NCT07227948

Repurposing Semaglutide for the Treatment of Cocaine Use Disorder

Repurposing Semaglutide for the Treatment of Cocaine Use Disorder: a Pilot Mechanistic Study

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 75 (estimated)
• Sponsor: The University of Texas Health Science Center, Houston · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The purpose of this study is to evaluate semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), in combination with cognitive behavioral therapy (CBT) for the treatment of cocaine use disorder (CUD). This project is part of the NIH Helping to End Addiction Long-term (HEAL) initiative (https://heal.nih.gov/).

Detailed description

The United States is facing a resurgence in cocaine use and cocaine-related mortality. Despite the significant public health burden, there are no FDA-approved pharmacotherapies for CUD, and existing behavioral interventions, such as cognitive behavioral therapy (CBT), demonstrate only modest efficacy when used alone. Identifying pharmacological agents that can enhance the effectiveness of behavioral treatments remains a critical public health priority. One particularly promising class of medications for CUD is glucagon-like peptide-1 receptor agonists (GLP-1RA). These agents are widely used to treat type 2 diabetes and obesity due to their ability to regulate blood glucose and support metabolic health. Importantly, GLP-1 receptors are expressed in brain regions involved in reward processing and hedonic behavior. Consistent with this, animal studies have shown that GLP-1RAs reduce the rewarding and reinforcing effects of various addictive substances, including cocaine. If similar effects are observed in humans, GLP-1RAs may improve treatment outcomes by directly reducing the motivational salience of cocaine and its cues, and/or by enhancing responsiveness to behavioral therapies such as CBT. The primary objective of this trial is to provide proof-of-concept evidence for the use of a GLP-1RA semaglutide as a treatment for CUD. The study hypothesizes that semaglutide will modulate three key reward-related target mechanisms underlying cocaine use: (1) motivational relevance of cocaine cues, assessed via event-related potentials (ERPs); (2) cocaine valuation, measured by behavioral economic demand for cocaine; and (3) subjective experience of craving. These mechanisms will be evaluated using a multimodal approach - neurophysiological, behavioral, and self-report- within a framework of a randomized clinical trial. In addition to assessing changes in the proposed target mechanisms, the study will evaluate the impact of semaglutide on cocaine use. This project addresses the urgent need to explore novel pharmacological targets using an experimental therapeutics framework and has the potential to accelerate the development of effective treatments for CUD. If successful, the findings will support a fully powered efficacy trial. Study data will be submitted to a HEAL Initiative-approved repository within the HEAL Data Ecosystem (NIDA Data Share), in accordance with NIH and HEAL initiative data-sharing requirements. Persistent identifiers, seeded with essential project metadata, will be generated. These identifiers with associated project metadata will be made publicly available. The data will be available at the time of publication or at the end of the project period. The data submission and release timeframes will be specified by the funding agency and policies, as described on NIH's data sharing webpage. Study data will be available to the research community for the duration required by NIDA's retention policies.

Conditions

• Cocaine Use Disorder

Interventions

Type	Name	Description
DRUG	Semaglutide	Participants will receive 14 weekly injections administered subcutaneously. Semaglutide will be initiated at a dose of 0.25 mg once weekly. After 4 weeks, the dose will be increased to 0.5 mg once weekly for an additional 4 weeks. Thereafter, the dose will be increased to 1 mg once weekly for 6 weeks
DRUG	Placebo	Sterile saline (0.9%) will serve as the placebo for semaglutide and will be administered subcutaneously once-weekly for 14 weeks. The placebo will be administered in the same blinded manner as semaglutide and will be volume-matched.
BEHAVIORAL	cognitive behavioral therapy (CBT).	Participants will receive fourteen weekly 1-hour sessions of individual cognitive behavioral therapy (CBT), an evidence-based behavioral therapy platform for evaluating pharmacotherapy for CUD. CBT focuses on (1) identifying situations that precipitate drug use and (2) preventing relapse by teaching cognitive and behavioral skills to reduce risk.

Timeline

• Start date: 2026-01-15
• Primary completion: 2029-01-28
• Completion: 2029-02-28
• First posted: 2025-11-13
• Last updated: 2026-03-19

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study