PROJECT SUMMARY This is a clinical observational study that will fill an important gap in our understanding of how marijuana use, and secondhand exposure, impact cardiovascular health. A likely consequence of marijuana legalization is that intentional smoking of cannabis, and involuntary secondhand exposure, will greatly increase in coming years. While some retrospective human association studies have failed to find clear-cut associations between marijuana smoking and cardiovascular disease, other studies have indicated that marijuana use increases the risk of subsequent myocardial infarction (MI) and heart failure. It is unclear whether these adverse effects are caused by the cannabinoids or the smoke. Nonetheless, despite public awareness that tobacco smoke is harmful, many people still assume that marijuana smoke is benign. Moreover, cardiovascular effects of secondhand smoke (SHS) exposure have remained relatively unexplored in human studies. There is increasing evidence in rats that both active marijuana smoking and marijuana SHS exposure causes vascular endothelial dysfunction. While the endothelial dysfunction is transient, clinical studies have shown that not only do tobacco smokers have endothelial dysfunction, but repeated exposures to SHS lead to chronic dysfunction as well. Therefore, it is important to determine in humans if chronic active or passive marijuana smoking similarly causes endothelial dysfunction. The overall hypothesis of this proposal is that active use of marijuana, or secondhand exposure, causes adverse cardiovascular consequences in humans. The overarching goal is to test this hypothesis by measur- ing a panel of functional indicators and circulating biomarkers of cardiovascular risk, in otherwise healthy sub- jects who are actively or passively exposed on a regular basis in their daily lives to cannabis (this proposal does not involve exposing humans to cannabis). The impact is that an improved understanding of the adverse cardiovascular effects of intentional or involuntary exposure to cannabis will better inform personal health behavior, advice of physicians to their patients, public health policy decisions, legal doctrines, and potential regulation of the cannabis industry and its products. Aim 1 is to determine if vascular function is impaired by chronic active or passive marijuana smoking in otherwise healthy individuals (age ≤50), relative to tobacco smokers and to people who avoid exposure to tobacco and marijuana. Aim 2 is to determine if these chronic exposure conditions increase biomarkers of cardiovascular risk in the blood. Aim 3 is to determine if cultured endothelial cells incubated in sera from exposed individuals undergo adverse functional changes relative to non-users’ sera, indicating potential mechanisms by which vascular function is being impaired by exposure to these products.