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.
Rationale A significant obstacle to an improved understanding of pathological dissociative and psychosis-like states is the lack of readily implemented pharmacological models of these experiences. Ketamine has dissociative and psychotomimetic effects but can be difficult to use outside of medical and clinical-research facilities. Alternatively, nitrous oxide (N2O) — like ketamine, a dissociative anaesthetic and NMDAR antagonist — has numerous properties that make it an attractive alternative for modelling dissociation and psychosis. However, development and testing of such pharmacological models relies on well-characterized measurement instruments. Objectives To examine the factor structures of the Clinician Administered Dissociative States Scale (CADSS) and Psychotomimetic States Inventory (PSI) administered during N2O inhalation in healthy volunteers. Methods Secondary analyses of data pooled from three previous N2O studies with healthy volunteers. Results Effect sizes for N2O-induced dissociation and psychotomimesis were comparable to effects reported in experimental studies with sub-anaesthetic ketamine in healthy volunteers. Although, like ketamine, a three-factor representation of N2O-induced dissociation was confirmed, and a more parsimonious two-factor model might be more appropriate. Bayesian exploratory factor analysis suggested that N2O-induced psychosis-like symptoms were adequately represented by two negative and two positive symptom factors. Hierarchical cluster analysis indicated minimal item overlap between the CADSS and PSI. Conclusion N2O and ketamine produce psychometrically similar dissociative states, although parallels in their psychosis-like effects remain to be determined. The CADSS and PSI tap largely non-overlapping experiences under N2O and we propose the use of both measures (or similar instruments) to comprehensively assess anomalous subjective states produced by dissociative NMDAR antagonists.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.