SMILE Trial - Imaging Sub-Study

March 23, 2026 updated by: Unity Health Toronto

Sustained Mood Improvement With Laughing Gas Exposure: A Randomized Controlled Pilot Trial - Sub-Study Protocol to Include Neuroimaging

This is a pilot sub-study of an ongoing trial comparing N2O to midazolam in MDD and will examine neuroimaging correlates of treatment response.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Magnetic resonance imaging (MRI) scans of MDD-affected brains have revealed changes in structural and functional connectivity compared to healthy subjects. This pilot sub-study examines structural and functional connectivity associated with MDD-affected patient participants' responsiveness to N2O compared to the midazolam placebo, which induces similar sedative effects. The investigators intend to address the changes in brain functional activity and connectivity between baseline and after a four-week intervention course involving weekly nitrous oxide inhalations measured by MRI.

Study Type

Observational

Enrollment (Actual)

11

Contacts and Locations

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

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5B 1M8
        • St. Michael's Hospital

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

Ages Eligible for Study

14 years to 61 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patient participants were diagnosed as suffering from major depressive disorder (MDD) that meets the criteria of the Diagnosis and Statistical Manual for Mental Disorders (DSM-5), will be eligible to participate in this data collection study. Participants who have agreed to receive N2O treatments as part of the Interventional Psychiatry Clinical Program at St. Michael's Hospital will be approached and recruited.

Description

Inclusion Criteria:

  • Eligible for main nitrous oxide (SMILE) study

Exclusion Criteria:

  • Contraindication for undergoing MRI scans (e.g., hip circumference < 180 cm or metal in the body)

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

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Experimental group
Participants assigned to this intervention arm in the main study will have been administered nitrous oxide at an inspiratory concentration of 50% with concurrent intravenous saline (100mL) for one hour.
Drug: Nitrous oxide gas for inhalation
This sub-study does not have an intervention and based on the main study the participants who have received N2O will be compared with the midazolam placebo group.
Other Names:
  • Nitrous oxide at an inspiratory concentration of 50% with concurrent intravenous saline (100mL)
Placebo group
Participants assigned to this intervention arm in the main study will have been administered 50% oxygen with intravenous midazolam (0.02mg/kg in 100mL) for one hour.
Drug: Midazolam injection
This sub-study does not have an intervention and based on the main study the participants who have received N2O will be compared with the midazolam placebo group.
Other Names:
  • 50% oxygen with intravenous midazolam (0.02mg/kg in 100mL)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brain functional activity and connectivity
Time Frame: 4 weeks from the baseline visit
Changes in brain functional activity and connectivity between baseline and after 4 weeks of receiving the intervention, measured by MR imaging.
4 weeks from the baseline visit

Collaborators and Investigators

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

Sponsor

Unity Health Toronto

Investigators

  • Principal Investigator: Venkat Bhat, MD MSc, Unity Health Toronto

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 (Actual)

March 7, 2023

Primary Completion (Actual)

March 30, 2024

Study Completion (Actual)

June 14, 2024

Study Registration Dates

First Submitted

September 2, 2022

First Submitted That Met QC Criteria

September 2, 2022

First Posted (Actual)

September 6, 2022

Study Record Updates

Last Update Posted (Actual)

March 27, 2026

Last Update Submitted That Met QC Criteria

March 23, 2026

Last Verified

June 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 22-139

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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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