In this episode, Dr. Nicholas DiPatrizio discusses how the endocannabinoid system helps regulate appetite, nutrient sensing, metabolism, and communication between the gut and brain. He describes findings from mouse studies showing how cannabinoid signaling in the intestinal lining may promote preferences for foods high in fat and sugar and interfere with signals that normally tell the brain when to stop eating. He also explores the “cannabis paradox,” in which cannabis can stimulate appetite while chronic users tend to have lower body weight and a reduced likelihood of type 2 diabetes. The conversation examines research comparing pure delta-9 THC with whole-cannabis extract, including evidence in obese mice that both reduced body weight but only the whole extract reversed diabetes-like metabolic dysfunction. A central message is that therapies targeting cannabinoid receptors specifically in the gut may one day improve metabolic health while limiting unwanted effects on the brain.