Nitrous oxide, otherwise known as laughing gas, may represent a new weapon in the fight against depression after a study found that inhaling the heady substance for just one hour produces lasting improvements in patients who have failed to respond to other treatments. Appearing in the journal Science Translational Medicine, the new research suggests that low doses of the gas are sufficient to produce a significant therapeutic effect, with none of the undesirable side-effects associated with higher doses.
"A large percentage of patients don't respond to standard antidepressant therapies – the patients in this study had failed an average of 4.5 antidepressant trials – and it's very important to find therapies to help these patients," explained study author Charles R. Conway in a statement.
"That we saw rapid improvements in many such patients in the study suggests nitrous oxide may help people with really severe, resistant depression."
Standard anti-depressants such as selective serotonin reuptake inhibitors work by interacting with serotonin receptors in the brain, yet can take several weeks to start producing results. Nitrous oxide, however, works on NMDA receptors, and is therefore capable of producing noticeable effects much faster.
In an earlier study, researchers found that inhaling a mixture containing 50 percent nitrous oxide and 50 percent oxygen generates rapid improvements in depressive symptoms. However, the patients enrolled in that study were only monitored for 24 hours, meaning the researchers were unable to determine whether these effects were long-lasting or transient. Furthermore, a number of participants developed side effects such as nausea, light-headedness, and sedation.
The study authors decided to investigate whether lower doses of the gas generate similar improvements, and how long these changes persist. To do so, they recruited 24 patients with treatment-resistant depression to take part in three dosing sessions spaced four weeks apart, during which they were asked to inhale laughing gas for one hour.
In one of these sessions, patients received laughing gas consisting of 50 percent nitrous oxide and 50 percent oxygen, while another saw them take in 25 percent nitrous oxide and 75 percent oxygen, and a placebo containing no nitrous oxide was supplied during the remaining session.
Results showed that the antidepressive effects produced by the inhalation of 25 percent nitrous oxide were comparable to those generated by the 50 percent concoction, and that the improvements associated with both concentrations lasted for a full four weeks.
However, the reductions in depression at the two-week point were slightly larger following treatment with 50 percent nitrous oxide than 25 percent. This extra benefit is offset, however, by the fact that the lower concentration was associated with a four-fold decrease in side effects.
“When [patients] received 25% nitrous oxide, no one developed nausea,” said Conway. “And that lower dose was just about as effective as the higher dose at relieving depression."
By the end of the study, 85 percent of participants saw their depressive symptoms improve by a full category, dropping from severe to moderate, for example. Fifty-five percent meanwhile, experienced improvements in at least half of their depressive symptoms, while 40 percent were in remission, meaning they no longer qualified for a clinical depression diagnosis.
In acting on NMDA receptors, laughing gas appears to work via the same mechanism as ketamine, which has been greatly celebrated as a fast-acting anti-depressive. However, the study authors note that the lack of side effects associated with low-dose nitrous oxide may make it a more suitable treatment.
"One potential advantage to nitrous oxide, compared with ketamine, is that because it's a volatile gas, its anesthetic effects subside very quickly," said Conway. "It's similar to what happens in a dentist's office when people drive themselves home after getting a tooth pulled.”
“After treatment with ketamine, patients need to be observed for two hours following treatment to make sure they are OK, and then they have to get someone else to drive them."