In a bold reveal, nitrous oxide—commonly known as laughing gas—shows the potential to lift depressive symptoms within hours, according to a new meta-analysis. The takeaway is that fast-acting antidepressant effects may be achievable when nitrous oxide is used in carefully planned, repeated sessions rather than as a one-off treatment.
A comprehensive review in eBioMedicine combined protocol papers, clinical trials, and exploratory studies to evaluate how effective nitrous oxide is for depression. The researchers concluded that administering nitrous oxide can produce rapid antidepressant effects within hours, but side effects tend to be short-lived and dose-dependent. Importantly, they call for more research to confirm and refine these findings.
Why there’s growing interest in ultra-rapid depression therapies
Depression affects more than 300 million people globally and arises from complex interactions among environmental, biological, and psychological factors that disrupt stress-regulation networks in the brain. Traditional antidepressants can take weeks to work and aren’t effective for everyone. This has intensified exploration of faster-acting options, especially for individuals with treatment-resistant depression who have exhausted standard approaches.
How nitrous oxide might work as an antidepressant
Research has increasingly focused on the glutamatergic system due to ketamine’s fast-acting antidepressant effects. Nitrous oxide is an NMDA receptor antagonist widely used as an anesthetic. Like ketamine, it can produce rapid mood improvements, though its adverse effects are typically short-lived and dose-related. The proposed mechanisms include modulating glutamate signaling, altering activity in the brain’s default mode network, and influencing dopamine and opioid pathways. Taken together, these actions place nitrous oxide among the most promising candidates for next-generation, fast-acting antidepressants.
Key findings from the clinical evidence base
- Eleven eligible studies were identified, including seven completed clinical trials (mostly randomized) and four protocol papers. Trials spanned Australia, Brazil, China, and the United States, with a total of 247 participants having major depressive disorder, treatment-resistant depression, or bipolar depression.
- Nitrous oxide was usually given at 25% or 50% concentrations via controlled inhalation for 20–60 minutes. Some studies used a single treatment; others used weekly or twice-weekly sessions. Many efficacy estimates were driven by single-session 50% protocols.
- Quick benefits after a single session: Depression scores often dropped within two hours of treatment. In early trials, 50% nitrous oxide led to lower depressive symptoms at two and 24 hours versus placebo, with more participants achieving meaningful improvement and some reaching remission within a day. In treatment-resistant cases, improvements appeared within hours but could fade within a week.
- Bipolar depression results were mixed; some studies suggested nitrous oxide helped more people early on, and certain brain-blood-flow patterns might predict who benefits most.
- Repeated dosing yielded stronger and longer-lasting effects: Across multiple-session studies, improvements typically peaked 24–48 hours after each treatment and accumulated over time. For example, eight sessions over four weeks significantly outperformed placebo in several trials.
- Dose-tolerability trade-offs: Lower doses (25%) reduced depressive symptoms over two weeks with fewer adverse events like nausea or dizziness, suggesting a balance between effectiveness and tolerability.
- The most extensive study to date found steady, cumulative improvement with weekly sessions over four weeks, with higher 50% doses providing stronger results.
What the meta-analysis suggests and where gaps remain
When data from several trials were pooled, nitrous oxide showed clear rapid antidepressant effects at two hours and at 24 hours post-treatment, with low heterogeneity. However, benefits did not persist at one week without ongoing treatment, indicating that the primary effects are short-term unless treatments are repeated. Some concerns remain: a small number of trials, potential publication bias, and possible imperfect blinding in certain studies, which could inflate perceived effects.
Overall, nitrous oxide appears to be a fast-acting antidepressant candidate that is generally well tolerated, though long-term safety and efficacy data are limited. More rigorous, larger, long-term trials are needed to better understand optimal dosing, predictors of response, and lasting outcomes.
Journal 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. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00467-0/f
