In August 1960, Leary traveled to the Mexican city of Cuernavaca with Russo and tried psilocybin mushrooms for the first time, an experience that drastically altered the course of his life. In 1965, Leary commented that he "learned more about... (his) brain and its possibilities... (and) more about psychology in the five hours after taking these mushrooms than... (he) had in the preceding fifteen years of studying doing research in psychology."
Upon his return to Harvard that fall, Leary and his associates, notably Richard Alpert (later known as Ram Dass), began a research program known as the Harvard Psilocybin Project. The goal was to analyze the effects of psilocybin on human subjects (in this case, prisoners and later students of the Andover Newton Theological Seminary) using a synthesized version of the then-legal drug— one of two active compounds found in a wide variety of hallucinogenic mushrooms including Psilocybe mexicana. The compound was produced according to a synthesis developed by research chemist Albert Hofmann of Sandoz Pharmaceuticals.
Leary argued that psychedelics, used with the right dosage, set and setting could, with the guidance of psychology professionals, alter behavior in unprecedented and beneficial ways. The goals of Leary's research included discovering better methods for treating alcoholism and to reform convicted criminals. Many of Leary's research participants reported profound mystical and spiritual experiences, which they claim permanently altered their lives in a very positive manner. According to Leary's autobiography, Flashbacks, they administered LSD to 300 professors, graduate students, writers and philosophers, and 75 percent of them reported it as being like a revelation to them and one of the most educational experiences of their lives.