ABSTRACT Human Immunodeficiency Virus-1 (HIV)-related neuropathic pain affects 55-67% of the 37.9 million infected individuals worldwide. Although antiretroviral therapy has successfully reduced the prevalence of AIDS, neuropathic pain continues to affect many individuals with HIV. Treatment options are limited and often ineffective, and adverse side effects are common. Better outcomes may be achieved by identifying favorable combinations of drugs that are already available or emerging as potential new analgesics or by developing new and more effective drugs. We propose to test a novel pharmacological combination therapeutic strategy involving constituents of cannabis, Beta-caryophyllene (ΒCP, a terpene), and cannabidiol (CBD, a minor cannabinoid), to effectively inhibit HIV-related chronic neuropathic pain without side effects and/or abuse potential. A preclinical dose-response study of the analgesic effect of CBD in a nerve-injury pain model showed that, although CBD has the potential to alleviate a chronic neuropathic pain state, it showed moderate efficacy. However, the analgesic effect of CBD was not associated with catalepsy, and did not impair motor performance or produce sedation over a wide range of doses. Interestingly, BCP also showed potential in managing chronic pain, but it exhibited moderate efficacy. Furthermore, a strategy to increase the analgesic efficacy of CBD without inducing potential side effects or abuse potential is urgently needed. The rationale for choosing this dual CBD-ΒCP strategy is based on its individual analgesic effects and safety profiles. Aim 1 will test the hypothesis that in comparison with CBD alone, BCP and CBD in combination will produce an enhanced analgesic effect (synergistic) in an improved and clinically relevant HIV chronic neuropathic pain model. We will assess multiple outcome measures capturing sensory and affective dimensions of chronic pain. Isobolographic analysis will demonstrate the nature of interaction (e.g. synergistic). Aim 2 will screen for any side effects, abuse potential and development of analgesic tolerance. The proposed studies will significantly impact the field of HIV-related chronic pain management by providing a new combination therapy, CBD and BCP, that has critical advantages over current therapies. It is safe, effective, and non-addictive. The anxiolytic and anti-depressive effects of CBD and BCP are of additional benefit to target chronic pain comorbidities. Furthermore, this combination therapy will have a significant impact on the opioid epidemic, because one of the key strategies to combat this epidemic (HEAL initiative) is through improved pain management by the development of non-addictive approaches . The natural product, BCP, is approved by the Food and Drug Administration (FDA) as a food additive, known for its favorable safety profile. Therefore, combination of the BCP with CBD for the treatment of HIV-related chronic neuropathic pain could lead to a rapid transl...