Extensive documentation exists showing that exercise induces analgesia and sedation. Despite decades of research attempting to explicate a neurochemical basis for these phenomena, the mechanism underlying these changes is unknown. Using trained male college students running on a treadmill or cycling on a stationary bike for 50 min at 70-80% of maximum heart rate, we report here the first evidence that exercise of moderate intensity activates the endocannabinoid system, suggesting a new mechanism for exercise-induced analgesia and possibly other physiological and psychological adaptations to exercise.