An Antidepressant That Works in Hours? The Effect of Laughing Gas in The Treatment of Depression

Depression affects millions of people and often doesn't improve with traditional treatments. Researchers are studying new alternatives, and one of them is nitrous oxide (the "laughing gas"). This gas seems to act quickly in the brain, regulating systems linked to emotions, pleasure, and stress. This scientific review compiled studies that tested N2O and found that it can reduce depressive symptoms in a few hours, with mild and transient effects. However, the benefits don't last long, and larger, longer studies are still needed to understand if it can become a real treatment in the future.

Depression is one of the most common and debilitating health conditions in the world, affecting more than 300 million people throughout their lives. It doesn't happen for a single reason; in fact, it involves a complex set of factors such as genetics, environment, personal experiences, chronic stress, and alterations in the brain's chemical systems.

For many years, it was believed that depression was mainly caused by an imbalance in monoamines, substances like serotonin and norepinephrine. But today it is known that this is only part of the story.

Research shows that depression also involves alterations in the functioning of the hypothalamic-pituitary-adrenal axis (a body system that regulates stress), as well as changes in important areas of the brain, such as the prefrontal cortex, which participates in the control of emotions and decision-making. Thus, the disorder is understood as a complex condition that affects the body, mind, and daily functioning.

In addition to causing emotional suffering, depression greatly impacts overall health. Depressed people often have more difficulty working, maintaining social relationships, and performing daily tasks, and have a lower quality of life than people with other chronic diseases such as asthma, arthritis, or diabetes.

The economic impact is also enormous: costs related to depression exceed €600 billion annually in Europe alone. The most common treatments include medications such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

However, between 30% and 50% of patients do not improve sufficiently with these treatments, and many take weeks to feel any effect. This is especially serious in people with treatment-resistant depression, who have already tried several options without success.

In recent years, there has been interest in treatments that act more quickly, especially those that affect the glutamate system, another important chemical in the brain. Ketamine was one such discovery: it acts quickly and works in people who do not respond to traditional treatments.

This paved the way for the investigation of other similar compounds, including nitrous oxide (N2O), a gas known for its use as an anesthetic and analgesic. N2O acts as an antagonist of the NMDA receptor, a type of receptor linked to glutamate. By blocking this receptor, N2O can help balance communication between brain cells that is altered in depression.

In addition, it increases blood flow in some areas of the brain, which can improve oxygenation and neural function. Studies show that it also acts on the opioid and dopaminergic systems, which regulate pleasure, motivation, and stress response, areas frequently affected in depression.

It is also believed that N2O influences specific neural networks linked to depression, such as the Default Mode Network (DMN), which is activated when we think about ourselves and when we ruminate on negative thoughts. In depressed individuals, this network is often hyperactivated, especially in areas linked to self-criticism and excessive worry.

There is evidence that N2O reduces this hyperconnectivity, allowing the brain to function in a more balanced way. All of this suggests that N2O may act on several mechanisms at the same time, which makes it interesting as a therapeutic alternative.

Mechanism of action of nitrous oxide (N2O) in modulating NMDA receptor activity. In the normal state (A), glutamate (glu) binds to NMDA receptors on the postsynaptic neuron, causing an influx of calcium (Ca2+) and sodium (Na+) ions, triggering excitatory signaling. In B), N2O partially blocks NMDA receptors, inhibiting glutamate binding and preventing Na+ and Ca2+ influx, thus reducing excitatory signaling. This ion modulation affects the excitatory and inhibitory balance in the central nervous system and is implicated in depression. Figure created with BioRender. Gill, K. (2025)

Several small and preliminary studies had already investigated N2O, but a comprehensive overview bringing together all the evidence was lacking, including completed clinical trials, ongoing studies, and protocols, documents showing how new studies are being planned.

This overview is particularly important because N2O is still in an early stage of research, and understanding what has already been tested, what worked, and what still needs to be studied is essential for planning new treatments.

To fill this gap, the researchers conducted a systematic review and a meta-analysis. A systematic review is a type of study that gathers and analyzes all relevant scientific work on a subject following strict search and selection rules.

The meta-analysis, in turn, combines the numerical results of several studies to calculate a more precise average effect. In addition, the authors used something called "evidence mapping," which functions as an organized survey of all existing research on the topic, including ongoing studies, to identify what we already know, what we don't yet know, and where data is lacking.

In simple terms, the method worked like this: researchers searched for clinical trials that tested N2O in people with major depression, treatment-resistant depression, and bipolar depression. They also included articles describing study protocols and ongoing research registered on the ClinicalTrials.gov platform.

In all cases, the aim was to determine if N2O reduced depressive symptoms and if it caused significant side effects. When the studies had sufficient data, the authors combined the results to calculate an average effect.

They primarily analyzed changes in symptoms a few hours after N2O administration, after 24 hours, and after 1 week. They also recorded adverse effects such as nausea, dizziness, and headache, and compared different concentrations of N2O, mainly 25% and 50%.

The results showed that, in three similar trials using 50% N2O in a single session, depression symptoms decreased significantly within 2 hours and were still reduced after 24 hours. However, after a week, this improvement was no longer evident. The side effects were mild and passed quickly, and the lower doses were better tolerated.

The authors observed that almost all studies were small and short-term, limiting the understanding of how N2O would work in the long term or in different populations. Evidence mapping showed that most research is still in its early stages and focused only on adults.

The researchers concluded that N2O has potential as a fast-acting antidepressant, but much remains to be investigated. Larger, longer, and more varied studies will be needed to understand how to maintain its effects over time, what the best dose is, how often it should be used, and in which types of patients it works best.

They also emphasize that future studies need to use standardized measures and include more diverse groups of participants. This will make it possible to understand whether N2O can truly become a safe and effective clinical option for the treatment of depression in the future.

READ MORE:

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, and Steven Marwaha

eBioMedicine. 106023. 30 November 2025

DOI: 10.1016/j.ebiom.2025.106023

Abstract:

Depression 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.We 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. Seven 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. 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 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. The funder had no role in study design, data collection, analysis, interpretation, or writing.