Hemopressin is a short, nine amino acid peptide (H-Pro-Val-Asn-Phe-Lys-Leu- Leu-Ser-His-OH) isolated from rat brain that behaves as an inverse agonist at the cannabinoid receptor CB1, and is shown here to inhibit agonist-induced receptor internalization in a heterologous cell model. Since this peptide occurs naturally in the rodent brain, we determined its effect on appetite, an established central target of cannabinoid signaling. Hemopressin dose-dependently decreases night-time food intake in normal male rats and mice, as well as in obese ob/ob male mice, when administered centrally or systemically, without causing any obvious adverse side effects. The normal, behavioral satiety sequence is maintained in male mice fasted overnight, though refeeding is attenuated. The anorectic effect is absent in CB1 receptor null mutant male mice, and hemopressin can block CB1 agonist-induced hyperphagia in male rats, providing strong evidence for antagonism of the CB1 receptor in vivo.We speculate that hemopressin may act as an endogenous functional antagonist at CB1 receptors and modulate the activity of appetite pathways in the brain.