Xylazine potentiates the lethal but not the rewarding effects of fentanyl in mice

Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism

“…Preclinical veterinary research has largely focused on xylazine’s sedative effects in combination with ketamine [ 22 , 23 ], and few studies have investigated xylazine alone or in the context of reward learning [ 24 – 26 ]. Additionally, these studies did not account for locomotor effects and the potential sedation induced by α 2 -AR agonists which could impede learning mechanisms in rodent models.…”

Evaluation of a hapten conjugate vaccine against the “zombie drug” xylazine

“…6 Examining lethality, fentanyl–xylazine drug combinations produced synergistic interactions represented by a decrease in the median lethal dose (LD 50 ) of each drug in the presence of the other in animal studies. 7,8 Additionally, worsening brain hypoxia has been proposed as one of the possible mechanisms contributing to xylazine-positive opioid-overdose deaths. 9 Perhaps more perplexing has been xylazine's ability to cause conspicuous wounds that are distinct from typical fentanyl injection site lesions.…”

“…13 Yet, despite the existence of α2-adrenergic receptor antagonists such as yohimbine, studies have shown that these drugs are not effective in preventing fentanyl–xylazine lethality. 7,8 This ineffectiveness may arise from the mutual allosteric modulation between adrenergic and opioid molecules and receptors. 14–16 Ultimately, the intricate interplay between opioids and the adrenergic system poses daunting challenges for a small molecule combatting xylazine related overdose.…”