PROJECT SUMMARY/ABSTRACT Cocaine (COC) use disorder (CUD) remains a significant medical, social, and legal public-health concern. Because behavioral therapies alone have limited efficacy, identification of pharmacotherapy that improves CUD treatment outcomes is sorely needed. Emerging preclinical evidence supports the potential clinical utility of stimulating the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) for treating CUD. Preclinical studies show that administration of a GLP-1R agonist attenuates COC self-administration, as well as COC-induced locomotor stimulation4, conditioned place preference, and dopamine release in the nucleus accumbens. Significantly, administering a GLP-1R agonist during abstinence following COC self-administration attenuated the reinstatement of drug-seeking behavior at doses that did not affect food intake or produce other adverse effects. Despite promising preclinical findings, and that COC administration significantly reduces serum concentrations of GLP-1 in humans, there has been only one human laboratory study in which administration of the GLP-1R agonist, exenatide, did not alter either the self-administration or subjective effects of COC in people with CUD. Multiple study limitations, including the use of an acute dose of exenatide rather than chronic pre-treatment, evaluation of only a single dose of COC, as well as the lack of both a placebo COC dose and an alternative to COC (i.e., a choice) in the free-access self-administration paradigm preclude drawing firm conclusions about the efficacy of exenatide for CUD. The overall objective of this application is to determine if GLP-1R agonism is a viable treatment strategy for CUD. This goal will be achieved through the conduct of a rigorous human clinical pharmacology study in which non-treatment seeking COC users (n=44) will be randomized (1:1) to a maintenance dose (0 mg (i.e., placebo) or 2 mg subcutaneously once a week) of extended-release (XR) exenatide for six weeks. The 6-week maintenance period, sufficient to achieve steady-state, will result in more stable concentrations of clinically effective doses before assessing treatment effects. Before and after the 6-week maintenance period, we will determine COC (0, 20, 40 mg: IV) self-administration rates. To accurately predict clinical efficacy, we will use forced-choice procedures in which participants choose to either self-administer COC or receive money. Our central hypothesis is that XR-exenatide will reduce COC self-administration compared to placebo. We expect that by (1) using a rigorous human laboratory experimental design, (2) testing treatment effects after achieving steady-state levels, and (3) employing appropriate endpoints for demonstrating treatment effectiveness in a laboratory setting, this project will provide definitive data regarding the potential of exenatide for reducing COC self-administration. The GLP-1R represents a substantial departure from previous treatment targets for CUD, and the drug-drug interaction safety data will provide the impetus for conducting a Phase II clinical trial. By repurposing an FDA-approved medication that does not have abuse potential, exenatide can advance through the development pipeline, thereby impacting clinical research and practice more quickly.

PROJECT NARRATIVE Cocaine (COC) use disorder (CUD) remains a significant concern for which there is no FDA-approved medication treatment. Preclinical studies provide ample support for the potential clinical utility of stimulating the glucagon- like peptide 1 (GLP-1) receptor (GLP-1R) to treat CUD. The design of the current human clinical pharmacology study will accurately predict the potential clinical efficacy of a GLP-1R agonist for reducing COC use.