Timothy Leary was early advocate of LSD experimentation. Leary taught psychology at Harvard and by 1960 was doing experiments with LSD and other hallucinogens, first on prison inmates and then on himself and his friends. LSD was not illegal at the time.

In 1960, Allen Ginsberg, supervised by Leary, ingested psilocybin mushrooms, (under the influence of the drug, he phoned Jack Kerouac, identifying himself as God to the telephone operator), and began to spread the word about the new powerful psychedelic drugs.

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.