Background: There is currently a severe dearth of safe, non-habit forming pharmacological interventions for chronic pain disorders, and the clinical need to develop efficacious new therapeutics has never been more urgent. Fueled by the worsening opioid crisis and further exacerbated by the COVID-19 pandemic, opioid and other drug overdose deaths have climbed to staggeringly high levels. The rapid development of pharmacological agents for the management of chronic pain conditions that are safe, well-tolerated, efficacious and non-addicting is thus of paramount importance. Neurosteroids are naturally occurring molecules that are enriched in human brain and potentially ideal candidates for the safe and effective treatment of pain. The proposed project is a randomized, double-blind, placebo-controlled adaptive design study to determine the safety and efficacy of two promising neurosteroid molecules for the treatment of chronic low back pain in Veterans. The project logically builds upon the findings from our prior randomized clinical trial (RCT) demonstrating that the highest dose of pregnenolone (500mg/day) significantly improves chronic low back pain (Naylor et al., 2020), while also suggesting that higher doses of this molecule a may be even more efficacious. A second neurosteroid molecule, dehydroepiandrosterone (DHEA) has also been implicated in the pathophysiology of pain. DHEA levels are inversely associated with pain and our preliminary data demonstrate that 8-weeks of DHEA treatment is well-tolerated and reduces pain symptoms. Our strong biomarker and clinical data suggest that both pregnenolone and DHEA appear to have great therapeutic potential for the treatment of chronic pain conditions. We will thus investigate if these molecules exhibit possible efficacy in low back pain and determine maximally well-tolerated doses that are safe and optimally efficacious in the proposed three-arm trial (pregnenolone, DHEA, placebo). Methods: The proposed project is a Phase II randomized clinical trial utilizing an adaptive design to determine the safety and efficacy of pregnenolone and DHEA for the treatment of chronic low back pain in Veterans. Participants will be randomized in a 1:1:1 ratio to 4 weeks of treatment with pregnenolone, DHEA or matching placebo (N=108, approximately 36 per group). Pregnenolone dosing will begin at 500mg/day and escalate every week by 500mg as tolerated (to a potential maximum dose 2000mg/day). DHEA dosing will begin at 100mg/day and increase weekly by 100mg/day (to a potential maximum dose 400mg/day). The primary endpoint will be post-treatment change scores in mean daily pain intensity ratings (numerical rating scale, 0- 10). Secondary endpoint will be changes in pain interference measures (Brief Pain Inventory). Safety will be thoroughly monitored throughout study participation (SAEs, AEs, clinical laboratory parameters, vital signs, ECG). Neurosteroid quantifications will be conducted by highly sensitive state-of-the...