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

Drug Alcohol Depend. 2021 Apr 1;221:108614. doi: 10.1016/j.drugalcdep.2021.108614. Epub 2021 Feb 15.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / blood
  • Cocaine-Related Disorders / drug therapy*
  • Cross-Over Studies
  • Double-Blind Method
  • Exenatide / pharmacology*
  • Female
  • Glucagon-Like Peptide 1 / blood
  • Glucagon-Like Peptide 1 / drug effects
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Humans
  • Incretins / pharmacology*
  • Insulin / blood
  • Islet Amyloid Polypeptide / blood
  • Islet Amyloid Polypeptide / drug effects
  • Male
  • Middle Aged
  • Self Administration
  • Treatment Outcome

Substances

  • Glucagon-Like Peptide-1 Receptor
  • Incretins
  • Insulin
  • Islet Amyloid Polypeptide
  • Glucagon-Like Peptide 1
  • Exenatide
  • Cocaine