PROJECT SUMMARY / ABSTRACT Knee osteoarthritis is a very common and debilitating condition, affecting >14 million Americans. Many people with knee osteoarthritis require total knee arthroplasty (TKA) to treat pain and improve function, and opioids remain the primary modality for treatment of pain after TKA. However, opioids carry significant side effects, with ~80% of surgical patients reporting at least one moderate or severe side effect (e.g. nausea, dizziness, constipation). Moreover, perioperative opioid exposure is associated with patients becoming dependent on opioids long after surgical recovery, and new chronic opioid dependence is subsequently associated with increased healthcare costs, the development of opioid use disorder (addiction), overdose, and death. Hence, research into opioid alternatives for postoperative pain is of critical importance. Cannabinoids, including cannabidiol (CBD), are one class of potential opioid-sparing pain medications. While CBD is used by an estimated 14% of the general public, most frequently for chronic pain and related symptoms (including as an opioid substitute), rigorous clinical research on CBD is limited. CBD shows great promise, as it is non- intoxicating, and reduces pain, anxiety and inflammation in animal studies. Previous research has found that CBD reduced opioid craving and anxiety, which further suggests it may decrease opioid use after surgery. It is also well tolerated across numerous medical conditions. Moreover, CBD (Epidiolex), the study drug we will use, is approved by the Food and Drug Administration for treating some seizure disorders, and it is not subject to the same regulatory restrictions as Δ -9-tetrahydrocannabinol (THC). In this study, we will recruit 380 patients undergoing primary total knee arthroplasty (TKA) from two large health systems. In this multi-site, 2x2 factorial, double-blind, randomized controlled trial, participants will receive one of four combinations of placebo or CBD (300 mg/day) for one week prior to surgery together with CBD or placebo for 4 weeks following surgery. Our primary outcome will be post-operative opioid consumption in the 4-week period following surgery. The study design will also allow us to investigate and untangle CBD's pre- and post-surgical effects, including reduction of anxiety, sleep disturbance and inflammation. We will also conduct detailed investigations of the side effects and adverse events, as well as pharmacokinetics of CBD throughout the treatment course. The successful completion of this study will give much needed evidence for the role of CBD as an opioid-sparing medication for pain after surgery. Given that there are more than 50 million surgeries each year in the United States, these findings could have much broader implications beyond TKA and would motivate important new lines of research into the role of CBD.