Nitrous Oxide for PTSD (N2OP)

Use of VA hospital research space is indefinitely delayed due to prioritization of clinical cases delayed by COVID

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 glutamate 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 the 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.

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, the investigators will first assess whether nitrous oxide treatment improves PTSD symptoms within 1 week. In parallel, the investigators will explore whether the treatment improves co-existing depression and pain. In addition, the investigators 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.

Randomized placebo-controlled clinical trial including two groups: Experimental (admixture of up to 50% nitrous oxide and 50% oxygen plus IV saline) and Active Comparator (admixture of up to 50% nitrogen and 50% oxygen plus 0.045mg/kg midazolam).

Blinding Protections: First, the investigators will separate personnel and location of the team providing study drug from the team performing psychiatric evaluations. Independent evaluators (IEs) blind to treatment assignment will assess participants . Second, records for drug administration will be kept separate from psychiatric assessment case report forms until completion of the study. Third, all participants will be blinded as to the nature of the inhaled gas and IV drug at each session; all participants will be informed that they will receive either nitrous oxide and IV saline or an air mixture with a high nitrogen component and IV midazolam. Integrity of the blinding will be assessed by recording each patient's guess as to which drug was received.

PTSD participants in this arm will receive and admixture of up to 50%nitrous oxide and 50% oxygen plus intravenous saline

PTSD participants in this arm will receive and admixture of up to 50%nitrogen and 50% oxygen plus intravenous 0.045mg/kg midazolam

PTSD participants in this arm will receive and admixture of up to 50% nitrous oxide and 50% oxygen plus intravenous saline

PTSD participants in this arm will receive and admixture of up to 50%nitrogen and 50% oxygen plus intravenous 0.045mg/kg midazolam

PTSD participants in this arm will receive and admixture of up to 50%nitrogen and 50% oxygen plus intravenous 0.045mg/kg midazolam

Improvement in the Severity of PTSD as Measured by the Clinician Administered PTSD Scale DSM5 (CAPS-5)

Improvement in PTSD severity is measured by the Clinician Administered PTSD Scale DSM-5 (CAPS-5). It measures frequency and intensity of PTSD-related symptoms. For the CAPS-5 the minimum units are 0 and maximum units are 80. The higher the number on the CAPS-5, the more severe the PTSD symptoms. Response is defined as a change in the CAPS-5 of at least 12 points, which represents meaningful improvement in clinical PTSD symptoms.

Inclusion Criteria: Veteran primary diagnosis of PTSD sufficient severity of PTSD symptoms capacity to provide informed consent Exclusion Criteria: psychiatric or medical conditions that make participation unsafe pregnant or nursing females concurrent use of any medications that might increase the risk of participation (e.g. drug interactions