Exploring Nitrous Oxide as Treatment of Mood Disorders

Abstract

Nitrous oxide (laughing gas) has shown early promise as a rapidly acting antidepressant in patients with treatment-resistant major depression and is currently investigated in several clinical trials. Because nitrous oxide is rarely administered outside operating rooms or dental practices, most psychiatrists are not familiar with how nitrous oxide is administered in a medical setting and what regulations guide its use. The goal of this brief review was to educate psychiatrists about the basic concepts of nitrous oxide administration and pharmacology. Furthermore, common misconceptions about nitrous oxide will be discussed.

Prolonged Remission of Major Depressive Disorder After Single Nitrous Oxide Inhalation Treatment

“…The patient approached us whether a treatment with nitrous oxide could be considered. In mid-December 2019 in our initial evaluation, the patient was severely depressed (PHQ-9 [Patient Health Questionnaire]: 22; GAD-7 [Generalized Anxiety Disorder Scale): 14) and after excluding potential contraindications for nitrous oxide (such as chronic vitamin B 12 deficiency, middle ear occlusion) ( 4 ) and providing informed consent, we treated the patient with 50% nitrous oxide (mixed with 50% oxygen) inhalation (Porter Sentry Sedate MXR-D, Porter Instrument Division, Parker Hannifin, Hatfield, PA) for 1 h under continuous standard monitoring conditions (pulse oximetry, non-invasive blood pressure, ECG, end-tidal CO 2 ) with an attending anesthesiologist continuously present. The patient experienced the treatment without any adverse events and recovered within a few minutes after cessation of gas administration.…”

“…While only a single case report, it represents evidence that a single 1-h inhalation treatment with 50% nitrous oxide may improve and even remit major depressive disorder for more than a month ( 4 ). The mechanism of nitrous oxide’s antidepressant effect is poorly understood and it presumed to involve NMDA-receptor antagonism ( 5 ).…”

Mini-Review: A Brief History of Nitrous Oxide (N2O) Use in Neuropsychiatry

“…These investigators suggest that the antidepressant actions of N 2 O are mainly mediated by blockade of NMDA receptors [5, 83]. However, the available evidence does not support their contention.…”

“…Particularly as they themselves [5, 83] are unable to explain a clear-cut discrepancy [4]. They note that while N 2 O and ketamine both have a notable influence on NMDA [5, 21, 83] and opioid receptors [14, 19, 20, 84, 85] and are antidepressant, memantine which acts at NMDA receptors but lacks significant opioid receptor activity [86] is not antidepressant [5, 83].…”

Repeated Nitrous Oxide Exposure Exerts Antidepressant-Like Effects Through Neuronal Nitric Oxide Synthase Activation in the Medial Prefrontal Cortex

“…For N 2 O, a clinical study by Nagele and colleagues applied short-term subanesthetic N 2 O exposure (50% N 2 O + 50% O 2 inhaled for 1 h in a single session), which showed antidepressant effects in TRMD. The subanesthetic dose of N 2 O was selected based on the routine use for analgesia and mild sedation in anesthesiology and dentistry (10,28). In the present study, the 50% N 2 O concentration was selected, but unlike appearances in humans, repeated 2 h rather than a single 1-h subanesthetic N 2 O exposure triggered antidepressant-like effects in mice.…”