Scientists Report Fast Depression Relief From Laughing Gas in New Review

Depression continues to affect millions of people worldwide, and many individuals do not find enough relief from standard treatments. Antidepressant medicines often take several weeks to show a meaningful change, and this slow response leaves a major gap for people who need rapid improvement. In recent years researchers have been exploring treatments that act within hours rather than weeks. Nitrous oxide, commonly known as laughing gas, has emerged as a surprising candidate. It influences several brain systems that regulate mood, which raises an important question. Can a short inhalation session provide fast and clinically meaningful relief from depression?

A new systematic review attempts to answer this question by bringing together all completed clinical trials of nitrous oxide for depression so far. The findings point toward a consistent pattern. The gas appears to work quickly, although the effect after a single session usually does not last long. The growing interest in this field, along with several ongoing trials, shows how rapidly this area of research is moving.

The scientific problem behind the study

Traditional antidepressants target serotonin based pathways, and although they are helpful for many people, they do not work for everyone. A major limitation is the delayed onset of improvement. People living with severe or treatment resistant depression often face days or weeks of waiting to see whether a medication will help. This delay can worsen suffering and increase risks for those experiencing suicidal thoughts.

Researchers are therefore investigating alternatives that influence different biological systems. One of the most promising targets is the glutamate system. Glutamate is the most abundant excitatory neurotransmitter in the brain, and abnormal glutamate activity has been linked with depression. Drugs like ketamine, which modulate glutamate through NMDA receptor activity, have already shown rapid antidepressant effects. Nitrous oxide interacts with the same pathway but has a different safety and sensory profile, which makes it an appealing candidate for controlled clinical testing.

The new review evaluates whether nitrous oxide can provide a rapid improvement in depressive symptoms, whether the effect is durable, and how well patients tolerate the treatment.

How the research team approached the question

To create a complete picture, the scientists systematically searched major scientific databases including PubMed, Embase, PsycINFO, Google Scholar, and ClinicalTrials.gov. They looked for all clinical trials that tested nitrous oxide for major depressive disorder, treatment resistant depression, or bipolar depression.

After screening the available literature, the researchers identified seven completed trials that involved 247 participants, along with four protocol papers describing upcoming or ongoing studies. These trials used either 25 percent or 50 percent nitrous oxide concentrations, delivered through a controlled inhalation system. Some trials tested a single session while others offered repeated inhalation sessions over several weeks.

The scientists then extracted data on symptom changes, dosing schedules, side effects, and methodological quality. They used established tools to rate the risk of bias and performed meta analyses wherever the study designs were comparable enough to combine.

This structured approach allowed them to estimate overall effect sizes and identify patterns that single trials alone could not capture.

Understanding the methodology in simple terms

Nitrous oxide is inhaled in a monitored clinical environment. As the gas enters the bloodstream it interacts with NMDA receptors, opioid pathways, and dopamine circuits that are involved in mood regulation and emotional processing. The trials measured changes in depression using standard rating scales, such as the Hamilton Depression Rating Scale.

Most studies followed a similar pattern. Participants inhaled nitrous oxide or a control gas for a short period, usually around one hour. Symptom scores were then measured a few hours later, the next day, and again after one week. In repeated dosing studies, this cycle was carried out over several weeks.

The meta analysis combined results from trials that used similar designs and time points. This allowed the researchers to calculate how much average symptom improvement came from nitrous oxide compared with the control group.

The key discovery, explained clearly

Across the included studies, a consistent pattern emerged. Nitrous oxide produced clear, measurable reductions in depressive symptoms within hours. The improvement was most pronounced at two hours and twenty four hours after inhalation.

The pooled analysis found:

• A decrease of about 2.7 points on depression rating scales at two hours.
• A larger decrease of about 3.3 points at twenty four hours.
• No significant difference from placebo at one week after a single session.

This shows that nitrous oxide acts quickly but the relief is generally short lived. However, the trials that used repeated dosing schedules reported stronger and more sustained improvements. Some participants reached remission or showed substantial reductions in symptoms after multiple sessions.

