Project Summary/Abstract Medical marijuana is rapidly becoming a popular treatment for chronic pain among older adults despite limited evidence on its benefits and risks for this vulnerable population. Our research indicates the presence of gene interaction modules for the pain-endocannabinoid system, and differing pain, psychological, and behavioral responses to medical marijuana treatment. Additionally, we have shown that measures of allostatic load, indicating individual health status or whole person health, are more informative than chronic pain severity in understanding the heterogeneity of health outcomes in individuals with chronic musculoskeletal pain.Our interdisciplinary team has expertise on the key proposed areas including: pain pathology and assessment, allostatic load, inflammation, machine learning applied to genomics, patient subgroup characterization, and gene expression analysis. The overall goal of the study is to delineate multi-level factors contributing to heterogeneous responses to medical marijuana treatment involving: (a) genetic, through targeted gene expression; (b) sociodemographic and (c) psychological/behavioral including consideration for comorbidities and medical marijuana treatment regimen confirmed by blood tests. We will extend the scientific merit of a recently funded prospective cohort study (R01 AG071729-01A) and aim to study the 3-month effects of medical marijuana among older adults with chronic musculoskeletal pain. A total of 80 patients who are seeking to initiate medical marijuana, and 40 who are not, will provide additional data at baseline and 3 months. Importantly, we will study the multi-level individual factors influencing the response to medical marijuana in older adults with chronic musculoskeletal pain via three Specific Aims: To identify gene modules associated (over- or under-expression) to medical marijuana treatment and change in chronic pain; AIM 2: To detect associations between changes in chronic pain severity and changes in allostatic load; AIM 3: To develop a casual, personalized medicine prediction model that can help identify patients who are more likely to benefit from medical marijuana treatment. Funding of this project will support a much-needed multi-level analysis of individual factors contributing to the heterogeneous responses to medical marijuana treatment in adults with chronic musculoskeletal pain. Findings from this study will provide valuable data on the key genetic, sociodemographic, psychological/behavioral factors predictive of response to medical marijuana treatment and ultimately inform and improve patient care through a personalized medicine approach.