A recent meta-analysis has found that nitrous oxide, commonly known as “laughing gas,” may offer rapid relief from depressive symptoms within hours of administration. The findings were published in the journal eBioMedicine and are based on a review of protocol papers, clinical trials, and exploratory studies.
Researchers concluded that nitrous oxide can quickly reduce symptoms of depression after it is administered, with effects generally lasting for a short period and side effects being mild and dose-dependent. However, they noted that further research is needed to confirm these results.
Depression affects more than 300 million people worldwide. Many patients do not respond adequately to standard antidepressants, prompting increased interest in therapies that act faster. Nitrous oxide is an NMDA receptor antagonist widely used as an anesthetic and has shown fast-acting antidepressant effects similar to those seen with ketamine.
The review included eleven studies—seven completed clinical trials and four protocol papers—from Australia, Brazil, China, and the United States. In total, 247 participants with major depressive disorder, treatment-resistant depression, or bipolar depression took part in the trials. Nitrous oxide was typically given at concentrations of 25% or 50%, through controlled inhalation sessions lasting between 20 and 60 minutes.
One early trial reported that a single session of 50% nitrous oxide for one hour led to lower depression scores compared to placebo at both two hours and twenty-four hours post-treatment. Participants receiving nitrous oxide were also more likely to show meaningful improvement or remission within a day.
Another study focusing on treatment-resistant depression found improvements within hours after treatment; however, these benefits diminished by one week. A third study observed sustained improvement in nearly half of participants one week after a single session.
For bipolar depression patients, results were mixed: both nitrous oxide and midazolam reduced symptoms but nitrous oxide showed greater benefit within the first two hours for some individuals. Some evidence suggested certain brain blood flow patterns might predict better response to treatment.
Repeated dosing appeared more effective than single treatments. Studies involving multiple sessions over several weeks demonstrated greater and longer-lasting reductions in depressive symptoms compared to placebo groups. For example, eight sessions over four weeks resulted in higher rates of improvement and remission.
Comparisons between low-dose (25%) and high-dose (50%) treatments indicated both doses reduced symptoms over two weeks; higher doses produced stronger effects but also caused more adverse events such as nausea or dizziness.
Combined data from several trials confirmed significant antidepressant effects at two hours and twenty-four hours following treatment across different studies. However, benefits did not persist beyond one week unless treatments were repeated regularly.
The authors emphasized limitations including small sample sizes, varying study designs, limited long-term follow-up data, incomplete safety information for extended use, differences in delivery methods among studies, possible publication bias due to asymmetry in funnel plots from pooled estimates analysis—and potential expectancy effects because blinding may have been imperfect in some cases.
"Overall," researchers wrote,"the evidence suggests that nitrous oxide is a fast-acting antidepressant candidate that is generally well tolerated...but larger,longer,and mechanistically informed trials are needed."
