Which is the best way of using nitrous oxide for treatment and research in neuropsychiatry?

Nitrous oxide (N2O), at low, anxiolytic, and non-anaesthetic doses, can ameliorate depression, with effects occurring immediately and enduring after administration. The antidepressant action likely involves opioid receptors rather than N-methyl-D-aspartate receptor (NMDAr) antagonism, as NMDAr blockade occurs only at higher N2O concentrations. Evidence from naloxone blocking ketamine's antidepressant effect and the ineffectiveness of NMDAr antagonists like memantine supports opioid receptor involvement. N2O may also serve as an adjuvant to routine antidepressant medication.

Study at a glance

Abstract

I welcome the excellent paper by Guimarães et al. which extends research on nitrous oxide (N2O) in neuropsychiatry – a neglected field, since our initial work in 1982 and then 1985 indicating that low, anxiolytic, and non-anaesthetic doses of N2O ameliorate depression. 3 Research has demonstrated that N2O, at subanaesthetic concentrations acts on opioid receptors. We therefore concluded that the antidepressant activity of N2O occurred via opioid activity. Interestingly, this latest work confirms our findings that the antidepressant action of N2O occurred immediately and endured after gas administration. It also supports our unpublished observation that the gas could be used as an adjuvant to routine antidepressant medication. Like Nagele’s group, Guimarães et al. believe that N2O and ketamine are antidepressant mainly via antagonism of the N-methyl-D-aspartate receptor (NMDAr). However, they provide two key references disputing NMDAr involvement. One showed that naloxone blocks the antidepressant action of ketamine, and the other that NMDAr antagonists (like memantine) are not antidepressant. These references and our work indicate that opioid receptors are more likely to be responsible for the antidepressant action of N2O and ketamine. Indeed, NMDAr blockade occurs only at N2O concentrations Table 1 Transition probabilities in respondent heterogeneity, controlled by educational level