Background: Anxiety and depression disorders can be very debilitating and result in substantial disability. These disorders are extremely common, occurring at rates that exceed other common medical illnesses such as hypertension, diabetes or asthma. Further, anxiety and depression disorders often co-occur (more the rule than the exception) and having one diagnosis substantially increases the risk for having the other. The clinical benefits of an intervention that ameliorates both anxiety and depression-related disability and clinical symptoms could be critically important, as odds of Veteran suicide completion significantly increase when depression co-occurs with anxiety disorders. Extensive preclinical and clinical data (from our group and others) support a novel neurosteroid intervention (pregnenolone/PREG) as a promising new treatment for anxiety and depression disorders. Furthermore, extensive evidence in rodent models and clinical biomarker candidate studies suggests substantial analgesic, anxiolytic, sleep and anti-inflammatory actions. PREG also significantly reduced low back pain in a randomized controlled trial of 94 OEF/OIF/OND-era Veterans compared to placebo, and allopregnanolone (ALLO) levels are inversely correlated with several commonly co-occurring symptoms, including sleep disturbance and pain disorders. Restoration of ALLO levels via a precursor loading strategy with PREG could thus ameliorate ALLO deficits and alleviate multiple functionally impairing and health-related symptoms. Additionally, PREG has been very well-tolerated in multiple clinical trials and exhibits a very favorable side effect profile – potentially supporting a superior safety and side effect profile advantage compared to existing pharmacological interventions. We thus propose to conduct a 10-week double-blind, randomized, placebo-controlled trial of PREG versus placebo in Veterans with anxiety and depression. Methods: The primary goal of this proposed project is to conduct a 10-week adaptive, randomized, double- blind, placebo-controlled trial to evaluate flexibly dosed pregnenolone [to improve functional impairment and disability associated with anxiety and depression. Following a 2-week placebo-only lead-in period, 84 subjects will be enrolled and randomly assigned to receive PREG or placebo for 8 weeks (flexible dosing strategy). We hypothesize that treatment with PREG will significantly reduce functional impairment and disability associated with anxiety and depression symptoms. Secondary outcomes include diagnostic improvements in anxiety and depression, pain symptoms and sleep quality. We hypothesize that PREG will improve symptoms of anxiety and depression, pain and sleep quality. Finally, we will quantify serum neurosteroid levels at baseline and post- treatment by highly sensitive and specific mass spectrometry-based techniques to determine if PREG and downstream neurosteroid metabolites such as ALLO are predictors of functional/therapeutic response....