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

Above: A figure from this paper. Below: Study authors Lyndsay Hastings*, Emma Frye*, Renata Marchette and George Koob

Featured Paper of the Month – June 2026

Published in JCI Insight by Lyndsay Hastings*, Emma Frye*, Renata Marchette and George Koob of the NIDA IRP Neurobiology of Addiction Section.

Summary

Alcohol use is reported in nearly 30% of fentanyl fatalities since both substances depress respiratory function—thus their combined effects can be lethal. In this study, we found that combining fentanyl and alcohol led to reductions in minute ventilation and severe apnea that were not fully reversed by naloxone. These findings improve our understanding of the role opioid/alcohol combinations play in overdoses, which advances research on preventing and reversing overdoses from poly-substance use.

Publication Information

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

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

In: JCI Insight, vol. 11, no. 6, 2026.

Abstract | Links

@article{10.1172/jci.insight.198059,

title = {Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone},

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

url = {https://pubmed.ncbi.nlm.nih.gov/41632547/},

doi = {10.1172/jci.insight.198059},

year  = {2026},

date = {2026-01-01},

urldate = {2026-01-01},

journal = {JCI Insight},

volume = {11},

number = {6},

publisher = {The American Society for Clinical Investigation},

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 coadministered with alcohol and their 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 plus 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}