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Nitrous oxide (N2O), commonly known as ‘laughing gas,’ continues to draw interest as a potential rapidly acting treatment for treatment-resistant depression (TRD), but data suggest the larger challenge is whether the drug’s effect is durable enough to make it a viable option.
Some early evidence suggests that repeated N2O sessions may be required to maintain antidepressant benefit, and because it appears to act on glutamate pathways similarly to ketamine, it may ultimately support a serial dosing strategy rather than one-off rescue use.
As research on N2O for depression continues, key questions remain about efficacy, optimal dose, therapeutic durability, and safety. And perhaps the most important question of all: Is the therapy ready for the clinic?
Why Laughing Gas for Depression?
World Health Organization data show that depression affects more than 300 million people worldwide and carries a lifetime prevalence of roughly 16%. Yet up to half of patients do not respond to common first-line therapies, such as selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors, underscoring the need for new treatment options.
In an effort to fill that void, attention has increasingly turned to glutamatergic-modulating treatments such as ketamine and N2O.
N2O is an N-methyl-D-aspartate receptor antagonist that has traditionally been used as a rapid-acting anesthetic and analgesic. Interest in the drug as an antidepressant grew after ketamine’s success put a spotlight on glutamatergic rapid-acting therapies, positioning N2O as a clinically familiar and mechanistically plausible candidate.
N2O does not carry the same risk for serious side effects as ketamine, including memory impairment and psychosis. The gas is administered in combination with oxygen, and its effects usually fade within 10-15 minutes after its use is discontinued. However, exactly how this drug works to achieve its rapid antidepressant effect is poorly understood.
A recent study published in Nature Communications showed that N2O may rapidly reverse stress-related hypoactivity in prefrontal circuits linked to depression, providing a potential mechanism for its rapid symptom relief.
What Does the Research Show?
One of the first studies to evaluate N2O for depression was a proof-of-concept trial published in 2015 by Peter Nagele, MD, and colleagues at Washington University School of Medicine in St. Louis.
In a blinded, placebo-controlled crossover trial, 20 patients with TRD received a 1-hour treatment with either a mixture of 50% N2O/oxygen or a placebo of oxygen/nitrogen. Depressive symptoms improved significantly in the treatment group at 2 hours (P = .002) and 24 hours (P > .001). Three patients in the N2O cohort even had a full remission.
In a subsequent 2021 phase 2b trial, Nagele and colleagues treated 24 patients with severe TRD with inhaled 25% or 50% N2O and found significantly greater symptom improvement than placebo (P = .01). Notably, the lower concentration was associated with fewer adverse events than the higher dose.
More recently, this team reported findings from another phase 2b trial involving 81 patients with major depressive disorder (MDD) who received either 50% or 25% inhaled N2O or a control oxygen/air intervention. Participants received a 1-hour treatment every week for 4 weeks. The primary endpoint — change in Hamilton Depression Rating Scale scores over 4 weeks — trended toward greater improvement in the N2O groups (P = .051). Patients in the treatment groups were also more likely to achieve remission during the first week (P = .03) and to show greater improvement in symptom severity and less risk for suicidal ideation.
“The goal is to get a patient into true remission, and the question is: Does a series of treatments accomplish this? And the evidence suggests the answer is yes,” said Nagele, who is now a professor of anesthesiology and psychiatry at the University of Chicago, Illinois.
Findings from a double-blind, single-dose randomized controlled trial (RCT) presented at the European College of Neuropsychopharmacology Congress 2025 also offered promising results. In 60 older adults with TRD, a single treatment with 50% inhaled N2O was linked to significantly improved symptoms compared with placebo as early as 24 hours (P = .002), with benefits persisting through the study’s 2-week endpoint (P < .001). Consistent with prior research, all adverse events were considered mild and transient.
Nagele’s studies were included in a 2025 meta-analysis that pooled data from seven RCTs and four published protocol papers with more than 200 participants with MDD, TRD, or bipolar depression. Findings showed that a single 50% inhaled N2O session was associated with significant reductions in depressive symptoms at 2 hours (mean difference [MD], -2.7; P = .007) and 24 hours (MD, -3.3; P < .0001) compared with placebo. However, the effect was no longer significant 1 week after treatment.
The 25% dose was also better tolerated than the 50% dose, with adverse events characterized as mild and transient. Most of the studies were early-phase and focused on short-term outcomes.
“Our analyses show that nitrous oxide could form part of a new generation of rapid-acting treatments for depression. Importantly, it provides a foundation for future trials to investigate repeated and carefully managed dosing strategies that can further determine how best to use this treatment in clinical practice for patients who don’t respond to conventional interventions,” first author Kiranpreet Gill, PhD, Institute for Mental Health, University of Birmingham, Birmingham, England, said in a release.
Study investigator Angharad N. de Cates, DPhil, MRCPsych, Institute for Mental Health, University of Birmingham, added that further studies are needed to determine the optimal dose, long-term safety, and how best to integrate N2O into existing treatment pathways.
While these and other small studies provide evidence of the antidepressant effect of inhaled N2O, important questions remain about how long those benefits last and what duration of effect is clinically meaningful.
Is N2O Safe?
Overall, treatment-related adverse events in clinical studies have been mostly mild, with nausea, dizziness, and headache the most commonly reported effects. Most reports suggest these events are transient and dose-dependent.
However, a separate concern is the growing misuse of consumer N2O products, including small “whippet” canisters and larger tanks sold online and in smoke shops under names such as Galaxy Gas and Miami Magic. Unlike medically administered formulations, these products are typically 100% N2O.
In June, the FDA issued an advisory warning that intentional inhalation of such products can cause serious adverse events, including death. Reports from Europe and the US have also linked recreational use to neurologic harm and rising misuse among adolescents and young adults.
Nagele emphasized that these consumer products are distinct from medical-grade N2O used in clinical settings. No clinician would administer 100% N2O because of the risk for hypoxia or asphyxiation, he noted, adding that his research suggests antidepressant effects may be achieved with concentrations as low as 25% mixed with air or oxygen.
“This treatment needs to be in the hands of clinicians and not available over the counter in the hands of people wanting to get high,” he added.
Is N2O Ready for the Clinic?
So where does the field stand now? While promising, most studies have been small with only short-term follow-up. As a result, de Cates said there is still insufficient evidence to definitively understand the long-term efficacy and safety of N2O for depression.
“Before it can be used clinically, we also need to confirm whether nitrous oxide works best as a standalone treatment or in combination with other treatments and optimal dosage regimes,” she said.
Nagele added that important practical questions also remain about how to deliver the treatment, particularly because N2O is not FDA-approved for depression.
“This is an off-label use, and, viewing it through the lens of the FDA, it’s still an experimental treatment,” he said. “We need to be cautious and let the research and science play out about how this fits into treatment options for depression and especially treatment-resistant depression.”
That next phase may now be taking shape. De Cates and colleagues said they are preparing what they describe as the first National Health Service trial in the UK to assess N2O for depression. Researchers say the study should help clarify the likely clinical niche for N2O and could potentially expand the range of innovative options for patients who have not benefited from standard approaches.
