Reynolds raises important issues regarding interpretation of evidence on nitrous oxide (N2O) in depression, particularly its safety and mechanism. Our review does not advocate long-term or unsupervised use of N2O for major depressive disorders (MDD).1 It synthesises early-phase trials data obtained under controlled conditions to assess whether a consistent signal of antidepressant effect exists. We highlight uncertainties regarding durability of antidepressant effects, optimal dosing, and longer-term safety, and conclude that larger, methodologically rigorous trials are required before clinical implementation can be considered.
Concerns regarding misuse and neurotoxicity of N2O are well recognised.2 Recreational use typically involves repeated, high-concentration exposure (>89%),2 and is associated with vitamin B12 inactivation and neurological complications, including mood and cognitive changes.2 Clinical trials have used brief intermittent inhalations of 25–50% N2O plus oxygen, and excluded individuals with known or suspected cobalamin or folate deficiencies. This makes acute metabolic effects an unlikely explanation for short-term mood changes. Adverse events were also mild and transient across studies. Nonetheless, absence of long-term safety data remains a key limitation, warranting careful investigation.
Reynolds proposes that N2O's antidepressant effects may be mediated by B12 inactivation and downstream effects on folate-dependent methylation pathways. Disturbances in folate and B12 metabolism are relevant to depression, and adjunctive methylfolate treatment can benefit some patients.3,4 However, we are unaware of any methodologically robust evidence demonstrating that the rapid antidepressant effects following N2O administration is mediated by B12 inactivation. Demonstrating such a mechanism would require clinical evidence that rapid mood improvement in depressed individuals is linked to biochemical markers of folate or B12 disruption. In contrast, existing clinical and preclinical data implicate glutamatergic modulation, opioid systems engagement, and alterations in large-scale brain network connectivity (e.g. the Default Mode Network).1 Whether metabolic pathways contribute to, or interact with these processes, are an interesting avenue for future research.
In summary, our review aimed to characterise early phase clinical evidence for N2O in depression, not to establish its mechanism of action or recommend clinical use.1 Further carefully regulated studies are needed to determine whether N2O has a safe and meaningful role in treating depressive disorders, and under what conditions.
Contributors
K.G. led the writing of the response with substantial contributions from S.M. All authors (K.G., A.N.de C., I.M.M, and S.M.) reviewed and approved the final manuscript.
Data sharing statement
The data are available in the original review paper.
Declaration of interests
K.G. is a Managing Editor for Trials (journal). S.M and A.N.de C receive support from the British Association of Psychopharmacology to attend their Summer Meeting and grant funding from the NIHR TRC Mental Health Mission. S.M also receives grant funding from NIHR HTA. A.N.de C has previously received fellowship support from The Wellcome Trust and The Guarantors of Brain. She also is a Section Editor/Editorial Board Member for the British Journal of Psychiatry and a member of the Royal College of Psychiatrists Psychopharmacology Committee.
Acknowledgements
This research was supported by the Office for Life Sciences and the National Institute for Health and Care Research (NIHR) Mental Health Translational Research Collaboration Mission, Midlands Translation Centre. K.G is funded by MRC Trials Methodology Research Partnership (TMRP) Doctoral Training Partnership (DTP), grant number MR/W006049/1. A.N.de C is supported by an NIHR Clinical Lectureship. K.G, A.N.de C, and S.M. also receive funding from the NIHR Oxford Health Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
References
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