WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• There are conflicting views in the literature as to whether cannabinoids have an impact on platelet activity and to what extent cannabinoid receptors are involved. This is an important issue to resolve because platelet effects of putative therapeutic cannabinoid inhibitors and stimulators will have an impact on their potential benefits and safety. WHAT THIS PAPER ADDS• The data presented in this manuscript clearly show that the endocannabinoid 2-arrachidonyl glycerol can activate platelet activity, but that the effects are mediated through an aspirin-sensitive pathway that is not affected by cannabinoid receptor antagonists or FAAH inhibition, but is abolished by MAGL inhibition. The findings question the role of cannabinoid receptors in platelet function and suggest that platelet function is unlikely to be directly affected by cannabinoid receptor antagonists, at least in the acute phase. AIMSCannabinoid receptor-1 (CB1) antagonists suppress appetite and induce weight loss. Direct antagonism of CB1 receptors on platelets might be an additional benefit for CB1 antagonists, but the role of CB1 receptors in platelets is controversial. We tested the hypothesis that the endocannabinoid, 2-arachidonyl glycerol (2-AG), induces platelet aggregation by a COX-mediated mechanism rather than through CB1 receptor activation, in blood obtained from healthy volunteers and patients with coronary artery disease receiving low dose aspirin. METHODSAggregatory responses to the cannabinoids 2-AG and D 9-THC were examined in blood sampled from healthy volunteers (n = 8) and patients (n = 12) with coronary artery disease receiving aspirin using whole blood aggregometry. The effects of CB1 (AM251) and CB2 (AM630) antagonists, as well as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) inhibitors and aspirin on 2-AG-induced aggregation were also assessed. RESULTSAM251 (100 nM-30 mM) had no effect on platelet aggregation induced by either ADP (P = 0.90) or thrombin (P = 0.86). 2-AG, but not D 9 -THC, induced aggregation. 2-AG-induced aggregation was unaffected by AM251 and AM630 but was abolished by aspirin (P < 0.001) and by the MAGL inhibitor, URB602 (P < 0.001). Moreover, the aggregatory response to 2-AG was depressed (by >75%, P < 0.001) in blood from patients with coronary artery disease receiving aspirin compared with that from healthy volunteers. CONCLUSIONS2-AG-mediated activation of platelets is via metabolism to arachidonic acid by MAGL, and not through direct action on CB1 or CB2

Health care systems are under increasing pressure to cope with shifting demographics, the threat of chronic and noncommunicable disease, and rising health care costs. The uptake of innovations to meet these challenges and to advance medicine and health care delivery is not as rapid as the pace of change. Greater emphasis on the diffusion of innovation and greater understanding of the structural and organizational levers that can be used to facilitate systemwide improvement are essential. This article describes the results of a qualitative and quantitative study to assess the factors and behaviors that foster the adoption of health care innovation in eight countries: Australia, Brazil, England, India, Qatar, South Africa, Spain, and the United States. It describes the front-line cultural dynamics that must be fostered to achieve cost-effective and high-impact transformation of health care, and it argues that there is a necessity for greater focus on vital, yet currently underused, organizational action to support the adoption of innovation.

The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPγS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1−/− and GPR55−/−) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPγS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55−/− mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55−/− mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control.