Abstract
Alcohol use disorder is a major global health problem, and current treatments often fail to produce lasting reductions in harmful drinking1,2. Psychedelic-assisted therapies may promote durable behavioural change by enhancing brain plasticity during emotionally meaningful experiences, but progress has been limited by a lack of experimental models that capture these context-dependent effects3,4. Here we show that the ibogaine-derived compound oxa-noribogaine reduces alcohol consumption by strengthening learning from negative drinking outcomes in translational rat models of alcohol dependence. The compound produces sustained decreases in alcohol intake and relapse-like drinking, matches or exceeds the efficacy of its parent compound ibogaine, and does so without detectable motor or cardiac liabilities. These behavioural effects are associated with transient changes in prefrontal brain activity, lasting alterations in glutamatergic signalling after aversion-related learning, and normalization of neurotrophic signalling in cortico-striatal circuits. The therapeutic effects generalize across several translational models, genetically diverse animals and independent study sites. Together, these findings identify oxa-noribogaine as a promising and potentially safer treatment candidate for alcohol use disorder. More broadly, the results establish a preclinical framework for studying psychedelic-inspired therapies that harness context-dependent neuroplasticity to reduce compulsive substance use and support adaptive behavioural change.