Absorbed residue studies have been used in subsistence research for decades. Only more recently have the chemical methods employed been used to explore the consumption of ritual concoctions such as those including cacao, yaupon holly, and alcohol. In this article we use mass spectrometry to identify Datura residues in prehistoric contexts from western Mexico and the American Southeast. Datura is a genus of flowering plants that contain hallucinogenic alkaloids. Their use in both regions is known historically and still continues today. This study sampled 55 pottery vessels and 18 shell vessels using both a traditional burr method and a water-based sonicator sampling method. Datura residues were found in 13 pottery vessels and 14 shell vessels using both sampling approaches. These results demonstrate that it is possible to identify Datura residue in pottery and shell vessels and that the use of Datura extends back into prehistory in both regions. The form and decoration of pottery vessels with Datura residues show correlations with specific motifs and themes. Historically, shell vessels were used in the Southeast for the consumption of another ritual beverage, called the Black Drink. The presence of Datura shows that those vessels were used for other kinds of beverages as well.