A rapid-acting antidepressant approach is gaining attention, as new analyses suggest that nitrous oxide—often known as laughing gas—can alleviate depressive symptoms within hours. This meta-analysis indicates that repeated, carefully scheduled administrations may achieve better and more durable benefits than a single exposure. But the evidence base remains early-stage and calls for larger, longer, and more rigorous studies to confirm these findings.
Rising Interest in Fast-Acting Treatments for Depression
Depression affects over 300 million people worldwide and stems from a complex mix of environmental, biological, and psychological factors that disrupt stress regulation and brain networks. Traditional antidepressants do not reliably help everyone, which has intensified interest in therapies that act quickly, especially for those with treatment-resistant depression or who need rapid relief.
Nitrous Oxide as a Mechanistic Candidate
Interest in fast-acting antidepressants has grown from ketamine’s notable effects, leading researchers to explore nitrous oxide, an NMDA receptor antagonist commonly used as an anesthetic. When inhaled in controlled settings, nitrous oxide can produce rapid mood improvements with side effects that are generally short-lived and dose-related. Its potential mechanisms include modulation of glutamate signaling, effects on brain networks linked to self-referential thought, and interactions with dopamine and endogenous opioid systems. Collectively, these actions position nitrous oxide as a promising subject for deeper investigation as a novel antidepressant.
What the clinical evidence shows
The review gathered eleven relevant studies, including seven completed clinical trials (mostly randomized) and four protocol papers. The trials spanned Australia, Brazil, China, and the United States, enrolling 247 participants with major depressive disorder, treatment-resistant depression, or bipolar depression. Nitrous oxide was usually given at 25% or 50% concentrations, delivered via inhalation for 20 to 60 minutes. Most studies explored a single treatment, while others used weekly or twice-weekly sessions. The strongest efficacy signals tended to come from single 50%-dose sessions.
Rapid effects after a single session
Across several investigations, a single nitrous oxide session consistently reduced depressive symptoms within a few hours. In early trials, a 60-minute 50% exposure produced lower depression scores versus placebo at 2 and 24 hours, with more participants achieving meaningful improvement and some reaching remission within a day. In treatment-resistant cases, improvements occurred within hours, though some results waned after about a week. Another study observed that nearly half of participants remained improved after one week, particularly among initial responders. Findings for bipolar depression were less uniform, but some benefits appeared in the first two hours, and there were hints that brain blood-flow patterns might help predict who responds best.
Enhanced benefits with repeated dosing
When sessions were repeated, depressive symptoms tended to improve more substantially and persist longer. In several trials, cumulative gains appeared within 24 to 48 hours after each treatment, and repeated courses yielded higher overall remission rates than placebo. For example, eight sessions over four weeks produced notable improvements, while both low (25%) and high (50%)-dose regimens reduced symptoms over two weeks, with the higher dose delivering stronger effects but the lower dose offering better tolerability due to fewer adverse events.
The most comprehensive study to date followed weekly nitrous oxide sessions for four weeks, showing steady, accumulating improvement. Remission rates in the nitrous oxide groups were higher than placebo in the first week, and the 50% dose consistently produced the strongest results.
Synthesis across studies and remaining questions
Pooled analyses indicate clear antidepressant effects at both two hours and 24 hours after treatment, with low heterogeneity across trials. Yet the one-week benefits did not clearly persist without ongoing treatment, highlighting the potential need for repeated dosing to maintain gains. Some publication bias and imperfect blinding in a subset of studies temper the certainty of these findings, and the small sizes and heterogeneity of trials constrain direct dose comparisons and predictor analyses.
Conclusions and gaps in knowledge
Current evidence suggests nitrous oxide can generate fast, short-term antidepressant effects, and that repeated dosing may extend and amplify these benefits. However, the body of research remains limited, with many early-phase trials, diverse methodologies, and incomplete long-term safety data for repeated use. More rigorous, larger-scale, mechanistically informed trials are necessary to establish optimal dosing, delivery methods, safety profiles, and predictors of response.
Reference
Gill, K., de Cates, A.N., Wiseman, C., Murphy, S.E., Williams, E., Harmer, C.J., Morales-Muñoz, I., Marwaha, S. (2025). Nitrous oxide for the treatment of depression: a systematic review and meta-analysis. eBioMedicine. DOI: 10.1016/j.ebiom.2025.106023.
