Not yet recruitingPHASE3INTERVENTIONAL

Sustained Mood Improvement With Laughing Gas Exposure

This study, called SMILE, is investigating if laughing gas (nitrous oxide) can significantly lift the mood of individuals experiencing severe depression that hasn't improved with typical treatments. It's a key part of finding new ways to help people living with what doctors call ‘treatment-resistant depression’. Participants will either receive laughing gas with a saline drip, or oxygen with a medicine called midazolam, once a week for four weeks. The study is designed to be 'blinded,' meaning neither you nor the study team will know which treatment you are receiving. Researchers will check in with you over several weeks to see how your mood, daily functioning, and quality of life are changing.

At a glance

Status

Not yet recruiting

Phase

PHASE3

Sponsor

Women's College Hospital

Enrolment target

120

Start

01 Feb 2026

Estimated completion

01 Sep 2028

Major Depressive Disorder Treatment Resistant Depression

What is this study about?

This study, known as SMILE, is a clinical trial exploring new ways to help people who have a type of severe depression called ‘treatment-resistant depression’. This means their depression hasn't gotten better with at least two different antidepressant treatments. The main idea behind this study is to see if laughing gas, also known as nitrous oxide, could be an effective treatment for improving mood in these patients.

The study is set up in a very careful way to make sure the results are reliable. It involves 120 people across various medical centres. Participants will be randomly assigned to one of two groups: one group will breathe in laughing gas while also receiving a saltwater drip (saline) into their vein, and the other group will breathe in pure oxygen while receiving a medicine called midazolam into their vein. Midazolam is used here as an 'active control', meaning it's a medicine that can have an effect, helping researchers understand if any mood changes are specifically due to the laughing gas. The study is also 'blinded', which means neither you nor the doctors giving the treatment will know which group you are in, to help keep things fair and unbiased.

You will receive your assigned treatment once a week for four weeks. After these sessions, the study team will keep in touch with you by phone over the next 12 weeks to see how you are doing. They will ask you to complete questionnaires about your mood, how you're managing in your daily life, and your general quality of life. This helps the researchers understand the long-term effects of the treatments. The aim is to find out if laughing gas could be a safe and effective new option for individuals struggling with severe depression.

Key takeaways

This study explores laughing gas for severe, hard-to-treat depression.
Participation involves weekly treatments for four weeks.
You will not know if you're getting laughing gas or oxygen.
The study includes follow-up check-ins over 12 weeks.
It aims to find new options for depression treatment.
Your safety and well-being are a top priority throughout the study.

Who may be eligible?

To be considered for this study, you need to be an adult between 18 and 65 years old and have a diagnosis of Major Depressive Disorder. Importantly, your current episode of depression must be moderate to severe and haven't improved after trying at least two different antidepressant treatments. If you're a woman who could become pregnant, you'll need to be using reliable birth control during the study.

There are also some reasons why you wouldn't be able to join. For instance, if you are currently having serious thoughts of harming yourself, or if you have been diagnosed with conditions like bipolar disorder, dementia, or schizophrenia. The study also cannot include anyone who has recently struggled with alcohol or drug misuse, or has certain medical conditions. This includes known allergies to the study medications (laughing gas or midazolam) or conditions where receiving laughing gas could be risky, such as certain lung or eye problems, or recent surgeries.

Finally, if you have severe heart or lung problems, or conditions like glaucoma or kidney failure that could make receiving midazolam unsafe, you wouldn't be eligible. The study team needs to make sure it's safe for everyone involved, so they'll check all these points carefully.

Could this study suit you?

Answer these quick questions to see if you may be eligible. This is a guide only — the research team makes the final call.

Are you between 18 and 65 years old?
Has your depression not improved after trying at least two different types of antidepressant medications?
Are you NOT currently having serious thoughts of harming yourself?
Have you NOT been diagnosed with bipolar disorder or schizophrenia?
Are you NOT allergic to laughing gas or midazolam?
Are you using effective birth control if you are a woman of childbearing age?

Answer every question to see your result.

What does participation involve?

If you decide to take part in this study, you will first have some checks to make sure the study is a safe and suitable option for you. If you qualify, you will be randomly assigned to one of two groups: one will receive laughing gas with a saline drip, and the other will receive oxygen with a midazolam drip. You won't know which treatment you are getting.

You will come to the study centre once a week over four weeks for your treatment sessions. Each session will involve breathing in either the laughing gas/oxygen and receiving the intravenous drip. After these four treatment sessions, the study team will follow up with you by phone. These phone calls will happen at 2 weeks, 4 weeks, and 12 weeks after your last treatment visit. During these follow-up calls, you will be asked to fill out questionnaires about how your mood, daily activities, and general well-being are changing. The total time you will be involved in the study, from your first visit to the last follow-up call, will be approximately 16 weeks.

Potential risks and benefits

Participating in this study might offer a potential benefit if the laughing gas helps to improve your depression symptoms, especially if other treatments haven't worked for you. However, there's no guarantee that you will personally benefit. As with any medical treatment, there are potential risks. Laughing gas can have temporary side effects like feeling lightheaded or sick, and there are specific medical conditions that make it unsafe to use. The study team will carefully screen you for these. Midazolam can also have side effects, such as drowsiness. You will be fully informed about all potential side effects before you agree to take part. It's very important to remember that joining a clinical trial is always voluntary, and you have the right to withdraw from the study at any time, for any reason, without it affecting your medical care.

Locations (5)

Sunnybrook Health Sciences Centre
Verified postcode
Toronto, Canada
St. Michael's Hospital (Unity Health)
Verified postcode
Toronto, Canada
Toronto General Hospital (UHN)
Verified postcode
Toronto, Canada
Women's College Hospital
Verified postcode
Toronto, Canada
Toronto Western Hospital (UHN)
Verified postcode
Toronto, Canada

Common questions

What is 'treatment-resistant depression'?

This is when someone's depression hasn't shown enough improvement after trying at least two different antidepressant medications at the right dose for enough time.

What is laughing gas?

Laughing gas, or nitrous oxide, is a gas sometimes used by dentists to help people relax, and it's also used in some medical settings for pain relief. It can make you feel a bit light-headed.

Will I know if I'm getting laughing gas or oxygen?

No, because this is a 'blinded' study, neither you nor the doctors will know which treatment you are receiving. This helps make the study results fair.

How long will I be involved in the study?

You will have weekly treatment sessions for four weeks, followed by phone check-ups for about 12 more weeks. So, about 16 weeks in total.

Can I stop participating in the study if I want to?

Yes, absolutely. Taking part is completely voluntary. You can decide to leave the study at any time, and it won't affect any of your other medical care.

How to find out more

Anesthesia Clinical Trials Unit

actu@uhn.ca 416-340-4800 Official trial record

Always speak to your GP or specialist before deciding to take part in a study.