Datura (Solanaceae) is an iconic genus of plants found throughout the world. It is primarily known for its beautiful flowers, but is also well documented as an entheogenic plant across numerous cultures, historically and contemporarily. Within many of these cultures, use of Datura is reportedly taboo, restricted to specific occasions, and handling/preparation is typically limited to certain adept individuals. Customary applications associated with Datura include rites of passage, recreation, and herbal remedies resulting from the psychotropic and medicinal properties of the plant. Datura’s entheogenic properties can be attributed to biologically active tropane alkaloids, likely anti-herbivore compounds, that can be dangerous or deadly to humans in large doses. In this study, we hypothesize that the observed restricted use is the result of a genetically based unpredictability of two tropane alkaloids: atropine and scopolamine (hyoscine). We completed a comprehensive meta-analysis of reported concentrations of atropine and scopolamine across the genus Datura. Our primary search utilized the Web of Science database and produced 89 papers, 18 of which we were able to extract data from. Our secondary search involved pulling sources from the original literature and completing detailed web searches for reported chemical concentrations of specific species. The combined searches resulted in a total database of 24 studies covering concentrations of tropane alkaloids from 13 Datura species. In addition to recording the variation of alkaloid concentrations, we searched ethnobotanical records and documented if a species of Datura was used widely or if use was restricted to a certain group of individuals within a culture. We observed that many cultures with restricted societal uses of Datura appeared to use species that have a higher variability of alkaloid concentrations. These cultural limitations may be an important measure that developed as a way to communicate the safe and responsible use of these entheogenic compounds.