Mid-20th-century American research on psychedelics evinced a stunning diversity of interpretations of hallucinogenic effects. While some researchers viewed psychedelics as invaluable tools for psychotherapy, others persisted in treating them as psychosis-inducing agents. As some groups considered psychedelics as catalysts for artistic creativity, others investigated their potential use as psychochemical weapons in the battlefield, or conversely as tools for spiritual ecstasy and revelation. This bewildering array of perceptions regarding the nature of hallucinogenic effects led to stark contrasts in the contexts (set and setting) of psychedelic research and experimentation, leading to wildly divergent outcomes and reports on the effects of the drugs, and strident disagreements between the actors in the field. Examining this remarkable historical moment of epistemological unclarity regarding psychedelics and their effects, this article describes how distinct scientific and cultural trends and moments of mid-20th-century America contributed to the creation of diverse microclimates of set and setting that reproduced investigator beliefs and attitudes and brought about a beguiling Pygmalion effect that left researchers befuddled and perplexed. I propose the concept of psychedelic modality to describe how distinct sociocultural microclimates lead to thematic aggregates in which distinct types of expectations, intentions as well as physical, social, and cultural environments all tend to cluster, producing characteristic outcomes and results. By exploring the historical context and consequences of the emergence of seven psychedelic modalities (psychotomimetic, military, psychotherapeutic, spiritual, artistic-creative, tech-innovative, and political) in mid-20th-century America, this article outlines the varieties of psychedelic experiences in their relationship with culture at large, and subcultures in particular.