Developing and testing a new treatment for Posttraumatic Stress Disorder (PTSD): Retrieval dependent Nitrous Oxide Therapy (R-NOT)
| ISRCTN | ISRCTN12553238 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12553238 |
| Integrated Research Application System (IRAS) | 1008993 |
| Protocol serial number | 178733 |
| Sponsor | University College London |
| Funder | Medical Research Council |
- Submission date
- 27/08/2025
- Registration date
- 01/12/2025
- Last edited
- 01/12/2025
- Recruitment status
- Not yet recruiting
- Overall study status
- Ongoing
- Condition category
- Mental and Behavioural Disorders
Plain English summary of protocol
Background and study aims
Posttraumatic stress disorder (PTSD) is a condition that can develop after experiencing or witnessing a traumatic event. Symptoms include distressing memories, avoidance of event reminders, and increased tension. While several effective treatments exist, they can take weeks to show results and may not work for everyone.
This study tests a new treatment targeting one of PTSDs most troubling symptoms: intrusive memories (IM) — unwanted, distressing recollections of traumatic events. The treatment being tested is called Retrieval-dependent Nitrous Oxide Therapy (R-NOT). It involves recalling an intrusive memory followed by inhaling a 50/50 mix of nitrous oxide and oxygen (also known as “gas and air”) for an hour. Is it thought that this gas can help weaken the emotional power of traumatic memories.
Who can participate?
Patients with PTSD who are referred from a collaborating NHS Talking Therapies Services (NHS-TTSs)
What does the study involve?
This study tests the effects of one treatment session of R-NOT. Participants will be recruited only from the NHS NHS-TTSs in London. The study aims to find out if R-NOT can be developed in a way that is easy to administer by trained professionals. The study also aims to test whether people with PTSD find R-NOT an acceptable and helpful treatment.
After a screening interview, participants will take part for approximately 14 days, during which they will be asked to complete some questionnaires and interviews about the treatment. There are two Research Sites that all participants will attend during their participation:
• Clinical Psychopharmacology Unit (CPU) at University College London (UCL)
• Clinical Research Facility (CRF) at University College London Hospital (UCLH)
Participants will first complete a screening call with the R-NOT study team to see if it is appropriate and safe for them to take part. They will then complete a Baseline visit at the CPU at UCL with a trained R-NOT research team member and then attend their Treatment visit at UCLH. The treatment session will be carried out by a trained health care professional. After that, there will be a Follow-up call with a trained R-NOT research team member. To test how the treatment affects your memories of the traumatic event, participants will be asked to make a note of any unpleasant memories about the event using an online diary and smartwatch for a week before and after the Treatment visit.
The results from the study will be used to conduct bigger studies with more people. If those studies are successful, R-NOT could provide an extra treatment option to patients in the NHS that may produce beneficial effects more quickly than existing treatments for PTSD.
What are the possible benefits and risks of participating?
Although the intervention will not guarantee an improvement in your PTSD symptoms, if R-NOT works as expected, participants might find that their PTSD symptoms improve. However, it is possible that they will not experience any benefits.
As with all research studies, there are also risks of taking part. However, because gas and air (50% nitrous oxide) is a very safe drug, the side effects mentioned here are generally mild and get better after you stop breathing the gas. The memory retrieval procedure used is also brief, and should not be more risky than ordinary everyday occurrences in your life. However, zero risk to participants cannot guaranteed.
Mild and short-lived side effects include unusual feelings of ‘floating’ or being outside of your body, or having unusual thoughts and feelings, dizziness and sleepiness. Some people also feel sick and may vomit while inhaling gas and air (50% nitrous oxide), so participants will be asked to avoid food and drink (except water) before the treatment visit. Research team members are trained to help participants with any short-lived distress while you are inhaling the gas. Serious side effects of gas and air (50% nitrous oxide) are extremely unlikely in the current study, because participants are only receiving a small amount of the gas.
Where is the study run from?
University College London (UCL), UK.
When is the study starting and how long is it expected to run for?
The study is starting in early 2026 and is going to run for approximately three months.
Who is funding the study?
Medical Research Council, UK.
Who is the main contact?
