Antidepressant Effects of Nitrous Oxide

May 11, 2026 updated by: University of Chicago

Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder

To evaluate the acute and sustained antidepressant effects of nitrous oxide in people with major depressive disorder; and further evaluate these effects by identifying the optimal dose and regimen to guide current practice, and to plan a future large pragmatic trial.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

The investigators are conducting a randomized controlled trial to evaluate the antidepressant effects of nitrous oxide in people with Major Depressive Disorder (MDD). MDD is a global medical condition that causes significant health and economic burden. Recent studies have shown that a single dose of ketamine, an NMDA-antagonist, has fast and long lasting anti-depressant effect. Nitrous oxide, another NMDA-antagonist, is widely used for anesthesia and analgesia, safer to administer and has fewer side effects than ketamine.

A randomized controlled crossover feasibility study showed significant reduction in depressive symptoms at 2 and 24 hours after a single 1-hour treatment session of inhaled nitrous oxide compared with placebo. Nitrous oxide is inexpensive and can be safely administered by any trained clinician. If found to be efficacious, it could be used to provide rapid anti-depressant effect whilst the benefit of traditional anti-depressants has its delayed effect. Another potential application could be in acutely suicidal patients.

This trial will enable confirmation and extension of the findings from the feasibility study, and identify the optimal dose and regimen in a broader population of those with MDD. Participants will be randomized to receive a weekly 1-hour inhalational session of either nitrous oxide or placebo (oxygen-air mixture) for 4 weeks, and the nitrous group will be further randomly assigned to a dose of 50% or 25% nitrous oxide. Depression severity and outcomes related to treatment responses will be continuously assessed by a 'blinded-to-randomization' psychiatry (MD) rater at weekly intervals during study patient participation, using validated psychiatric diagnostics (Hamilton Depression Rating Scale-21 [HDRS-21 or HAM-D]; Profile of Mood States [POMS]; Computerized Adaptive Test-Mental Health [CAT-MH]; Sheehan-STS [S-STS]; Visual Analog Scale [VAS]).

Study Type

Interventional

Phase

  • Phase 2

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

  • Australia
    • Victoria
      • Melbourne, Victoria, Australia, 3004
        • The Alfred Hospital
  • United States
    • Illinois
      • Chicago, Illinois, United States, 60637
        • University of Chicago Medicine

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 and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  1. Adult (≥18 years, both sexes)
  2. DSM-5 criteria for MDD without psychosis, as determined using a structured clinical interview [Mini International Neuropsychiatric Interview], MDD, defined by a pre-treatment score >16 on the HDRS-21 scale and meeting DSM-5 for MDD

Exclusion Criteria:

  1. A current or past history of bipolar disorder, schizophrenia, or schizoaffective disorder.
  2. Current obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses
  3. Active suicidal intention, as determined by clinical interview assessment tool (Sheehan-STS) and clinical examination
  4. Active or recent (<12 months) substance use disorder; excluding nicotine
  5. Administration of NMDA-antagonists (e.g., ketamine) in previous 3 months
  6. Ongoing treatment with ECT
  7. Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease
  8. Pregnancy or breastfeeding
  9. Any contraindications to the use of nitrous oxide (e.g., pneumothorax, middle ear occlusion, elevated intracranial pressure, chronic cobalamin or folate deficiency unless treated with folic acid or vitamin B12).

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
Intervention / Treatment
Active Comparator: Treatment; Nitrous Oxide 50% or 25%, group
Four-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned.
Drug: Nitrous oxide gas for inhalation

60-minute sessions of inhaled 50% nitrous oxide in oxygen (FiO2 0.5) or 25% nitrous oxide in oxygen (FiO2 0.75), administered weekly for 4-weeks.

Administration will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.

Other Names:
  • N2O
  • Laughing gas
  • Nitrous Oxide
  • Nitrous
Placebo Comparator: Control; Oxygen-air mixture, group
Four-weekly, 60-minute inhalation sessions of an oxygen and air mixture.
Drug: Placebo

60-minute sessions of inhaled oxygen-air mixture (FiO2 ≈0.3) to be administered weekly for 4-weeks.

Administration will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in HDRS-21 score
Time Frame: Over 4-weeks from baseline

Monitor changes in Hamilton Depression Rating Scale-21 (HDRS-21) scores to determine whether a series of four, 60-minute sessions of inhaled nitrous oxide vs placebo (once-per-week) has significant antidepressant activity.

The HDRS-21 is an interview-based psychiatric diagnostic used to evaluate depression severity. Scores are calculated by using the first 17 responses of this 21 item questionnaire.

Higher scores are associated with more severe depression:

0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression > 23 = Very Severe Depression Max score = 52
Over 4-weeks from baseline

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treatment response
Time Frame: At 24-hours (following treatment-1)
Treatment response (≥50% reduction on HDRS-21) to nitrous oxide vs placebo will be measured.
At 24-hours (following treatment-1)
Changes in 'Profile of Mood States' scores
Time Frame: Up to 1-week (following treatment-1)

Monitoring daily mood changes using the Profile of Mood States (POMS) a validated 'self-report' psychological diagnostic containing 65 emotions or 'mood states' to determine the pattern of treatment response

Patients rank their current mood states using a scale of 'not-at-all', 'a-little', 'moderately', 'quite-a-lot', 'extremely'. Responses are scored to calculated the Total Mood Disturbance (TMD):

TMD = (tension + depression + anger + fatigue + confusion) - Vigor
Up to 1-week (following treatment-1)
Sustainability of treatment response
Time Frame: Over 7-weeks (length of study participation).

