Antidepressant Effects of Nitrous Oxide

NCT05357040 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: IRB18-1856
• Study Type: interventional
• Target: 172
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Major Depressive Disorder; Treatment Resistant Depression

Keywords

Depression; Antidepressant; Nitrous Oxide

Outcome Measures

Primary Outcomes (1)

• Change in HDRS-21 score

  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 Outcomes (11)

• Treatment response

  At 24-hours (following treatment-1)

• Changes in 'Profile of Mood States' scores

  Up to 1-week (following treatment-1)

• Sustainability of treatment response

  Over 7-weeks (length of study participation).

• Treatment dose response comparison

  Over 7-weeks (length of study participation)

• Treatment cycle compliance

  Over 4-weeks (weekly treatment sessions)

Other Outcomes (1)

• Adverse Events

  Over 7-weeks (length of study participation).

Study Arms (2)

Treatment; Nitrous Oxide 50% or 25%, group

ACTIVE COMPARATOR

Four-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned.

Drug: Nitrous oxide gas for inhalation

Control; Oxygen-air mixture, group

PLACEBO COMPARATOR

Four-weekly, 60-minute inhalation sessions of an oxygen and air mixture.

Drug: Placebo

Interventions

Nitrous oxide gas for inhalation DRUG

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.

Also known as: N2O, Laughing gas, Nitrous Oxide, Nitrous

Treatment; Nitrous Oxide 50% or 25%, group

Placebo DRUG

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.

Control; Oxygen-air mixture, group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult (≥18 years, both sexes)
• 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

You may not qualify if:

• A current or past history of bipolar disorder, schizophrenia, or schizoaffective disorder.
• Current obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses
• Active suicidal intention, as determined by clinical interview assessment tool (Sheehan-STS) and clinical examination
• Active or recent (\<12 months) substance use disorder; excluding nicotine
• Administration of NMDA-antagonists (e.g., ketamine) in previous 3 months
• Ongoing treatment with ECT
• Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease
• Pregnancy or breastfeeding
• 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).

Sponsors & Collaborators

• University of Chicago: lead
• The Alfred: collaborator

Study Sites (2)

University of Chicago Medicine

Chicago, Illinois, 60637, United States

RECRUITING

The Alfred Hospital

Melbourne, Victoria, 3004, Australia

RECRUITING

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MeSH Terms

Conditions

Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Depression

Interventions

Endothelium-Dependent Relaxing Factors; Inhalation; Nitrous Oxide

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Vasodilator Agents; Cardiovascular Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Respiratory Mechanics; Respiration; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena; Nitrogen Oxides; Gases; Inorganic Chemicals; Nitrogen Compounds; Oxides; Oxygen Compounds

Study Officials

• Peter Nagele, MD, MSc

  University of Chicago, Department of Anesthesia and Critical Care

  PRINCIPAL INVESTIGATOR

• Paul Myles, MD

  The Alfred Hospital, Department of Anesthesiology and Perioperative Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Frank Brown Jr

CONTACT

773-834-5778; fbrown@dacc.uchicago.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Patient and assessor blinded to study group assigned.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Parallel-group, controlled trial; randomized participants (1:1) to nitrous oxide (Nitrous group) or oxygen-air mixture (FiO2 ≈0.3, Control group). The Nitrous group will be further randomly assigned to either 50% nitrous oxide in oxygen (FiO2 0.5) or 25% nitrous oxide in oxygen (FiO2 0.75).

Study Record Dates

• First Submitted: November 9, 2021
• First Posted: May 2, 2022
• Study Start: June 30, 2021
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: January 12, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); US (1)