Cocaine (COC) use disorder (CUD) remains a significant medical, social, and legal concern. According to the 2019 National Survey on Drug Use and Health, approximately 1 million Americans meet the criteria for CUD. Behavioral therapies, such as cognitive-behavioral therapy (CBT), are the mainstay of current treatment approaches for CUD. However, because CBT alone has limited efficacy, the identification and development of pharmacotherapy that enhances the effectiveness of CBT is a high priority. Therefore, developing evidence-based interventions to reduce adverse outcomes associated with drug use and support the long-term recovery of people following treatment are top priorities for National Institute on Drug Abuse (NIDA) research. To that end, NIDA supports a dual strategy to accelerate medication development for CUD: (1) translating preclinical knowledge to target novel pathways and circuits and (2) repurposing medications already approved for other indications.

There is now substantial preclinical evidence that glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists attenuate behaviors that model both the consumption and seeking of highly palatable food and several commonly abused drugs, including alcohol, cocaine, and nicotine. The neurobiological mechanisms underlying food intake and drug-seeking overlap to a degree. Homeostatic and hedonic pathways regulate food intake. The homeostatic pathway regulates energy balance, while the hedonic pathway can override homeostatic regulation during periods of relative energy abundance, increasing the desire to consume highly palatable foods. In the homeostatic pathway, food intake stimulates the production and secretion of incretin hormones and satiation factors, like GLP-1, via both intestinal L-cells and neurons in the nucleus of the solitary tract (NTS). GLP-1-producing neurons of the NTS project to the arcuate nucleus (ARC) of the hypothalamus. In the ARC, GLP-1R activation suppresses feeding by activating anorexigenic neurons, which contain cocaine- and amphetamine-regulated transcript (CART), and inhibiting orexigenic neurons. NTS neurons also project to the ventral tegmental area (VTA), the nucleus accumbens (NAc), the laterodorsal tegmental nucleus (LDT), and the lateral septum. GLP-1 binding, messenger ribonucleic acid (mRNA), and immunoreactivity are detected in these same areas, as well as on VTA projections to the NAc and LDT projections to both the NAc and VTA. Direct activation of GLP-1R in the VTA,\[10\] NAc, LDT, or the lateral septum decreases palatable food intake, underscoring the critical role of GLP-1 in regulating the hedonic value of food.

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 placebo or extended-release (XR) exenatide (i.e., exenatide dose is a between-subject factor) 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, the investigators will determine COC (0, 20, 40 mg: IV) self-administration rates. To accurately predict clinical efficacy, the investigators will use forced-choice procedures in which participants choose to either self-administer COC or receive money.