Xylazine Reshapes the Sleep and Respiratory Consequences of Chronic Fentanyl Exposure in a Sex-Dependent Manner

The recent changes in the illicit drug supply have led to a rise in exposure to xylazine, but the long-term effects of combining fentanyl and xylazine are not well understood. This study examined the behavioral and molecular impacts of chronic fentanyl and xylazine use in male and female mice.

When fentanyl and xylazine were used together, they caused different, sex-specific changes in sleep patterns. These changes included alterations in the recovery of NREM sleep, the dynamics of REM sleep, and a shorter duration of sleep bouts compared to fentanyl alone. The 2-adrenergic receptor antagonist yohimbine helped to partly reverse these sleep changes, but only in a sex-dependent manner.

Furthermore, the combination of fentanyl and xylazine made respiratory depression worse than fentanyl alone, especially in male mice. Unlike with fentanyl, there were no skin lesions observed in the mice. The molecular analysis showed that co-administration of fentanyl and xylazine increased peripheral Fibroblast growth factor 21, a substance that is connected to reduced preference for opioids and lower alcohol consumption.

Overall, these findings show that xylazine greatly changes the physical and neurobiological consequences of long-term fentanyl exposure, and this alteration is different depending on the sex of the mice. This research provides a preclinical model to better understand the increasing public health issue of using fentanyl and xylazine together.