The topic: Laughing gas may offer rapid relief for depression, at least in early clinical studies. A new meta-analysis suggests that nitrous oxide can alleviate depressive symptoms within hours, though the benefits appear to require multiple exposures for sustained effect. The authors reviewed protocol papers, clinical trials, and exploratory studies to evaluate how well nitrous oxide works for depression and what risks it might carry.
But here’s where it gets controversial… the evidence so far points to quick, mostly short-lived improvement, with stronger and longer-lasting results seen when dosing is repeated rather than a single treatment. This raises important questions about optimal dosing schedules, safety over time, and which patients are most likely to respond.
Rising interest in fast-acting depression therapies
Depression affects more than 300 million people globally. Its origins are multifaceted, arising from complex interactions among environmental, biological, and psychological processes that disrupt how stress is regulated and how neural circuits function.
Traditional antidepressants often fail to provide relief for many individuals, especially those with treatment-resistant depression. This reality has driven researchers to pursue faster-acting options that could bridge the gap for people in urgent need of help.
Nitrous oxide’s rationale as a potential antidepressant
Research into nitrous oxide has gained momentum partly due to the success of ketamine, another fast-acting antidepressant that targets the glutamatergic system. Nitrous oxide, a well-known NMDA receptor antagonist used in anesthesia, has demonstrated rapid mood improvements in early studies, accompanied by short-lived, dose-related side effects.
The proposed mechanisms involve modulating glutamate signaling, altering activity in brain networks linked to self-referential thinking, and affecting dopamine and opioid systems. Taken together, these actions position nitrous oxide as a promising candidate for further exploration as a novel antidepressant.
Clinical evidence base for nitrous oxide
The systematic review identified eleven eligible studies, including seven completed trials (mostly randomized controlled trials) and four protocol papers. The research spanned Australia, Brazil, China, and the United States, enrolling a total of 247 participants with major depressive disorder, treatment-resistant depression, or bipolar depression.
Nitrous oxide was typically given at 25% or 50% concentrations, delivered by controlled inhalation for 20–60 minutes. Some studies used a single session, while others employed weekly or biweekly repeated sessions. Most efficacy estimates were driven by single-session 50% protocols.
Rapid antidepressant effects from a single dose
Across the board, one treatment session could yield noticeable mood improvements within roughly two hours. In early work, a 60-minute exposure to 50% nitrous oxide produced lower depression scores than placebo at two and 24 hours post-treatment. Responders were more likely to show meaningful improvement (about 20% improvement versus 5% with placebo), with some participants achieving remission within a day.
In a separate trial involving treatment-resistant depression, anxiety and mood symptoms improved within hours but tended to fade by the end of the first week. A third study observed that about half of participants still showed improvement one week after a single session, particularly among those who responded strongly initially.
Results for bipolar depression were less consistent. One study found that nitrous oxide and the comparison drug had similar short-term effects, but nitrous oxide helped more participants improve within the first two hours. Some brain-blood-flow patterns hinted at potential predictors of response.
Enhanced and sustained benefits with repeated dosing
When dosing was repeated, improvements tended to be larger and longer lasting. Across repeated-dose studies, the strongest gains typically appeared within 24–48 hours after each session and accumulated across treatments.
For example, eight sessions over four weeks yielded substantial improvement and remission rates compared with placebo. Another trial showed that both 25% and 50% doses reduced symptoms over two weeks, with the higher dose delivering greater benefits. The lower dose offered a better tolerability profile due to fewer adverse effects like nausea or dizziness.
The most extensive study to date used weekly sessions for four weeks, producing steady, cumulative improvement. Remission in the first week was more common with nitrous oxide than placebo, with 50% concentration delivering the strongest outcomes.
Pooled findings from meta-analytic synthesis
When results from several trials were combined, nitrous oxide demonstrated clear antidepressant effects at two hours and at 24 hours post-treatment. Early improvements were consistent across studies and showed very low heterogeneity. Yet, the data did not reveal lasting benefits at one week, suggesting that the core effects are short-term unless treatments are repeated.
Because only a handful of trials contributed to the pooled estimates, there is some concern about publication bias, and blinding may have been imperfect in a few studies, which could influence expectancy effects.
Conclusions and research gaps
Overall, early-phase trials indicate that nitrous oxide can produce rapid, short-term antidepressant effects, with repeated dosing enhancing both magnitude and duration. Most studies were small and varied in design, limiting long-term follow-up and the ability to distinguish optimal doses or identify predictors of response. Differences in delivery, comparators, and outcome measures further complicate cross-study comparisons. Safety data look generally reassuring, but long-term or repeated-use safety remain incompletely understood.
Bottom line: nitrous oxide is a promising fast-acting antidepressant candidate that appears well tolerated in the short term, but definitive conclusions require larger, longer, and more mechanistically informed trials.
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
