PROJECT SUMMARY/ABSTRACT Chronic pain, one of the most common reasons adults seek medical care, has been linked to restrictions in mobility and daily activities, anxiety and depression, and poor perceived health or reduced quality of life. Treatment options are limited and often ineffective, contributing to current opioid prescription and abuse issues. Better outcomes can be achieved by developing new and improved therapeutic approaches or more immediately by identifying favorable combinations of available or emerging drugs. This research proposal will to test the effectiveness of a novel pharmacological combination strategy involving a minor cannabinoid (cannabidiol, CBD) and terpene (Beta-caryophyllene (ΒCP) to effectively inhibit chronic pain without abuse potential. CBD has gained attention as a therapeutic agent over the past several years due to its lack of psychoactivity. A preclinical dose-response study of the analgesic effect of CBD in a chronic pain model showed that although CBD has potential in managing chronic pain condition, it exhibited moderate efficacy. However, the beneficial analgesic effect of CBD was not associated with any of the common side effects of cannabinoids or abuse potential. Therefore, a strategy is needed to increase the analgesic efficacy of CBD without the potential for abuse. ΒCP has been approved by the Food and Drug Administration (FDA) as a food additive, known for its favorable safety profile. Found in plants including basil, black pepper, cloves, and cannabis sativa. BCP is a natural selective agonist for the cannabinoid type 2 receptor (CB2). In various experimental models, BCP has an analgesic effect without causing negative psychoactive effects, presumably due to its selectivity to the CB2 receptor; at the same time, BCP does have anti-depressant and anxiolytic effects which are of interest in addressing common comorbidities of chronic pain. This project will test the novel hypothesis that in comparison with CBD and BCP alone, CBD and ΒCP in combination produces an enhanced (e.g. synergistic) analgesic effect in chronic pain without abuse potential. Aim 1 will use behavioral assays and pharmacological tools to determine the beneficial of CBD and ΒCP in combination in the well-establish chronic arthritis pain model (Complete Freund’s Adjuvants, CFA). We will use the behavioral assessment of sensory and affective pain. Isobolographic analysis will demonstrate the nature of interaction (e.g. synergistic). The abuse potential of CBD and ΒCP in combination will also be tested. The proposed studies will significantly impact the field of chronic pain management by providing a new combination therapy, CBD and ΒCP, that is effective and nonaddictive. Furthermore, if effective, this combination therapy will have a significant impact on the opioid epidemic by offering a safe alternative to opioids that lacks abuse potential.