Repurposing semaglutide as an adjunctive treatment for cocaine use disorder: protocol for a randomised controlled trial.

INTRODUCTION: Cocaine use disorder (CUD) is a significant public health concern in the USA, with considerable prevalence and mortality and no Food and Drug Administration (FDA)-approved pharmacotherapies. Recent advances in addiction science emphasise the need for novel, mechanism-based treatments. Glucagon-like peptide-1 receptor agonists, such as semaglutide, have shown promise in modulating reward-related behaviours and may offer therapeutic benefits for CUD. We present a study protocol evaluating semaglutide, as an adjunct to cognitive behavioural therapy (CBT), as a novel approach for treating CUD. METHODS AND ANALYSIS: This is a randomised, double-blind, placebo-controlled trial enrolling 75 treatment-seeking adults with CUD. Participants will be randomised 1:1 to receive either once-weekly semaglutide (0.25-1.0 mg) or placebo injections over 14 weeks, alongside weekly individual CBT. Primary outcomes include changes in neurophysiological reactivity to drug-related and non-drug-related motivationally relevant cues (late positive potential), behavioural economics (cocaine demand), craving (Cocaine Craving Questionnaire) and cocaine use (self-report, urine drug screens). Exploratory aims assess associations between mechanistic changes and cocaine use, consumption of other substances (ie, tobacco, alcohol and cannabis) and dose-response relationships. Data will be analysed using Bayesian statistical methods using an intention-to-treat approach. ETHICS AND DISSEMINATION: The study has been approved by the UTHealth Committee for the Protection of Human Subjects (HSC-MS-25-0412) and is registered on ClinicalTrials.gov. All participants will provide written informed consent. Findings will be disseminated through peer-reviewed publications and scientific conferences. TRIAL REGISTRATION NUMBER: NCT07227948.