This paper reports on changes in substance use and substance dependence symptoms—without intervention—among young adult multidrug users in the club scene, ages 18–29, (N = 444) who participated in a natural history study. Computer-assisted personal interviews at baseline and 6-, 12-, and 18-month follow-ups included well-tested measures of substance use and dependence. Changes in substance dependence symptoms and drug use frequencies were calculated using Cohen's d statistic. Mean age was 22; 40% were female; 58% were Hispanic, 17% White, and 21% Black. At 18-month follow-up assessment, participants reported significantly fewer days of cocaine (d = − .85 at 18 months), ecstasy (d = − .93), benzodiazepine (d = − .82), and prescription opioid (d = − .81) use, as well as reduced substance dependence symptoms (d = − .42). These results, together with data from focus groups with completers, suggest that comprehensive health and social risk assessments may have quite strong intervention effects among young adult multidrug users.