ABSTRACT Chronic pain is a significant burden to United States Veterans and is a particular concern for Veterans with diabetes. Diabetic Veterans have a higher risk of chronic diabetic peripheral neuropathy (CDNP) than civilians with diabetes, and CDNP is more disabling for Veterans than it is for civilians. Frontline treatment for CDNP, including enhanced glycemic control, exercise, and pharmacotherapies, show inconsistent outcomes for individuals with CDNP due to poor adherence and side effects. The ongoing opioid crisis has led to significant interest in safe and effective alternatives for pain control, and there is a significant need for research on desirable options for pain control that are likely to improve treatment adherence and outcomes. Veterans groups and Veterans Affairs clinicians have expressed significant interest in cannabis and its principal constituents (delta-9-tetrathydrocannabinol, THC; cannabidiol, CBD) for pain management, but the extant research describing the potential risks and benefits of cannabis for pain is weak. The present study represents the first significant effort to examine the potential benefits and risks of cannabinoids for Veterans with CDNP through a collaboration between a nationally-recognized cannabis research expert (Dr. D’Souza), a Veteran chronic pain research expert (Dr. McGeary), the Hines Cooperative Studies Program Coordinating Center, and the Albuquerque Cooperative Studies Program Clinical Research Pharmacy Coordinating Center. This research collaboration was developed to meaningfully expand on the extant research using a 4-arm, randomized, double-blind, placebo-controlled, parallel group design. This randomized trial was developed as a proof of concept study to determine if cannabis constituents (THC, CBD) or their combination (THC+CBD) are superior to placebo in reducing pain in Veterans with CDNP. Additionally, this will weigh the safety and tolerability of the interventions against the identified efficacy. The investigators will work with 5 VAMCs to recruit a sample of 320 adult Veterans who meet diagnostic criteria for high-impact CDNP, are on stable treatment(s) for CDNP, are not current cannabis users and who do not meet diagnostic criteria for Cannabis Use Disorder. Enrolled Veterans will be randomly assigned to one of four study arms: 1) 5 mg THC P.O BID; 2) 400 mg CBD P.O BID; 3) 5mg THC + 5 mg CBD P.O BID; or 4) placebo P.O BID. Participants will complete a 2-week titration phase (to minimize side effects and improve tolerability) followed by 4 weeks on the target treatment dose and a subsequent 2-week down titration (to minimize cannabis withdrawal symptoms). The primary outcome of this research is mean change in Numeric Rating Scale of pain (NRS) based on a standardized pain diary completed three times daily producing an average daily pain score. Secondary outcomes include measures of pain quality, functioning/disability, health-related quality of life, perceived improvement and tr...