# Nitrous Oxide for Posttraumatic Stress Disorder (PTSD): A Phase IIa Trial

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2022 · —

## Abstract

Post-traumatic stress disorder (PTSD) seriously disrupts the lives of many Veterans. Current first-line treatments,
serotonin reuptake inhibitors or prolonged exposure therapy, take weeks to months to bring meaningful
improvement, leaving Veterans experiencing prolonged suffering. A promising new treatment approach for
rapidly reducing PTSD symptoms is nitrous oxide, an inhalation anesthetic and putative N-methyl-D-aspartate
receptor (NMDAR) modulator that diminishes depression symptoms within 1 day and has limited side effects. If
shown to be similarly effective in PTSD, nitrous oxide may add dramatically to our treatment armamentarium by
bringing rapid symptom decrease before longer-term therapies take hold. The proposed projects test the efficacy
of nitrous oxide in relieving Veteran’s PTSD symptoms and, in parallel, explore how nitrous oxide may modify
cognitive and pain outcomes.
Nitrous oxide is FDA-approved for use in anesthesia and pain management, and may be a new approach for
managing PTSD. Nitrous oxide’s favorable pharmacokinetics (rapid offset in minutes) prevent the transient
cognitive and psychotomimetic side effects (delusions, hallucinations) sometimes seen with other NMDA
glutamate modulators. Nitrous oxide may be suited to Veterans in view of: 1) their older age (which brings greater
probability of age-associated cognitive impairments), and 2) higher prevalence of co-morbid pain than in the US
population. As an anesthetic, nitrous oxide has robust evidence regarding its application in pain, and a superior
safety record as an analgesic for dental procedures and childbirth.
The proposed projects will examine the efficacy of nitrous oxide in relieving Veteran’s PTSD symptoms and in
parallel, explore whether nitrous oxide improves cognitive and pain outcomes. Specifically, we will first assess
whether nitrous oxide treatment improves PTSD symptoms within 1 week. In parallel, we will explore whether
the treatment improves co-existing depression and pain. In addition, we will explore nitrous oxide’s effects on a
PTSD-associated impairment that is often overlooked - disruption in cognitive control, a core neurobiological
process critical for regulating thoughts and for successful daily functioning. We will test whether the magnitude
of nitrous oxide’s effect on PTSD symptoms or pain depends on the Veteran’s baseline capacity for cognitive
control or on changes induced in cognitive control. If diminished PTSD symptoms are related to changes in
cognitive control, these findings would signal that cognitive control may merit examination in a larger study of
mechanism of action. Taken together, if nitrous oxide is found to rapidly relieve Veterans’ PTSD symptoms and
modify cognitive and pain outcomes, and these results are replicated in a larger study, it could transform
psychiatric treatment of PTSD.

## Key facts

- **NIH application ID:** 10409688
- **Project number:** 5I01CX001789-03
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** Carolyn I Rodriguez
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409688

## Citation

> US National Institutes of Health, RePORTER application 10409688, Nitrous Oxide for Posttraumatic Stress Disorder (PTSD): A Phase IIa Trial (5I01CX001789-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10409688. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*