Sustained Mood Improvement With Laughing Gas Exposure: A Randomized Controlled Pilot Trial

Inclusion criteria

• 18 to 65 years of age
• Meeting Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria for Major Depressive Disorder (MDD)
• Current major depressive episode as confirmed by the Mini International Neuropsychiatric Interview (MINI) for DSM-5
• Experiencing moderate to severe depressive episode, as defined by the Hamilton Depression Rating Scale (HAMD)>17
• Failure of two trials of antidepressant therapy of adequate dose and duration, during the current depressive episode
• For women of childbearing potential, use of highly effective or double-barrier methods of contraception. Abstinence is acceptable if it is the preferred and usual lifestyle of the female participant
• Capacity to provide informed consent.

Exclusion criteria

• Acute suicidality defined as score ≥3 on HAMD item 3
• Major Depressive Episode in people with Bipolar Disorder
• Current substance abuse or dependence and/or history of alcohol abuse or dependence within the past year
• Dementia
• Current or lifetime history of schizophrenia or schizoaffective disorder
• Current history of dissociative disorders
• Known history of hypersensitivity or allergy to Nitrous Oxide, Midazolam or any ingredients in the study formulations
• Contraindication to receiving nitrous oxide
• Chronic cobalamin or folate deficiency
• Contraindication to receiving the placebo midazolam
• Use of centrally acting medicinal products, such as opioid agonists, morphine derivatives, benzodiazepines and/or other central nervous system depressants such as barbiturates and alcohol
• Pregnancy or breastfeeding in female participants
• Electroconvulsive therapy within the current depressive episode
• Receiving ketamine treatment within the current depressive episode
• Unwilling to maintain current antidepressant regimen.