Treatment of Post‑Traumatic Stress Disorder with inhaled nitrous oxide, oxygen, and nitrogen in adults: a multicenter randomized controlled trial

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What is this study about?

Post-Traumatic Stress Disorder is a condition that can develop after a very stressful or frightening event, causing unwanted memories, heightened alertness, and avoidance of reminders. In this study participants will breathe a gas mixture containing nitrous oxide, which is a medication that can produce short‑term relaxation, or a comparison mixture of medical air. While inhaling the gas, each person will listen to a recording of their own personal traumatic story, a process meant to help the brain process the memory.

The aim of the trial is to see whether the nitrous oxide mixture reduces PTSD symptoms more than the medical air mixture. Participants will attend four weekly sessions where the inhalation and story listening take place, and they will be evaluated before the first session, after the last session, and again three months later. Symptom changes will be measured using several questionnaires, including the clinician‑administered interview called CAPS-5, a self‑report checklist called PCL-5, a depression screen named PHQ-9, an anxiety rating called STAI, a dissociation questionnaire known as DES-28, and a brief assessment of daily functioning called FAST. Any side effects will be recorded throughout the study.

1 baseline assessment (day 0)

you will attend an initial visit where a clinician conducts the caps-5 interview, a structured questionnaire that measures the severity of post‑traumatic stress disorder symptoms. you will also complete several self‑report questionnaires: the pcl-5 (a checklist of 20 ptsd symptoms), the phq-9 (a depression screening tool), the stai‑state (a measure of current anxiety), the des‑28 (questions about dissociative experiences), and the fast (a brief assessment of overall functioning). after these assessments you will be randomly assigned to receive either nitrous oxide (also known as laughing gas) or medical air (compressed air containing nitrogen and oxygen) for the treatment sessions.

2 first treatment session (week 1)

you will sit in a comfortable chair while a mask delivers the assigned gas by inhalation. the gas will be administered for 45 minutes. during this time a recording of your own personal traumatic script will be played, allowing you to recall the event in a controlled setting. staff will monitor you for any side effects or discomfort throughout the session.

3 second treatment session (week 2)

the procedure is repeated as in the first session: 45 minutes of inhalation of the same gas while listening to your personal traumatic script. observations for adverse events continue.

4 third treatment session (week 3)

you will again receive 45 minutes of the assigned gas by inhalation while the traumatic script is played. staff will keep recording any reactions.

5 fourth treatment session (week 4)

the final weekly session follows the same pattern: 45 minutes of inhalation of the study gas with the personal script. after the gas administration, you will complete the same set of questionnaires as at baseline (caps-5, pcl-5, phq-9, stai‑state, des‑28, fast) to evaluate immediate changes.

6 one‑month follow‑up

approximately one month after the last treatment session you will be asked to complete the self‑report questionnaires (pcl-5, phq-9, stai‑state, des‑28, fast) to track progress. no additional gas administration occurs.

7 three‑month follow‑up (primary outcome)

three months after the final session you will undergo the primary assessment using the caps-5 interview, which determines the main result of the study. you will also repeat the self‑report questionnaires (pcl-5, phq-9, stai‑state, des‑28, fast) to provide additional information on symptom changes.

8 six‑month follow‑up

at six months post‑treatment you will again complete the self‑report questionnaires (pcl-5, phq-9, stai‑state, des‑28, fast) to monitor longer‑term effects.

9 nine‑month follow‑up

the final follow‑up occurs nine months after the last session, with the same set of questionnaires (pcl-5, phq-9, stai‑state, des‑28, fast) to assess durability of any changes.

10 adverse event monitoring

throughout the entire study period, from the first treatment session to the final follow‑up, any unwanted side effects or health problems you experience will be recorded and compared between the nitrous oxide and medical air groups.

Who Can Join the Study?

Be between 18 and 65 years old.
Have experienced interpersonal violence such as sexual, physical, or psychological abuse.
Have post‑traumatic stress disorder (PTSD) that did not get better after at least one type of therapy, counseling, or a medication called a selective serotonin reuptake inhibitor (SSRI).
PTSD must be diagnosed using the DSM‑5 guidelines (a standard set of rules doctors use) and have lasted for more than 6 months.
Score at least 35 on the CAPS‑5 questionnaire (a detailed interview that measures how severe PTSD symptoms are).
Be able to receive MEOPA (medical nitrous oxide) or medical oxygen through a face mask.
Be able to understand and speak French.
Be enrolled in the Social Security system.
Sign the informed consent form, which shows you agree to take part in the study.
If you are a woman who could become pregnant, you must use a suitable method of contraception during the trial.

