Repurposing Semaglutide for the Treatment of Cocaine Use Disorder: a Pilot Mechanistic Study - PROJECT SUMMARY The United States is experiencing a resurgence in cocaine use and cocaine related mortality. In 2021, approximately 1.4 million Americans met criteria for cocaine use disorder (CUD) with cocaine involved in nearly 25,000 overdose deaths, a 22% increase since 2020. No FDA-approved pharmacotherapies for CUD exist, and traditional behavioral interventions such as cognitive-behavioral therapy (CBT) show modest treatment effects when used alone. Identifying pharmacological interventions to enhance the effectiveness of behavioral therapies remains a high priority area in NIDA’s Strategic Plan. A highly promising class of pharmacotherapies for CUD treatment is glucagon-like peptide receptor agonists (GLP-1RAs). These medications regulate blood glucose and facilitate other metabolic processes, making them effective treatments for type 2 diabetes and obesity. Importantly, GLP-1Rs are expressed in many brain regions, including the neural pathways associated with hedonic and reward-seeking behaviors. In animal studies, GLP-1RAs reduce cocaine self-administration, locomotor stimulation, conditioned place preference, and dopamine release in the nucleus accumbens. Clinical support for similar effects in humans would lead to enhanced treatment outcomes either directly by reducing the motivational effects of cocaine and cocaine cues and/or indirectly by enhancing response to therapies such as CBT. The primary objective of this R01 Stage IIA study is to provide initial proof-of-concept evidence for semaglutide, a GLP-1RA, as a treatment for CUD. We hypothesize that, mechanistically, semaglutide will modulate three key reward-related target mechanisms underlying cocaine use: motivational relevance of cocaine cues as measured by event-related potentials (ERPs); cocaine valuation as measured by behavioral economic demand for cocaine; and the subjective experience of craving. We will conduct a multimodal (neurophysiological, behavioral, self-report) assessment within the framework of a randomized clinical trial comparing 14 weeks of once-weekly semaglutide versus placebo, as an adjunct to CBT, among persons seeking treatment for CUD (N=75). In addition to modifying putative target mechanisms (Aim 1), semaglutide is expected to reduce cocaine use (Aim 2), potentially correlated with changes in target mechanisms (Aim 3). Beyond cocaine, we will explore off-target effects of semaglutide on alcohol, tobacco and marijuana consumption (Aim 4), and utilize semaglutide’s titration schedule from 0.25 mg/week to 1 mg/week to explore treatment effects at each level, toward identifying a minimal effective dose (Aim 5). This project responds to the urgent call for testing novel medication targets through an experimental therapeutics approach with the goal of identifying new purposes for approved medications. If successful, results will support a fully-powered efficacy trial, potentially marking a major breakthrough in medication development for CUD.
