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Abstract

Opioid mixed with cocaine has been increasingly implicated in overdose deaths, including both intentional co-use of opioid and cocaine and fentanyl-adulterated drug supply. As ghrelin plays an important role in drug reward and can also influence insulin, this study aimed to assess responses of the circulating ghrelin, insulin, and glucose levels to the combined use of fentanyl and cocaine (a polydrug) in rats by performing combined animal behavioral experiments and biochemical analysis. The experimental data consistently revealed that the fentanyl and cocaine co-use can significantly elevate both the acyl-ghrelin and desacyl-ghrelin levels and significantly decrease the insulin level without significant effects on the glucose level. These findings suggest that, like cocaine itself, the fentanyl–cocaine polydrug can self-promote its rewarding effects via elevating the ghrelin level, and that the ghrelin system might serve as a potential pharmacological target for treatment of substance use disorders caused by polysubstance use involving fentanyl and cocaine. Additionally, based on the insulin data obtained in this study, the insulin level was always downregulated significantly and considerably, implying that the fentanyl and cocaine polydrug might have a stronger cardiovascular toxicity to the patients with insulin resistance and diabetes. Further studies are required to examine this possibility.

Document Type

Article

Publication Date

2025

Notes/Citation Information

© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.3390/ijms26052341

Funding Information

This work was supported by the National Institutes of Health (R01 DA056646, U18 DA052319, U01 DA051079, UH2/UH3 DA041115, UG3 NS134920, R01 DA035552, R01 DA032910, and R01 DA013930).

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