PROJECT SUMMARY (Project 4) MDMA (Ecstasy) and ketamine are drugs of abuse steadily gaining in popularity. Compared to more traditional stimulants, however, less is known about their mode of action, their subjective effects, and how these effects promote continued use. Our objective is to integrate self-report, behavior and neural measures to develop a detailed characterization of the real-time effects of MDMA and ketamine. In doing so we will advance our understanding of how drug altered brain states give rise to acute drug experiences and drug use outcomes. We will first use neuroimaging to map both acute influence of these drugs on human experience, focusing on dissociative, affective, and reward-related responses. Second, we will probe drug-induced effects on behavioral targets that directly translate to targets used in rodent models. Third, we use functional neuroimaging at rest and during affective as well as reward-related tasks to quantify neural circuit dynamics that underlie experiences and behaviors induced by ketamine and MDMA. We will extend our approach to characterizing individual variability in drug-induced brain-behavior-experience profiles and anchor our interpretation of these profiles by accounting for potential confounding factors that include baseline inter-subject variability and drug-induced biochemical stress. We use precisely controlled designs to address our aims and the important question of how brain- behavior mechanisms produce the subjective effects of these drugs, helping to understand who seeks to use them and why. The findings will advance our scientific understanding of what motivates people to use these drugs and promise to provide a foundation for investigating tailored intervention strategies. Armed with this knowledge, our field will ultimately be better positioned to suggest more effective strategies prevention of the harmful use of these drugs.