The R-NOT study team, r-not@ucl.ac.uk
Contact information
Public
Clinical Psychopharmacology Unit at UCL, 1-19 Torrington Place
London
WC1E 7HB
United Kingdom
| Phone | +44 (0)207 679 2000 |
|---|---|
| r-not@ucl.ac.uk |
Scientific
Clinical Psychopharmacology Unit at UCL, 1-19 Torrington Place
London
WC1E 7HB
United Kingdom
 ORCID ID |
0000-0003-2197-0826 |
|---|---|
| Phone | +44 (0)207 679 2000 |
| sunjeev.kamboj@ucl.ac.uk |
Principal investigator
University College London Hospitals NHS Foundation Trust, 235 Euston Road London NW1 2BU
London
WC1E 7HB
United Kingdom
| georges.iskandar@nhs.net |
Study information
| Primary study design | Interventional | |
|---|---|---|
| Allocation | N/A: single arm study | |
| Masking | Open (masking not used) | |
| Control | Uncontrolled | |
| Assignment | Single | |
| Purpose | Treatment | |
| Scientific title | Developing and testing a novel memory-therapeutic treatment for PostTraumatic Stress Disorder (PTSD): Retrieval-dependent Nitrous Oxide Therapy (R-NOT) | |
| Study acronym | R-NOT for PTSD | |
| Study objectives | This is an initial external pilot/prototyping study in which we will design and iteratively refine a prototype of the ‘unit-of-treatment’ of a novel therapy for posttraumatic stress disorder (PTSD). The objective, therefore, is to develop a replicable treatment session (the unit-of-treatment) of Retrieval-dependent Nitrous Oxide Therapy (R-NOT) that is optimised for feasibility, tolerability and acceptability. Through an assessment of side effects, we will determine whether aspects of the session need to be modified to increase tolerability (e.g. by using prophylactic or rescue anti-emetics) and/or reduce participant burden (e.g. to reduce or eliminate the use of a wrist-worn monitor; frequency of assessments). Essential elements of a treatment manual will be developed as part of this study. A mixed methods approach will be used to assess response to treatment and acceptability; analyses will be descriptive. Although primary and secondary ‘outcome measures’ will be used, these are not intended to assess efficacy. Rather, their inclusion is to preliminarily determine their acceptability and likely sensitivity to change in the subsequent studies of R-NOT. | |
| Ethics approval(s) |
Approved 12/11/2025, London – Central (3rd Floor, 3 Piccadilly Place, London Road, Manchester, M1 3BN, United Kingdom; +44 (0)207 104 8000; londoncentral.rec@hra.nhs.uk), ref: 25/LO/0693 | |
| Health condition(s) or problem(s) studied | Posttraumatic stress disorder (PTSD) | |
| Intervention | The single-session R-NOT intervention is comprised of two interactive components: a standardised intrusive memory (IM) retrieval procedure followed by inhalation of a premixture of 50% nitrous oxide + 50% oxygen (for up to 60 minutes). | |
| Intervention type | Drug | |
| Phase | Not Applicable | |
| Drug / device / biological / vaccine name(s) | 50% nitrous oxide premixed with 50% oxygen | |
| Primary outcome measure(s) |
| |
| Key secondary outcome measure(s) |
| |
| Completion date | 01/04/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 18 Years |
| Upper age limit | 65 Years |
| Sex | All |
| Target sample size at registration | 10 |
| Key inclusion criteria | 1. Aged 18–65 years 2.Ability to provide informed consent 3. Meeting DSM-5 criteria for PTSD as determined by the CAPS-5 4. Experiencing ≥1 distressing intrusive memories per week 5. Sufficient level of English understanding and expression to allow independent completion of assessment instruments and provide written descriptions of memories 6. Access to the internet and a smartphone or similar device on a daily basis 7. Awaiting psychological treatment for PTSD 8. Female participants of childbearing potential (i.e. are not surgically sterilised or postmenopausal) must be willing to use an effective method of contraception (hormonal or barrier method of birth control) or be abstinent from consent to 48 hours after treatment discontinuation |
| Key exclusion criteria | 1. Currently engaged in a psychological therapy for PTSD 2. Change in psychotropic medication in last four weeks or planned change during the course of the study 3. Concomitant treatment with ketamine or memantine 4. Recreational use of nitrous oxide more than once in the past 6 months 5. Current alcohol or substance dependence (other than nicotine and caffeine) as suggested by the AUDIT and SDS, and judgement of the team after discussions 6. The diagnostic instrument used to assess depression severity (MADRS) alongside judgement of the team after discussions suggests that depression is the primary diagnosis 7. Current psychosis 8. Active suicide risk 9. Currently participating in another research study or clinical trial related to PTSD, or research that involves a medication 10. Pregnancy or actively attempting to conceive (female participants) 11. Medical contraindications including, but not limited to (at the discretion of the CI/treating clinician): 11.1. Pneumothorax (current or recent ) 11.2. Middle ear disease, infection or recent surgery 11.3. Recent cranial surgery or head trauma 11.4. Respiratory disease (COPD, severe asthma, interstitial lung disease) 11.5. Diagnosed chronic vitamin B12 or folate deficiency 11.6. Risk factors associated with chronic vitamin B12 or folate deficiency without vitamin supplementation (coeliac or inflammatory bowel disease; vegan diet) 11.7. Use of medications known to impair B12 absorption (e.g. metformin, H2-receptor antagonists and proton-pump inhibitors) 11.8. Recent (less than 2 weeks) dental work: extractions, implants, sinus lifts 11.9. Neurological conditions (stroke, encephalopathy, Parkinson’s, brain tumour, multiple sclerosis, poorly controlled epilepsy, dementia or diagnosed cognitive impairment) |
| Date of first enrolment | 15/01/2026 |
| Date of final enrolment | 01/04/2026 |
Locations
Countries of recruitment
- United Kingdom
- England
Study participating centres
University College London
1-19 Torrington Place
London
WC1E 7HB
England
St. Pancras Hospital
4 St. Pancras Way
London
NW1 0PE
England
Results and Publications
| Individual participant data (IPD) Intention to share | Yes |
|---|---|
| IPD sharing plan summary | Stored in non-publicly available repository |
| IPD sharing plan | Study data will be shared with others in accordance with the local policies, ethical requirements and data protection and sharing regulations. Anonymised study data will be shared with others via the dissemination of publications and presentation of results at relevant conferences. Anonymised study data may also be uploaded and stored in suitable and secure repositories, in line with funder requirements. |
Editorial Notes
27/08/2025: Trial's existence confirmed by NHS HRA.
