The increasing prevalence of so-called cognitive-enhancing drugs is well documented in American higher education. There has been little historical analysis, however, specifically exploring the role of postsecondary institutions in this evolving drug narrative. This paper traces substance use and research trends in American higher education over the past half-century, divided into three eras defined by their disparate approaches to drug policy and public health. Contextualised by historic events, shifting policies and epidemiological data, this multidisciplinary analysis contends that functional, academically oriented drug use is likely to continue rising on US campuses, while recreational drug use will evolve and persist. As history provides a useful lens for understanding the involvement of academe in the first era of drug concern in America, ongoing innovations in medical and social science may be instructive to help ensure that institutions respond judiciously in the present era of new drug synthesis and drug policy recession.