NCT03435055

Network-Level Effects of Nitrous Oxide in the Human Brain

Completed Phase 4 Results posted Last updated 30 November 2021

What this trial tests

Phase 4 trial testing Nitrous Oxide Gas for Inhalation in Healthy in 21 participants. Completed in 11 October 2019.

Timeline

21 July 2017

Primary endpoint
11 October 2019

11 October 2019

Quick facts

Lead sponsor	University of Michigan
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	basic science
Enrollment	21
Start date	21 July 2017
Primary completion	11 October 2019
Estimated completion	11 October 2019
Sites	1 location across United States

Drugs / interventions tested

• Nitrous Oxide Gas for Inhalation — full drug profile →

Conditions studied

• Healthy — all drugs for Healthy →

Sponsor

University of Michigan

Who can join

Adults 21 to 40, any sex, with Healthy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Functional Connectivity During Nitrous Oxide Primary · Baseline to 50 minutes

Functional connectivity measures will be assessed at rest (baseline) and during sub anesthetic dose nitrous oxide (nitrous oxide). Seed-to-whole brain functional connectivity (Fisher's r-transformed z) will be measured from the left anterior insula, previously shown to be involved in pain and sensory processing. Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. The z-score descriptors represent the Fishers-r-to-z transformed. Here the z-score is a transformation of the Pearson's (r) correlation coefficient of

L superior frontal gyrus

Group	Value	95% CI
Pre-Nitrous	0.1123	± 0.0639
Nitrous Oxide - Subanesthetic Dose	0.0358	± 0.0620

R superior frontal gyrus

Group	Value	95% CI
Pre-Nitrous	0.1492	± 0.1179
Nitrous Oxide - Subanesthetic Dose	0.0394	± 0.0950

Functional Connectivity Associated With Tonic Stimulus Primary · Baseline to 50 minutes

Functional connectivity measures will be assessed at rest (baseline) and during a tonic cuff stimulus (6-minutes). Seed-to-whole brain functional connectivity (Fisher's r-transformed z) will be measured from the left anterior insula, previously shown to be involved in pain and sensory processing. Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. The z-score descriptors represent the Fishers-r-to-z transformed. Here the z-score is a transformation of the Pearson's (r) correlation coefficient of the BOLD timeser

Group	Value	95% CI
Pre-Tonic Cuff	-0.0509	± 0.0822
Tonic Cuff Stimulus	0.0486	± 0.1001

Tonic Stimulus Intensity During Nitrous Oxide Secondary · Baseline to 50 minutes

Participants will receive a tonic (6 minutes) pressure applied to the lower leg at baseline and under subanesthetic dose of nitrous oxide (35% inhaled concentration). Following each pressure stimulus, participants will rate the pain intensity of the tonic stimulus (0 ="no pain", 10= "worst pain imaginable", Visual Analog Scale, e.g pain intensity).

Group	Value	95% CI
Pre-nitrous	4.9688	± 1.217
Nitrous Oxide - 35% Inhaled Concentration	2.500	± 2.309

Spectral Power of Sub-anesthetic Dose of Nitrous Oxide Secondary · Baseline to 50 minutes

Brain imaging data were obtained from functional magnetic resonance imaging (fMRI) data recorded simultaneously with electroencephalography (EEG) data at baseline and under a sub-anesthetic dose of nitrous oxide. Spectral data were averaged from EEG data at all electrodes collected during the baseline and sub-anesthetic dose (35%) of nitrous oxide to observe changes in spectral power. The EEG power spectrum was divided into three frequency bands: Delta = 1-3 Hz; Theta = 4-7 Hz; and Alpha = 8 - 13 Hz

Delta

Group	Value	95% CI
Pre-Nitrous	13.31	± 2.20
Nitrous Oxide - Subanesthetic Dose	14.65	± 2.56

Theta

Group	Value	95% CI
Pre-Nitrous	11.88	± 1.89
Nitrous Oxide - Subanesthetic Dose	12.80	± 1.87

Alpha

Group	Value	95% CI
Pre-Nitrous	6.72	± 1.92
Nitrous Oxide - Subanesthetic Dose	6.97	± 2.05

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse event data was collected for 24 hours.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Nitrous Oxide - Inhaled

Serious: 0/19 (0%)

Deaths: 0/19

Other adverse events (2 terms — click to expand)

Reaction	System	Nitrous Oxide - Inhaled
Tachycardia	General disorders	—
Emesis	General disorders	—

Data from ClinicalTrials.gov NCT03435055 adverse events section.

Sponsor's own description

The purpose of this study is to understand how a commonly used drug, nitrous oxide, acts on the brain to reduce pain. Nitrous oxide is commonly used in anesthesiology but there is limited knowledge on how this drug affects functional networks in the brain.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Psychedelic concentrations of nitrous oxide reduce functional differentiation in frontoparietal and somatomotor cortical networks.
   Dai R, Huang Z, Larkin TE, Tarnal V, et al · · 2023 · cited 7× · PMID 38114805 · DOI 10.1038/s42003-023-05678-1