Nitrous Oxide for Depression

(SMILE Trial)

Not yet recruiting at 4 trial locations

Overseen By Anesthesia Clinical Trials Unit

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Women's College Hospital

Must be taking: Antidepressants

Must not be taking: Opioids, Benzodiazepines, Barbiturates, Alcohol

Disqualifiers: Bipolar, Schizophrenia, Substance abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether nitrous oxide, commonly known as "laughing gas," can aid individuals with depression unresponsive to other treatments. The study compares nitrous oxide to a common sedative to determine which more effectively reduces depression symptoms. Suitable candidates for this trial include those with moderate to severe depression who have not found relief from at least two different antidepressants. As a Phase 3 trial, it represents the final step before FDA approval, providing participants an opportunity to contribute to a potentially groundbreaking treatment for depression.

Will I have to stop taking my current medications?

The trial requires participants to maintain their current antidepressant regimen, so you won't have to stop taking those medications. However, if you are using certain other medications like opioids, benzodiazepines, or alcohol daily, you may need to stop those before participating.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that nitrous oxide, or "laughing gas," is generally safe for short-term use. Studies have found that a one-hour dose of 50% nitrous oxide is usually well-tolerated by patients. Common side effects might include dizziness, nausea, or euphoria, but these effects are typically mild and temporary. In studies involving individuals with treatment-resistant depression, no serious safety issues were reported. This suggests that nitrous oxide could be a safe option for those considering it for depression relief. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Most treatments for depression, like SSRIs and psychotherapy, can take weeks to show effectiveness. But nitrous oxide works differently, offering the potential for rapid mood improvement. Researchers are excited because nitrous oxide acts on NMDA receptors in the brain, a unique mechanism compared to traditional antidepressants. This quick action and novel approach could offer a new lifeline for those who don't respond well to traditional treatments.

What evidence suggests that nitrous oxide might be an effective treatment for depression?

Research has shown that nitrous oxide might help with depression. One study found that people with severe depression felt better after using nitrous oxide. Another study showed that it quickly improved mood soon after use. In this trial, participants in the intervention group will receive nitrous oxide at an inspiratory concentration of 50% with concurrent intravenous saline for one hour. A controlled study also found that a one-hour session with nitrous oxide reduced depression symptoms within a day. These findings suggest that nitrous oxide could be a promising treatment for people whose depression hasn't improved with other treatments. ^{1 2 3 5 6}

Who Is on the Research Team?

Karim Ladha, MD

Principal Investigator

Women's College Hospital

Are You a Good Fit for This Trial?

This trial is for individuals with treatment-resistant major depressive disorder, meaning their depression hasn't improved after trying other treatments. Specific eligibility details are not provided, but typically participants must meet certain health standards and not have conditions that could interfere with the study.

Inclusion Criteria

Meeting Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria for Major Depressive Disorder (MDD)

I am between 18 and 65 years old.

I have been diagnosed with a major depressive episode.

Exclusion Criteria

Acute suicidality defined as score > 4 on MADRS item 10

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive their respective study intervention once a week for four weeks for a total of four sessions

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with follow-up visits conducted over the phone

12 weeks

3 visits (phone)

What Are the Treatments Tested in This Trial?

Interventions

• Nitrous Oxide

Trial Overview

The study tests if inhaling laughing gas (nitrous oxide) combined with an IV saline solution can reduce depression symptoms compared to inhaling pure oxygen paired with an IV of midazolam, a sedative. Participants are randomly assigned to one of these two options in equal numbers without knowing which one they receive.

How Is the Trial Designed?

Group I: Intervention Group Experimental Treatment 1 Intervention

Nitrous oxide+ intravenous Saline

Group II: Active Control Group Active Control 1 Intervention

100% oxygen+ intravenous midazolam

Who Is Running the Clinical Trial?

Women's College Hospital

Lead Sponsor

Trials

108

Recruited

43,700+

Anesthesia Clinical Trials Unit (Department of Anesthesia and Pain Management)

Collaborator

University Health Network, Toronto

Collaborator

Trials

1,555

Recruited

526,000+

Sunnybrook Health Sciences Centre

Collaborator

Trials

693

Recruited

1,569,000+

Unity Health Toronto

Collaborator

Trials

572

Recruited

470,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40503328/

Antidepressant Effects of Nitrous Oxide in Major ...

We found some evidence that nitrous oxide had beneficial and persistent antidepressant effects in people with severe depression.

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S2352396425004670

Nitrous oxide for the treatment of depression: a systematic ...

N2O shows promise as a rapid-acting intervention to alleviate depressive symptoms, particularly in MDD and TRD. However, further research is ...

3.

sciencedaily.com

sciencedaily.com/releases/2025/12/251202052213.htm

Fast depression relief? Nitrous oxide shows remarkable ...

The meta-analysis reported robust evidence that nitrous oxide can improve mood over the short term after administration. At the same time, the ...

4.

psychiatryonline.org

psychiatryonline.org/doi/10.1176/appi.ajp-rj.2024.200207

Nitrous Oxide in the Treatment of Depression: A Brief Review

Results from a recent RCT (N=38; 15) revealed that a 1-hour dose of inhaled 50% N2O can increase functional connectivity between depression- ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03869736

Nitrous Oxide for the Treatment of Major Depressive Disorder

A randomized controlled crossover feasibility study showed significant reduction in depressive symptoms at 2 and 24 hours after a single 1-hour treatment ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT07262008

Sustained Mood Improvement With Laughing Gas Exposure

SMILE is a multi-centre, parallel-group, blinded randomized controlled trial of 120 patients with treatment resistant depression.