Nitrous Oxide for Suicidal Thoughts

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

50 Participants Needed

Trial Summary

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 nitrous oxide safe for human use?

Nitrous oxide is generally considered safe when used in medical settings as an anesthetic, but recreational use can lead to side effects like dizziness, disorientation, and vitamin B12 deficiency, which can cause nerve damage and anemia. Excessive use may also lead to serious health issues such as neurological disorders and, in rare cases, heart problems. ^{1 2 3 4 5}

How does nitrous oxide differ from other drugs for suicidal thoughts?

Nitrous oxide is unique because it acts quickly to produce a euphoric and calming effect, which may help alleviate suicidal thoughts rapidly. Unlike traditional antidepressants that take weeks to work, nitrous oxide's effects are felt within seconds to minutes, making it a potentially fast-acting option for acute situations. ^{5 6 7 8 9}

What is the purpose of this trial?

Most clinical major depression responds to standard treatments (medication and psychotherapy); however, a significant subset of depressed patients (15-20%) do not respond to these treatments and are referred to as treatment-resistant major depression (TRMD). New treatments for TRMD are needed, and one promising line of research are drugs known as N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. In a recent pilot study, the investigators of this study demonstrated that the NMDA antagonist nitrous oxide is effective in TRMD, reducing depressive symptoms, guilt, and suicidal thinking. To more closely investigate suicidal thinking, this study is designed as a double-blind, randomized, prospective, inpatient trial comparing inhaled nitrous oxide (N2O) plus treatment as usual versus inhaled placebo plus treatment as usual. All unipolar depressed, acutely suicidal inpatients will receive standard treatment for their depression/ suicidal thinking (TAU). Additionally, participants will undergo a maximum of four one hour inhalation sessions as inpatients and 2 booster sessions as outpatients during which they will receive either inhaled nitrous oxide (50% nitrous oxide/50% oxygen = active treatment) or placebo gas (50% nitrogen/50% oxygen). A target total of 50 patients with suicidal ideation and unipolar depression will be enrolled, 25 of whom will be assigned to the TAU control group and 25 of whom will be assigned to the N2O + TAU experimental group.

Research Team

Charles R Conway, MD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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]

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]

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]

References

1. United States 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. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

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

3. Italy pubmed.ncbi.nlm.nih.gov

Acute cognitive disorder as the initial manifestation of nitrous oxide abusing: a case report. [2021]

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

Case report of an acute myocardial infarction after high-dose recreational nitrous oxide use: a consequence of hyperhomocysteinaemia? [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Recreational nitrous oxide use: Prevalence and risks. [2022]

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

Nitrous oxide induced subacute combined degeneration with longitudinally extensive myelopathy with inverted V-sign on spinal MRI: a case report and literature review. [2022]

7. Netherlands 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. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

[Not Available]. [2019]

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

Subacute combined degeneration induced by nitrous oxide inhalation: Two case reports. [2022]