N2O for Acute Suicidality and Depression in the ED

NCT ID: NCT05710887

Last Updated: 2026-01-12

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-10-01
• Study Completion Date: 2028-10-01

Brief Summary

Investigators are conducting this double-blind, randomized control trial (RCT), to compare inhaled N2O+ treatment as usual (TAU) versus inhaled placebo+TAU; demonstrating the feasibility and tolerability of the intervention in an emergency department (ED) setting on an acutely suicidal population.

Detailed Description

Past studies have shown that a single dose of ketamine, an NMDA- receptor antagonist has fast and long lasting anti-depressant effect. Although a promising antidepressant and potential anti-suicidal agent, ketamine has very significant side effects including: dissociation, hallucinations, delusional thinking, cognitive impairment, and significant sympathetic nervous system activation.

Nitrous Oxide (N2O) is an NMDA-receptor antagonist with a well-known safety profile used as an analgesic. In a proof-of-concept pilot study, this study's investigator recently demonstrated that N2O also has rapid and marked antidepressant effects in patients with severe treatment-resistant depression (TRD); further sub-analyses showed N2O significantly reduced suicidal ideation (SI). While N2O administration may lead to a reduction in SI, it remains unknown whether severely suicidal patients requiring hospitalization on inpatient psychiatric units would benefit. Investigators hypothesize that N2O will rapidly and safely dampen suicidal thinking with minimal side effects in this population.

Participants will be randomized to receive either N2O or placebo. The study intervention is in tandem with prescribed treatment-as-usual (TAU) by emergency department physicians relating to diagnosis (depression, anxiety, suicidal ideation); which typically involves anxiolytic medications and/or brief psychotherapy administered by care team psychiatry providers.

Study intervention response will be assessed using a self-administered psychiatric diagnostic tool (Computerized Adaptive Testing Mental Health [CAT-MH] scores relating to suicide, depression, and anxiety; to determine whether a single 45-minute inhalation of nitrous oxide vs placebo reduces symptoms.

Conditions

Suicidal Ideation; Major Depressive Disorder; Treatment Resistant Depression

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Treatment; Nitrous Oxide 50%

A single 45-minute session of inhaled 50% nitrous oxide.

Group Type: ACTIVE_COMPARATOR

Nitrous oxide gas for inhalation

Intervention Type: DRUG

Administration of inhaled 50% nitrous oxide in oxygen (FiO2 0.5) 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

A single 45-minute session of inhaled Oxygen-air mixture

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Administration of the placebo (oxygen-air mixture \[FiO2 ≈0.3\]), 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.

Interventions

Nitrous oxide gas for inhalation

Administration of inhaled 50% nitrous oxide in oxygen (FiO2 0.5) 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.

Intervention Type: DRUG

Placebo

Administration of the placebo (oxygen-air mixture \[FiO2 ≈0.3\]), 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.

Intervention Type: DRUG

Other Intervention Names

Nitrous Oxide; Nitrous; N2O; Laughing Gas; Sham

Eligibility Criteria

Inclusion Criteria

• Patients 18-65 years of age, acutely suicidal, presenting to the adult emergency department with documented history of non-psychotic major depressive disorder.

Exclusion Criteria

• Current psychotic or catatonic symptoms as determined by the hospital care team.
• Unable or unwilling to give consent for study participation (ability to provide consent will be established by treating physician)
• Lifetime DSM-V (medical history) diagnoses of schizophrenia, schizoaffective disorders, bipolar disorder, obsessive-compulsive disorder, and panic disorders.
• Meets current DSM-V substance use disorder of greater than mild severity (other than nicotine or marijuana)
• Significant pulmonary disease and/or requiring supplemental oxygen.
• Administration of other NMDA-receptor antagonist treatment (e.g., ketamine) within two weeks of entry into study.
• Contraindications for N2O (pneumothorax, bowel obstruction, middle ear occlusion, elevated intracranial pressure)
• Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12.
• Women who are pregnant or breastfeeding
• Any other factor that in the investigators' judgment may affect patient safety or compliance.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Chicago

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Nagele, MD, MSc

Role: PRINCIPAL_INVESTIGATOR

University of Chicago, Department of Anesthesia and Critical Care

Locations

University of Chicago Medicine

Chicago, Illinois, United States

Countries

United States

Central Contacts

Frank Brown

Role: CONTACT

ftbrownjr@uchicagomedicine.org

773-834-5778

Peter Nagele

Role: CONTACT

pnagele@bsd.uchicago.edu

773-702-2545

Facility Contacts

Frank Brown

Role: primary

ftbrownjr@uchicagomedicine.org

773-834-5778

Other Identifiers

IRB18-1083

Identifier Type: -

Identifier Source: org_study_id