The “laughing gas” often used as an anesthetic may someday offer more than pain relief in a dentist’s chair. In the future, it may help people battling treatment-resistant depression.  

A team led by 2007 NARSAD Young Investigator grantee Charles R. Conway, M.D., of Washington University School of Medicine, has found the first evidence that the gas nitrous oxide reduces symptoms in patients whose depression has not responded to long-term treatments. Such treatments include psychotherapy and common antidepressants such as fluoxetine (Prozac) in the class of medications known as selective serotonin reuptake inhibitors. The research appeared online December 9th in Biological Psychiatry.

Nitrous oxide is referred to as “laughing gas” for its ability to induce feelings of euphoria––as anyone who has felt giddy receiving the anesthetic before oral surgery can attest. But the real reason researchers expected nitrous oxide to have antidepressant effects is because it limits activity at so-called NMDA receptors (N-methyl-D-aspartate), “docking ports” for the neurotransmitter glutamate. The most common of the message-carrying chemicals that excite nerve cells in the brain, glutamate has been implicated in the pathology of depression and in information processing throughout the brain. Ketamine––a human and animal anesthetic––blocks NMDA receptors and has been shown experimentally to reduce depressive symptoms in some people with treatment-resistant depression.

In Dr. Conway’s new research, his team found that compared to placebo, nitrous oxide significantly increased (and in a few cases eliminated) depressive symptoms in patients with treatment-resistant depression. The gas had this effect both two and 24 hours after being administered, suggesting it has true antidepressant effects and did not merely lift mood temporarily by inducing euphoria. What the team did not expect to find was that the gas reduced depressive symptoms for as long as a week after it was given, lending stronger support to nitrous oxide’s potential as a source of lasting relief for intractable depression.

The study was a proof-of-concept trial, rather than a large-scale trial to fully test nitrous oxide’s clinical effectiveness. This means the researchers tested the gas on a small group to determine whether it might be a safe, feasible option. Unlike ketamine, which in certain circumstances has been associated with hallucination, nitrous oxide appears to have had no such effects among patients in this study. The patients experienced other temporary side effects, chiefly nausea, vomiting, and brief emotional distress.

The researchers say that the risk of these temporary side effects must be examined more carefully, given that nitrous oxide would likely have to be administered repeatedly to have long-term antidepressant effects. For this same reason, those looking to nitrous oxide as a possible treatment must also consider that the gas––like other agents that temporarily but dramatically lift mood––may lead to dependency if given regularly at certain doses. Repeated use of nitrous oxide can also inactivate vitamin B12 in the body. In the long-term, depleted B12 can lead to complications such as anemia (insufficient functional red blood cells) or myelopathy (abnormalities at the spinal cord).

To make sure that nitrous oxide is indeed a safe option for difficult-to-treat depression, researchers say more research is needed on the antidepressant potential of the gas, and more generally on agents that block NMDA receptors, including ketamine.

Read the abstract.