Anandamide is a key mediator of alcohol-induced cardiac mitochondrial dysfunction

Binge alcohol drinking is an escalating public health concern in the United States, contributing to rising rates of alcohol-related cardiovascular complications. We recently identified a role for the endocannabinoid (EC) anandamide (AEA) and its receptor, cannabinoid type 1 receptor (CB1R), in acute alcohol-induced cardiac dysfunction. Although CB1R activation in the myocardium is known to impair cardiac contractility and vascular tone, it remains unclear whether alcohol-driven increases in AEA directly compromise mitochondrial function, thereby contributing to impaired cardiomyocyte performance. We hypothesize that acute alcohol-induced AEA synthesis decreases cardiomyocyte mitochondrial bioenergetics and reduces cardiac performance through CB1R-dependent mechanisms. Here, we provide the first evidence linking acute alcohol-induced elevations in cardiac AEA to disruption of mitochondrial bioenergetics. Using a mouse model of acute alcohol intoxication, we show that oral alcohol administration (5 g/kg) rapidly elevates myocardial AEA levels, coinciding with cardiac dysfunction and accumulation of 4-hydroxynonenal, a marker of lipid peroxidation. RNA sequencing revealed significant upregulation of AEA-synthesis genes (Abhd4, Gde-1) three hours post-alcohol exposure, with strong positive correlations to differentially expressed genes involved in mitochondrial regulation and cellular energy homeostasis. To directly assess AEA’s impact on mitochondrial function, neonatal mouse cardiomyocytes were exposed to physiologically relevant concentrations of AEA prior to Seahorse analysis. AEA elicited dose-dependent reductions in maximal respiration, spare respiratory capacity, and ATP production, demonstrating a potent inhibitory effect on mitochondrial oxidative phosphorylation. Together, these findings identify anandamide as a previously unrecognized mediator of alcohol-induced mitochondrial dysfunction in cardiomyocytes. This work uncovers a novel EC-driven mechanism by which acute alcohol impairs cardiac bioenergetics and contractile function, offering new insight into early molecular events underlying alcohol-associated cardiac dysfunction. Supported by T32AA007577-2, R00AA028300, and LSUHSC start-up funds This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.