Evidence map›Paper›PMID 41326290›Full record

SynthesisEBioMedicine2025

Nitrous oxide for the treatment of depression: a systematic review and meta-analysis.

Kiranpreet Gill, Angharad N de Cates, Chantelle Wiseman, Susannah E Murphy, Ella Williams, Catherine J Harmer, Isabel Morales-Muñoz, Steven Marwaha

Abstract readSystematic ReviewMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in EBioMedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Kiranpreet GillInstitute for Mental Health, University of Birmingham, Birmingham, UK. Electronic address: k.gill.2@bham.ac.uk.
Angharad N de CatesInstitute for Mental Health, University of Birmingham, Birmingham, UK.
Chantelle WisemanInstitute for Mental Health, University of Birmingham, Birmingham, UK.
Susannah E MurphyDepartment of Psychiatry, University of Oxford, Oxford, UK; Oxford Health Foundation Trust, Warneford Hospital, Oxford, UK.
Ella WilliamsDepartment of Psychiatry, University of Oxford, Oxford, UK; Oxford Health Foundation Trust, Warneford Hospital, Oxford, UK.
Catherine J HarmerDepartment of Psychiatry, University of Oxford, Oxford, UK; Oxford Health Foundation Trust, Warneford Hospital, Oxford, UK.
Isabel Morales-MuñozInstitute for Mental Health, University of Birmingham, Birmingham, UK.
Steven MarwahaInstitute for Mental Health, University of Birmingham, Birmingham, UK; Severe Mood Disorders Clinic, Birmingham and Solihull Mental Health NHS Trust, Birmingham, UK.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundDepression remains a global public health challenge, prompting interest in translational targets which allow for more effective and rapidly acting interventions. Nitrous oxide (N2O), an N-methyl-d-aspartate receptor antagonist, has demonstrated potential as a rapid-acting antidepressant. This study synthesised existing data on the efficacy and safety of N2O in depressive disorders.

methodsWe systematically reviewed clinical trials, exploratory studies, and protocol papers evaluating N2O for the treatment of depression, including major depressive disorder (MDD), treatment-resistant depression (TRD), and bipolar depression, following PRISMA guidelines. Meta-analysis was completed where possible. Primary outcomes were change in depressive symptoms and adverse events (AEs). Pooled mean differences (MD) and relative risk ratios were calculated using random- or fixed-effects models. Evidence mapping described trial characteristics across completed and ongoing studies.

findingsSeven clinical trials involving 247 participants with depressive disorders, and four protocol papers were reviewed. N2O was administered via inhalation at 25% or 50%, as single or repeated sessions, with comparators including air, oxygen, or midazolam. Pooled results from three trials administering 50% N2O in a single session showed significant reductions in depressive symptoms at 2 h (pooled MD -2.74, 95% Confidence Interval (CI): -4.72 to -0.76; p = 0.007) and 24 h (MD -3.32, 95% CI: -5.09 to -1.55; p < 0.0001), but not at 1 week post-inhalation (MD -1.52; 95% CI: -4.07 to 1.03; p = 0.24). AEs were mild and transient, with 25% N2O generally being better tolerated. Evidence mapping showed that most trials are early-phase and focused on short-term outcomes in adults with MDD and TRD.

interpretationN2O demonstrates rapid, reproducible antidepressant effects in early-phase trials. Its future clinical value depends on whether these effects can be sustained over time through optimised dosing and extended/repeated use. Improved trial design, outcome standardisation, and population diversity is required to clarify its full potential for the treatment of depression.

fundingThe funder had no role in study design, data collection, analysis, interpretation, or writing.

Indexed as

Antidepressive AgentsDepressionNitrous OxideClinical Trials as TopicHumansMajor Depressive DisorderTreatment OutcomeAntidepressive AgentsNitrous OxideAntidepressantDepressionMajor depressive disorderNitrous oxideN-methyl-d-aspartate receptorTreatment-resistant depression

Identifiers

PMID41326290
PMCPMC12790589

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.