Fentanyl and Xylazine Interactions: Toxicity Produced by "Tranq-Dope"

PROJECT SUMMARY Recently, both the Center for Disease Control and the US Drug Enforcement Administration identified xylazine-adulterated fentanyl as a significant public health threat; however, very little empirical research has been conducted on this drug combination. Forensic medical reports describe the increasing prevalence of these drugs in both fatal and nonfatal opioid overdoses, but we are not aware of any prospectively designed clinical studies describing the toxicity of these drugs. Complicating matters further, there are no pharmacological rescue interventions for this drug combination, other than anecdotal reports that naloxone is only minimally effective at reversing overdoses. A final complication is the emergence of new fentanyl analogues and new alpha 2 adrenergic (α2A) agonists in DEA seizures for which even less is known. The goal of this project is to collect data on this public health threat that will be of immediate use to clinicians, scientists, and public health officials. Aim 1 will quantify the interactions between intravenously administered mu opioid receptor (MOR) agonists and α2A agonists on measures of cardiorespiratory functioning (i.e., heart rate, respiratory rate, O2 saturation). Aim 2 will quantify the reversal of these cardiorespiratory effects by potential rescue medications comprising opioid and α2A receptor antagonists. Importantly, the interactions between several novel MOR and α2A agonists that have been identified in recent DEA seizures but have not yet been examined experimentally will be tested. This project should provide critical information to scientists and clinicians about the effects of fentanyl-xylazine interactions that contribute to lethal overdoses, as well as identifying potential rescue medications that may be examined in future clinical trials.