How fast does it work, and how long does the effect last?
Nitrous oxide works within hours — far faster than standard antidepressants, which typically take weeks. In pooled results from three trials, a single 50% nitrous oxide session significantly reduced depression scores at 2 hours and at 24 hours, but the benefit was no longer statistically significant at one week [1]. Another meta-analysis confirmed this pattern: a large improvement at 24 hours (standardized mean difference -2.36, meaning a very large effect) that shrank but remained significant at one week (SMD -0.60, a moderate effect) [2]. For context, a standardized mean difference of -2.36 means the average treated patient improved more than 98% of placebo patients. So the answer is: rapid onset, but the effect fades within days to a week after a single dose.
What dose works best, and is it safe?
The best evidence supports a 25% nitrous oxide concentration as the sweet spot — it appears similarly effective to 50% but with fewer side effects. One review noted that 25% nitrous oxide had comparable antidepressant efficacy to 50% while being better tolerated [4]. Across all studies, side effects were mild and transient — mostly nausea, dizziness, or dissociation that resolved quickly after the gas was stopped [1]. The 25% dose caused fewer of these effects [1][4]. No serious adverse events were reported in any of the trials reviewed. So for someone considering this treatment, 25% nitrous oxide seems to offer a good balance of benefit and tolerability.
The big catch: we don't yet know if repeated dosing works long-term
All the positive results come from single-dose studies. The key question for real-world use — can you give nitrous oxide weekly or monthly to keep depression at bay? — remains unanswered. One ongoing pilot trial is testing exactly this: 40 participants will receive weekly 50% nitrous oxide for 4 weeks and be followed for 6 weeks total [3]. The results aren't out yet. Another review emphasized that the future clinical value of nitrous oxide depends entirely on whether repeated or optimized dosing can sustain the antidepressant effect [1]. So while the early data is promising for a rapid rescue treatment, no one can yet say it works as a maintenance therapy.
About These Sources
This answer is built on 5 peer-reviewed studies — published from 2022 to 2026, 3 from 2024 or later, 2 in Q1 journals — selected as the most relevant from 5 studies that passed quality screening, drawn from 26 papers retrieved from a database of over 500 million.
Sources used in this answer
Nitrous oxide for the treatment of depression: a systematic review and meta-analysis
In a systematic review and meta-analysis of 7 clinical trials (247 participants), a single 50% nitrous oxide session significantly reduced depression at 2 and 24 hours but not at 1 week; side effects were mild and transient, with 25% concentration better tolerated.
Use of nitrous oxide in the treatment of major depressive disorder and treatment-resistant major depressive disorder: A systematic review and meta-analysis nitrous oxide in depressive disorders
In a meta-analysis of 2 randomized trials (109 patients with treatment-resistant depression), nitrous oxide produced a very large effect at 24 hours (SMD -2.36) and a moderate effect at 1 week (SMD -0.60), confirming rapid but fading benefit.
Sustained Mood Improvement with Laughing Gas Exposure (SMILE): Study protocol for a randomized placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression
This protocol describes an ongoing pilot trial testing weekly 50% nitrous oxide for 4 weeks in 40 participants with treatment-resistant depression, aiming to assess feasibility and preliminary efficacy of repeated dosing.
Nitrous Oxide in Treatment Resistant Major Depression: Should We Laugh About It?
This review of published literature reports that two randomized clinical trials since 2018 found nitrous oxide had significant antidepressant effects in treatment-resistant depression lasting at least 2 weeks, and that 25% concentration had similar efficacy to 50% with fewer side effects.
Evaluation of brexpiprazole as adjunctive therapy in treatment-resistant depression: Real-world data
This study evaluated brexpiprazole (an antipsychotic) as adjunctive treatment for treatment-resistant depression in 30 patients, finding significant improvement in depression and anxiety scores; it is unrelated to nitrous oxide.