Sex differences in drug abuse are evident across all stages, including initiation, escalation, addiction, and relapse. Women tend to start using drugs at lower doses, escalate use more rapidly, and are at higher risk for relapse after abstinence compared to men. These differences are observed in both humans and animal models. Neuroendocrine mechanisms, particularly involving estradiol, play a key role in mediating these sex differences. In humans, women use alcohol, marijuana, opioids, and cocaine more rapidly than men, and are more likely to become addicted and struggle to quit. Women also exhibit greater negative affective responses to nicotine withdrawal cues. In animal studies, female rats acquire self-administration of drugs more quickly and show greater sensitivity to drug effects during the estrous cycle. Estradiol enhances cocaine self-administration and motivation, while progesterone can counteract estradiol's effects. Sex differences in drug abuse are also influenced by gonadal hormones. Estradiol enhances dopamine release and motivation, while progesterone may reduce these effects. In rodents, sex differences in drug responses are linked to variations in dopamine receptor activity and striatal function. Studies on gonadectomized rats show that estradiol enhances cocaine self-administration and motivation, while progesterone can counteract this. In mice, sex chromosome complement and gonadal hormones both influence drug-related behaviors. For example, XX mice acquire food-reinforced habits faster than XY mice, and AMPH potentiates brain stimulation reward more in XY mice. These findings suggest that sex differences in drug abuse are influenced by both hormonal and genetic factors. Estradiol plays a key role in enhancing drug motivation and reinforcing effects, while progesterone may modulate these effects. Understanding these mechanisms is crucial for developing effective treatments for drug abuse in both males and females.Sex differences in drug abuse are evident across all stages, including initiation, escalation, addiction, and relapse. Women tend to start using drugs at lower doses, escalate use more rapidly, and are at higher risk for relapse after abstinence compared to men. These differences are observed in both humans and animal models. Neuroendocrine mechanisms, particularly involving estradiol, play a key role in mediating these sex differences. In humans, women use alcohol, marijuana, opioids, and cocaine more rapidly than men, and are more likely to become addicted and struggle to quit. Women also exhibit greater negative affective responses to nicotine withdrawal cues. In animal studies, female rats acquire self-administration of drugs more quickly and show greater sensitivity to drug effects during the estrous cycle. Estradiol enhances cocaine self-administration and motivation, while progesterone can counteract estradiol's effects. Sex differences in drug abuse are also influenced by gonadal hormones. Estradiol enhances dopamine release and motivation, while progesterone may reduce these effects. In rodents, sex differences in drug responses are linked to variations in dopamine receptor activity and striatal function. Studies on gonadectomized rats show that estradiol enhances cocaine self-administration and motivation, while progesterone can counteract this. In mice, sex chromosome complement and gonadal hormones both influence drug-related behaviors. For example, XX mice acquire food-reinforced habits faster than XY mice, and AMPH potentiates brain stimulation reward more in XY mice. These findings suggest that sex differences in drug abuse are influenced by both hormonal and genetic factors. Estradiol plays a key role in enhancing drug motivation and reinforcing effects, while progesterone may modulate these effects. Understanding these mechanisms is crucial for developing effective treatments for drug abuse in both males and females.