PROJECT SUMMARY Hypertension (HTN) is a primary risk factor for cardiovascular disease (CVD). The Systolic Blood Pressure Intervention Trial (SPRINT) was performed in hypertensive individuals with high CVD risk. The study showed that blood pressure (BP) target of <120mm Hg compared with <140mm Hg significantly reduced CVD events and all-cause deaths [1]. However, almost 15% of all SPRINT participants experienced serious adverse events (SAEs) including hypotension, syncope, bradycardia, acute kidney injury (AKI), and electrolyte abnormalities [1]. Our data point towards the contribution of the endocannabinoid system (ECS) in this process. EC system is an ancient, preserved, but only recently discovered biological system shown to play a pivotal role in regulation of BP [2]. The ECS is composed of endocannabinoids, including anandamide (AEA), the enzymes that produce and degrade endocannabinoids and their receptors. Interestingly, similarly to subjects that reported SAEs within the SPRINT trial, acute cannabis users present with bradycardia, hypotension, syncope and electrolyte abnormalities [3, 4]. Supporting studies in hypertensive animals have indicated the essential role of AEA-mediated signaling in the development of bradycardia and hypotension [5-10]. Interestingly, renin- angiotensin system, which is the main target of antihypertensive therapy, seems to be reciprocally regulated with the ECS e.g. increase in AEA reduces vasoconstrictive and hypertensive effects of angiotensin II [11, 12]. In our previous data, we showed reduced plasma levels of AEA in hypertensive non-CKD subjects and CKD as well as autosomal dominant polycystic kidney disease (ADPKD) patients as compared to healthy subjects [13]. Furthermore, intensive BP control in ADPKD patients (SBP <110mm Hg) as performed within the HALT-PKD trial, led to an increase of plasma levels of AEA and its congeners [13]. Based on these data, we hypothesize that intensive (<120mm Hg) as compared to standard (<140mm Hg) BP control in SPRINT participants will be accompanied by higher levels of AEA and its congeners. We also hypothesize that subjects with a greater rate of AEA increase will present with a higher incidence of SEAs including hypotension, syncope and bradycardia. The knowledge gained from this first-of-its-kind study will allow to better understand the role of the EC system in regulation of the blood pressure. With the increased use of cannabis and its active ingredients among general population, the understanding of the interplay between the EC system and the cardiovascular function will be of utmost importance for current patient management and future drug development studies.