95% CI −6.5 to −0.3, p = 0.035; Cohen's d = 0.71). Alcohol craving measured by PACS decreased markedly at week 1 (mean change −8.9 points, 95% CI −14.0 to −3.7, p = 0.003, Cohen's d = 0.97), with sustained reductions at week 4 (−5.9, 95% CI −10.56 to −1.23, p = 0.018, d = 0.77) and a borderline change at week 12 (−5.1, 95% CI −10.2 to 0.06, p = 0.052, d = 0.61). Self-efficacy increased substantially: +17.6 points at week 1 (95% CI 4.3 to 30.8, p = 0.015, d = 2.39), +18.7 at week 4 (95% CI 9.44 to 27.96, p = 0.001, d = 2.72), and +18.5 at week 12 (95% CI 9.34 to 27.65, p = 0.001, d = 2.67). Measures of trait mindfulness, psychological flexibility and depressive symptoms showed no significant change from baseline to week 12. Individual-level data indicated that nine of ten participants had significantly reduced drinks per day at week 4 and seven of ten maintained significant reductions at week 12. Safety and feasibility outcomes were favourable: there were no serious adverse events reported, cardiovascular monitoring (blood pressure and heart rate) alongside repeated blood sampling was feasible and well tolerated in this psychiatric patient group. The authors note that missing clinical outcome data were imputed using worst-observed values for those who relapsed, and missing PK/SDI values were carried forward, as reported in the methods.

Jensen and colleagues interpret the findings as evidence that a single fixed 25 mg psilocybin dose delivered within a structured therapeutic course is feasible, well tolerated and associated with reductions in alcohol consumption and craving over a 12-week follow-up in this small open-label sample of treatment-seeking adults with severe AUD. Pharmacokinetic analyses revealed notable inter-individual variation in psilocin exposure, but these differences did not appear to compromise safety or overall clinical response. The close temporal correspondence between plasma psilocin concentrations and subjective drug intensity supports the expected PK–PD coupling; however, plasma concentrations were not clearly linked to medium-term drinking outcomes in the exploratory analyses. The investigators situate their results within accumulating evidence that subjective, including mystical-type, experiences during psychedelic sessions may mediate therapeutic benefit; their exploratory analyses suggested an association between profound mystical-type experiences and sustained reductions in heavy drinking days. They also highlight the practical importance of demonstrating that repeated blood sampling for PK/PD work is feasible in an AUD clinical population, opening opportunities to investigate biological mechanisms such as neuroplasticity and inflammation in future work. Key limitations acknowledged by the authors include the small sample size, limited representation of women (two of ten), the open-label single-arm design without a control or placebo, potential selection bias from self-referral and elevated expectations due to media coverage, and consequent inability to draw causal inferences about efficacy. The authors therefore call for larger, randomised, placebo-controlled single-dose trials to confirm these preliminary findings and to clarify the roles of pharmacokinetics and subjective experience in clinical outcomes. The extracted text notes that such trials are underway.