“Tranq-dope”, the combination of fentanyl, a synthetic mu-opioid receptor agonist, and xylazine, an alpha-2 adrenergic receptor agonist, was declared an emerging national health threat by the White House Office of National Drug Control Policy (White House, 2023). Xylazine is a veterinary anesthetic that is not approved for human use and has not been scheduled by the United States Drug Enforcement Agency (DEA). Thus, there are no human studies and few preclinical studies addressing the behavioral pharmacology, addiction liability, and functional dose range of this drug combination.

Self-reports of fentanyl and xylazine co-use among drug-using populations differ markedly across individuals. Some individuals report alteration of the experience of fentanyl following co-administration of xylazine, whereas others do not. Some people report unwilling and unknowing use of xylazine (Eger et al., 2024, Michaels et al., 2024, Spadaro et al., 2023), whereas others seek out this drug combination (Eger et al., 2024, Spadaro et al., 2023), reporting that xylazine lengthens fentanyl’s short duration of action (Edinoff et al., 2024). The extent to which xylazine enhances or prolongs the effects of fentanyl is an important consideration of the addiction liability of this drug combination relative to fentanyl alone.

The aim of the present study was to characterize the mu-opioid mediated discriminative stimulus effects of fentanyl-xylazine combinations. To this end, male and female rats were trained to discriminate the prototypical mu-opioid agonist, morphine, from saline, and substitution tests were conducted with fentanyl, xylazine, and fentanyl-xylazine combinations. Dose-response experiments and time-course experiments were conducted to determine the functional dose range of this drug combination and determine whether xylazine enhances or prolongs the mu-opioid mediated discriminative stimulus of fentanyl.