Molecular Psychiatry
June 1, 2026
Charles F Zorumski, Joseph Cichon, Yukitoshi Izumi et al.
5 citations
The success of ketamine, a dissociative anesthetic and non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, as a rapidly acting antidepressant has ignited efforts to identify other novel depression treatments. In recent years, several clinical trials indicated that nitrous oxide (N2O), an inhalational dissociative anesthetic in clinical use for over 150 years, also has rapid and...
Biological Psychiatry Global Open Science
July 1, 2025
Paul S Myles, Jayashri Kulkarni, Jessica Kasza et al.
Nitrous oxide ("laughing gas") is an NMDA receptor antagonist. In the current study, our aim was to investigate the efficacy, safety, and likely optimal dose of nitrous oxide in adults with major depressive disorder (MDD). In this phase 2b randomized, double-blind trial, 81 patients with MDD were allocated on a 1:1 basis to receive nitrous oxide or oxygen/air (control); the nitrous group was...
Nature Communications
April 3, 2025
Joseph Cichon, Thomas Joseph, Xinguo Lu et al.
Nitrous oxide (N2O) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N2O induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions. N2O-induced L5 activation rescues a stress-associated...
medRxiv : the preprint server for health sciences
August 17, 2024
Charles R Conway, Ben Julian A Palanca, Thomas Zeffiro et al.
preprint
While nitrous oxide (N2O) has demonstrated antidepressant properties in treatment-resistant major depression (TRD), little is known about neural mechanisms mediating these effects. Employing serial resting-state functional magnetic resonance imaging (rs-fMRI), we compared spatiotemporal effects of inhaled N2O on brain functional connectivity in TRD patients (n=14) and non-depressed healthy...
Biological Psychiatry Global Open Science
October 1, 2023
Ben Julian A Palanca, Charles R Conway, Thomas Zeffiro et al.
Nitrous oxide holds promise in the treatment of major depressive disorder. Its psychotropic effects and NMDA receptor antagonism have led to comparisons with ketamine. Despite longstanding use, persistent effects of nitrous oxide on the brain have not been characterized. Sixteen healthy volunteers were recruited in a double-blind crossover study. In randomized order, individuals underwent a...
Biological Psychiatry
June 1, 2022
Yukitoshi Izumi, F. Hsu, C. Conway et al.
BACKGROUND: Nitrous oxide (N2O) is a non-competitive inhibitor of NMDA receptors (NMDARs) that appears to have ketamine-like rapid antidepressant effects in patients with treatment resistant major depression. In preclinical studies, ketamine enhances glutamate-mediated synaptic transmission in hippocampus and prefrontal cortex. The present study examined effects of N2O on glutamate transmission...
Science Translational Medicine
June 9, 2021
Peter Nagele, Ben J Palanca, Britt M Gott et al.
Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with...
Frontiers in Psychiatry
July 17, 2020
Peter Nagele, Frank Brown, Victoria Bass et al.
Nitrous oxide (N2O, laughing gas) has shown early promise as a rapidly acting treatment for treatmentresistant major depression (1–3). Antidepressant effects of nitrous oxide in these studies started within 2 h and lasted up to 1 week. Due to the study design, however, it was impossible to determine whether antidepressant efficacy lasted beyond 1 week after nitrous oxide administration. There...
Journal of the Neurological Sciences
May 15, 2020
Molly C Kalmoe, Alvin Janski, Charles F Zorumski et al.
N-methyl-d-aspartate receptor (NMDAR) antagonists, including ketamine and nitrous oxide, are currently intensely studied as rapid-acting antidepressant agents. Interestingly, both of these compounds are also drugs of abuse. Intravenous ketamine, a dissociative anesthetic that induces complex downstream effects via NMDARs, rapidly reduces depressive and suicidal symptoms in treatment-resistant...
Journal of Clinical Psychopharmacology
April 1, 2018
Peter Nagele, Charles F Zorumski, Charles R Conway
Nitrous oxide (laughing gas) has shown early promise as a rapidly acting antidepressant in patients with treatment-resistant major depression and is currently investigated in several clinical trials. Because nitrous oxide is rarely administered outside operating rooms or dental practices, most psychiatrists are not familiar with how nitrous oxide is administered in a medical setting and what...
Biological Psychiatry
July 1, 2015
Peter Nagele, Andreas Duma, Michael Kopec et al.
N-methyl-D-aspartate receptor antagonists, such as ketamine, have rapid antidepressant effects in patients with treatment-resistant depression (TRD). We hypothesized that nitrous oxide, an inhalational general anesthetic and N-methyl-D-aspartate receptor antagonist, may also be a rapidly acting treatment for TRD. In this blinded, placebo-controlled crossover trial, 20 patients with TRD were...
Frontiers in Psychiatry
2015
Charles F Zorumski, Peter Nagele, Steven Mennerick et al.
Major depressive disorder (MDD) remains a huge personal and societal encumbrance. Particularly burdensome is a virulent subtype of MDD, treatment resistant major depression (TMRD), which afflicts 15-30% of MDD patients. There has been recent interest in N-methyl-d-aspartate receptors (NMDARs) as targets for treatment of MDD and perhaps TMRD. To date, most pre-clinical and clinical studies have...
Joseph Cichon, Thomas Joseph, Andrzej Z Wasilczuk et al.
Abstract Nitrous oxide (N2O) induces rapid and durable antidepressant effects in patients suffering from treatment-resistant depression1,2. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N2O induces rapid and specific activation of layer V (L5) pyramidal neurons in the prefrontal cortex of rodents exposed to chronic stress...
Joseph Cichon, Thomas Joseph, Xinguo Lu et al.
Abstract Nitrous oxide (N2O) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N2O induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions. N2O-induced L5 activation rescues a...