Nitrous Oxide for Acute Suicidality

Overseen By David Beiser, MD, MSc, FACEP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Chicago

Must not be taking: Ketamine, Folic acid, Vitamin B12

Disqualifiers: Schizophrenia, Bipolar, Pulmonary disease, others

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

Compensation: Varies

Number of Visits: 1

Duration: 45 minutes

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing whether inhaling nitrous oxide gas, along with regular treatment, can quickly reduce suicidal thoughts in patients who are in immediate danger. The gas works by affecting brain chemicals to improve mood rapidly. Researchers hope it will be a safe and effective way to help these patients with minimal side effects. Nitrous oxide has been used for over a century in various medical fields for pain relief and sedation, and recent studies suggest it may be effective for depression that hasn't improved with other treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have taken NMDA-receptor antagonists like ketamine within two weeks before joining the study.

What evidence supports the effectiveness of nitrous oxide as a treatment for acute suicidality?

Research shows that nitrous oxide, commonly known as laughing gas, has been effective in improving symptoms of major depression, especially in cases where other treatments have failed. This suggests it might help with acute suicidality, as depression and suicidality are often linked. ^{1 2 3 4 5}

Is nitrous oxide safe for human use?

Nitrous oxide is generally considered safe when used properly in medical settings, but misuse can lead to serious health issues. Rare cases of death and cognitive problems have been reported, mostly related to recreational use or incorrect administration. ^{3 6 7 8 9}

How is nitrous oxide different from other drugs for acute suicidality?

Nitrous oxide is unique because it acts quickly as an antidepressant and is inhaled, unlike most traditional antidepressants that are taken orally and take longer to work. It has shown promise in treating mood disorders like treatment-resistant major depression, which suggests it might be effective for acute suicidality as well. ^{1 3 5 9 10}

Research Team

Peter Nagele, MD, MSc

Principal Investigator

University of Chicago, Department of Anesthesia and Critical Care

Eligibility Criteria

This trial is for adults aged 18-65 who are acutely suicidal, have non-psychotic major depressive disorder, and are in the emergency department. It's not for those with certain mental health disorders (like schizophrenia or bipolar), severe substance use issues, significant lung disease, pregnant/breastfeeding women, recent NMDA-receptor antagonist treatment users, or specific vitamin deficiencies.

Inclusion Criteria

I am between 18-65 years old, feeling very suicidal, and have major depression without psychosis.

Exclusion Criteria

I am able and willing to give consent for the study.

I haven't taken NMDA-receptor blockers like ketamine in the last two weeks.

Any other factor that in the investigators' judgment may affect patient safety or compliance

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

Treatment

Participants receive a single 45-minute inhalation session of either nitrous oxide or placebo

45 minutes

1 visit (in-person)

Immediate Response Assessment

Evaluate acute reduction in symptoms based on CAT-MH scores at 30-minutes to 1-hour following treatment

1 hour

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and sustained response

24 hours

Treatment Details

Interventions

• Nitrous oxide gas for inhalation
• Placebo

Trial Overview The study tests if inhaling nitrous oxide gas can help people with acute suicidality and depression in the ED compared to a placebo. Both groups also receive standard care. Participants don't know which treatment they get as it's a double-blind RCT.

Participant Groups

Group I: Treatment; Nitrous Oxide 50% Active Control 1 Intervention

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

Group II: Control; Oxygen-air mixture Placebo Group 1 Intervention

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

Nitrous oxide gas for inhalation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Nitrous Oxide for:

• Anesthesia
• Pain relief

Approved in European Union as Nitrous Oxide for:

• Anesthesia
• Pain relief

Approved in Canada as Nitrous Oxide for:

• Anesthesia
• Pain relief

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Findings from Research

Nitrous oxide (N2O) demonstrated a significant reduction in depression severity scores in patients with major depressive disorder (MDD) at 2 hours, 24 hours, and after 2 weeks, indicating both rapid and sustained antidepressant effects based on a meta-analysis of 4 studies involving 133 patients.

While N2O showed promising efficacy in improving depression symptoms, it was associated with a higher risk of nausea and vomiting, suggesting that safety considerations are important when using this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and tolerability of inhaled nitrous oxide in major depressive disorder: a systematic review and meta-analysis. Qiu, Y., Li, L., Duan, A., et al.[2023]

This study aims to investigate whether a single inhaled dose of nitrous oxide (N2O) can provide rapid antidepressant effects in adolescents with major depressive disorder, with assessments at 2 and 24 hours post-administration.

The research will also explore if combining N2O with the SSRI fluoxetine leads to greater mood improvements over 12 weeks compared to fluoxetine alone, addressing the common delay in symptom relief associated with SSRIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide (N2O) and subsequent open-label SSRI treatment of adolescents with depression (NOTAD): study protocol for a randomised controlled trial. Stewart, RM., Wong, JWY., Runions, KC., et al.[2022]

A case of acute nitrous oxide poisoning in a 72-year-old male during surgery highlights the risks associated with incorrect administration of medical gases, emphasizing the importance of proper assembly and handling in clinical settings.

The study suggests that immunohistochemical markers like E-selectin, P-selectin, and HIF 1-α can aid forensic pathologists in diagnosing N2O-related deaths, providing a potential method for identifying hypoxic insults even when traditional signs are nonspecific.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lethal nitrous oxide (N2O) intoxication during surgery: the contribution of immunohistochemistry in identifying the cause of death: a case report. Cioffi, A., Cecannecchia, C., Bosco, MA., et al.[2023]

An 18-year-old female developed severe cognitive dysfunction and encephalatrophy after 5 months of recreational N2O use, suggesting that long-term exposure can lead to significant neurological issues.

Treatment with hyperbaric oxygen therapy (HBOT) over approximately 20 days resulted in a complete recovery of cognitive function, indicating that HBOT may be an effective intervention for N2O-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy to improve cognitive dysfunction and encephalatrophy induced by N2O for recreational use: a case report. Luo, D., Xu, J., Hu, L., et al.[2020]

Nitrous oxide, while commonly used as an anesthetic and analgesic, poses serious risks when abused, as demonstrated by a case of fatal accidental asphyxia.

The case involved a hospital worker who died from hypoxemia and asphyxiation after inhaling nitrous oxide, highlighting the dangers of misuse even in individuals with access to medical supplies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accidental death by nitrous oxide inhalation. Winek, CL., Wahba, WW., Rozin, L.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

The efficacy and tolerability of inhaled nitrous oxide in major depressive disorder: a systematic review and meta-analysis. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Exploring Nitrous Oxide as Treatment of Mood Disorders: Basic Concepts. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Nitrous oxide (N2O) and subsequent open-label SSRI treatment of adolescents with depression (NOTAD): study protocol for a randomised controlled trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Subjective and psychomotor effects of nitrous oxide in healthy volunteers. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Nitrous oxide misuse reported to two United States data systems during 2000-2019. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Lethal nitrous oxide (N2O) intoxication during surgery: the contribution of immunohistochemistry in identifying the cause of death: a case report. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy to improve cognitive dysfunction and encephalatrophy induced by N2O for recreational use: a case report. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Death from Nitrous Oxide. [2018]

10. Ireland pubmed.ncbi.nlm.nih.gov

Accidental death by nitrous oxide inhalation. [2019]