Brazilian native communities already knew various drugs, such as tobacco, ayahuasca, mate, or guaraná, but after the arrival of Portuguese colonizers, sugarcane became the main economic activity for production of sugar and brandy (cachaça), with tobacco ranking second. Ayahuasca became, in the 20th century, the sacrament of syncretic and mixed religions. Pharmaceutical regulations since the late 19th century, especially of painkillers and cocaine, as well as the prohibition of folk healers, tightened state controls that particularly stigmatized cannabis as an expression of an African heritage to be extirpated. Adherence to international treaties and the establishment of bodies that centralized drug policy, such as the National Commission for the Inspection of Narcotic Drugs (CNFE), in 1938 were accompanied by repressive legislation, with a large increase in criminal indictment and incarceration. Brazil’s 20th-century drug history, encompassing the sphere of pharmaceuticals and illicit and licit substances such as alcoholic, stimulants, and tobacco, reflects shifting socioeconomic, political, and cultural contexts.