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

I welcome the excellent paper by Guimarães et al.¹ which extends research on nitrous oxide (N₂O) in neuropsychiatry – a neglected field, since our initial work in 1982 and then 1985² 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.²,³ We therefore concluded that the antidepressant activity of N₂O occurred via opioid activity.²,³

Interestingly, this latest work¹ confirms our findings that the antidepressant action of N₂O occurred immediately and endured after gas administration.²,³ It also supports our unpublished observation that the gas could be used as an adjuvant to routine antidepressant medication.²,³

Like Nagele’s group,¹ Guimarães et al.¹ 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.¹ One showed that naloxone blocks the antidepressant action of ketamine, and the other that NMDAr antagonists (like memantine) are not antidepressant.¹ These references and our work²,³ 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 which are anaesthetic and not subanaesthetic,⁴ making it unlikely that the NMDAr mediates the antidepressant action observed.¹,⁴

The dental technique (using identical equipment as here¹) never has a fixed goal-concentration, but titrates N₂O using each individual’s dose-response to reach concentrations achieving maximum relaxation while maintaining consciousness. In short, the concentration varies, depending on each individual’s dose-response to N₂O.²,³ Apart from avoiding anaesthesia it also minimises side effects.³

Because a relatively loose nasal mask was used without N₂O end tidal measurements¹ the inhaled gas concentration at the alveolus cannot be assumed. Thus, the reading of 50% on the rotameter alone is a poor reflection of the actual gas volume inhaled.³ Indeed, nasal masks produce N₂O concentrations at the alveolus which are less than half the rotameter setting.³

Guimaraes et al chose 50% N₂O mistakenly believing that it produces minimal sedation and refer to the American Anesthesiology Association Guidelines.¹,⁵ These guidelines clearly states: “less than 50%” N₂O is required to produce minimal sedation, which encompasses the dental titration method.³ Since a fixed goal concentration ignores the individual sensitivities to the gas, it is unsurprising that they “could find no data” giving the “best concentration of N₂O”¹ for depression. Perhaps, this indicates that the correct antidepressant dose is best achieved by titrating, to each individual’s requirements, without an anaesthetist.²-⁵

References

• ¹
  Guimarães MC, Guimarães TM, Hallak JE, Abrão J, Machado-de-Sousa JP. Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial. Braz J Psychiatry. 2021 Feb 15:S1516-44462021005005201. doi: http://10.1590/1516-4446-2020-1543 Epub ahead of print</pub-tl>.
  » http://10.1590/1516-4446-2020-1543
• ²
  Gillman MA, Matussek N, Lichtigfeld FJ. Effect of nitrous oxide on depressive patients and volunteers. In: Pichot P, Berner P, Wolf R, Thau K, eds. Biological psychiatry, higher nervous activity. Boston: Springer; 1985. p. 397-403.
• ³
  Gillman MA. Mini-review: a brief history of nitrous oxide (N2O) use in neuropsychiatry. Curr Drug Res Rev. 2019;11:12-20.
• ⁴
  Jevtović-Todorović V, Todorović SM, Mennerick S, Powell S, Dikranian K, Benshoff N, et al. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998;4:460-3.
• ⁵
  American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology. 2002;96:1004-17.

Publication Dates

• Publication in this collection
  10 May 2021
• Date of issue
  Jul-Aug 2021

History

• Received
  15 Mar 2021
• Accepted
  29 Mar 2021