Key takeaways
- Small clinical trials found that a supervised one-hour session of nitrous oxide mixed with oxygen lowered depression scores in people whose depression had not responded to other treatments.
- The effects showed up within hours and lasted from a few days to a few weeks. It is still unclear exactly how long these benefits last.
- Do not attempt this at home. Using nitrous oxide recreationally and repeatedly can lead to vitamin B12 deficiency and may damage your nerves and spinal cord.
Laughing gas might help some people whose depression has not improved with standard treatments, but only as an experimental option given by medical professionals. Using it on your own is dangerous. This article covers what the trials tested, what they found, and why trying it at home is risky and unlikely to help.
What is nitrous oxide, and why test it for depression?
Nitrous oxide, or laughing gas, is an anaesthetic often used in medical and dental care. Researchers started studying it for depression because it blocks NMDA receptors, similar to ketamine, which can quickly improve depression in tough cases. Scientists still do not fully understand how nitrous oxide works for depression, but it likely involves these receptors.
Treatment-resistant depression means that someone has not improved after trying at least two different antidepressants. A pilot study found that up to 30% of people with major depression fall into this group, which is why researchers are looking for new options.
What the 2018 paper is
You may have seen the paper by Nagele, Zorumski, and Conway in the Journal of Clinical Psychopharmacology (2018;38(2):144-148), titled “Exploring Nitrous Oxide as Treatment of Mood Disorders: Basic Concepts.” This is a concepts paper from the research team, not a clinical trial. The authors disclose that Dr Nagele filed for intellectual property protection on nitrous oxide in major depression, and Dr Zorumski is on the scientific advisory board of Sage Therapeutics. These disclosures do not mean the findings are wrong, but they are important to know.
What the clinical trials show
| Study / Phase | Cohort Size & Design | Primary Clinical Findings |
| Proof-of-Concept Trial (2015) | $20$ adults with TRD; 1-hour $50\%$ $\text{N}_2\text{O}$ vs. placebo crossover | Significant drop in HDRS-21 depression scores at $2$ hours and $24$ hours post-inhalation. |
| Phase 2 Dosing Trial (2021) | $20$ adults with TRD; comparing $50\%$, $25\%$, or placebo | $25\%$ concentration offered similar antidepressant gains as $50\%$ while significantly reducing side effects (nausea/headaches). |
| Phase 2b Repeated Dosing Trial | $81$ adults with major depression; repeated sessions over 3 weeks | Demonstrated persistent antidepressant responses over multi-week follow-up periods. |
| SMILE Pilot Trial | Randomized trial vs. midazolam active control | Confirmed feasibility and safety protocols for larger multi-center clinical trials. |
| Suicidal Ideation Analysis | $24$ patients pooled across trials | Exploratory analysis found rapid reductions in acute suicidal ideation. |
A single reported case of remission lasting more than a month after one treatment is encouraging but is one patient. Early studies have shown effects for only up to a week, and the authors of that report noted that no evidence yet shows how long antidepressant effects last.
The results so far are promising, but it is still early. The trials have been small, usually with about 20 people, and only short follow-up periods. They tested carefully measured doses of gas given in a clinic setting.
Why home use is dangerous
The trial results cannot be copied at home, and trying is a real health risk.
- How the harm happens. Nitrous oxide’s toxic effects mainly result from a functional vitamin B12 deficiency, so the damage is chiefly neurologic and blood-related. Most recreational users get it from whipped-cream cartridges, not medical-grade supplies.
- The harm is documented. The largest case series to date included 119 patients with nitrous oxide myeloneuropathy. The authors note it is the second most common recreational drug among 16- to 24-year-olds in the UK, that tingling and numbness were the most common complaint, and that weekly canister use correlated with a blood marker of B12 deficiency.
- It can be serious. In another case series of heavy users, 40% had clearly low B12, 55% showed signs of spinal cord damage on MRI, and 23% were admitted to hospital.
- Treatment is not simple. The main step is stopping the gas, with vitamin B12 and methionine supplements.
- Trials screen people out. A registered trial excluded people with pneumothorax, middle ear occlusion, increased intracranial pressure, or chronic B12 or folate deficiency unless treated. A case report describes similar screening before treatment.
In short, trials used a measured mix of 25% or 50% nitrous oxide with oxygen, for about an hour, with screening and monitoring. Nothing in them supports regular, unsupervised use.
If you are struggling with depression
Start with standard care. Talk to a doctor or mental health professional about treatments that are already approved.
If treatments have not worked, ask your psychiatrist whether you could join a registered clinical trial. You can search ClinicalTrials.gov.
Do not self-treat with nitrous oxide. If you have used it often and notice numbness, tingling or balance problems, seek medical care promptly.
Get urgent help when needed. If you are in crisis or thinking about harming yourself, contact your local emergency services now. In the US, call or text 988.
The bottom line
Nitrous oxide is an interesting experimental option for treatment-resistant depression, with small but encouraging trials of supervised, carefully dosed inhalation. It is not a home remedy, and the same gas used repeatedly outside medical care can cause lasting nerve damage. Follow the trials, and talk to a psychiatrist about proven options and research studies.
Related on Scientifix Digest: Homocysteine Levels Linked to Fatigue and Motivation · Can Probiotics Help Treat Depression in Older Adults?
References
Nagele P, Zorumski CF, Conway C. (2018): Exploring nitrous oxide as treatment of mood disorders: basic concepts. Journal of Clinical Psychopharmacology, 38(2):144-148.
DOI: 10.1097/JCP.0000000000000837
Nagele P, Duma A, Kopec M, et al. (2015): Nitrous oxide for treatment-resistant major depression: a proof-of-concept trial. Biological Psychiatry, 78(1):10-18.
DOI: 10.1016/j.biopsych.2014.11.016
Nagele P, Brown F, Bass V, Yohanna D. (2020): Prolonged remission of major depressive disorder after single nitrous oxide inhalation treatment. Frontiers in Psychiatry, 11:692.
Journal of Neurology, Neurosurgery and Psychiatry (2023): Nitrous oxide-induced myeloneuropathy: a clinical case series. JNNP, 94(9):681-688.
ClinicalTrials.gov. Nitrous Oxide for Major Depressive Disorder, NCT03932825.
Pharmacy Times. Laughing Gas May Treat Depression.