Nitrous Oxide for Aggression

Overseen By Julian Roberts, R.N.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Ohio State University

Must not be taking: Antipsychotics

Disqualifiers: Psychopathy, Depression, Schizophrenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 7

Duration: 1 week

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if inhaling nitrous oxide can help normalize brain function in people with impulsive aggression. Participants with and without aggressive tendencies will inhale the gas and undergo brain scans to see if it improves their brain activity. The goal is to find a potential treatment for those with Intermittent Explosive Disorder. Nitrous oxide has been shown to reduce involuntary movements in cerebral palsy patients, indicating its potential to affect brain function.

Will I have to stop taking my current medications?

The trial requires participants to be free of antipsychotic medication for two weeks before joining. However, if you are taking SSRIs, SNRIs, or mood stabilizers, you can continue using them as long as you still experience impulsive aggressive behaviors.

What data supports the effectiveness of the drug nitrous oxide for treating aggression?

Nitrous oxide is known for its anesthetic and pain-relieving properties, making it useful in various medical settings. Its ability to be safely administered by trained professionals and even self-administered by patients suggests it could have potential in managing conditions like aggression, although specific studies on aggression are not mentioned. ^{1 2 3 4 5}

Is nitrous oxide generally safe for human use?

Nitrous oxide is generally considered safe when used in medical settings, like dentistry, for its anesthetic and anti-anxiety effects. However, heavy or prolonged use can lead to vitamin B12 deficiency, causing nerve damage and blood problems. Recreational use can also lead to accidents and, in rare cases, serious health issues. ^{3 6 7 8 9}

How is nitrous oxide different from other drugs for treating aggression?

Nitrous oxide is unique because it is traditionally used as an anesthetic and for its calming effects in dentistry, but it is now being explored for its potential to treat psychiatric conditions like aggression at lower, non-anesthetic doses. This approach is novel compared to standard treatments, which typically involve medications like antipsychotics or mood stabilizers. ^{1 3 10 11 12}

Research Team

Emil Coccaro, Dr

Principal Investigator

Ohio State University

Eligibility Criteria

This trial is for adults aged 21-55 with Intermittent Explosive Disorder (IED) and high aggression scores, but no major psychiatric disorders like psychosis or bipolar disorder, nor current severe substance abuse. Healthy participants without any psychiatric conditions and low aggression can also join.

Inclusion Criteria

Aggressive (IED) Study Participants (n = 25 Completed; 75 Enrolled):

Negative for a history of psychosis, bipolar disorder, developmental disorder, intellectual disability or a current substance use disorder.

I am physically healthy with no significant medical conditions.

Exclusion Criteria

Intellectual disability [i.e., IQ < 70].

History of N2O abuse/dependence.

I have a serious health condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

2 visits (in-person)

Treatment

Participants undergo a 60 minute inhalation session with 50% Nitrous Oxide or room air, followed by an fMRI scan 24 hours later

1 week

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Nitrous Oxide
• Room Air

Trial Overview Researchers are testing if inhaling Nitrous Oxide changes brain function in people with impulsive aggression compared to healthy controls. Participants breathe in either Nitrous Oxide or room air for an hour and have a brain scan the next day.

Participant Groups

Group I: Nitrous Oxide Inhalation Active Control 1 Intervention

60 minute session inhaling Nitrous Oxide gas.

Group II: Room Air Placebo Group 1 Intervention

60 minute session inhaling Room Air.

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?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

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]

In a study of 124 children aged 1-17 undergoing procedures in the emergency department, nitrous oxide (N2O) was used for analgesia, but pain scores showed that 34% of patients experienced significant pain (scores of 70 mm or greater) during procedures, indicating limited efficacy for very painful interventions.

Despite the pain management limitations, both parents (96% satisfaction) and staff (92% rated sedation and analgesia as adequate) reported high satisfaction with the use of N2O for procedural sedation in the emergency department.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Limited analgesic efficacy of nitrous oxide for painful procedures in children. Babl, FE., Oakley, E., Puspitadewi, A., et al.[2022]

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]

Nitrous oxide (N2O) abuse primarily affects young individuals, leading to acute neurological disorders in 86% of cases, with symptoms including movement dysfunction and sensory deficits.

The prognosis for patients with N2O neurotoxicity is generally good, especially after treatment with Vitamin B12, which helps restore serum levels and improve imaging findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversible Neuropsychiatric Disturbances Caused by Nitrous Oxide Toxicity: Clinical, Imaging and Electrophysiological Profiles of 21 Patients with 6-12 Months Follow-up. Zheng, R., Wang, Q., Li, M., et al.[2022]

Nitrous oxide (N2O) is a safe and effective anesthetic and analgesic gas that can be used in various medical situations due to its low incidence of adverse effects.

It can be administered by trained medical providers or even self-administered by patients, making it a versatile option in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on nitrous oxide and its use in anesthesia practice. Zafirova, Z., Sheehan, C., Hosseinian, L.[2019]

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]

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 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]

Healthcare professionals exposed to high levels of nitrous oxide (N2O) in the past faced significant reproductive risks, including congenital anomalies and reduced fertility rates, but these risks have been reduced due to occupational safety measures.

Recreational users of N2O often exceed safe exposure limits by a large margin, putting themselves at risk for similar reproductive issues, highlighting the need for increased awareness about these dangers among users, especially those who are pregnant or planning to become pregnant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide-induced reproductive risks: Should recreational nitrous oxide users worry? van Amsterdam, J., van den Brink, W.[2022]

Nitrous oxide (N2O) has a long history of use, initially discovered in 1772 and later recognized for its psychotropic properties in the late 18th century, leading to its application in dentistry and psychiatry.

At low doses, N2O mixed with oxygen is used safely in modern dentistry to avoid adverse effects, and it has been explored for treating psychiatric conditions since the 1980s, highlighting its potential beyond just anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mini-Review: A Brief History of Nitrous Oxide (N2O) Use in Neuropsychiatry. Gillman, MA.[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]

Chronic abuse of nitrous oxide can lead to vitamin B12 deficiency, which may cause severe psychiatric symptoms such as bizarre behavior and delusions, as seen in a case of a 33-year-old male.

Treatment with intramuscular vitamin B12 (cobalamin) effectively resolved the patient's psychosis, emphasizing the importance of screening for vitamin B12 deficiency in individuals with a history of nitrous oxide use presenting with psychiatric symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide "whippit" abuse presenting with cobalamin responsive psychosis. Sethi, NK., Mullin, P., Torgovnick, J., et al.[2021]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

Limited analgesic efficacy of nitrous oxide for painful procedures in children. [2022]

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

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

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

Reversible Neuropsychiatric Disturbances Caused by Nitrous Oxide Toxicity: Clinical, Imaging and Electrophysiological Profiles of 21 Patients with 6-12 Months Follow-up. [2022]

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

Update on nitrous oxide and its use in anesthesia practice. [2019]

6. Netherlands pubmed.ncbi.nlm.nih.gov

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

7. 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]

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

[Not Available]. [2019]

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

Nitrous oxide-induced reproductive risks: Should recreational nitrous oxide users worry? [2022]

10. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Mini-Review: A Brief History of Nitrous Oxide (N2O) Use in Neuropsychiatry. [2020]

11. Ireland pubmed.ncbi.nlm.nih.gov

Accidental death by nitrous oxide inhalation. [2019]

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

Nitrous oxide "whippit" abuse presenting with cobalamin responsive psychosis. [2021]