Who Cannot Join the Study?

You cannot join the study if you have a current addiction or a past addiction, if you have severe depression or severe anxiety that is not well‑controlled, or if you have serious mental health conditions such as psychotic disorders (loss of touch with reality), bipolar disorder (extreme mood swings), dissociative identity disorder (multiple personalities), eating disorders, obsessive‑compulsive disorder that is not stable, or major personality (Axis II) disorders.
Pregnancy or breastfeeding prevents participation.
If you are under a legal guardian or otherwise unable to understand what the study involves, you cannot take part.
You must not have any condition that makes using medical nitrous oxide unsafe, including any situation where air could be trapped in the body and expand dangerously, such as:
- Pneumothorax (air in the space around the lung)
- Emphysema (damage to the air sacs in the lungs)
- Intestinal obstruction (a blockage in the bowel)
- Intracranial hypertension (high pressure inside the skull)
- Untreated deficiency of vitamin B12 or vitamin B9 (folate) confirmed by a recent blood test
- Needing pure‑oxygen ventilation (machine‑assisted breathing with only oxygen)
- Any loss of consciousness that would stop you from cooperating
- Recent head injury
- Gas embolism (air bubbles in the blood vessels)
- Recent diving accident
- Abdominal gas distension (excess gas in the stomach or intestines)
- Recent eye surgery that used a gas bubble (such as SF6, C3F8, or C2F6) that is still present
- Any recent or ongoing neurological problems
If a recent blood test shows that your vitamin B12 or vitamin B9 levels are below the normal range, you cannot participate.
If a recent blood test shows that your homocysteine level is above the normal range, you cannot participate.
If you have a high risk of suicide, measured by a score of 4 or more on the C‑SSRS (Columbia‑Suicide Severity Rating Scale), you are excluded.
Any current treatments that could affect the study’s results make you ineligible.
Being in ongoing psychotherapy (regular psychological counseling) excludes you from the trial.

Where you can join this trial?

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Other Sites

Site Name	City	Country
Centre Hospitalier Universitaire De Nantes	Nantes	France
Cbilrn Hiezuxjnbuk Rbjfnkjg Ufczsidfrqzxk Df Tqegd	Tours	France
Cneuip Hlrvsimmzue Rdgedyqu Daoozgrszjgvlk	Angers	France

Trial status

Country	Status	Recruitment Start
France	Not yet recruiting	01.01.2027

Trial locations

Investigated Drugs:

KALINOX 50%/50% is a medicinal gas that contains a mixture of nitrous oxide (often called laughing gas) and oxygen. In the study, participants breathe this gas through a mask for a short period while they listen to a recording of their own personal traumatic story. The nitrous oxide is expected to help reduce anxiety and make the traumatic memory easier to process, while the oxygen keeps the breathing safe. This combination is the experimental treatment being tested to see if it can lessen PTSD symptoms.

Medical Air is a gas made up of nitrogen and oxygen, similar to the normal air we breathe. In the trial, participants also breathe this gas through a mask while listening to their personal traumatic script. It serves as the comparison or control treatment, allowing researchers to see whether any benefit comes from the nitrous oxide itself rather than just the breathing process or the exposure to the trauma story.

Investigated Diseases:

Post-traumatic stress disorder

Post-Traumatic Stress Disorder – It develops after a person experiences or witnesses a traumatic event, leading to persistent distressing memories, avoidance of reminders, negative mood changes, and heightened alertness. Symptoms may begin shortly after the trauma or emerge weeks to months later, and they can wax and wane over time. Without resolution, the condition can shift from an acute reaction to a more chronic pattern, often intensifying when the individual encounters stressors that resemble the original trauma.

Trial ID:

2026-525826-39-00

Protocol code:

DR250344

Trial Phase:

Therapeutic exploratory (Phase II)

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Treatment of Post‑Traumatic Stress Disorder with inhaled nitrous oxide, oxygen, and nitrogen in adults: a multicenter randomized controlled trial

What is this study about?

Who Can Join the Study?

Who Cannot Join the Study?