Studies have shown that women and men differ in their patterns of substance abuse and dependence. Gender differences in the effects of THC, the primary psychoactive substituent of marijuana, have been reported in humans, but the mechanisms responsible for these differences are unclear and are the focus of this research at RTI International. This study aims to determine whether gender differences in the antinociceptive and dependence-related effects of THC, respectively, are modulated by gonadal hormones, estradiol, and progesterone in females and testosterone in males. Gender differences in tolerance to the pain relieving effects of THC, one of the potential therapeutic indications of cannabinoid-based medications, will also be evaluated. Understanding these basic mechanisms underlying sex differences will facilitate development of gender-specific approaches to treat marijuana dependence and to use cannabinoid-based medications therapeutically, specifically in the treatment of pain.