Subjective, idiopathic, non-pulsatile tinnitus ("tinnitus") is perception of sound without the presence of an external acoustic stimulus. Approximately 50 million Americans experience chronic tinnitus and of these, 10 million have bothersome tinnitus. Bothersome tinnitus is associated with poorer working memory, slower processing speeds and reaction times, and deficiencies in selective attention.

Currently, effective therapies for tinnitus remain limited. Examples of therapies include external sound therapy to mask the perceived sound, behavioral therapy to habituate the patient to the perceived sound, and counseling such as cognitive behavioral therapy to address the bother and impact that tinnitus has on people's lives. Surgical treatment such as nerve transection remains controversial given its lack of efficacy and adverse event profile. There are no drugs approved by the FDA for the treatment of tinnitus. Antidepressant and antianxiety medications are prescribed to patients with tinnitus with limited benefit.

Nitrous oxide is an N-methyl-D-aspartate (NMDA) receptor antagonist, a class of drugs shown to have antidepressant effects. A previous trial examined the use of nitrous oxide as a treatment for major depressive disorder (MDD). Generally, NMDA receptors promote excitation at synapses throughout the auditory pathway and play diverse roles in synaptic development and auditory information processing. In the setting of chronic damage to the auditory system, overactivation of NMDA receptors leads to aberrant spontaneous neuronal firing in the cochlea and auditory brainstem structures, which can further perpetuate damage and disease in a feed-forward mechanism. Studies by Guitton et al. and Puel et al. showed that administration of NMDA receptor antagonists prior to the administration of salicylate was effective in preventing acute excitotoxic tinnitus, establishing that salicylate induces tinnitus through its action on NMDA receptors. Thus, NMDA receptors are thought to be implicated in the generation and perpetuation of several auditory diseases including tinnitus. The investigators hypothesized that the administration of nitrous oxide, an NMDA receptor antagonist, may be a therapeutic strategy in the treatment of tinnitus.

The study was a randomized placebo-controlled crossover trial. Each participant attended two intervention sessions, one "treatment" and one "placebo". Participants eligible to participate in the study were randomly assigned to receive either placebo followed by nitrous oxide or nitrous oxide followed by placebo, according to a computer-generated randomization sequence. Only the statistician and the anesthesiology team directly involved in administration of nitrous oxide and placebo had access to the group assignments. All participants and other study team members administering survey assessments remained blinded. The two intervention sessions were held at least two weeks apart and were indistinguishable in setting, setup, and monitoring in order to maintain blinding for the participants and study team members. All intervention sessions were performed at the Washington University Clinical Research Unit, a component of the Center for Applied Research Sciences.