Depression is one of the leading causes of disability worldwide, with estimated costs exceeding €600 billion annually in Europe (1). In Spain, the Mental Health Strategy of the National Health System (SNS) was only renewed in 2021, after a decade without updates. The most recent plan proposed in 2025 has been met with significant criticism, particularly due to reductions in the number of training placements for mental health professionals—raising concerns about the system’s capacity to meet growing demand.
At Clínica Synaptica, we believe there is a pressing need for both stronger public policies and the development of innovative, evidence-based treatments. Many patients continue to experience inadequate responses to conventional antidepressants, long waiting times for care, and limited access to specialized interventions. As a result, a substantial proportion of individuals with depression remain undertreated or treatment-resistant, highlighting an urgent gap in current mental health care.
In recent years, new therapeutic approaches have begun to emerge, particularly those targeting the glutamatergic system. Among these are agents such as ketamine and nitrous oxide (N₂O), which act through mechanisms distinct from traditional antidepressants and have shown rapid-acting effects in clinical research. Today, we will focus on nitrous oxide and its potential role as a novel treatment for depression.
What is nitrous oxide (laughing gas) and what effects does it have?
Nitrous oxide (N₂O), commonly known as “laughing gas,” is a chemical compound composed of nitrogen and oxygen. It was first synthesized in 1772 by the English chemist Joseph Priestley. Not long after its discovery, researchers observed its potent analgesic and anesthetic properties, suggesting potential use in surgery. However, it took several decades before nitrous oxide gained widespread acceptance within the medical community. In contrast, its recreational use became popular much earlier, particularly among the British upper classes by the late 18th century.
Nitrous oxide is administered via inhalation and is rapidly absorbed through the lungs into the bloodstream. From there, it diffuses into the brain and nervous system, where it exerts its effects. Because the human body does not metabolize nitrous oxide, it is eliminated unchanged through exhalation.
The effects of nitrous oxide are short-lived, typically lasting only a few minutes. Users commonly experience a brief sense of euphoria, relaxation, and disinhibition, which explains its association with laughter. In some cases, mild perceptual changes or hallucinations may occur. Adverse effects can include nausea, dizziness, and headache, particularly at higher doses or with prolonged exposure.
Medical-grade nitrous oxide is produced in controlled laboratory and industrial settings. It also occurs naturally in the atmosphere in small quantities, where it plays a role in the Earth’s nitrogen cycle.
Today, nitrous oxide remains widely used in clinical practice, particularly in settings such as emergency care, dentistry, obstetrics and pediatrics, where its rapid onset and short duration of action make it especially useful.
Evidence from latest systematic review
A recent paper published in eBioMedicine (2025) analyzed data from 7 studies involving 247 participants diagnosed with depression, including major depression disorder, treatment resistant depression and bipolar depression. The findings suggest that nitrous oxide may produce rapid antidepressant effects, often within hours of administration, a striking contrast to traditional antidepressants that can take weeks to show benefit.
Most studies investigated the effects of a single session lasting between 20 and 60 minutes.
Single dose effects seemed to peak between 2 and 48 hours after the session, and diminish by one week. This means that N₂O had antidepressant effects for two days after the session, however with a single dose these effects were seemingly transitory. Only three studies used a repeated administration protocol, but results indicate a more sustained antidepressant effect with this protocol.
Two of the studies investigated two different doses, with results suggesting a possible dose-dependent response, with higher doses showing a bigger reduction in depressive symptomatology. However, higher doses were also associated with a greater percentage of adverse effects, such as nausea and dizziness. No severe side effects were recorded, and all resolved within the hour. This indicates that nitrous oxide appears to be generally well tolerated, with most side effects being mild and short-lived.
Nevertheless, the authors emphasize that the current evidence base is still limited, consisting largely of small, early-phase trials with heterogeneous designs. As such, further large-scale studies are needed to determine optimal dosing strategies, long-term safety, and how this treatment could be integrated into routine clinical practice.
Mechanisms of action of nitrous oxide in depression
Although the exact mechanism is not yet fully understood, nitrous oxide (N₂O) is thought to exert its antidepressant effects primarily through blockade of NMDA receptors within the glutamatergic system, similar to ketamine. This inhibition triggers downstream pathways that enhance synaptic plasticity and increase factors such as BDNF, which are often reduced in depression.
In addition, N₂O modulates GABAergic and opioid systems, contributing to its rapid mood-elevating and anxiolytic effects. Its overall action is therefore multimodal, targeting neural circuits involved in mood regulation in a way that differs from traditional antidepressants and may explain its rapid onset of effect.
Some final considerations
Nitrous oxide represents a promising, fast-acting approach for patients with depression, particularly those who have not responded to conventional treatments. Early clinical trials show encouraging results, and more work should be done to determine optimal dosing and session scheduling. Nitrous oxide can offer several important advantages over conventional treatments, as ostensibly it would not require daily dosing. Additionally, it could offer advantages over other psychedelic treatments due to its short duration, making treatment more economically viable and easy to fit into daily life.
References
- European Union. Health at a Glance: Europe 2020 State of Health in the EU Cycle. OECD publishing; 2020.
- https://www.eleconomista.es/salud-bienestar/noticias/13296907/04/25/la-gran-olvidada-la-salud-mental-recibe-el-7-de-los-presupuestos.html
- https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00467-0/fulltext
