Nitrous Oxide for Suicidal Thoughts

Enrolling by invitation at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must not be taking: NMDA antagonists

Disqualifiers: Schizophrenia, Bipolar, Substance abuse, others

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether inhaled nitrous oxide can reduce suicidal thoughts in individuals with treatment-resistant major depression (TRMD). Researchers compare nitrous oxide, a gas often used for sedation, with a placebo to determine its effectiveness as a treatment. The trial targets those with unipolar depression who currently experience suicidal thoughts and have not found relief from standard treatments. Participants will receive either nitrous oxide or a placebo during several inhalation sessions as part of their standard care. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

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 participate if you have taken NMDA-receptor antagonists like ketamine within two weeks before the study.

Is there any evidence suggesting that nitrous oxide is likely to be safe for humans?

Research has shown that nitrous oxide is generally safe in medical settings. It often helps patients relax during dental and surgical procedures. Earlier studies found that patients with depression unresponsive to other treatments reported fewer suicidal thoughts after receiving nitrous oxide. Specifically, 54% of these patients experienced a significant reduction in such thoughts. This is notable because nitrous oxide acts quickly, often within just two sessions.

While nitrous oxide is usually safe, some individuals might experience mild side effects like dizziness or nausea, which typically resolve quickly. The current study is in an early stage, focusing primarily on assessing the treatment's safety. This phase ensures the treatment is safe for participants before further research proceeds. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Unlike most treatments for suicidal thoughts, which often include antidepressants or psychotherapy, nitrous oxide offers a unique approach. It's an NMDA antagonist, meaning it works on different brain pathways than traditional medications. This novel mechanism might provide rapid relief, potentially showing effects in just hours or days instead of weeks. Researchers are excited because it could offer a fast-acting option for those in acute crisis, which is not typical of existing treatments.

What evidence suggests that nitrous oxide might be an effective treatment for suicidal thoughts?

Research has shown that nitrous oxide, or "laughing gas," may reduce suicidal thoughts in individuals with treatment-resistant major depression (TRMD). In a small study, 54% of TRMD patients who received nitrous oxide experienced fewer suicidal thoughts, compared to 12% who did not receive the treatment. Participants in this trial will receive either nitrous oxide or a placebo gas. Nitrous oxide blocks certain brain receptors involved in mood control. It has demonstrated short-term antidepressant effects and can quickly reduce suicidal thinking. These promising results suggest that nitrous oxide might be a helpful option for those not responding to standard depression treatments. ^{2 3 6 7 8}

Who Is on the Research Team?

Charles R Conway, MD

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with major depressive disorder without psychosis, experiencing acute suicidal thoughts. They must score ≥18 on the HDRS-21 scale and be admitted voluntarily to a specific hospital's inpatient Psychiatric Units. Excluded are those with certain psychiatric diagnoses, recent NMDA antagonist treatment, severe personality disorders, significant pulmonary disease, past head trauma or substance abuse.

Inclusion Criteria

I have been diagnosed with major depression without psychosis.

I have been diagnosed with major depression without psychosis.

Moderate to severe suicidal ideation (SI) defined as a score ≥3 on the HDRS-21 suicide item (item #3)

Exclusion Criteria

You have struggled with drug or alcohol addiction, not including smoking, in the past year.

I am currently undergoing electroconvulsive therapy.

I am not pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Inpatient Treatment

Participants receive a maximum of four one-hour inhalation sessions of either nitrous oxide or placebo gas as inpatients

7 days

4 visits (in-person)

Outpatient Booster Sessions

Participants receive 2 booster sessions of inhalation treatment as outpatients

Approximately 53 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nitrous Oxide
• Placebo gas

Trial Overview The study tests if inhaling nitrous oxide can help reduce suicidal thoughts in patients with treatment-resistant depression. It compares standard treatments plus nitrous oxide inhalation against standard treatments plus placebo gas over several sessions both as inpatients and outpatients.

How Is the Trial Designed?

Group I: Nitrous Oxide Experimental Treatment 1 Intervention

Nitrous oxide, an odorless, colorless gas typically used as an induction agent for general anesthesia or for dental sedation, is a known N-methyl-D-aspartate (NMDA) antagonist. It will be given at 50% nitrous oxide/50% oxygen in this study. Participants will undergo a maximum of four one hour inhalation sessions as inpatients and 2 booster sessions as outpatients during which they will receive inhaled nitrous oxide.

Group II: Placebo Gas Placebo Group 1 Intervention

Placebo gas given at 50% nitrogen \[inert\]/50% oxygen. Participants will undergo a maximum of four one hour inhalation sessions as inpatients and 2 booster sessions as outpatients during which they will receive placebo gas.

