Xylazine does not enhance fentanyl reinforcement in rats: a behavioral economic analysis

Abstract

The adulteration of illicit fentanyl with the alpha-2 agonist xylazine has been designated an emerging public health threat. The clinical rationale for combining fentanyl with xylazine is currently unclear, and the inability to study fentanyl/xylazine interactions in humans warrants the need for preclinical research. We studied fentanyl and xylazine pharmacokinetic and pharmacodynamic interactions in male and female rats using drug self-administration behavioral economic methods. Fentanyl, but not xylazine, functioned as a reinforcer. Xylazine combined with fentanyl resulted in a xylazine-proportion dependent depression of behavior without significantly altering fentanyl reinforcement. Fentanyl and xylazine did not result in changes to pharmacokinetic endpoints. The present results demonstrate that xylazine does not enhance the addictive effects of fentanyl or alter fentanyl plasma concentrations. As there appears to be no pharmacologic rationale for their use in combination, these preclinical results suggest that the fentanyl/xylazine combinations may represent a novel form of chemical warfare.