Written before Leary's incarceration on drug-related charges, it is an autobiographical account of his experiences from 1959 to 1962, a period that roughly coincides with his employment as a lecturer in clinical psychology at Harvard University.

The book is written in the form of 16 "trips", each involving a "guide", among whom are such influential 1960s figures as Aldous Huxley, Allen Ginsberg, Richard Alpert (Ram Dass), Ralph Metzner, Huston Smith, and William S. Burroughs.

In some of his writing in High Priest, Leary adapts lyrics from the Beatles' 1967 album Sgt.

Pepper's Lonely Hearts Club Band, which he considered "an instant drug-culture classic".

It also includes detailed reports of his psychedelic experiences while using psilocybin pills, LSD, and DMT.