Rewarding Subjective Effects of the NMDAR Antagonist Nitrous Oxide (Laughing Gas) Are Moderated by Impulsivity and Depressive Symptoms in Healthy Volunteers

Abstract

Background Nitrous oxide (N2O) is an anaesthetic gas with both therapeutic and abuse potential. As an NMDAR antagonist, its effects are expected to resemble those of the prototypical NMDAR antagonist, ketamine. Here, we examine the subjective rewarding effects of N2O using measures previously employed in studies of ketamine. We also test for moderation of these effects by bipolar phenotype, depressive symptoms, and impulsivity. Methods Healthy volunteers were randomised to either 50% N2O (n=40) or medical air (n=40). Self-reported rewarding (liking and wanting), and alcohol-like effects were assessed pre-, peri- and post-inhalation. Results Effect sizes for the various rewarding/alcohol-like effects of N2O were generally similar to those reported in studies of moderate-dose ketamine. Impulsivity moderated the subjective reinforcing (liking) effects of inhaled gas, while depressive symptoms moderated motivational (wanting [more]) effects. However, depression and impulsivity had opposite directional influences, such that higher impulsivity was associated with higher N2O-liking, and higher depression, with lower N2O-wanting. Conclusion To the extent that static (versus longitudinal) subjective rewarding effects are a reliable indicator of future problematic drug use, our findings suggests that impulsivity and depression may respectively predispose and protect against N2O abuse. Future studies should examine if these moderators are relevant for other NMDAR antagonists, including ketamine, and novel ketamine-like therapeutics and recreational drugs. Similarities between moderate-dose N2O and moderate-dose ketamine in the intensity of certain subjective effects suggest that N2O may, at least partially, substitute for ketamine as a safe and easily-implemented experimental tool for probing reward-related NMDAR function and dysfunction in humans.

Opioid Properties of Nitrous Oxide and Ketamine Contribute to Their Antidepressant Actions

“…Moreover, in humans, high impulsivity has been positively correlated with high opioid receptor concentrations in the brain, particularly in regions important for motivational behavior and substance abuse ( Love et al, 2009 ). Significantly, Kamboj et al (2021) observed a positive correlation between liking for N 2 O and impulsivity. Since subanaesthetic N 2 O and ketamine have opioid properties ( Smith et al, 1987 ; Sarton et al, 2001 ; Matussek, 2003 ; Emmanouil and Quock, 2007 ; for additional references, see Gillman, 2019a , 2019b), these observations ( Kamboj et al, 2021 ) are more likely to have been due to opioid activity rather than NMDAR blockade.…”

“…Significantly, Kamboj et al (2021) observed a positive correlation between liking for N 2 O and impulsivity. Since subanaesthetic N 2 O and ketamine have opioid properties ( Smith et al, 1987 ; Sarton et al, 2001 ; Matussek, 2003 ; Emmanouil and Quock, 2007 ; for additional references, see Gillman, 2019a , 2019b), these observations ( Kamboj et al, 2021 ) are more likely to have been due to opioid activity rather than NMDAR blockade.…”

“…First, I disagree with the notion, held by these workers and most current investigators in the field, that the psychotropic properties of ketamine and subanaesthetic N 2 O are mainly produced by N-Methyl-D-Aspartate receptor (NMDAR) antagonism (for references, see Kamboj et al, 2021 ). While there is evidence that both N 2 O and ketamine interact with the NMDAR, there is compelling evidence that both substances also interact with opioid receptors ( Smith et al, 1987 ; Sarton et al, 2001 ; Matussek, 2003 ; Emmanouil and Quock, 2007 ; for additional references, see Gillman, 2019a , 2019b) to exert their psychotropic actions.…”

“…I welcome the paper by Kamboj et al (2021) , which continues the recent upsurge of research into the psychotropic properties of non-anaesthetic nitrous oxide (N 2 O). However, I would like to comment on a number of matters raised in their paper ( Kamboj et al, 2021 ).…”

“…Third, these researchers ( Kamboj et al, 2021 ) state N 2 O has “also been tested as a treatment for acute alcohol withdrawal.” This may give the wrong impression. Not only has it been tested ( Gillman et al, 2007 ), but it has been widely and successfully used to treat alcoholic withdrawal states in South Africa and Finland, “and in South Africa.…”