Effect of Nitrous Oxide on Aggression.

Nitrous Oxide and Cortico-Limbic Function in Aggression

The goal of this experimental medicine clinical trial is to test the hypothesis that nitrous oxide inhalation will result in a change in neurocircuit function in healthy controls and in individuals with impulsive aggressive tendencies. The main question aims to answer are: Does Nitrous Oxide normalize brain circuit function in impulsively aggressive individuals 24 hours after inhalation. Participants will undergo a 60 minute inhalation session with 50% Nitrous Oxide (or room air at another session) and then undergo an fMRI scan 24 hours later. Researchers will compare healthy controls and impulsively aggressive individuals to see if Nitrous Oxide can normalize the function of cortico-limbic circuits in the latter group.

Study Overview

• Status: Recruiting
• Conditions: Intermittent Explosive Disorder
• Intervention / Treatment: Drug: Nitrous oxide; Drug: Room Air

Detailed Description

This study is designed to see if inhalation of 50% nitrous oxide (N2O) also known as laughing gas, can normalize cortico-limbic circuit functioning in impulsively aggressive human subjects. If the study results are positive, it would allow further studies of this potential treatment modality for those with recurrent, problematic, impulsive aggressive behavior (Intermittent Explosive Disorder: IED). IED is a disorder in which there are frequent and sudden outbursts of anger (yelling, throwing and breaking things, hitting people) that lead to problems with other people socially or at work. It affects about 4% of the US population lifetime, and does not have any approved treatments. The study will test if N2O can normalize brain activity 24 hours after infusion, in participants with a diagnosis of IED compared with healthy, non-aggressive, controls. This is a double-blinded-randomized study with comparison between groups (controls and IED patients) and comparison for each participant between N2O and placebo (air) inhalation. Participants will receive one type of inhalation 24 hours before undergoing an fMRI. Participants will be randomized to the order in which they receive N2O or air. Participants and study personnel involved in collection of outcome measures will be blinded to the type of inhalation. The study includes up to 7 visits. Visits 1/2 include interviews and questionnaires. At visits 3 and 5, participants receive the N2O or air inhalation. At visits 4 and 6, participants undergo fMRI while completing computer tasks. Visit 7 is to assure data collection is complete.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jayla Copland, B.A.; Phone Number: 614-327-1707; Email: jayla.copland@osumc.edu
• Study Contact Backup: Name: Julian Roberts, R.N.; Email: julian.roberts@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Wexner Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

All participants:

• Between 21 and 55 years of age.
• Physically healthy (no clinically significant medical condition as confirmed by medical history/physical exam).
• Able to give informed consent.

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

• Current DSM-5 Criteria for IED
• LHA Aggression scores > 12
• Negative for a history of psychosis, bipolar disorder, developmental disorder, intellectual disability or a current substance use disorder.

Healthy, Non-Aggressive, Controls (n = 25 Completed, 75 Enrolled).

• Do not meet current/lifetime DSM-5 Criteria for any psychiatric disorder
• LHA aggression scores < 12

Exclusion Criteria:

• PCL Screening Version Score > 13; i.e., subject is likely to be psychopathic.32
• Current DSM-5 Major Depressive Episode.
• Life history of bipolar disorder/schizophrenia/organic mental syndrome.
• Intellectual disability [i.e., IQ < 70].
• History of N2O abuse/dependence.
• Clinically significant medical condition.
• Current alcohol/drug use disorder of moderate or severe severity (i.e., subject is not in full remission from moderate to severe alcohol/drug use).
• Two weeks free of antipsychotic medication. (Note: Because a large number of individuals with aggressive tendencies in the community are already taking SSRIs, SNRIs, or mood stabilizers, these individuals will not be excluded if they continue to report impulsive aggressive behaviors at time of study.)
• Unwilling/unable to sign informed consent document.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nitrous Oxide Inhalation; 60 minute session inhaling Nitrous Oxide gas.	Drug: Nitrous oxide; Nitrous oxide gas.
Sham Comparator: Room Air; 60 minute session inhaling Room Air.	Drug: Room Air; Room Air

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortico-Limbic Response to Anger Faces	Orbito-Frontal and Amygdala responses to Anger Faces in fMRI	24 hours after Nitrous Oxide and Room Air
Brain Connectivity	Resting State	24 hours after Nitrous Oxide and Room Air

Collaborators and Investigators

• Sponsor: Ohio State University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Emil Coccaro, M.D., Ohio State University

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2022
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: November 1, 2023
• First Submitted That Met QC Criteria: November 1, 2023
• First Posted (Actual): November 7, 2023

Study Record Updates

• Last Update Posted (Actual): March 27, 2025
• Last Update Submitted That Met QC Criteria: March 26, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: IED
• Additional Relevant MeSH Terms: Aberrant Motor Behavior in Dementia; Mental Disorders; Behavioral Symptoms; Aggression; Disruptive, Impulse Control, and Conduct Disorders; Physiological Effects of Drugs; Peripheral Nervous System Agents; Anesthetics; Central Nervous System Depressants; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anesthetics, General; Anesthetics, Inhalation; Nitrous Oxide
• Other Study ID Numbers: 2020H0368

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No