Molecular psychiatry
June 1, 2026
Charles F Zorumski, Joseph Cichon, Yukitoshi Izumi et al.
5 citations
Nitrous oxide (N2O), an inhalational anesthetic used for over 150 years, shows rapid and durable antidepressant effects in patients with major depressive disorder and treatment-resistant depression, according to recent clinical trials. Like ketamine, N2O inhibits N-methyl-D-aspartate receptors (NMDARs) but through distinct mechanisms. Cellular and neuronal circuit studies are early but suggest N2O shares some downstream mechanisms with ketamine while also having unique effects on neurophysiology and signaling. Human neuroimaging studies have begun identifying acute and persisting effects of N2O on brain circuits relevant to antidepressant responses. This review highlights current clinical and preclinical research, major unanswered questions, future directions, and potential barriers to clinical use.
medRxiv : the preprint server for health sciences
August 17, 2024
Charles R Conway, Ben Julian A Palanca, Thomas Zeffiro et al.
preprint
Nitrous oxide (N2O) reduces functional connectivity in mood-related brain networks in people with treatment-resistant major depression (TRD) but increases connectivity in healthy controls. In a crossover trial, 14 TRD patients and 16 healthy controls received one-hour inhalations of 50% N2O or placebo. Resting-state fMRI scans before, 2 hours, and 24 hours after inhalation showed that N2O progressively decreased connectivity in TRD patients across five brain networks (salience, default mode, reward, cingulo-opercular, and the dorsal nexus), while increasing connectivity in controls. The findings suggest N2O's antidepressant effects involve specific alterations in depressed brains.
Biological psychiatry global open science
October 1, 2023
Ben Julian A Palanca, Charles R Conway, Thomas Zeffiro et al.
In healthy volunteers, a single 1-hour inhalation of 50% nitrous oxide produced changes in brain connectivity that lasted at least 24 hours. Using resting-state functional MRI, the study found increased global connectivity in the occipital cortex at 2 and 24 hours after inhalation, particularly between the visual network and the dorsal attention network. Weaker connectivity changes were observed between the visual cortex and frontoparietal and default mode networks. No significant connectivity changes followed inhalation of air/oxygen. These persistent cortical effects suggest nitrous oxide induces neurophysiological changes beyond its acute psychotropic effects.