Reinforcing effects of fentanyl/xylazine mixtures in monkeys responding under a food-versus-drug choice procedure.

Overdose deaths involving opioids and xylazine, a nonopioid adulterant with sedative, analgesic, and muscle-relaxant properties, have increased dramatically over the past decade. Anecdotal reports suggest xylazine enhances some effects of opioids; however, motivations for their co-use remain unclear. This study examined the reinforcing effects of fentanyl/xylazine mixtures in nonhuman primates responding under a food-versus-drug choice procedure. Rhesus monkeys ( n  = 4) responded under a concurrent schedule where responding on one lever delivered a sucrose pellet while responding on the other lever delivered an intravenous infusion of fentanyl (0.032-1.0 µg/kg/infusion) alone or in combination with xylazine (1.0-100 µg/kg/infusion). Unit dose of drug increased across blocks within each session, and the ratio of xylazine to fentanyl (10 : 1, 32 : 1, 100 : 1, and 320 : 1) varied across conditions. Choice of infusions increased and choice of food decreased with increasing unit dose of fentanyl, whether available alone or in combination with xylazine. Xylazine increased the choice of otherwise ineffective doses of fentanyl, resulting in a shift in the fentanyl dose-effect curve leftward 2- to 6-fold across monkeys. Combining xylazine with relatively small doses of fentanyl increased choice of infusions over food compared with fentanyl alone. These data suggest that xylazine enhanced the potency (and possibly effectiveness) of fentanyl to function as a reinforcer, which might contribute to increased potential for abuse.