A new meta-analysis led by the University of Birmingham provides strong, yet carefully interpreted evidence that clinically administered nitrous oxide (N2O) – often referred to by the public as "laughing gas" – can very quickly alleviate symptoms of major depression, including cases where standard antidepressants have not provided a satisfactory effect. The paper was published on November 30, 2025, in the journal eBioMedicine and currently represents the most comprehensive consolidation of available clinical data on the effects of single and repeated inhalation sessions in adults with major depressive disorder (MDD) and treatment-resistant depression (TRD). The focus of interest was the speed of onset of relief, the duration of the beneficial effect, and the safety profile under controlled medical conditions.
Why the topic is important: when standard therapies are not enough
Treatment-resistant depression is commonly defined as the persistence of clinically significant symptoms despite at least two treatment attempts with different antidepressants at adequate doses and duration. Although details of the definition vary among expert groups, the common denominator is that a large portion of patients do not achieve remission with standard approaches. In the literature, the prevalence of TRD is estimated at approximately one-third of sufferers, and some analyses suggest even higher numbers when observing "insufficient response" after multiple therapeutic cycles. Such an epidemiological picture creates a large public health burden and explains why expectations are rising for rapid-acting interventions that could open a "therapeutic window" while longer-term strategies are still being adjusted.
What the meta-analysis covered
Researchers from the University of Birmingham, in collaboration with colleagues from Oxford and the Birmingham and Solihull Mental Health NHS Foundation Trust, systematically reviewed and quantitatively synthesized the results of seven clinical trials and several protocol papers. In most studies, medical N2O was administered at a concentration of 50% in a mixture with oxygen during a single session of approximately 60 minutes, with measurement of depressive symptoms immediately after administration (within 2–24 hours), and in the following days and weeks. A smaller number of studies examined the effects of repeated sessions over several weeks. The analytical focus was on the magnitude of change on validated depression scales, sustainability of effect, and adverse events.
One session: rapid but transient relief
In studies examining a one-hour inhalation of 50% N2O, a clinically and statistically significant reduction in symptoms was recorded within a few hours and up to 24 hours after treatment. This is particularly relevant for patients with pronounced suffering, where even a short-term "release of the grip" can have therapeutic meaning. However, the effect generally fades gradually over the following week, so a single administration, while useful for acute relief, rarely represents a solution on its own without a planned continuation.
Repeated sessions: towards a more sustainable effect
In protocols that included multiple sessions distributed over several weeks, the beneficial effect lasted longer and was more stable. Studies used different numbers and intervals of sessions, which makes direct comparison and standardization difficult. Nevertheless, the common pattern is clear: repeating the administration increases the likelihood of sustainable clinical improvement. Therefore, the authors emphasized the need for future papers that will precisely define the optimal "regimen" – how often, how long, and at what doses.
Possible mechanism of action: glutamate system and NMDA receptor
Nitrous oxide acts as an NMDA receptor antagonist and thereby modulates glutamate neurotransmission, a mechanism it shares with ketamine. It is believed that such modulation temporarily "resets" dysfunctional networks in the brain involved in mood regulation, so the effect occurs faster than with drugs that act indirectly via monoamine systems. Although the biological basis is reasonable and aligns with findings for ketamine, clinical questions remain open: which populations are the best candidates, how many sessions are needed, how long the cumulative benefit lasts, and what is the upper limit of safety in serial inhalations.
Dosage: 50% versus 25% – what direct comparisons show
An important contribution to understanding dosage was made by a randomized phase 2 trial with a crossover design, in which adults with severe TRD received three separate single inhalations: 50% N2O, 25% N2O, and placebo (a mixture of air and oxygen). Results showed that both active doses reduce symptoms compared to placebo, while 25% was not inferior to 50% – with a lower frequency of side effects such as nausea and dizziness. These data encourage the planning of protocols targeting lower concentrations and better tolerability, especially when a cycle of repeated sessions over several weeks is foreseen.
Safety profile and side effects
In the meta-analysis and previous systematic reviews, the most commonly reported immediate side effects were headache, nausea, and dizziness, mostly of mild to moderate intensity and short duration. Higher concentration (50%) was associated with somewhat more frequent side effects than lower (25%). Serious acute safety problems in controlled medical conditions were not recorded. However, there are specific risks with repeated or long-term exposure: N2O can inactivate vitamin B12 (cobalamin) by oxidizing cobalt, leading to a functional deficiency and potential neurological and hematological complications. This risk particularly concerns individuals with borderline nutritional status, vegetarians and vegans, and those with malabsorption. Therefore, in longer protocols, targeted laboratory monitoring and clinical observation are recommended, with the possibility of timely supplementation when indicated.
