Sustained Mood Improvement With Laughing Gas Exposure

NCT07262008 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: 5428-CTO
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Major Depressive Disorder; Treatment Resistant Depression

Outcome Measures

Primary Outcomes (1)

• Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score

  The MADRS is a 10-item clinician-rated scale used to assess the severity of depressive symptoms and to detect changes over time in response to treatment. It is commonly used in randomized controlled trials due to its sensitivity to change and strong psychometric properties. The MADRS is also recognized by regulatory and health technology assessment agencies, including the U.S. Food and Drug Administration (FDA) and the Canadian Agency for Drugs and Technologies in Health (CADTH), as an established measure for evaluating treatment efficacy in depression. Higher scores indicate worse outcomes and greater severity of depression.

  Baseline to the 2-week follow-up (Visit 6 - Day 35).

Secondary Outcomes (8)

• Proportion of patients who achieved a response

  2-week and 12-week follow-ups post last intervention visit

• Proportion of patients who achieved remission

  2-week and 12-week follow-ups post last intervention visit

• Change in self-reported depressive symptoms

  2-week and 12-week follow-ups post last intervention visit

• Change in cognitive function

  2-week and 12-week follow-ups post last intervention visit

• Change in functioning and disability

  2-week and 12-week follow-ups post last intervention visit

Study Arms (2)

Intervention Group

EXPERIMENTAL

Nitrous oxide+ intravenous Saline

Drug: Inhalation of Nitrous oxide (Laughing gas) + intravenous saline

Active Control Group

ACTIVE COMPARATOR

100% oxygen+ intravenous midazolam

Drug: inhalation of %100 oxygen + intravenous midazolam

Interventions

Inhalation of Nitrous oxide (Laughing gas) + intravenous saline DRUG

Nitrous oxide at an inspiratory concentration of 50% with concurrent intravenous saline (20ml) for one hour.

Also known as: Nitrous oxide

Intervention Group

inhalation of %100 oxygen + intravenous midazolam DRUG

Inspiration of 100% oxygen with concurrent intravenous midazolam (0.02mg/kg, up to 2 mg) for one hour.

Also known as: Midazolam

Active Control Group

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Women's College Hospital: lead
• Anesthesia Clinical Trials Unit (Department of Anesthesia and Pain Management): collaborator
• University Health Network, Toronto: collaborator
• Sunnybrook Health Sciences Centre: collaborator
• Unity Health Toronto: collaborator
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (5)

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

St. Michael's Hospital (Unity Health)

Toronto, Ontario, M5B 1W8, Canada

Location

Toronto General Hospital (UHN)

Toronto, Ontario, M5G 2C4, Canada

Location

Women's College Hospital

Toronto, Ontario, M5S 1B2, Canada

Location

Toronto Western Hospital (UHN)

Toronto, Ontario, M5T 2S8, Canada

Location

Related Publications (1)

• 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 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant

Interventions

Nitrous Oxide; Midazolam

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Nitrogen Oxides; Gases; Inorganic Chemicals; Nitrogen Compounds; Oxides; Oxygen Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Karim Ladha, MD

  Women's College Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anesthesia Clinical Trials Unit

CONTACT

416-340-4800; actu@uhn.ca

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: As noted above, only the individual administering the intervention will be aware of allocation assignment due to safety. The participant and outcomes assessors will be blinded to minimize bias.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD MSc FRCPC

Model Details: This study will be a phase III, double-blind, randomized, active placebo-controlled, superiority trial with two parallel arms.

Study Record Dates

• First Submitted: November 21, 2025
• First Posted: December 3, 2025
• Study Start: February 1, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): September 1, 2028
• Last Updated: December 10, 2025

Record last verified: 2025-12

Locations

CA (5)