By Clare Wilson

Nitrous oxide, also known as laughing gas, has shown promise as a treatment for depression. When people inhaled a low dose as part of a small study, their depression improved over the next two weeks.

It has long been known that nitrous oxide can give a short boost to mood as well as relieving pain – hence its original name of laughing gas – but the effect is thought to wear off quickly. Nitrous oxide is one of the most common anaesthetics, used by hospitals, dental surgeries and paramedics, as well as being available illegally in small capsules for recreational use.

The gas seems to chiefly affect the brain by blocking molecules on nerve cells called N-methyl-D-aspartate (NMDA) receptors. This is the same thing targeted by the stronger anaesthetic ketamine, which also relieves depression; a similar chemical to ketamine has recently been approved as a new intranasal spray treatment.

It isn’t known how NMDA receptors change mood. But as the antidepressant effects of ketamine started to emerge, Peter Nagele, then an anaesthetist at Washington University School of Medicine in St Louis, Missouri, wondered if nitrous oxide had similar potential.

In 2014, he found that one hour’s inhalation of nitrous oxide reduced symptoms for up to a day in people with depression who hadn’t improved after trying standard antidepressant medicines, but the study didn’t record whether the effect lasted any longer.

Prolonged nitrous oxide use can can lead to nausea and headaches. So, in the latest study, Nagele’s team compared half-dose nitrous oxide and full-dose treatment with inhaling a placebo mixture of air and oxygen, in 24 people with treatment-resistant depression. They were given one dose a month for three months.

At two weeks, after the half-dose treatment, depression symptoms had reduced by an average of five points on a commonly used depression rating scale, compared with placebo, a significant benefit. After the full-dose treatment, depression symptoms reduced a little more, although the difference was so small that it could have arisen by chance. The half-dose group also had a much lower incidence of side effects, such as nausea, headaches and light-headedness.

As with ketamine, nitrous oxide has the benefit of improving mood quickly, says Nagele, who is now at the University of Chicago in Illinois. “Something happens in the brain – it’s like flipping a switch. But how this works, no one knows.”

Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.abe1376