Medical application is not the same as recreation
Recreational use of N2O ("balloons") is increasingly widespread and is often associated with neurological damage precisely due to frequent, uncontrolled inhalation and lack of medical supervision. Clinical application is significantly different: medical gas of precisely defined composition is used, in a supervised environment with monitoring of vital functions, with standardized protocols and trained teams. Such a context significantly reduces risk and makes potential side effects more predictable and easier to manage. Separating these two practices is crucial for the safety profile and public health communication.
How N2O fits into current guidelines
According to recent British guidelines, the treatment of moderate to severe depression and TRD relies on optimization of pharmacotherapy (switching, increasing dose, augmentation), psychotherapeutic approaches and, if necessary, neuromodulation techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS). Rapid-acting options are already present, for example, intranasal esketamine. Nitrous oxide is not yet a standard of care, but results of the meta-analysis indicate that, with further confirmation in larger and longer trials, it could be positioned as a rapid, supervised intervention in tertiary centers – especially as a "bridge" to more stable, long-term strategies.
What the meta-analysis means for practice: who are potential candidates
In practice, candidates for N2O could be adults with MDD who, despite two or more adequate treatment attempts, still have a high symptom burden. Clinical goals may include rapid reduction of psychological pain, alleviation of anhedonia and psychomotor retardation, and temporary improvement of functioning, to enable intensification of psychotherapy or adjustment of pharmacotherapy. The role of N2O here is not a replacement for existing strategies, but potentially a complementary method in carefully selected patients, with clear inclusion and exclusion criteria and systematic monitoring of benefits and risks.
Methodological limitations and open questions
The authors of the paper clearly highlight the limitations of available evidence: small samples, differences in protocols (dose, number and interval of sessions), heterogeneous outcome measures, and relatively short follow-up. In the field of inhaled gases, an additional challenge is the design of a credible placebo, because the sensory experience of the treatment can lead to "unblinding". Therefore, larger, multicenter, double-blind trials with longer follow-up, standardized measurements, and clear safety algorithms are needed. It is equally important to determine how to assess outcomes that patients consider most important – functionality, work capacity, and quality of life – alongside traditional symptom scales.
Preparations for the first NHS trial and existing infrastructure
The research team from the University of Birmingham, within the Mental Health Mission Midlands Translational Centre and with the support of the NIHR Oxford Biomedical Research Centre, announced the preparation of the first trial within the NHS that will assess whether N2O can be safely and acceptably offered as a therapeutic option for major depression. Preparation relies on existing infrastructure, including the Clinic for Advanced Mood Disorders (CALM), where rapid and advanced therapies such as ketamine and various forms of neuromodulation have already been introduced. It is expected that the results of the upcoming trial will inform on the feasibility, acceptability, and potential place of N2O in NHS care pathways.
Operational questions for hospitals and centers
- Infrastructure and logistics: systems for medical gases, adequate ventilation, and constant monitoring are needed, along with trained staff and protocols for emergencies.
- Selective inclusion: criteria should cover the number and quality of previous therapeutic attempts, level of compliance with treatment, and individual risks, including dietary habits and possible B-vitamin deficiency.
- Measurement of effect: besides depression scales, it is advisable to monitor functionality, work and social inclusion, and quality of life, to get a complete picture of benefits.
- Combinations and sequence: it is reasonable to consider N2O as an adjunct to pharmacotherapy and psychotherapy and as a bridging intervention to more stable remission or to the introduction of longer-term solutions.
Long-term safety: what we know so far
The safety of single and short cycles is increasingly well supported, but the long-term effects of multi-month or multi-year serial administration are not yet clearly defined. Due to possible functional vitamin B12 deficiency, it is prudent to consider laboratory monitoring and nutritional counseling in longer protocols, especially in at-risk groups. Published clinical reports and reviews emphasize that laboratory B12 values may not always reflect functional status, so clinical judgment and monitoring of neurological symptoms remain key. With good candidate selection and supervision, available data support further, methodologically stricter testing of this approach.
The bigger picture: rapid action, realistic expectations
N2O fits into the growing spectrum of rapid antidepressant approaches focused on glutamate pathways. Its advantages are speed of effect, good acute tolerability, and the existence of technical infrastructure in many healthcare institutions. Limitations are the need for repetition to maintain benefit, uncertainty of long-term effects, and the need for clear safety protocols. Evidence coming from larger, standardized trials will be crucial for defining the place of this intervention in care for MDD and TRD – whether N2O will have the role of a rapid "switch" or will profile itself as part of a broader, personalized treatment plan.