Sustained Mood Improvement With Laughing Gas Exposure (SMILE)

December 3, 2025 updated by: Karim Ladha, Women's College Hospital

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

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
120

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.
  • 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
      • 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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score
Time Frame: Baseline to the 2-week follow-up (Visit 6 - Day 35).

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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Proportion of patients who achieved a response
Time Frame: 2-week and 12-week follow-ups post last intervention visit
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
Time Frame: 2-week and 12-week follow-ups post last intervention visit
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
Time Frame: 2-week and 12-week follow-ups post last intervention visit

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
Time Frame: 2-week and 12-week follow-ups post last intervention visit

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
Time Frame: 2-week and 12-week follow-ups post last intervention visit

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
Time Frame: 2-week and 12-week follow-ups post last intervention visit
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
Time Frame: 2-week and 12-week follow-ups post last intervention visit
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
Time Frame: Baseline to Week 12

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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Women's College Hospital

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
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

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Karim Ladha, MD, Women's College Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 1, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 1, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 1, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 21, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 21, 2025

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 3, 2025

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 10, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 3, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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