For more than a century, nitrous oxide—better known as “laughing gas”—has been used to dull pain in dentists’ offices and operating rooms. However, a growing body of research suggests this familiar anesthetic could serve a far more unexpected purpose: rapidly reducing the symptoms of major depression, including forms that resist conventional treatment.
A new review and meta-analysis published in eBioMedicine brings the most comprehensive assessment yet of nitrous oxide’s antidepressant potential.
By pooling data across seven clinical trials and examining four additional study protocols, researchers found consistent evidence that laughing gas can quickly alleviate depressive symptoms within hours.
Yet major questions still remain. Researchers say the benefits often fade within a week, its safety profile shifts with dose, and the field still lacks the large, long-term trials needed to determine whether the laughing gas can function as a durable treatment.
This gap, the authors argue, is now a central obstacle. “N2O demonstrates rapid, reproducible antidepressant effects in early-phase trials. Its future clinical value depends on whether these effects can be sustained over time through optimized dosing and extended/repeated use.”
Taken together, the findings signal both promise and caution, a common theme in the race to develop fast-acting antidepressants as an alternative or complement to other unconventional remedies like ketamine or psychedelics.
A Rapid Antidepressant in Minutes Instead of Weeks
The new meta-analysis reviewed clinical trials involving 247 participants with major depressive disorder (MDD), treatment-resistant depression (TRD), and bipolar depression. In most studies, participants inhaled either 25% or 50% nitrous oxide for 20–60 minutes.
Across these trials, the results were strikingly consistent. Depressive symptoms dropped within two hours, and the improvement typically persisted for at least 24 hours.
In one early crossover trial of adults with treatment-resistant depression, patients receiving 50% nitrous oxide showed significant symptom improvement at both the 2-hour and 24-hour marks, outperforming placebo.
Another trial in China found nearly identical effects: a single session of nitrous oxide produced clinically meaningful symptom reductions within 24 hours.
“Pooled results from three trials administering 50% N2O in a single session showed significant reductions in depressive symptoms at 2 h… and 24 h,” researchers report.
In the world of mental health treatment—where standard antidepressants can take four to six weeks to work—this speed is remarkable.
The Catch: Effects Fade Quickly
While nitrous oxide works fast, it doesn’t appear to work for long—at least not yet.
Across the trials, improvements generally plateaued by 24–48 hours and largely dissipated within a week. Researchers highlighted this limitation, noting “effects were not sustained beyond 1 week.”
This raises a crucial question of whether repeated dosing could extend the impact of laughing gas.
Early evidence suggests the answer might be yes. In a Brazilian clinical trial involving 8 sessions over 4 weeks, 75% of participants achieved remission, far exceeding placebo. Similarly, a recent multi-week study showed stronger and more durable symptom reduction with repeated dosing than with a single session.
Nevertheless, researchers note that the field is still young, and only a small handful of repeated-dose studies exist.
How Laughing Gas Works in the Brain
Laughing Gas’s antidepressant effects appear to operate through several overlapping biological mechanisms. Like ketamine, it partially blocks NMDA receptors—key players in the brain’s glutamate system, which is increasingly understood to be central to depression.
However, laughing gas may also modulate opioid receptors, dopamine pathways, and brain blood flow. It also appears to reduce hyper-connectivity in parts of the “default mode network,” which plays a major role in rumination—a hallmark of depression.
Although the mechanisms overlap with ketamine, laughing gas’s effects tend to be milder, shorter-lasting, and less dissociative, with fewer intense side effects.
Overall, nitrous oxide was well tolerated. No serious adverse events were reported across any of the studies in the review. The most common side effects included nausea, dizziness, headache, and brief dissociative sensations—typically resolving within minutes.
However, researchers found that dosage plays a key role, noting that “25% N2O generally being better tolerated,” while “50% N2O significantly increased the risk of headache… dizziness or light-headedness… as well as nausea and vomiting.”
This trade-off between potency and tolerability is likely to shape future dosing strategies.
Laughing Gas and Emerging Psychedelic Therapies
In recent years, ketamine has dominated the conversation around rapid-acting antidepressants. Originally developed as an anesthetic in the 1960s, ketamine has emerged as a groundbreaking, albeit unconventional, psychiatric treatment after studies showed it could lift severe depressive symptoms within hours, even in patients who had failed multiple medications.
Its rapid action helped reshape scientific thinking around glutamate, synaptic plasticity, and what fast-acting mood treatments might look like.
Laughing gas now enters that same landscape with a different mix of strengths and limitations. Unlike ketamine, it is already widely used in medical settings and works quickly without triggering the intense dissociation or perceptual disturbances ketamine is known for.
Laughing gas also appears generally safe across the studies reviewed. Yet its benefits tend to be shorter-lived, and that remains a significant challenge.
Researchers draw a direct comparison between the two drugs, noting that ketamine typically produces stronger and more durable antidepressant effects than laughing gas.
Yet ketamine’s advantages come with trade-offs, including more significant side effects and ongoing methodological questions that continue to shape how its findings are interpreted.
The Road Ahead: Larger Trials, Longer Timelines
Perhaps the most significant takeaway from the new review is the enormous gap between what early data suggests and what’s needed to turn laughing gas into a real-world therapy.
“Larger, methodologically rigorous RCTs are needed to confirm the durability of N2O’s antidepressant effects beyond short-term improvements, and to evaluate longer-term safety,” the researchers write.
Significant questions still surround the use of laughing gas as a depression treatment. Researchers do not yet know how long symptom relief can be maintained with repeated dosing, which patients are most likely to benefit—whether those with major depression, treatment-resistant depression, bipolar disorder, suicidality, cognitive impairments, or comorbid anxiety—or what dosing strategy best balances safety and effectiveness. There is also increasing interest in whether biomarkers could eventually help identify likely responders before treatment begins.
Despite these uncertainties, momentum around laughing gas research is increasing. Multiple clinical trials are now underway, including studies testing booster sessions, examining adolescent populations, and exploring biomarker-guided treatment strategies.
For now, laughing gas stands as an intriguing addition to the expanding toolkit of rapid-acting antidepressants. The science shows clear, measurable effects—fast and reproducible—but not yet sustained.
If future studies succeed in extending those effects over days or weeks, laughing gas could become one of the most accessible and scalable treatments for severe depression. If not, it may still play an important short-term role, particularly in urgent clinical settings where rapid symptom reduction could be life-saving.
“N2O shows promise as a rapid-acting intervention for depression, addressing an urgent need for faster-acting antidepressant treatments,” the researchers conclude. “Rigorous and standardized clinical trials are essential to strengthen the evidence base for N2O and establish its role within the evolving landscape of antidepressant therapies.”
Tim McMillan is a retired law enforcement executive, investigative reporter and co-founder of The Debrief. His writing typically focuses on defense, national security, the Intelligence Community and topics related to psychology. You can follow Tim on Twitter: @LtTimMcMillan. Tim can be reached by email: tim@thedebrief.org or through encrypted email: LtTimMcMillan@protonmail.com