Nitrous Oxide and EMOtional Cognition (NEMO)

Investigating the Neuropsychological Effects of Nitrous Oxide

The goal of this study is to uncover the underlying neuropsychological mechanisms of nitrous oxide, which may be relevant to its reported antidepressant effects. In particular, the study is designed to determine whether nitrous oxide changes the way in which healthy volunteers aged 18-40 years remember negative autobiographical memories.

The main question the study aims to answer is:

• Does nitrous oxide interfere with the emotional aspects of negative autobiographical memories?

Other neuropsychological effects will also be assessed (e.g., emotional processing, emotional memory, response inhibition, and cognitive flexibility).

Researchers will compare ENTONOX (50% nitrous oxide: 50% oxygen) with medical air.

Participants will:

• Attend three research visits (screening, inhalation, follow-up)
• Take part in a 30 minute inhalation session of ENTONOX or medical air
• Complete a series of cognitive tasks
• Finish a series of self-report questionnaires

Study Overview

• Status: Recruiting
• Conditions: Depression
• Intervention / Treatment: Drug: Entonox; Drug: Medical Air

Detailed Description

Questions regarding the mechanisms of nitrous oxide and its effects on the brain and behaviour in the context of its reported antidepressant effects remain largely unanswered. Thus, in the present study, the investigators aim to elucidate the more general effects that nitrous oxide might have on a series of neurocognitive processes which may be relevant to the treatment of depression. Namely, the study will investigate: 1) reconsolidation of autobiographical memories, 2) measures of emotional processing and emotional memory, 3) response inhibition, 4) cognitive flexibility and 5) sleep stages.

• Study Type: Interventional
• Enrollment (Estimated): 88
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Oxford, United Kingdom, OX3 7JX
    • Recruiting
    • Psychiatry Department
    • Contact: Catherine Harmer; Phone Number: 01865 618200; Email: catherine.harmer@psych.ox.ac.uk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Aged 18-40 years
• Good vision and hearing
• Willing and able to give informed consent
• Body mass index (BMI) within the range of 18-35kg/m2 (This is to ensure we exclude underweight individuals who might have more substantial reactions to the nitrous oxide).
• Sufficiently fluent in English to understand tasks
• Willing to avoid drinking any alcohol from 3 days prior to Visit One until the end of Visit Three
• Willing to avoid using recreational drugs for 3 months prior to Visit One and throughout the duration of the study

Exclusion Criteria:

• Receiving or seeking treatment for any mental health condition (covered in Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-5 (SCID) assessment in screening procedures)
• History of any mental health condition (covered in SCID assessment in screening procedures)
• Attention deficit hyperactivity disorder (ADHD) requiring treatment with stimulant or other centrally-acting drugs
• A positive drug test for any of the following: amphetamine, barbiturates, benzodiazepines, buprenorphine, cocaine, marijuana, methadone, methamphetamine, methylenedioxymethamphetamine (MDMA), morphine, methaqualone, opiates, phencyclidine, propoxyphene, tricyclic antidepressants, tramadol, ketamine, oxycodone, cotinine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), fentanyl, synthetic marijuana, 6-mono-acetyl-morphine (6-MAM).
• Regularly drink 14 or more units of alcohol a week
• Any eye, throat or ear surgery or a medical procedure requiring intravenous injection or line into a vein in the last 6 months
• A head injury causing concussion or unconsciousness in the past 6 months
• A collapsed lung or lung surgery (e.g., pneumothorax)
• A history of cardiac arrhythmias
• Current injuries of the face or mouth (including ulcers or dental problems)
• Dental surgery in the past month
• Deep diving or scuba diving (which has a risk of decompression sickness) in past month
• Pregnancy / intention to become pregnant during the study
• Breastfeeding during the study
• Asthma, emphysema or any medical condition that affects the lungs or breathing
• Diagnosed vitamin B12 deficiency
• Any use of recreational drugs in the last three months
• Participation in any other drug study in the last three months
• Participation in any other study with the same tasks in the last year

OPTIONAL SLEEP STUDY ADD-ON Exclusion Criteria:

• Unable to undergo cardiac monitoring
• Unable to wear the sleep patch device for full monitoring period
• Implanted neurostimulator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ENTONOX (50% nitrous oxide:50% oxygen); ENTONOX to be administered for 30 minutes.	Drug: Entonox; 30 minute inhalation using demand valve and mouthpiece
Placebo Comparator: Medical Air; Medical Air to be administered for 30 minutes.	Drug: Medical Air; 30 minute inhalation using demand valve and mouthpiece

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Emotional Ratings of Personal Memories (Memory Reconsolidation)	Negative/positive valence ratings associated with personal memories. A series of positive and negative adjectives will be presented to participants and they will have to rate on a scale of 1(not at all) to 10 (extremely) to what extent these words apply to how they feel when recalling the memory.	2 days before and 1 day after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Performance on Emotional Processing Tasks	Performance on the Emotional Testing Battery (ETB), which contains an emotional word categorisation task, an emotional facial recognition task, and two emotional memory tasks.	Immediately before and after treatment and 1 day after treatment
Performance on Cognitive Flexibility Task	Performance on a probabilistic reversal learning task in which participants have to learn which strategy on a computer-task leads to a reward.	1 day after treatment
Performance on Response Inhibition Task	Performance on an emotional go/no-go task in which participants have to inhibit their responses to certain stimuli based on rules given at the start of each block of the task.	1 day after treatment

Collaborators and Investigators

• Sponsor: University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2024
• Primary Completion (Estimated): August 15, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: July 19, 2024
• First Submitted That Met QC Criteria: August 13, 2024
• First Posted (Actual): August 16, 2024

Study Record Updates

• Last Update Posted (Actual): July 31, 2025
• Last Update Submitted That Met QC Criteria: July 28, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Healthy Volunteers
• Additional Relevant MeSH Terms: Behavioral Symptoms; Depression; Physiological Effects of Drugs; Anesthetics; Central Nervous System Depressants; Anesthetics, Combined; Entonox
• Other Study ID Numbers: NEMO_Study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No