Nitrous Oxide: an emerging novel treatment for treatment-resistant depression

Over several decades antidepressant development focused on monoamine systems, yet an estimated 20-25% of people with major depressive disorder (MDD) do not respond to standard pharmacotherapies and are commonly described as having treatment-resistant depression (TRD). Interest in novel mechanisms has therefore intensified, with NMDA receptor antagonists such as ketamine and its enantiomer esketamine showing rapid antidepressant effects and prompting investigation of other NMDA-targeting agents. Nitrous oxide (N2O), a long‑used inhalational anaesthetic and analgesic, has emerged as a candidate because preclinical and early clinical evidence suggest it may have antidepressant properties. Quach and colleagues set out to review the emerging literature on nitrous oxide as a treatment for depression. The review aims to describe how N2O is administered in psychiatric settings, summarise clinical evidence for its antidepressant efficacy and tolerability, outline proposed mechanisms of action, and identify gaps and priorities for future research and clinical development.

The review synthesises clinical and preclinical findings rather than reporting new primary data. Key clinical trials summarised include a pilot study, a Phase II dose-ranging trial, and a parallel-group randomised trial. Nagele and colleagues conducted an early double-blind, placebo-controlled crossover pilot in 20 subjects with severe TRD (defined as failure of at least two adequate current trials and at least three lifetime trials, with an average of eight prior failed antidepressant trials). One‑hour inhalations of 50% N2O in oxygen were compared with placebo (50% oxygen/50% room air). Treatment produced a statistically significant reduction on the Hamilton Depression Rating Scale, 21 items (HDRS-21). The overall response rate was 20% and three participants achieved remission. Reductions in depressive symptoms were apparent at 2 hours and 24 hours post‑treatment. Nausea and vomiting were the most common adverse events; no psychosis or vitamin B12 changes were reported. In a Phase II, prospective, randomised, double‑blind crossover trial, the antidepressant effects of 50% and 25% N2O (one‑hour inhalations) were compared with placebo in 24 TRD subjects (median of 4.5 prior adequate antidepressant trials). The primary outcome was HDRS-21 measured up to two weeks post‑inhalation. Both 25% and 50% concentrations produced statistically significant reductions in HDRS-21 versus placebo, with week‑2 differences versus placebo of −5.19 points (P=0.02) for 25% N2O and −7.00 points (P=0.001) for 50% N2O. No significant HDRS-21 difference was observed between the two active doses, but adverse effects were significantly lower with 25% N2O (P<0.0001). Antidepressant effects were sustained up to two weeks in the group average, and some participants maintained benefit longer: 8 of 20 remained in remission at three months in the follow‑up described. Guimaraes and colleagues tested adjunctive N2O in a randomised, placebo‑controlled, double‑blind, parallel trial in 23 people with MDD (not selected for treatment resistance). Participants received 50% N2O (60 minutes) or placebo (100% O2) twice weekly for four weeks; 21 subjects were included in the final analysis and the primary measure was the HDRS‑17. The N2O group showed a statistically significant reduction in depressive symptoms versus placebo. After four weeks, remission and response rates in the N2O arm were 75% and 91.7% respectively, compared with 11.1% remission and 44.4% response in the placebo arm. The intervention was generally tolerable; five of 96 N2O sessions were discontinued early. Common adverse events across studies included somnolence, paresthesia, nausea, headache and transient dizziness. Safety and pharmacological profile summaries note that N2O is commonly administered in oxygen mixtures up to inspiratory concentrations of 70% and has a low blood–gas solubility producing rapid onset and recovery. In a large non‑psychiatric survey of 35,828 hospital patients receiving N2O, side effects occurred in 4.4% and were typically mild and brief. Chronic or heavy exposure is associated with inactivation of vitamin B12 and risk of subacute combined degeneration of the spinal cord. Preclinical mechanistic findings reported include electrophysiology and behavioural studies supporting non‑competitive NMDA receptor antagonism by N2O, with evidence that N2O inhibits NMDA agonist‑induced currents and that NMDA receptors are required for some behavioural effects in invertebrate and murine models. N2O weakly inhibits AMPA/kainate receptors and modulates other targets including opioid receptors, low‑voltage‑activated calcium channels, GABAA/C receptors, glycine receptors and 5‑HT3 receptors. Human neurophysiological data are limited but include electroencephalography findings of decreased functional connectivity in superficial parietal networks and frontal slowing in delta frequencies during N2O exposure.

The authors interpret the assembled evidence as indicating that nitrous oxide is a promising candidate for treating MDD and TRD, with rapid onset of antidepressant effects demonstrated across small controlled trials and an apparently favourable tolerability and safety profile in short‑term use. Phase II data provided preliminary information on dose, showing comparable efficacy between 25% and 50% N2O but fewer adverse effects at the lower concentration, and suggest that therapeutic effects can persist for days to weeks in some participants. Quach and colleagues position these findings alongside the ketamine literature: both agents are non‑competitive NMDA antagonists used historically as anaesthetics and more recently explored as rapid‑acting antidepressants, but they differ at the molecular level (ketamine acts as an open‑channel “trapping” blocker whereas N2O is a partial, weakly voltage‑dependent inhibitor). Clinically, N2O may offer practical advantages such as rapid recovery and lower regulatory constraints, and no research reports to date of N2O‑induced psychosis have been cited. Key limitations acknowledged include the small size and heterogeneity of the clinical trials to date, limited duration of follow‑up, and an incomplete understanding of mechanism. The authors note that human mechanistic data are sparse and preclinical findings do not yet clarify which receptor systems or downstream pathways mediate antidepressant effects. Safety concerns that require continued attention include the known risks of chronic exposure (vitamin B12 inactivation) and the need to monitor for adverse events in larger samples. For future research and clinical practice the authors advocate replication in larger, multi‑centre trials to define optimal dosing, frequency and maintenance schedules and to compare N2O directly with established rapid‑acting treatments such as ketamine. They also recommend mechanistic studies in humans and animals, exploration of potential indications beyond unipolar depression (for example post‑traumatic stress disorder, bipolar disorder), and assessment of effects on suicidality. If larger trials confirm efficacy and safety, the authors envisage possible integration of N2O delivery into specialised clinical settings or supervised outpatient practice.