The dentist's office might be the last place you'd look to find a quick cure for an implacable bout of depression.

New research, however, suggests that laughing gas — the mixture of nitrous oxide and oxygen that eases the pain and anxiety of having dental work — may help ease treatment-resistant depression in about the time it takes to fill a cavity.

Interest in laughing gas as an antidepressant began with another sedative-turned-party-drug — ketamine.

The anesthetic ketamine induces a euphoric "out-of-body" high. When administered to the suicidally depressed, it is thought to be a promising "rescue" drug that offers quick relief, filling the four-to-six-week gap needed for many standard antidepressant medications to take full effect.

Like ketamine, nitrous oxide is an antagonist of the brain's NMDA receptor, a key bit of the cerebral machinery. Psychiatrists and anesthesiologists at Washington University in St. Louis wondered whether nitrous oxide — a far less addictive drug than ketamine and one that may have fewer unforeseen side effects — might have the same benefits.

In a small pilot study published in the journal Biological Psychiatry, researchers compared the effects of an hour of inhaled nitrous oxide on 20 patients whose depression had failed to yield to standard antidepressants.

Each subject had a session of laughing gas as well as a placebo, spaced a week apart. The researchers gauged the patients' depressive symptoms two hours after their session, 24 hours later and a week later.

One day after nitrous oxide treatment, three patients reported that their symptoms had disappeared almost completely, while another seven reported significant improvement. Seven patients reported mild improvement in their symptoms. No patients said their symptoms worsened after treatment with nitrous oxide.

A day after they received the placebo treatment, none of the patients reported their depression was virtually gone, and one patient reported feeling worse the next day.

As is common in antidepressant trials, some placebo effect was evident: five patients reported feeling mild improvement and two reported significant improvement in their symptoms a day after receiving the sham treatment.

Washington University anesthesiologist Dr. Peter Nagele said it's still a mystery why nitrous oxide and ketamine would have such a rapid antidepressant effect.

It's clear that NMDA receptors — docks throughout the brain at which the neurotransmitter glutamate can anchor — play a key role in depression. But how ketamine or nitrous oxide change glutamate's action to ease depression "is the million-dollar question," Nagele said.

Nitrous oxide is relatively simple to administer and appears to be a more benign drug than ketamine.

But Nitrous oxide appears to have some side effects: Three depression patients reported nausea and vomiting after a dose, two complained of headaches and three reported anxiety. Some safety issues also need to be addressed for laughing gas to be used as an antidepressant bridge. After receiving nitrous oxide, patients in other studies have shown temporarily altered metabolism of vitamin B12.

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