# Neurosteroid Intervention for PTSD in Iraq/Afghanistan-era Veterans

> **NIH VA I01** · DURHAM VA MEDICAL CENTER · 2021 · —

## Abstract

There is an acute and urgent need to develop new and effective pharmacological interventions for
posttraumatic stress disorder (PTSD), as there are currently only two FDA-approved medications for the
treatment of PTSD (both of which are from the same drug class and have shown only moderate effect sizes in
FDA registration trials). Many Veterans with PTSD thus remain symptomatic despite the availability of these
treatments, increasing the likelihood of receiving pharmacological treatment interventions for which there is
little or no empirical evidence. Randomized controlled trials (RCT) utilizing new medication approaches are
thus acutely needed in the Iraq/Afghanistan-era Veteran population, a cohort that may be less treatment-
refractory (particularly if treated early in the course of PTSD symptom development). The investigation of
promising pharmacological agents for this Veteran cohort could thus not be more timely or urgent.
Increasing evidence supports a potential role for neurosteroids in the neurobiology and treatment of PTSD. For
example, allopregnanolone (a downstream metabolite of pregnenolone) has anxiolytic, antidepressant, anti-
aggressive, fear-reductive, neuroprotective, anti-inflammatory, and neurogenesis-enhancing actions – and
these properties could have clear therapeutic utility for PTSD. Our preliminary data also demonstrate that
serum allopregnanolone levels are significantly decreased in patients with PTSD compared to control
participants in two independent cohorts. We have shown in multiple studies that pregnenolone administration
elevates downstream allopregnanolone levels 5-10 fold, and can thus potentially serve as a precursor loading
strategy to restore deficient allopregnanolone levels in PTSD. Furthermore, recent neuroimaging studies
demonstrate that allopregnanolone plays a role in the modulation of brain function associated with negative
emotion, and enhances activity associated with emotional regulatory processes (Sripada, 2013; Priority
Communication, Biological Psychiatry). In addition, our preclinical rodent models demonstrate that pre-
treatment with pregnenolone mitigates anxiety-like behaviors in rodents following predator stress exposure.
Finally, we have demonstrated that PTSD symptoms improve in Veterans with mild Traumatic Brain injury
(mTBI) following administration of pregnenolone in both a pilot RCT and in a larger follow-up RCT in mTBI. In
both studies, Veterans with mTBI randomized to pregnenolone showed marked elevations in serum
allopregnanolone and pregnenolone levels post-treatment. A precursor loading strategy to enhance deficient
levels of endogenous allopregnanolone may thus be an efficacious treatment for PTSD. We therefore propose:
 1.) To investigate the potential efficacy of pregnenolone to treat PTSD in Iraq/Afghanistan-era Veterans by
conducting an RCT of pregnenolone vs. placebo (primary endpoint CAPS-5 change; [90 randomized
 participants; n=45 per group;] 8-week duration of treatment)...

## Key facts

- **NIH application ID:** 10129889
- **Project number:** 5I01CX001784-03
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** JENNIFER C NAYLOR
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129889

## Citation

> US National Institutes of Health, RePORTER application 10129889, Neurosteroid Intervention for PTSD in Iraq/Afghanistan-era Veterans (5I01CX001784-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129889. Licensed CC0.

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