Role of the endocannabinoid system, metabolic disease progression, and associated cardiovascular risk

The National Heart, Lung, and Blood Institute awarded Cedars-Sinai Medical Center $854,391 on September 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the role of the endocannabinoid system in metabolic disease progression and associated cardiovascular risk.

The research examines how circulating endocannabinoid species, including anandamide and 2-arachidonoylglycerol, contribute to the parallel progression of obesity to diabetes and the accompanying two- to three-fold rise in cardiovascular disease risk. The project will conduct a comprehensive prospective investigation to clarify the interrelations among circulating endocannabinoids and their role in human metabolic physiological and pathophysiological processes. Prior preliminary work identified distinct endocannabinoids and related lipid species concordantly related to risk for both incident diabetes and incident cardiovascular disease; recent findings indicate that a subset of these bioactive lipids associates with metabolic-related cardiovascular disease in a context-dependent manner, potentially explaining mixed results from prior clinical trials of cannabinoid receptor inhibitors or inverse agonists. The findings are intended to inform development of new and tailored metabolic therapies.

The award is a Project Grant with a period of performance from September 1, 2026, through May 31, 2030. Work is performed in West Hollywood, California.

Abstract

Individuals who progress from having obesity to developing overt diabetes will experience, in parallel, a steady two- to three-fold rise in their risk for cardiovascular disease. The dynamic and complex drivers of both advancing metabolic disease and its associated cardiovascular risk remain unclear. The endocannabinoid system is an endogenous network of small lipid signaling molecules including circulating endocannabinoid species, such as anandamide and 2-arachidonoylglycerol, which normally interact with cannabinoid receptors to regulate energy balance, appetite, and lipid metabolism. Overactivation of the endocannabinoid system is known to contribute to the progression of metabolic diseases while concurrently interfacing with pro-atherogenic vascular mechanisms. Pharmacological interventions designed to target the endogenous endocannabinoid system have demonstrated the potential to mitigate these metabolic disturbances in clinical studies. Despite these advances, however, progress has been stymied by a still limited understanding of the complex interrelations among circulating endocannabinoids and their role in contributing to human metabolic physiological and pathophysiological processes. In preliminary work, we have identified a number of distinct endocannabinoids and related species that appear concordantly related to risk for both incident diabetes and incident cardiovascular disease. Our most recent findings now indicate that a subset of these bioactive lipids is associated with metabolic related cardiovascular disease in a context dependent manner - offering a potential explanation for the mixed results seen in prior clinical trials of cannabinoid receptor inhibitors or inverse agonists. To inform ongoing efforts to develop new and tailor existing metabolic therapies, we now propose a comprehensive prospective investigation designed to more precisely identify the key endocannabinoid pathways that underlie progressive metabolic disease and its associated cardiovascular risk. We anticipate this work will provide the critical insights needed to effectively develop and tailor interventions, including existing and novel therapies, aimed at mitigating excess cardiovascular risks for all persons with metabolic disease including those with obesity and/or diabetes.