Urgent need for reversal agents for xylazine and other imidazolines in illicit fentanyl.

The epidemic of illicit fentanyl use continues in the United States. Xylazine, a veterinary tranquilizer closely related to clonidine, is now a widespread adulterant in illicit fentanyl. More recently medetomidine (racemic version of dexmedetomidine) has appeared with increasing frequency in the fentanyl supply. Specific reversal agents for xylazine and medetomidine such as atipamezole and tolazoline have decades of approved use in animals and favorable experimental use in humans. However, an expert panel in 2024 opined that research into human use of alpha-adrenergic agonist was neither "necessary nor worthwhile". We disagree. We outline the unmet need for reversal agents for xylazine and medetomidine, discuss their human evidence of effectiveness, and suggest the path forward as the fentanyl epidemic continues to evolve.