In April 2023, the United States Office of National Drug Policy, designated illicitly manufactured fentanyl (IMF) adulterated with xylazine (“tranq”) as an emerging public threat (Gupta, 2023). From January 2019 to June 2022, the monthly percentage of IMF and xylazine-related deaths rose 276% in the United States (Kariisa et al., 2023). Xylazine is an alpha-2 agonist that is structurally similar to clonidine and routinely used as a veterinary anesthetic, but unlike clonidine, xylazine currently has no medically approved human use (Nunez et al., 2021). The combination of xylazine with IMF is colloquially referred to as “tranq dope” (Friedman et al., 2022). People who use drugs report that xylazine gives fentanyl “legs” by potentially prolonging the fentanyl “high” and decreasing injection frequency, increasing the amount of sedation, and/or delaying opioid withdrawal signs (Friedman et al., 2022, Spadaro et al., 2023).

An emerging preclinical literature suggests that xylazine combined with fentanyl enhances some fentanyl pharmacodynamic effects. For example, xylazine and other alpha-2 agonists such as clonidine and medetomidine enhance the antinociceptive potency of fentanyl in rats (Meert and De Kock, 1994). Xylazine also potentiates the hypoxic effects of fentanyl (Choi et al., 2023) and enhances fentanyl-associated lethality in rodents (Acosta-Mares et al., 2023, Smith et al., 2023). However, recent rodent studies suggest that xylazine decreases fentanyl consumption in drug self-administration procedures (Khatri et al., 2023, Sadek et al., 2024) and morphine reward in a conditioned place preference procedure (Samini et al., 2008). Whether these xylazine effects on measures of fentanyl reward and reinforcement are due to generalized sedative or cognitive impairment effects of xylazine or selective for reward/reinforcement processes are unclear. Furthermore, potential pharmacokinetic interactions that might mediate these xylazine and fentanyl pharmacodynamic interactions remain unknown. Therefore, we examined whether xylazine pharmacodynamically or pharmacokinetically enhanced fentanyl reinforcement in a rat drug self-administration model. We utilized published behavioral economic methods and analyses to rigorously determine the reinforcing effects of fentanyl alone, xylazine alone, and a range of fixed-proportion fentanyl/xylazine combinations in male and female rats (Townsend et al., 2019).