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Not yet recruiting NCT07262008

Sustained Mood Improvement With Laughing Gas Exposure

Phase III Interventional Major Depressive Disorder Treatment Resistant Depression

For patients and families

In plain language

An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.

What is being studied
The protocol lists: Inhalation of Nitrous oxide (Laughing gas) + intravenous saline, inhalation of %100 oxygen + intravenous midazolam.
Who it may be relevant to
Registry conditions: Major Depressive Disorder, Treatment Resistant Depression. Basic parameters: 18 years — 65 years · All.
What needs checking
Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
Where it takes place
Canada
Next step
Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →

Unsure about the terms? Read our patient guide →

Official title

Sustained Mood Improvement With Laughing Gas Exposure: A Randomized Controlled Double-Blind Trial

Overview

Multi-centre, parallel group, blinded, 1:1 randomized controlled trial to determine the effect of nitrous oxide on reducing symptoms of depression in patients with treatment resistant depression.

Detailed description

SMILE is a multi-centre, parallel-group, blinded randomized controlled trial of 120 patients with treatment resistant depression. Consented eligible patients will be randomized to 1) Inhalation of Nitrous Oxide + Intravenous Saline (intervention Group)or 2) Inhalation of Oxygen + Intravenous Midazolam (Active Control Group). Participants will receive their respective study intervention once a week for four weeks for a total of four sessions. Follow-up visits will be conducted over the phone 2-weeks, 4-weeks, and 12-weeks following the last intervention visit. Questionnaires will be administered to assess change in depressive symptoms, function, and quality of life.

Interventions

  • Drug Inhalation of Nitrous oxide (Laughing gas) + intravenous saline
    Nitrous oxide at an inspiratory concentration of 50% with concurrent intravenous saline (20ml) for one hour.
  • Drug inhalation of %100 oxygen + intravenous midazolam
    Inspiration of 100% oxygen with concurrent intravenous midazolam (0.02mg/kg, up to 2 mg) for one hour.

Primary outcome measures

  • Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score [Time frame: Baseline to the 2-week follow-up (Visit 6 - Day 35).]
Secondary outcome measures (8)
  • Proportion of patients who achieved a response [Time frame: 2-week and 12-week follow-ups post last intervention visit]
  • Proportion of patients who achieved remission [Time frame: 2-week and 12-week follow-ups post last intervention visit]
  • Change in self-reported depressive symptoms [Time frame: 2-week and 12-week follow-ups post last intervention visit]
  • Change in cognitive function [Time frame: 2-week and 12-week follow-ups post last intervention visit]
  • Change in functioning and disability [Time frame: 2-week and 12-week follow-ups post last intervention visit]
  • Change in anxiety symptoms [Time frame: 2-week and 12-week follow-ups post last intervention visit]
  • Change in quality of life [Time frame: 2-week and 12-week follow-ups post last intervention visit]
  • Assessment of Safety via FIBSER Scale [Time frame: Baseline to Week 12]

Eligibility criteria

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 episodes, as defined by the Montgomery-Åsberg Depression Rating Scale (MADRS) > 21
  • 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 > 4 on MADRS item 10
  • Diagnosis of 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
  • Known history of hypersensitivity or allergy to nitrous oxide, midazolam or any ingredients in the study formulations
  • Contraindication to receiving nitrous oxide (e.g. any condition where air is entrapped within a body and its expansion might be dangerous such as, pneumothorax, elevated intracranial pressure, air embolism, recent middle ear, vitreoretinal or bowel obstruction surgeries, etc.)
  • Known chronic cobalamin or folate deficiency (e.g. signs of anemia or neurological symptoms, with plasma levels of homocysteine over 15 µmol/L and abnormal red blood cells and leukocytes on a complete blood count CBC) or current methotrexate use
  • Contraindication to receiving the placebo midazolam (e.g. shock, chronic heart failure, chronic obstructive pulmonary disease, closed-angle glaucoma, renal failure, patients with limited pulmonary reserve or those with severe decline of vital signs)
  • Daily use of centrally acting medicinal products, such as opioid agonists, (e.g. naloxone and naltrexone) morphine derivatives (e.g. oxycodone, hydrocodone, oxymorphone, codeine), benzodiazepines (e.g. diazepam, clonazepam, alprazolam) and/or other central nervous system depressants such as barbiturates (e.g. phenobarbital, pentobarbital, amobarbital) and alcohol within the past week.
  • Pregnancy or breastfeeding
  • Received electroconvulsive therapy within the past six months
  • Received ketamine treatment within the past six months
  • Received repetitive transcranial magnetic stimulation within the past six months
  • Unwilling to maintain current antidepressant regimen.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation
Randomized
Model
Parallel assignment
Masking
Double blind
Primary purpose
Treatment

Study locations

Canada · 5 centers
  • Sunnybrook Health Sciences Centre — Toronto
  • St. Michael's Hospital (Unity Health) — Toronto
  • Toronto General Hospital (UHN) — Toronto
  • Women's College Hospital — Toronto
  • Toronto Western Hospital (UHN) — Toronto

Publications

  • Ladha KS, Lee J, Mattina GF, Pazmino-Canizares J, Wijeysundera DN, Nezhad FG, Tassone VK, Adamsahib F, Lou W, Kennedy S, Bhat V; SMILE Study Investigators. Sustained mood improvement with laughing gas exposure (SMILE): a randomised, placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression. BJPsych Open. 2025 Sep 12;11(5):e208. doi: 10.1192/bjo.2025.10823. PMID 40936464

Identifiers

NCT: NCT07262008 · 5428-CTO

Primary sources (government registries)

View this study on ClinicalTrials.gov ↗