The endocannabinoid and paracannabinoid systems in natural reward processes: possible pharmacological targets?

Natural rewards such as food, mating, and social interaction are essential for survival and species preservation, and their regulation involves a complex interplay of motivational, cognitive, and emotional processes. Over the past two decades, increasing attention has been directed toward the endocannabinoid system and its paracannabinoid counterpart as key modulators of these behaviors. This review aims to provide an integrated overview of the roles played by the endocannabinoid and paracannabinoid systems in regulating natural reward-driven behaviors, focusing on feeding, reproductive behavior, and social interaction. We highlight how the endocannabinoid system-mainly through CB1 receptor signaling-modulates central and peripheral circuits involved in energy homeostasis, reward processing, and emotional regulation. In parallel, we explore the role of paracannabinoids, such as oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA), which act primarily via non-cannabinoid receptors and contribute to the regulation of appetite, sexual motivation, and social behavior. Special attention is given to the relevance of these systems in the pathophysiology of obesity, eating disorders, sexual dysfunctions, and social impairments, as well as their potential as pharmacological targets. Overall, the evidence discussed supports a broader conceptualization of endocannabinoid and paracannabinoid signaling as pivotal regulators of natural rewards and opens new avenues for the development of targeted interventions for motivational and reward-related disorders.