Semaglutide to be evaluated as adjunctive therapy for cocaine use disorder in a randomized controlled trial

Cocaine use disorder (CUD) remains a significant public health challenge in the USA, marked by high prevalence and mortality, yet lacking any FDA-approved pharmacotherapies. Current addiction science emphasizes the need for novel, mechanism-based treatments. Glucagon-like peptide-1 receptor agonists (GLP-1R agonists) like semaglutide have demonstrated potential in modulating reward-related behaviors, suggesting a possible therapeutic role for CUD by influencing dopamine pathways and reward circuitry.

This paper outlines the protocol for a randomized, double-blind, placebo-controlled trial enrolling 75 treatment-seeking adults diagnosed with CUD. Participants will be randomized 1:1 to receive either once-weekly semaglutide (titrated from 0.25 mg to 1.0 mg) or placebo injections over 14 weeks. All participants will concurrently engage in weekly individual cognitive behavioral therapy (CBT). Primary outcomes include changes in neurophysiological reactivity to drug cues (measured by late positive potential), behavioral economics (via cocaine demand), craving (using the Cocaine Craving Questionnaire), and objective cocaine use (assessed by self-report and urine drug screens).

This publication is a study protocol, detailing the design and planned methodology for a randomized controlled trial, rather than presenting completed findings. The trial aims to evaluate the efficacy of semaglutide as an adjunctive treatment for cocaine use disorder. Researchers will analyze primary outcomes including changes in neurophysiological reactivity to drug-related and non-drug-related motivationally relevant cues, specifically focusing on the late positive potential (LPP) as a biomarker of attentional bias. They will also measure shifts in behavioral economics related to cocaine demand, assess subjective craving using the Cocaine Craving Questionnaire, and objectively quantify cocaine use through self-report and urine drug screens. Exploratory aims include investigating associations between mechanistic changes and cocaine use, evaluating consumption of other substances (tobacco, alcohol, cannabis), and characterizing dose-response relationships. Bayesian statistical methods will be employed for data analysis using an intention-to-treat approach. The study is currently recruiting, with results anticipated following its completion in 2029.