Testing the effects of the GLP-1 receptor agonist exenatide on cocaine self-administration and subjective responses in humans with cocaine use disorder
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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.
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Although animal studies suggest an interference of GLP-1 receptor agonists with cocaine self-administration, this was not confirmed in a clinical trial with short-term exenatide administration.
“Although animal studies suggest an interference of GLP-1 receptor agonists with cocaine self-administration, 118 this was not confirmed in a clinical trial with short-term exenatide administration.119”
From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [119]
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- Authors
- Angarita, G. A., Matuskey, D., Pittman, B., Costeines, J. L., Potenza, M. N., Jastreboff, A. M., Schmidt, H. D., & Malison, R. T.
- Affiliations
- Yale University (US)
- University of Pennsylvania (US)
- Corresponding author
- Angarita, Gustavo A.
- ORCID
- Venue
- Drug and Alcohol Dependence
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 221
- Pages
- 108614
- ISSN
- 0376-8716 (ISSN-L)
- PMC
- PMC8026565
- OpenAlex
- W3131216226
- Cited by
- 75
- References
- 49
- Citations by year
- 2026: 24 · 2025: 24 · 2024: 11 · 2023: 5 · 2022: 7 · 2021: 4
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Drug and Alcohol Dependence (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- exenatide, GLP-1 receptor agonists, cocaine self-administration, cocaine dependence, subjective effects of cocaine, euphoria, glucagon-like peptide-1, insulin, amylin, pharmacological treatment of addiction
- MeSH terms
- Exenatide, Glucagon-Like Peptide-1 Receptor Agonists, Adult, Cocaine, Double-Blind Method, Female, Humans, Insulin, Male, Middle Aged, Self Administration, Treatment Outcome, Cross-Over Studies, Cocaine-Related Disorders, Glucagon-Like Peptide 1, Incretins, Islet Amyloid Polypeptide
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