Sustained Mood Improvement With Laughing Gas Exposure (SMILE)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Major Depressive Disorder; Treatment Resistant Depression
• Intervention / Treatment: Drug: Inhalation of Nitrous oxide (Laughing gas) + intravenous saline; Drug: inhalation of %100 oxygen + intravenous midazolam

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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anesthesia Clinical Trials Unit; Phone Number: 4221 416-340-4800; Email: actu@uhn.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5S 1B2
      • Women's College Hospital
      • Contact: Didem Bozak; Phone Number: 4163236008; Email: didem.bozak@wchospital.ca
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital (UHN)
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital (Unity Health)
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital (UHN)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18 to 65 years of age
2. Meeting Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria for Major Depressive Disorder (MDD)
3. Current major depressive episode as confirmed by the Mini International Neuropsychiatric Interview (MINI) for DSM-5
4. Experiencing moderate to severe depressive episodes, as defined by the Montgomery-Åsberg Depression Rating Scale (MADRS) > 21
5. Failure of two trials of antidepressant therapy of adequate dose and duration, during the current depressive episode
6. 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
7. Capacity to provide informed consent.

Exclusion Criteria:

1. Acute suicidality defined as score > 4 on MADRS item 10
2. Diagnosis of Bipolar Disorder
3. Current substance abuse or dependence and/or history of alcohol abuse or dependence within the past year
4. Dementia
5. Current or lifetime history of schizophrenia or schizoaffective disorder
6. Known history of hypersensitivity or allergy to nitrous oxide, midazolam or any ingredients in the study formulations
7. 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.)
8. 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
9. 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)
10. 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.
11. Pregnancy or breastfeeding
12. Received electroconvulsive therapy within the past six months
13. Received ketamine treatment within the past six months
14. Received repetitive transcranial magnetic stimulation within the past six months
15. Unwilling to maintain current antidepressant regimen.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Group; Nitrous oxide+ intravenous Saline	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.; Other Names: Nitrous oxide
Active Comparator: Active Control Group; 100% oxygen+ intravenous midazolam	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.; Other Names: Midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients who achieved a response	Defined as a 50% reduction in MADRS score between baseline and the 2- and 12-week follow-ups.	2-week and 12-week follow-ups post last intervention visit
Proportion of patients who achieved remission	Defined as achieving both a response and a MADRS score <10 at the 2- and 12-week follow-ups.	2-week and 12-week follow-ups post last intervention visit
Change in self-reported depressive symptoms	Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR-16) Higher scores are associated with increased severity in depressive symptoms Total scores range from 0-27 Normal/No Depression 0-5 Mild Depression 6-10 Moderate Depression 11-15 Severe Depression 16-20 Very Severe Depression 21-27	2-week and 12-week follow-ups post last intervention visit
Change in cognitive function	Assessed using the Digit Symbol Substitution Test (DSST) The Digit Symbol Substitution Test (DSST) measures processing speed, attention, and executive function by assessing a person's ability to quickly and accurately pair numbers with symbols according to a key. To score it, the total number of correct symbol-for-number substitutions completed within a timed period (typically 90-120 seconds) is counted. Higher scores indicate better performance.	2-week and 12-week follow-ups post last intervention visit
Change in functioning and disability	Assessed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) Total Score Range: 0-100 0 = No disability 100 = Full disability WHODAS 2.0 scores reflect overall functioning across six domains (cognition, mobility, self-care, getting along, life activities, and participation). Higher scores indicate greater functional impairment.	2-week and 12-week follow-ups post last intervention visit
Change in anxiety symptoms	Assessed using the Generalized Anxiety Disorder 7-item scale (GAD-7) A GAD-7 score is interpreted based on its total score, with the range being 0-21, where higher scores indicate more severe anxiety. The standard interpretation is: 0-4 (minimal anxiety), 5-9 (mild anxiety), 10-14 (moderate anxiety), and 15-21 (severe anxiety)	2-week and 12-week follow-ups post last intervention visit
Change in quality of life	Assessed using the EuroQoL 5-Dimension 5-Level scale (EQ-5D-5L) The EQ-5D-5L is a standardized, participant-reported measure of health-related quality of life. It assesses five dimensions-mobility, self-care, usual activities, pain/discomfort, and anxiety/depression-each rated across five levels of severity (no problems to extreme problems). Responses are converted into a single index score, typically ranging from <0 (health states worse than death) to 1.0 (full health).	2-week and 12-week follow-ups post last intervention visit
Assessment of Safety via FIBSER Scale	Safety outcomes will be assessed by evaluating adverse events in both general and specific terms using the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale. FIBSER ; higher score indicates worse outcomes. Clinical Relevance of Question 3: 0-2 = no changes needed; 3-4 = side effects should be addressed; 5-6 = change treatment.	Baseline to Week 12

Collaborators and Investigators

• Sponsor: Women's College Hospital
• Collaborators: University Health Network, Toronto; Sunnybrook Health Sciences Centre; Canadian Institutes of Health Research (CIHR); Unity Health Toronto; Anesthesia Clinical Trials Unit (Department of Anesthesia and Pain Management)
• Investigators: Principal Investigator: Karim Ladha, MD, Women's College Hospital

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: November 21, 2025
• First Submitted That Met QC Criteria: November 21, 2025
• First Posted (Estimated): December 3, 2025

Study Record Updates

• Last Update Posted (Actual): December 10, 2025
• Last Update Submitted That Met QC Criteria: December 3, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Inorganic Chemicals; Nitrogen Compounds; Benzazepines; Oxides; Oxygen Compounds; Gases; Benzodiazepines; Nitrogen Oxides; Midazolam; Nitrous Oxide
• Other Study ID Numbers: 5428-CTO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No