Xylazine adulteration modulates heroin-induced behavioral responses

Introduction: The United States is currently facing a severe crisis involving opioids and opioid use disorder (OUD), which is characterized by compulsive use despite its harmful effects. The American Society of Addiction Medicine defines addiction as “a treatable, chronic medical disease involving complex interactions among brain circuits, genetics, the environment, and an individual’s life experiences.” In 2022, opioids were involved in 81.8% of 51,435 fatal overdose deaths in the U.S., and there were 96,332 reported non-fatal opioid overdose emergency visits based on CDC data. However, these figures, collected from only 30 states for fatal cases and 21 states for non-fatal cases, likely underestimate the true scale of the crisis. Compounding the epidemic is the growing concern over drug adulteration, particularly with xylazine, a veterinary anesthetic with no approved use in humans. Xylazine has been linked to severe side effects, including injection site lesions, respiratory depression, and other harmful physical effects. However, the impact of Xylazine adulteration on behavioral modalities is not clearly understood. Currently, there are no studies performed to examine how xylazine adulteration influences heroin-induced behavioral outcomes.

Methods: Adult Sprague-Dawley rats were tested in a self-administration paradigm to investigate the impact of xylazine adulteration preclinically. Subjects were divided into four groups: saline, heroin, xylazine, and a heroin-xylazine cocktail. Following jugular vein catheter implantation, rats selfadministered their assigned drugs for two hours daily over ten days. On the 11th day, a progressive ratio test measured motivation, followed by an extinction protocol (abstinence days 5-14) and a cue-induced reinstatement experiment on abstinence day 15.

Results: Rats in the heroin group exhibited significantly higher self-administration levels compared to the heroin-xylazine group despite showing similar motivation in the progressive ratio test. Cue-induced reinstatement revealed no differences in the extinction of drug-paired cues between the heroin and heroin-xylazine groups.

Conclusions: This suggests that xylazine adulteration may decrease active heroin-taking behavior while preserving opioid motivation comparable to heroin alone. It appears following cue-induced reinstatement that xylazine adulteration neither slows nor accelerates cue extinction. These compelling findings warrant further investigation into the neurobiological changes induced by xylazine in heroinexposed animals that drive these behavioral outcomes.