Although these repeated dosing trials were small, the findings suggest that the antidepressant effect of nitrous oxide might build over time, similar to how ketamine responds to maintenance dosing.

What this discovery means for the future of depression treatment

The idea that a simple inhaled gas can reduce depressive symptoms within hours is both scientifically intriguing and clinically valuable. Such rapid action could play an important role in emergency psychiatric settings, during acute depressive episodes, or as a bridge therapy while waiting for long term treatments to take effect.

If future research confirms these results, nitrous oxide might become a complementary option for people who do not respond to conventional antidepressants or who need short term symptom relief. It could also help researchers better understand the role of the glutamate system in mood disorders and lead to the development of new, faster acting antidepressant therapies.

The rapid onset of action provides an important window into how brain circuits respond to certain kinds of modulation. This window could shape the next generation of mental health treatments.

Safety, tolerability, and side effects

The trials reported no serious adverse events. Most side effects were mild, short lived, and resolved soon after the inhalation session ended. The most common effects included dizziness, nausea, headache, and brief dissociative sensations. These effects were more common at the 50 percent concentration, while 25 percent nitrous oxide was better tolerated.

Importantly, clinical use of nitrous oxide is very different from recreational misuse. Recreational inhalation of high concentration nitrous oxide can cause vitamin B12 inactivation and neurological complications. The clinical trials avoided these risks by using controlled medical gas mixtures with oxygen, careful monitoring, and limited dosing schedules.

Even though the trials showed a favorable safety profile, long term studies are still needed to understand whether repeated treatments could have cumulative effects.

Caveats, unanswered questions, and the road ahead

Although the findings are promising, several limitations make it clear that more research is needed.

• The sample sizes were small and most studies were early phase trials.
• Assessment time points differed across studies, which affects comparability.
• Blinding quality varied, and some participants correctly guessed their treatment.
• Delivery systems were not uniform, which may influence dose accuracy.
• Long term safety remains unknown, especially for repeated dosing.

These limitations prevent nitrous oxide from being considered a fully validated clinical treatment. However, they also provide a roadmap for how future research should be designed.

Large, multi site randomized trials with standard outcome measures, longer follow up periods, and stronger blinding controls are essential. The field is expanding, and several such trials are already under way.

How nitrous oxide compares to ketamine and other fast acting therapies

Nitrous oxide and ketamine both act on glutamatergic pathways and produce rapid antidepressant effects. Ketamine, however, has stronger evidence for sustained improvement, especially when given repeatedly. Its side effect profile is also more intense for some patients.

Nitrous oxide may become a gentler alternative for individuals who do not tolerate ketamine well. It may also be easier to deliver in some clinical environments, given that nitrous oxide has been used safely in anesthesia and dentistry for decades.

Still, direct comparisons between the two are very limited at this stage. Only future trials that test both treatments side by side can determine how they truly differ in real world outcomes.

The broader implications for neuroscience and mental health

Beyond its immediate clinical potential, nitrous oxide offers insights into how depression may be rooted in disrupted neural circuits rather than solely chemical imbalances. The rapid shift in symptoms suggests that fast acting treatments may reset certain brain networks that become rigid or overactive in depression.

This reinforces a growing scientific view that depression involves complex changes in connectivity, cognition, and neural regulation. Rapid acting treatments provide a unique window to observe how the brain recalibrates during recovery.

Such insights can guide new therapeutic strategies that blend biological, psychological, and behavioral approaches.

Final thoughts

This new systematic review shows that nitrous oxide has genuine potential as a rapid acting antidepressant, with effects appearing within hours and peaking around one day. The benefit fades after a week when given only once, but repeated sessions appear to extend the relief. Side effects are generally mild and short lived. Although the results are encouraging, the field is still in its early stages, and larger trials are needed before nitrous oxide can be considered a standard treatment.

For now, the findings highlight an important direction in mental health research. They show that rapid relief for depression is possible, and they open the door to new therapies that act on different biological pathways. As the scientific community continues to study nitrous oxide and related compounds, the hope is to develop faster, safer, and more effective treatments that bring real and timely relief to those who need it most.

The research was published in eBioMedicine on November 30, 2025.