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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether inhaling nitrous oxide gas can help individuals with acute suicidal thoughts and major depressive disorder. Participants will receive either a 45-minute session of nitrous oxide inhalation or a placebo (a fake treatment), alongside their usual care. The trial aims to determine if this treatment is safe and manageable in an emergency department setting. It seeks individuals diagnosed with non-psychotic major depressive disorder who are currently experiencing suicidal thoughts. As a Phase 2 trial, it measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that nitrous oxide is usually well-tolerated for mental health issues like depression and suicidal thoughts. In one study, 54% of patients with treatment-resistant depression experienced a significant reduction in suicidal thoughts after using nitrous oxide, compared to only 12% who did not use it. Another study found that nitrous oxide quickly lowered the risk of suicide in people with bipolar disorder after just two short sessions. These studies suggest that nitrous oxide can be a safe option, with no major side effects reported in these cases. However, since this trial remains in the early stages, more research is needed to confirm its safety for people with severe suicidal thoughts. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for acute suicidality, such as antidepressants and psychotherapy, which can take weeks to show effects, nitrous oxide offers a rapid-acting intervention. Researchers are excited about nitrous oxide because it is inhaled and can potentially provide relief in just a single 45-minute session. This gas acts differently from typical treatments by modulating the brain's glutamate system, which may quickly alleviate symptoms of acute suicidality. This unique approach holds promise for providing immediate support to those in crisis.

What evidence suggests that nitrous oxide gas might be an effective treatment for acute suicidality?

Research shows that nitrous oxide, or "laughing gas," may quickly reduce suicidal thoughts. In this trial, participants will receive either a single 45-minute session of inhaled 50% nitrous oxide or a placebo of an oxygen-air mixture. Studies have found that nitrous oxide can lessen suicidal thinking in people with treatment-resistant depression and those with bipolar disorder. One study found a strong connection between fewer suicidal thoughts and less overall depression shortly after using nitrous oxide. Another study observed a noticeable decrease in both depression and suicidal risk after just two sessions with nitrous oxide. These findings suggest that nitrous oxide could be a promising option for quickly addressing severe suicidal thoughts. ^{1 2 4 6 7}

Who Is on the Research Team?

Peter Nagele, MD, MSc

Principal Investigator

University of Chicago, Department of Anesthesia and Critical Care

Are You a Good Fit for This Trial?

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.

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03736538

NCT03736538 | Nitrous Oxide- Suicidal Ideation In a recent pilot study, the investigators of this study demonstrated that the NMDA antagonist nitrous oxide is effective in TRMD, reducing depressive symptoms, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12273121/

Inhalational nitrous oxide as a transdiagnostic approach for ... The primary outcome is the change in Beck Scale for Suicidal Ideation scores between the day before and the day after inhalation. A second ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2667174325001053

No Laughing Matter: Nitrous Oxide and Depression They have shown that nitrous oxide has significant short-term antidepressant effects and can meaningfully reduce suicidal thinking in individuals with TRD.

4. bbrfoundation.org bbrfoundation.org/content/nitrous-oxide-laughing-gas-may-have-rapid-acting-anti-suicidal-effects

Nitrous Oxide (“Laughing Gas”) May Have Rapid-Acting ... Also, the team noted, 24 hours post-inhalation, “there was a strong relationship between reduction in suicidal ideation and reduction in total ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0013700625000636

Nitrous oxide reduced suicidal ideation in bipolar ... N 2 O showed rapid efficacy in reducing suicidal risk after two sessions of 20 and 40 mins, with a notable decrease in depressive symptoms and suicidal ...

6. psychiatrist.com psychiatrist.com/jcp/nitrous-oxide-reduced-suicidal-ideation-in-treatment-resistant-major-depression/

Nitrous Oxide Reduced Suicidal Ideation in Treatment- ... In this exploratory analysis, 54% of TRD patients receiving nitrous oxide had a reduction in suicidal ideation, compared with 12% in the ...

7. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp-rj.2024.200207

Nitrous Oxide in the Treatment of Depression: A Brief Review A pooled analysis of three RCTs (N=30) testing N2O as a depression treatment (18) revealed no effect of N2O on suicidal ideation at 2 hours ...