This chapter traces the formalisation of psychoactive substance use in the early states of Egypt, Mesopotamia, India, and Mesoamerica. It explores how mind-altering plants and compounds were embedded in religious, medical, and elite ritual practices, often regulated by priesthoods and royal authorities. The chapter contrasts medicinal use (e.g., opium, mandrake, soma) with ecstatic religious practices and considers how control over such substances became a form of political power. Art, texts, and material remains are used to reconstruct symbolic associations and ritual contexts. The chapter also examines gendered dimensions of usage and the sociopolitical implications of prohibitions and monopolies. Overall, it portrays ancient civilisations as sites of controlled psychoactive innovation and illustrates the deep roots of contemporary debates about access, morality and consciousness alteration.