1 Research Centre, Centre Hospitalier de l'Universite de Montreal, Montreal, Québec, Canada.
2 Department of Psychiatry and Addictology, Université de Montréal, Montreal, Québec, Canada.
3 Department of Psychology, Concordia University, Montreal, Québec, Canada.
4 McGill Group for Suicide Studies, McGill University & Douglas Mental Health Research Institute, Montreal, Québec, Canada.
5 CISSS des Laurentides, Saint-Jérôme, Québec, Canada.
6 Department of Mental Health, Quatuor MD, Montreal, Québec, Canada.
7 Department of Psychology, Université de Sherbooke, Sherbrooke, Québec, Canada.
8 Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA.
9 Centre de recherche, Centre Hospitalier de l'Universite de Montreal, Montreal, Québec, Canada.
10 Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Québec, Canada.
11 Department of Psychiatry, McGill University, Montreal, Québec, Canada.
12 Research Centre, Centre Hospitalier de l'Universite de Montreal, Montreal, Québec, Canada nicolas.garel@umontreal.ca.
13 Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA.

Background: Alcohol use disorder and treatment-resistant depression (TRD) often co-occur, presenting a major clinical challenge with limited effective treatments. However, ketamine produces rapid antidepressant effects and has shown promise in reducing alcohol use, and acceptance and commitment therapy (ACT) can be effective for both substance use and mood disorders. This study explores the feasibility and acceptability of combining ACT with ketamine within the framework of the Montreal Model-a structured, integrative psychedelic ketamine therapy developed for severe TRD.

Methods and analysis: This study is a single-group, open-label feasibility trial at the Centre hospitalier de l'Université de Montréal (CHUM) Neuromodulation Ketamine Clinic in Montreal, Canada. 30 participants diagnosed with both alcohol use disorder and treatment-resistant depression will receive eight weekly in-person or virtual ACT sessions in addition to six intravenous ketamine infusions. The primary outcome is feasibility, assessed through study completion and protocol adherence. Secondary outcomes include recruitment rate, tolerability, safety, data completeness and healthcare resource use. Exploratory measures will examine changes in depressive symptoms, alcohol use and quality of life using validated tools. A subset of participants will participate in semistructured qualitative interviews to explore their experiences.

Ethics and dissemination: This study was approved by the ethics committee of the CHUM on 14 May 2025. The results of the trial, including primary and secondary outcomes, will be published in peer-reviewed scientific journals.

Trial registration number: NCT06620276.