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

Approved in European Union as Nitrous oxide for:

• Anesthesia
• Pain relief
• Hypoxic respiratory failure in neonates

Approved in United States as Nitrous oxide for:

• Anesthesia
• Pain relief
• Hypoxic respiratory failure in neonates

Approved in Canada as Nitrous oxide for:

• Anesthesia
• Pain relief
• Hypoxic respiratory failure in neonates

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

American Foundation for Suicide Prevention

Collaborator

Trials

36

Recruited

10,500+

Published Research Related to This Trial

Chronic abuse of nitrous oxide (N2O) in pediatric patients can lead to serious neurological issues, including symptoms like limb numbness and weakness, as seen in a study of 9 patients diagnosed with N2O-induced spinal cord degeneration.

Vitamin B12 deficiency was common among these patients, and while all received B12 supplementation and recovered muscle power within 2 months, some experienced lasting sensory deficits, highlighting the importance of prompt treatment to prevent permanent damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recreational nitrous oxide abuse related subacute combined degeneration of the spinal cord in adolescents - A case series and literature review. Lan, SY., Kuo, CY., Chou, CC., et al.[2022]

A case study revealed that very high-dose nitrous oxide use, especially when combined with cannabis, can lead to serious health issues like acute myocardial infarction due to thrombus formation in the coronary artery.

The patient exhibited low vitamin B12 levels and hyperhomocysteinaemia, suggesting that nitrous oxide abuse may cause vitamin deficiencies that increase the risk of blood clotting, challenging the perception of nitrous oxide as a safe recreational drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report of an acute myocardial infarction after high-dose recreational nitrous oxide use: a consequence of hyperhomocysteinaemia? Oomens, T., Riezebos, RK., Amoroso, G., et al.[2022]

Nitrous oxide (N2O) is widely used as a safe anesthetic and has a rapid onset of euphoric effects when inhaled recreationally, particularly among clubbers and festival-goers, with usage rates between 40% and 80%.

While N2O is generally considered safe for moderate use, heavy or sustained use can lead to vitamin B12 deficiency and associated neurological issues, highlighting the need for user education about these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recreational nitrous oxide use: Prevalence and risks. van Amsterdam, J., Nabben, T., van den Brink, W.[2022]

Nitrous oxide (N2O) is an effective analgesic and sedative used in dentistry, offering benefits like rapid onset and both pain relief and anxiety reduction.

Despite its advantages, nitrous oxide can lead to vitamin B12 deficiency and has potential risks such as infertility and neurological issues, highlighting the importance of using scavenger systems to reduce occupational exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Not Available]. Liakoni, E., Liechti, ME.[2019]

Two patients developed serious neurological issues, including limb weakness and numbness, after long-term recreational use of nitrous oxide (N2O), leading to a diagnosis of subacute combined degeneration (SCD).

Treatment involved stopping N2O use and administering vitamin B supplements, which significantly improved their symptoms, highlighting the need for awareness of N2O's neurotoxic effects and the importance of early diagnosis to prevent irreversible damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subacute combined degeneration induced by nitrous oxide inhalation: Two case reports. Zhao, B., Zhao, L., Li, Z., et al.[2022]

A systematic review of 34 studies on recreational nitrous oxide (N2O) use highlights a concerning increase in its use and associated harms, particularly among young people, yet there is a lack of awareness about these risks.

The review calls for improved harm reduction strategies, emphasizing the need for both policy changes and service delivery improvements to better address the growing issue of N2O use and its potential dangers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of Recreational Nitrous Oxide Use: Implications for Policy, Service Delivery and Individuals. Allan, J., Cameron, J., Bruno, J.[2023]

A systematic review identified 59 cases of nitrous oxide (N2O) use disorder and 17 cases of EMONO use disorder, highlighting the potential for addiction, especially when used in larger quantities and for longer durations than intended.

The study suggests that N2O use disorder can develop not only from recreational use but also from medical exposure, indicating a need for careful monitoring of its use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide: What do we know about its use disorder potential? Results of the French Monitoring Centre for Addiction network survey and literature review. Fidalgo, M., Prud'homme, T., Allio, A., et al.[2020]

A case study of a young girl revealed that excessive recreational use of nitrous oxide (N2O) led to acute cognitive impairment, highlighting a potential risk associated with its abuse.

The girl's cognitive function fully recovered after receiving vitamin B12 supplementation, suggesting that vitamin B12 may play a role in mitigating the neurological effects of nitrous oxide abuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute cognitive disorder as the initial manifestation of nitrous oxide abusing: a case report. Shen, Q., Lu, H., Wang, H., et al.[2021]

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. 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 ...

4. 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.

5. 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 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03736538

NCT03736538 | Nitrous Oxide- Suicidal Ideation This study is designed as a double-blind, randomized, prospective, inpatient trial comparing inhaled nitrous oxide (N2O) plus treatment as usual versus inhaled ...

7. 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 ...

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

Nitrous Oxide in the Treatment of Depression: A Brief Review Given this observation, safety data ... Nitrous oxide reduced suicidal ideation in treatment-resistant major depression in exploratory analysis.