Determine sustained response and remission following study treatments (nitrous vs placebo) using Hamilton Depression Rating Scale-21 (HDRS-21) score.

The HDRS-21 is an interview-based psychiatric diagnostic used to evaluate depression severity. Scores are calculated by using the first 17 responses of this 21 item questionnaire.

Higher scores are associated with more severe depression:

0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression > 23 = Very Severe Depression Max score = 52
Over 7-weeks (length of study participation).
Treatment dose response comparison
Time Frame: Over 7-weeks (length of study participation)

Compare dose response of 25% vs 50% nitrous oxide to establish whether the concentration is related to outcome.

Determined with treatment-by-dose (group) interaction term in a logistic regression model to assess for statistical significance.
Over 7-weeks (length of study participation)
Treatment cycle compliance
Time Frame: Over 4-weeks (weekly treatment sessions)

Evaluate compliance to complete 4-cycle inhalation treatments of nitrous oxide vs placebo.

Determined by ability, inability, or refusal to receive all 4-treatments of randomized inhalation sessions (nitrous oxide vs placebo).
Over 4-weeks (weekly treatment sessions)
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'depression' scores
Time Frame: Over 7-weeks (length of study participation) from Baseline

This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'depression'.

Generated scores include severity and liklihood percentile:

- depression = (%) normal, mild, moderate, severe
Over 7-weeks (length of study participation) from Baseline
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'anxiety' scores
Time Frame: Over 7-weeks (length of study participation) from Baseline

This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'anxiety'.

Generated scores include severity and liklihood percentile:

- anxiety = (%) normal, mild, moderate, severe
Over 7-weeks (length of study participation) from Baseline
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'suicide' scores
Time Frame: Over 7-weeks (length of study participation) from Baseline

This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'suicide'.

Generated scores include severity and liklihood percentile:

- suicide = (%) low, intermediate, high
Over 7-weeks (length of study participation) from Baseline
Suicidal ideation tracking
Time Frame: Over 7-weeks (length of study participation) from Baseline

Suicidal ideation will be be tracked using the Sheehan Suicidality Tracking Scale (S-STS), a validated self-report diagnostic tool designed to assess and monitor suicidality.

The standard S-STS consists of 14 core questions related to suicidality phenomena and is designed for use in clinical research studies and in clinical settings.

Scores are summed based on individual responses 'not-at-all = 0', 'a little = 1', 'moderately = 2', 'very = 3', 'extremely = 4', to generate a summated score (total score), individual factor scores for suicidal ideation, suicidal intent, suicidal planning, suicidal behavior, and non-suicidal self-injury.

All results are monitored in real time by a trained psychiatry (MD) rater.
Over 7-weeks (length of study participation) from Baseline
Visual Analog Scale (VAS)
Time Frame: At Baseline (Prior to treatment-1)

The VAS is a unidimensional measure of pain intensity and use in the field of psychology to measure 'well-being'.

Patients mark on a line the point that they feel represents their perception of their current state, with the score determined by measuring in millimetres from the left hand end of the line to the point that the patient marks.

The range of score from 0-100 mm and represent: no pain (0-4 mm), mild pain(5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm).
At Baseline (Prior to treatment-1)
Treatment remission
Time Frame: At 24-hours (following treatment-1)
Treatment remission (HDRS-21 ≤7 points) to nitrous oxide vs. placebo will be measured.
At 24-hours (following treatment-1)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse Events
Time Frame: Over 7-weeks (length of study participation).

Psychiatric AEs, such as new suicidal ideation and psychotic symptoms; AEs such as nausea and vomiting; or any other AEs determined probably, possibly, or unrelated to the study intervention.

Study patient safety is monitored by the investigators (MD) with experience in critical care anesthesia, and psychiatry, as well as an experienced clinical research team responsible for monitoring and reporting events.
Over 7-weeks (length of study participation).

Collaborators and Investigators

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

Sponsor

University of Chicago

Collaborators

The Alfred

Investigators

  • Principal Investigator: Paul Myles, MD, The Alfred Hospital, Department of Anesthesiology and Perioperative Medicine
  • Principal Investigator: Peter Nagele, MD, MSc, University of Chicago, Department of Anesthesia and Critical Care

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 (Actual)

June 30, 2021

Primary Completion (Actual)

February 27, 2026

Study Completion (Actual)

February 27, 2026

Study Registration Dates

First Submitted

November 9, 2021

First Submitted That Met QC Criteria

April 26, 2022

First Posted (Actual)

May 2, 2022

Study Record Updates

Last Update Posted (Actual)

May 14, 2026

Last Update Submitted That Met QC Criteria

May 11, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB18-1856

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

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

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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