AzTrials
AzTrials

Major Depressive DisorderPhase 3SMILENCT07262008

Sustained Mood Improvement With Laughing Gas Exposure

A Phase 3 study testing Inhalation of Nitrous oxide (Laughing gas) + intravenous saline and inhalation of %100 oxygen + intravenous midazolam in people with Major Depressive Disorder and Treatment Resistant Depression, run by Women's College Hospital at 5 sites in Canada.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 65 years
What is being tested?
Inhalation of Nitrous oxide (Laughing gas) + intravenous saline and inhalation of %100 oxygen + intravenous midazolam
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
120 participants
Where
5 sitesCanada
Study dates
1 Feb 2026to 1 Sep 2028
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 15Show fewer
  • 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.

Trial locations and contacts

5 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Anesthesia Clinical Trials Unit contact

416-340-4800 ext. 4221

actu@uhn.ca

5 sites in 1 country

Canada5 sites

  • Sunnybrook Health Sciences Centre

    Toronto, Ontario, M4N 3M5

  • St. Michael's Hospital (Unity Health)

    Toronto, Ontario, M5B 1W8

  • Toronto General Hospital (UHN)

    Toronto, Ontario, M5G 2C4

  • Women's College Hospital

    Toronto, Ontario, M5S 1B2

    Didem Bozak, 4163236008, didem.bozak@wchospital.ca

  • Toronto Western Hospital (UHN)

    Toronto, Ontario, M5T 2S8

Other trials in Canada

About this study

Official title: 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.

Read the 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.

Being tested
Inhalation of Nitrous oxide (Laughing gas) + intravenous saline, inhalation of %100 oxygen + intravenous midazolam
Medical subject headings
Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Inhalation of Nitrous oxide (Laughing gas) + intravenous salineDrug

    Also called Nitrous oxide

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

  • inhalation of %100 oxygen + intravenous midazolamDrug

    Also called Midazolam

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

Study groups in NCT07262008
Study groupRoleWhat they receive
Intervention GroupExperimentalNitrous oxide+ intravenous Saline
Receives: Drug: Inhalation of Nitrous oxide (Laughing gas) + intravenous saline
Active Control GroupActive comparator100% oxygen+ intravenous midazolam
Receives: Drug: inhalation of %100 oxygen + intravenous midazolam

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (8)

  1. 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.

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

  2. 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.

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

  3. 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

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

  4. 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.

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

  5. 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.

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

  6. 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)

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

  7. 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).

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

  8. 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.

    Measured: Baseline to Week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Dec 2025
  2. Study start1 Feb 2026 (estimated)
  3. Primary completion1 Feb 2027 (estimated)
  4. Study completion1 Sep 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
This study will be a phase III, double-blind, randomized, active placebo-controlled, superiority trial with two parallel arms.
Masking
Double blind
Who is masked
Participant, Outcomes assessor
Enrolment
120 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07262008
Sponsor's protocol ID
5428-CTO
Acronym
SMILE
Status last verified
Dec 2025
First submitted
21 Nov 2025
Last updated
10 Dec 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

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.

    PubMed 40936464

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Inhalation of Nitrous oxide (Laughing gas) + intravenous saline and inhalation of %100 oxygen + intravenous midazolam in people with Major Depressive Disorder and Treatment Resistant Depression, run by Women's College Hospital at 5 sites in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 10 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Anesthesia Clinical Trials Unit (416-340-4800 ext. 4221, actu@uhn.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score (time frame: Baseline to the 2-week follow-up (Visit 6 - Day 35).). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07262008, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Dec 2025.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in