The Psychoactive Imagination in Early Modern Literature argues that seventeenth-century English writers used the language of intoxication, ingestion, and chemical alteration to theorize the capacities and limits of English-Protestant selfhood. Across devotional lyrics, epic poetry, and epistolary colonial writing, authors deploy metaphors of drugs not merely as moralizing topoi but as flexible rhetorical instruments for articulating agency, the distinction between perception and knowledge, and the instability of meaning. By tracing how writers imagined, described, and mobilized psychoactive substances during the seventeenth century, this dissertation demonstrates that early modern literature made chemically-altered mental experience central to its explorations of interiority, persuasion, and imperial desire. Chapter 2 shows how George Herbert transforms the vocabulary of intoxication into a poetry for devotional self-analysis, oscillating between alcoholic metaphors, inebriating imagery, and the theological pressures of Reformation piety. Chapter 3 turns to Paradise Lost to argue that John Milton’s representation of ambiguous intoxication mobilizes a lexicon of epistemic doubt and sensory alteration to underscore the poem’s theodicy. Chapter 4 examines Sir Thomas Roe’s 1610/11 Guiana letter and its description of tobacco as “freighting smoke,” arguing that the colonial-agent uses the rhetoric of drugs to anticipate imperial futures and to imagine consumption as a mode of colonial knowledge-making. Taken together, these chapters assert the dissertation’s central claim: that early modern English writers relied on the conceptual force of psychoactivity to shape literary form, negotiate devotional and political pressures, and interrogate the porous boundary between the material body and the imagination.