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A new clinical study, presented at the 38th European College of Neuropsychopharmacology (ECNP) Congress in October 2025, has found that a single inhalation session of nitrous oxide—commonly known as laughing gas—can rapidly and sustainably reduce symptoms of treatment-resistant depression (TRD) in older adults, potentially offering hope for individuals who do not respond to conventional antidepressant therapies.
Study Findings: Rapid, Sustained Results
Researchers reported that participants receiving a 60-minute treatment with nitrous oxide (N₂O) by face mask experienced significant improvements in depression symptoms within 24 hours—a benefit that persisted for at least two weeks post-treatment. The study builds on growing evidence from previous clinical trials that suggest even low-dose nitrous oxide can yield antidepressant effects in patients with TRD, a population consistently underserved by existing medications.
Key study metrics include:
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A single, one-hour inhalation resulted in measurable symptom reduction within one day.
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Clinically meaningful declines in depression scores persisted for at least two weeks compared to placebo.
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Both 25% and 50% concentrations of nitrous oxide have been shown to be effective, with lower doses resulting in fewer side effects.
Expert Perspectives
Dr. Thomas Desmidt, MD, PhD, head of the Department of Old Age Psychiatry at the University Hospital of Tours in France and senior investigator on the new ECNP study, noted: “Our findings suggest that N₂O offers a new therapeutic strategy with rapid, sustained, and safe antidepressant effects in older adults with TRD”.
Other experts in the field have called the findings “exciting,” but also urge caution. Dr. Charles R. Conway, professor of psychiatry at Washington University School of Medicine, who was not involved in the study, praised the speed of symptom relief seen with nitrous oxide, highlighting its potential as an alternative for individuals with severe depression unresponsive to standard antidepressants.
Background: Why Seek Alternatives?
Major depressive disorder (MDD) affects millions globally, with conventional treatments—including selective serotonin reuptake inhibitors (SSRIs)—often failing to bring relief for 15% to 30% of patients. This group, classified as having treatment-resistant depression, faces heightened risks of chronic illness and suicide.
Current alternatives like ketamine infusions have shown benefit but are often limited by concerns about abuse potential and side effects. Nitrous oxide, an NMDA receptor antagonist like ketamine, is already widely used in medical and dental practice as a sedative and anesthetic, with a long history of safety when administered by trained professionals.
Clinical and Statistical Context
A phase 2 crossover trial published in Science Translational Medicine randomized 24 patients with severe TRD to 50% or 25% nitrous oxide, or placebo. At two weeks, both active doses produced significant reductions in scores on the Hamilton Depression Rating Scale (HDRS-21) compared to placebo—by as much as 5 to 7 points. Notably, adverse effects such as nausea, light-headedness, and headache were less common at the lower dose.
A recent meta-analysis found that, across four clinical trials, nitrous oxide’s rapid antidepressant effects peaked within 24 hours and remained evident for up to two weeks, with a standardized mean difference of approximately -2.36 on the HDRS after 24 hours.
Mechanism and Safety
Nitrous oxide is believed to exert its antidepressant effect by blocking the NMDA receptor, modulating glutamatergic neurotransmission similarly to ketamine but with fewer severe side effects. Unlike ketamine, nitrous oxide does not appear to cause dependence.
Most side effects were described as mild and transient, resolving within hours. The most common were dizziness, headache, and nausea, with a clear dose-response relationship favoring the lower 25% solution for better tolerability.
Public Health Implications
Given the substantial burden of treatment-resistant depression and the limited availability of effective, rapid-acting alternatives—especially for older adults—these findings suggest nitrous oxide could be an accessible outpatient intervention with the potential to fill a significant treatment gap.
However, experts caution that much remains to be learned about durability of these effects, optimal dose scheduling, and patient selection. Widespread clinical use should be preceded by further large-scale studies and the development of standardized guidelines to ensure safety, efficacy, and ethical administration.
Study Limitations and Counterpoints
While the results are encouraging, researchers acknowledge several limitations:
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The number of participants in published studies has been relatively small, with some trials ending early due to external factors like the COVID-19 pandemic.
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The duration of follow-up has been limited, leaving questions about longer-term benefit and safety unanswered.
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Most research to date has focused on short-term effects; more study is needed to determine the frequency and duration of retreatment for sustained remission.
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Potential exclusions include individuals with active substance use, respiratory illnesses, or certain cardiovascular risks.
Skeptics note that while nitrous oxide’s safety profile is well established for surgical and dental uses, its repeated or chronic use in depression remains understudied.
Practical Takeaways for Patients and Clinicians
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Nitrous oxide may soon be considered for older adults with severe, treatment-resistant depression, but it remains an investigational therapy.
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Patients should not attempt to self-medicate with nitrous oxide, as medical supervision is critical to prevent complications.
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Treatment would likely be offered in specialized settings by trained professionals if further studies confirm its safety and efficacy.
Medical Disclaimer
“Medical Disclaimer: This article is for informational purposes only and should not be considered medical advice. Always consult with qualified healthcare professionals before making any health-related decisions or changes to your treatment plan. The information presented here is based on current research and expert opinions, which may evolve as new evidence emerges.”
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