Testing the effects of the GLP-1 receptor agonist exenatide on cocaine self-administration and subjective responses in humans with cocaine use disorder

Abstract

Background: Preclinical rodent studies have demonstrated reduced cocaine taking after administration of glucagon-like peptide 1 (GLP-1) analogues. We investigated effects of a GLP-1 analogue (exenatide) on behavioral and subjective effects of cocaine in individuals with cocaine use disorder (CUD).

Methods: Non-treatment-seeking CUD subjects underwent two human laboratory cocaine self-administration test sessions following an acute 3 -h pre-treatment with exenatide (5 mcg; subcutaneously) or placebo. Primary outcomes consisted of infusions of cocaine and visual analog scale self-ratings of euphoria and wanting cocaine. Secondary outcomes consisted of pertinent hormone levels (GLP-1, insulin, and amylin).

Results: Thirteen individuals completed the study. Acute pretreatment with exenatide versus placebo did not change cocaine infusions (8.5 ± 1.2 vs. 9.1 ± 1.2; p = 0.39), self-reported euphoria (4.4 ± 0.8 vs. 4.1 ± 0.8; p = 0.21), or wanting of cocaine (5.6 ± 0.9 vs. 5.4 ± 0.9; p = 0.46). Exenatide vs. placebo reduced levels of GLP-1 (p = 0.03) and insulin (p = 0.02). Self-administered cocaine also reduced levels of GLP-1 (p < 0.0001), insulin (p < 0.0001), and amylin (p < 0.0001).

Conclusions: We did not find evidence that low dose exenatide alters cocaine self-administration or the subjective effects of cocaine in people with CUD. Limitations such as single acute rather than chronic pre-treatment, as well as evaluation of only one dose, preclude drawing firm conclusions about the efficacy of exenatide. Exenatide and cocaine independently reduced levels of GLP-1 and insulin, while cocaine also reduced levels of amylin.

Keywords: Addictive behaviors; Cocaine self-administration; Cocaine use disorder; Exenatide; GLP-1; Substance-related disorders.

Figure 1.. Study Design, Training, and Cocaine Sessions

1A: Subjects participated in 3 experimental, human laboratory, sessions. Sessions were separated by > 36 hours. 1B: The training session consisted of a safety-eligibility and a self-administration phase. The safety-eligibility phase consisted of a 60-minute, fixed-order, fixed-interval (FI; 20 min), ascending-dose regimen of three, sequential, intravenous (IV) cocaine boluses (4, 8, and 16 mg/70 kg). The self-administration phase consisted of a 90-minute period of self-regulated (“binge”), IV cocaine administration (16 mg/70kg/infusion) under a fixed-ratio 1, 5-min time-out (FR1:5minTO) schedule. 1C: Cocaine sessions were identical to the training session with the exception that they were preceded by pre-treatment with exenatide or placebo. As a result, the safety eligibility phase is called the Drug-Drug Interaction (DDI) phase.

Figure 2.. CONSORT Flow Diagram

Flow diagram of the progress from telephone screening to completion of study procedures

Figure 3.. Behavioral Effects

Number of infusions after acute pre-treatment with exenatide vs. placebo. Error bars represent standard errors of the mean.

Figure 4.. Subjective Effects

4A: Self-reported VAS scores for euphoria after acute pre-treatment with exenatide vs. placebo. Error bars represent standard errors of the mean. 4B: Self-reported VAS scores for wanting cocaine after acute pre-treatment with exenatide vs. placebo. Error bars represent standard errors of the mean.