A conceptual review links CB1 signaling with stress, sleep and appetite

The endocannabinoid system (ECS) plays a central role in the regulation of stress, sleep, feeding behavior, and energy metabolism. This conceptual review proposes a neurobiological model in which cannabinoid type 1 receptor (CB1) signaling acts as a convergence mechanism linking these physiological domains. Evidence from neuroendocrinology, chronobiology, and cannabinoid pharmacology indicates that CB1 signaling participates in the regulation of hypothalamic-pituitary-adrenal (HPA) axis activity, circadian fluctuations in endocannabinoid tone, and neural circuits involved in energy homeostasis, reward processing, and feeding behavior. Stress-related HPA-axis activation modifies the availability of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), thereby influencing stress responsivity and feeding behavior. Similarly, sleep restriction and circadian disruption alter the temporal dynamics of endocannabinoids and are associated with increased hunger, preference for highly palatable foods, and greater metabolic vulnerability. In addition, CB1-modulating ligands such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabigerol (CBG), and noladin ether may influence food intake through mechanisms dependent on dose, biological context, and cell type, involving proopiomelanocortin (POMC) neurons, β-endorphin signaling, reward circuits, and mitochondrial adaptations related to uncoupling protein 2 (UCP2). Enzymatic regulation of endocannabinoid tone by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), together with individual genetic factors, may further shape susceptibility to metabolic, affective, and sleep-related phenotypes. Collectively, these observations support a model in which CB1 signaling connects stress, sleep, reward, and feeding behavior within the broader endocannabinoidome. This model remains hypothesis-generating and requires prospective translational validation.