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.
Nature communications
April 3, 2025
Joseph Cichon, Thomas T Joseph, Xinguo Lu et al.
A single dose of inhaled nitrous oxide (N2O) rapidly and durably activates a specific population of neurons in the cingulate cortex of rodents exposed to chronic stress. This activation rescues a stress-induced hypoactivity state in layer V (L5) pyramidal neurons and is necessary for N2O's antidepressant-like effects. Although N2O is believed to work primarily by blocking NMDA receptors, L5 neurons still activate when NMDA receptor function is inhibited. Instead, N2O inhibits calcium-sensitive potassium (SK2) channels, driving L5 neuron activity and antidepressant-like effects. These findings identify a novel molecular and circuit mechanism for N2O's fast antidepressant action.
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.
Science translational medicine
June 9, 2021
Peter Nagele, Ben J Palanca, Britt Gott et al.
A single 1-hour inhalation of 25% nitrous oxide improves depressive symptoms in patients with severe treatment-resistant major depression as effectively as 50% nitrous oxide, but with substantially fewer adverse effects. In a phase 2 crossover trial with 24 patients, both concentrations significantly reduced depression scores on the Hamilton Depression Rating Scale compared to placebo over two weeks. The 25% dose showed significant improvements at week 1 and week 2, while the 50% dose showed significant improvement at week 2. Adverse events declined substantially with the lower dose.
Journal of the neurological sciences
May 15, 2020
Molly C Kalmoe, Alvin M Janski, Charles F Zorumski et al.
NMDAR antagonists like ketamine and nitrous oxide are being studied as rapid-acting antidepressants. Intravenous ketamine rapidly reduces depressive and suicidal symptoms in treatment-resistant depression (TRD), as shown by several trials. The FDA has approved intranasal esketamine for TRD, with a REMS program to minimize misuse. Nitrous oxide, a gas used for anesthesia and analgesia, also acts as an NMDAR inhibitor. A recent double-blind, prospective, cross-over study found that nitrous oxide reduced depressive symptoms in severely ill TRD patients, though further research is needed.
Journal of clinical psychopharmacology
April 1, 2018
Peter Nagele, Charles F Zorumski, Charles Conway
Nitrous oxide (laughing gas) is being studied as a fast-acting antidepressant for treatment-resistant major depression, but most psychiatrists are unfamiliar with its medical administration and regulations. This review educates psychiatrists on nitrous oxide's pharmacology and administration basics, and addresses common misconceptions about the gas.
Biological psychiatry
July 1, 2015
Peter Nagele, Andreas Duma, Michael Kopec et al.
In a small blinded, placebo-controlled crossover trial, 20 patients with treatment-resistant depression inhaled either 50% nitrous oxide or a placebo gas for about one hour. Depressive symptoms improved significantly more after nitrous oxide than after placebo, both at 2 hours and at 24 hours after treatment. Four patients (20%) showed a treatment response and three (15%) achieved full remission after nitrous oxide, compared with one response and no remission after placebo. All side effects were brief and mild to moderate; no serious adverse events occurred. The results suggest that nitrous oxide can produce rapid antidepressant effects in patients with treatment-resistant depression.
Frontiers in psychiatry
January 1, 2015
Charles F Zorumski, Peter Nagele, Steven Mennerick et al.
Treatment-resistant major depression (TRMD) affects 15-30% of people with major depressive disorder. N-methyl-d-aspartate receptors (NMDARs) have become targets for treating depression, with most research focusing on ketamine, though its psychotomimetic and other side effects may limit its use. A recent pilot clinical trial tested nitrous oxide, an NMDAR antagonist that works through a different mechanism than ketamine, in patients with severe TRMD. This paper reviews TRMD as a subtype of MDD, the development of ketamine as a fast-acting antidepressant, and clinical and basic science studies supporting the possible use of nitrous oxide as a rapid antidepressant.