Rewarding Subjective Effects of the NMDAR Antagonist Nitrous Oxide (Laughing Gas) Are Moderated by Impulsivity and Depressive Symptoms in Healthy Volunteers.
Sunjeev K. Kamboj, Hannah Zhao, Luzia Troebinger, Giulia Piazza, Emma Cawley, Vanessa Hennessy, Georges Iskandar, Ravi Das
The International Journal of Neuropsychopharmacology July 23, 2021 DOI: 10.1093/ijnp/pyab009 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Longitudinal Peer reviewed |
|---|---|
| Sample size | 80 |
| Population | Healthy volunteers |
| Interventions | Nitrous oxide Medical air |
| Dose | 50% N2O |
| Topics | Ketamine |
| Keywords | Nmda receptor Alcohol Nitrous oxide Reward |
| Key findings | Nitrous oxide produces subjective rewarding effects similar to moderate-dose ketamine, with impulsivity increasing liking and depressive symptoms decreasing wanting. |
Abstract
Nitrous oxide (N2O) is an anesthetic gas with both therapeutic and abuse potential. Because N2O is an NMDA receptor (NMDAR) antagonist, its effects are expected to resemble those of the prototypical NMDAR antagonist, ketamine. In this study, we examined the subjective rewarding effects of N2O using measures previously employed in studies of ketamine. We also tested for moderation of these effects by bipolar phenotype, depressive symptoms, and impulsivity. Healthy volunteers were randomly assigned 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. 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. 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 predispose and protect, respectively, against N2O abuse. Future studies should examine if these moderators are relevant for other NMDAR antagonists, including ketamine, and novel ketamine-like therapeutic 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 to some extent, serve as substitute for ketamine as a safe and easily implemented experimental tool for probing reward-related NMDAR function and dysfunction in humans.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cited by 6
- Pharmacological modelling of dissociation and psychosis: an evaluation of the Clinician Administered Dissociative States Scale and Psychotomimetic States Inventory during nitrous oxide (‘laughing gas’)-induced anomalous states Psychopharmacology March 26, 2022
- Development and validation of a short-form (6-item) version of the clinician-administered dissociative states scale (CADSS-SF). European Journal of Psychotraumatology June 15, 2026
- Nitrous oxide controls the DCN to VTA dopamine circuit by enhancing AMPA receptor functions during rewarding behavior. Molecular Psychiatry May 13, 2026
- Inhalational nitrous oxide as a transdiagnostic approach for the treatment of suicidal ideation and suicidality in psychiatric inpatients: protocol for a double-blind randomised, controlled clinical single-centre trial. BMJ Open July 16, 2025
- Novel and emerging anesthetic drugs for the treatments of major depression: a comprehensive review of efficacy, mechanism, and outlook. Frontiers in Psychiatry 2025
and 1 more in the library
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- Features of Dissociation Differentially Predict Antidepressant Response to Ketamine in Treatment-Resistant Depression Journal of Affective Disorders February 17, 2018
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