Before 1906, most of what we think of today as "controlled substances" weren't illegal in the US because the government didn't have the means to identify and regulate ("control") them. You could buy heroin, cocaine, etc., in over-the-counter "patent" medicines. The Pure Food and Drug Act, passed in 1906 (after publication of Upton Sinclair's novel, "The Jungle") created a framework for testing, identifying and regulating narcotics.

In the first decade of the 20th Century, Don Vito Cascio Ferro emigrated to America and set up the basis of today's Five Families. He also established a drugs pipeline from Europe to America that all families participated in. Charlie Luciano was arrested in 1923 for dealing drugs, and got off because he ratted out his partner. In 1957, Joe Bonanno and his cousin, Stefano Magaddino (Don of Buffalo, NY), met with Luciano in Sicily, and established a framework in which Sicilian dealers would import and help distribute heroin and other drugs on a large scale in the US. The famously aborted Apalachin meeting of 1957 was called by Vito Genovese, in part to bless the trafficking in drugs and also so he could get a piece of the action that Bonanno and Magaddino had put in motion earlier that year. In the Seventies, Carmine Galante, Bonanno's former consigliere, established the "Pizza Connection" in which Sicilians ("zips") flooded the US with cheap drugs.