AMSTERDAM — A single inhalation of nitrous oxide (N₂O) was associated with significant, rapid, and sustained improvement of treatment-resistant depression (TRD) in older adults, a new study showed.

Depression symptoms decreased within 24 hours of receiving one 60-minute treatment of N₂O by face mask. Two weeks after treatment, those who received N₂O showed a clinically meaningful decrease in depression scores compared to placebo.

The study adds to a growing body of research that points to a possible benefit from N₂O — also known as “laughing gas” — in people with depression.

“Our findings suggest that N₂O offers a new therapeutic strategy with rapid, sustained, and safe antidepressant effects in older adults with TRD,” reported senior investigator Thomas Desmidt, MD, PhD, head of the Department of Old Age Psychiatry at the University Hospital of Tours, Tours, France.

The findings were presented on October 13 at the 38th European College of Neuropsychopharmacology Congress (ECNP) 2025.

A Focus on Older Adults

Earlier research on N₂O — also known as laughing gas — has shown that the treatment with the gas is associated with improvement in depression symptoms.

One study, previously reported by Medscape Medical News, showed that an 1-hour treatment with N₂O was associated with significant improvements in depressive symptoms for about 85% of patients. However, as with many other N₂O trials, the cohort was younger (median age, 39 years).

As a geriatric psychiatrist, Desmidt was interested in whether the treatment would be effective in older adults. Late-life depression is often resistant to conventional antidepressants, and the dose escalation can be contraindicated due to possible renal or cardiovascular impairment, he explained.

To study the effect of N₂O in older adults, researchers conducted a double-blind, single-dose, randomized, placebo-controlled clinical trial from November 2021 to December 2024, enrolling 60 participants with a mean age of 72 years (66% female).

Participants had no history of cognitive impairment and had depression that did not respond to at least one previous trial of antidepressants.

The groups were well balanced at baseline in terms of current antidepressant, antiepileptic, and benzodiazepine use, with a Montgomery-Åsberg Depression Rating Scale (MADRS) of between 30 and 31.6, and a Maudsley staging of between 8.4 and 8.8, showing “a moderate” level of TRD.

BMI was 25.6 in the N₂O group and 28.5 in the control group.

Participants in both groups received a single inhalation exposure for 60 minutes through a face mask, the treatment group receiving a 50% concentration of N₂O with oxygen, and the control group receiving an ambient air mixture of 78% nitrogen and 21% oxygen (placebo ).

Patients who received N₂O experienced a significant antidepressant effect compared to those on placebo, with significant improvements noted as early as 24 hours (P = .002).

At the 2-week endpoint, the N₂O group showed a significantly greater and clinically meaningful reduction in MADRS scores compared to the control group (mean difference, -6.2 points; P < .001).

These positive findings were supported by both clinician- and self-rated questionnaires, including the Hamilton Depression Rating Scale, the Quick Inventory of Depressive Symptomatology Scale, the State-Trait Anxiety Inventory Scale, the visual analog scale for well-being, the Clinical Global Impression severity rating, and the Scale for Suicide Ideation.

Good Safety Profile

“Nitrous oxide has a very well-established safety profile, even in frail older adults,” Desmidt noted.

In this trial, side effects including anxiety during administration, which was mild and transient, occurring in 17.2% of the treatment arm and also in 10.3% of the control group. That suggests that treatment may not have been the only cause of the anxiety, but possibly also the mask, Desmidt said.

Additionally, numbness, dizziness, and panic attack were reported by 14%, 10%, and 7%, respectively, of those on N₂O vs none in the control group.

Adverse events after exposure were mostly panic attack, reported by 10% of those on N₂O compared to 3% of control participants.

Although there were no dissociative effects with N₂O, there was a small, but statistically significant increase in manic and delusional symptoms with N₂O, “which were not clinically meaningful but probably warrant caution,” he said.

Blinding was “probably achieved” he said, because after the administration, participants were asked if they thought they knew which treatment they received and about half of the N₂O group guessed correctly, “which is close to the chance level,” Desmidt added.

He said blinding to N₂O is plausible in older adults, who are less likely than younger people to experience dissociation or nausea during the treatment.

It is not clear from the literature whether similar antidepressant effects are possible with a shorter duration of N₂O exposure. However, Desmidt said that in his own experience with treating older adults with N₂O in the experimental setting, some patients respond very well to a duration as short as 20 minutes.

Data are also scarce on long-term response to, “but in my experience of routine use of N₂O, it’s not rare to observe an effect lasting several weeks or months after one or two sessions,” Desmidt said.

Ready for the Clinic?

Asked to comment, session co-chair Mark Weiser, MD, chairman, Division of Psychiatry, Sheba Medical Center, Ramat Gan, and professor of psychiatry at the Tel Aviv University School of Medicine, Tel Aviv, both in Israel, said that although the efforts at blinding could have been improved, the findings are promising.

“It’s very encouraging. I’m a practicing clinical psychiatrist and a lot of my drugs don’t work. A lot of my drugs cause side effects. A lot of my drugs are far from being perfect. So this is wonderful,” Weiser told Medscape Medical News.

Paul Myles, MD, from the Department of Anesthesiology and Perioperative Medicine at the Alfred Hospital in Melbourne, Australia, and lead author of another recent study on this topic, said the results of the current study are “compelling” and consistent with previous similar studies.

“I think there is enough evidence now to support a consideration of nitrous oxide therapy in people who have failed at least two conventional treatments, but only if supervised by a psychiatrist — mainly to ensure conventional options have been thoroughly tried beforehand, and to protect against inappropriate and recreational use,” he told Medscape Medical News.

The study funding was not disclosed. Desmidt reported holding shares in Synaptys Neuroscience, serving as a consultant for Bristol Myers Squibb, and receiving personal fees from Janssen and Lundbeck. Weiser and Myles reported having no relevant disclosures.