Abstract Knee osteoarthritis (KOA) is a common and debilitating condition, affecting >14 million Americans. Many KOA patients require total knee arthroplasty (TKA) to restore adequate function. Postoperatively, pain control is delivered through multimodal analgesia, including opioids. However, opioids carry significant side effects, and up to 6.5% of people develop new persistent use following surgery, contributing to the US opioid crisis. Therefore, developing alternative opioid sparing analgesics is critical for preventing opioid dependence following surgery. One class of potential opioid-sparing analgesic is cannabidiol (CBD), an active compound in Cannabis sativa. CBD is non-intoxicating and well tolerated across numerous medical conditions, and exerts anti-inflammatory, analgesic, and anxiolytic effects in preclinical studies. In recent clinical trials, CBD improved pain and function in chronic pain due to knee OA and other conditions. Further, small clinical trials have shown that acutely administered CBD reduces opioid craving and anxiety – the latter being associated with worse surgical outcomes and greater pain following surgery. Taken together, this evidence suggests that CBD may be opioid sparing in surgical settings. However, while CBD is widely used by the general public for pain, arthritis, and anxiety, no studies with CBD have been conducted in post-surgical settings. The proposed study represents the first step in planning a rigorous, double-blind, randomized controlled trial (RCT) to assess if CBD is opioid-sparing following surgery. We will leverage the recent FDA approval of Epidiolex (Schedule V, CBD drug) to ensure study drug standardization and improve generalizability of our findings. The primary objective is to develop a clinical trial plan to examine whether post-operatively administered CBD is opioid- sparing following TKA, and to harness the capacity at our institution to prepare and submit a subsequent U01 application to run this trial. Our overarching hypothesis is that CBD exerts opioid-sparing effects through anti- inflammatory, analgesic, and anxiolytic mechanisms. To develop our plan, we propose two aims. 1: Design a clinical trial protocol that assesses whether oral CBD reduces opioid consumption following TKA. 2: Complete the following milestones to prepare us for a successful U01 application: 1) Develop a manual of operating procedures; 2) Design and test our study database; 3) Develop and test recruitment procedures; 4) Obtain an Investigational New Drug License; 5) Initiate a IRB application, develop informed consent document; and 6) Develop a Data Safety and Monitoring Plan. The proposed development plan would be the first step towards elucidating CBD effects in a post-surgical setting. While our proposed study will be performed in TKA, the results will have broad implications regarding appropriate CBD use in the postoperative period for a wide variety of elective surgeries. Our results will contribute to th...