Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone

Emma V. Frye; Lyndsay E. Hastings; Aniah N. Matthews; Adriana Gregory-Flores; Janaina C.M. Vendruscolo; Lindsay A. Kryszak; Shelley N Jackson; Aidan J. Hampson; Nora D. Volkow; Leandro F. Vendruscolo; Renata C.N. Marchette; George F. Koob

doi:10.1172/jci.insight.198059

Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone

Emma V. Frye,¹ Lyndsay E. Hastings,¹ Aniah N. Matthews,¹ Adriana Gregory-Flores,¹ Janaina C.M. Vendruscolo,¹ Lindsay A. Kryszak,² Shelley N Jackson,² Aidan J. Hampson,³ Nora D. Volkow,⁴ Leandro F. Vendruscolo,⁵ Renata C.N. Marchette,¹ and George F. Koob¹

Published February 3, 2026 - More info

View PDF

Abstract

The high frequency of opioid overdose deaths often involves co-use of alcohol, which is reported in approximately 30% of fentanyl fatalities. Both substances depress respiratory function, and their combined effects can be lethal. The present study investigated physiological parameters of respiratory-depressant effects of fentanyl when co-administered with alcohol and its sensitivity to naloxone reversal using whole-body plethysmography in male and female Long-Evans rats. Administration of a high, sedative-like dose of alcohol alone or fentanyl alone resulted in no mortality, but fentanyl+alcohol led to mortality rates of 42% and 33% in females and males, respectively. The fentanyl+alcohol combination reduced minute ventilation and increased apneic pauses compared with either drug alone. Lower, binge-like alcohol doses, when combined with fentanyl, also amplified respiratory depression. Pretreatment with naloxone did not fully restore normal respiration. Naloxone administered after fentanyl+alcohol transiently reversed the decrease in minute ventilation but did not reverse apneic pauses. Fentanyl-dependent rats were partially tolerant to fentanyl- and fentanyl+alcohol-induced respiratory depression, but alcohol-dependent rats exhibited sensitization to alcohol- and fentanyl+alcohol-induced apnea. These findings highlight physiological parameters of severe respiratory risks with fentanyl+alcohol co-use, which are inadequately reversed by naloxone, underscoring the need for targeted strategies to manage opioid+alcohol overdoses.

Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone

Emma V. Frye,¹ Lyndsay E. Hastings,¹ Aniah N. Matthews,¹ Adriana Gregory-Flores,¹ Janaina C.M. Vendruscolo,¹ Lindsay A. Kryszak,² Shelley N Jackson,² Aidan J. Hampson,³ Nora D. Volkow,⁴ Leandro F. Vendruscolo,⁵ Renata C.N. Marchette,¹ and George F. Koob¹

Article tools

Metrics

Go to

Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone

Emma V. Frye,1 Lyndsay E. Hastings,1 Aniah N. Matthews,1 Adriana Gregory-Flores,1 Janaina C.M. Vendruscolo,1 Lindsay A. Kryszak,2 Shelley N Jackson,2 Aidan J. Hampson,3 Nora D. Volkow,4 Leandro F. Vendruscolo,5 Renata C.N. Marchette,1 and George F. Koob1

Article tools

Metrics

Go to

Sign up for email alerts

Emma V. Frye,¹ Lyndsay E. Hastings,¹ Aniah N. Matthews,¹ Adriana Gregory-Flores,¹ Janaina C.M. Vendruscolo,¹ Lindsay A. Kryszak,² Shelley N Jackson,² Aidan J. Hampson,³ Nora D. Volkow,⁴ Leandro F. Vendruscolo,⁵ Renata C.N. Marchette,¹ and George F. Koob¹