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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if inhaling nitrous oxide (commonly known as laughing gas) can help normalize brain function in people with impulsive aggression. Participants will inhale nitrous oxide or room air for 60 minutes and undergo a brain scan the next day to check for changes. Good candidates are individuals who experience impulsive aggressive behavior but do not have conditions like bipolar disorder or substance use issues. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that nitrous oxide, or laughing gas, is under study for its effects on brain activity in individuals with impulsive aggression. This gas is commonly used safely in medical settings for pain relief and sedation, though its overall safety remains under investigation. Reports suggest that misuse of nitrous oxide can lead to neurological and psychological issues, such as hallucinations or personality changes, particularly in large amounts. However, these problems are generally associated with abuse, not controlled medical use.

In controlled environments, nitrous oxide is generally safe. The FDA has approved it for certain medical procedures, indicating a level of established safety. In studies with controlled doses, like those in this trial, side effects are usually mild and may include dizziness or nausea, which typically resolve quickly after stopping inhalation. The trial carefully monitors participants to ensure safety and minimize potential risks. ^{1 2 3 4 5}

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

Unlike the typical medications for aggression, which often involve antipsychotics or mood stabilizers, the treatment with nitrous oxide is unique because it uses a gas known for its rapid action. Nitrous oxide, commonly known as laughing gas, is inhaled, allowing it to act quickly on the brain, potentially providing fast relief from aggressive behaviors. Researchers are excited about this treatment because it offers a non-invasive and immediate alternative to traditional medications that can take weeks to become effective and often come with significant side effects. This novel approach could change how aggression is managed, offering a quicker, more patient-friendly option.

What evidence suggests that nitrous oxide might be an effective treatment for impulsive aggression?

This trial will compare the effects of Nitrous Oxide inhalation with Room Air inhalation on aggression. Research has shown that nitrous oxide might help individuals with impulsive aggression by affecting brain areas related to aggressive behavior. Early studies suggested that nitrous oxide can help balance these brain areas, possibly reducing aggression. Although specific data on aggression is limited, nitrous oxide is known for its calming effects, prompting its testing for this purpose. It is important to note that while nitrous oxide is often used in medical settings to promote relaxation, more research is needed to confirm its effectiveness in reducing aggression. ^{1 2 3 4 6}

Who Is on the Research Team?

Emil Coccaro, Dr

Principal Investigator

Ohio State University

Are You a Good Fit for This Trial?

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

I have a serious health condition.

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

History of N2O abuse/dependence.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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) 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06118567

NCT06118567 | Effect of Nitrous Oxide on Aggression. Healthy, Non-Aggressive, Controls (n = 25 Completed, 75 Enrolled). Do not meet current/lifetime DSM-5 Criteria for any psychiatric disorder; LHA aggression ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2468266724002986

Tackling the growing burden of nitrous oxide-induced ... The ACMD found little evidence of association with violence in the majority ... Using machine learning to identify factors related to nitrous oxide (laughing gas) ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38241247/

Study protocol for a randomized placebo-controlled pilot ... Other exploratory clinical outcomes include remission (defined as MADRS score <10), response (defined as ≥ 50% reduction in MADRS score), and ...

4. withpower.com withpower.com/trial/phase-2-aggression-8-2022-36d24

Nitrous Oxide for Aggression This trial tests if inhaling nitrous oxide can help normalize brain function in people with impulsive aggression. Participants with and without aggressive ...

5. thelancet.com thelancet.com/journals/lanpub/article/PIIS2468-2667(24)00298-6/fulltext

Tackling the growing burden of nitrous oxide-induced ... ... nitrous oxide with anti-social behaviour. The ACMD found little evidence of association with violence in the majority of users,. 6. UK ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5925601/

Neuropsychiatric Symptoms Induced by Large Doses of ... Nitrous oxide abuse can cause auditory hallucinations, persecutory delusions, unstable emotions, personality changes, muscle weakness, and numbness.