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Psychoactive drugs are widely used, it is thought, because they hijack reward-related neural circuitry. If so, drugs should be equally appealing to children and to adults of both sexes. Many drugs, however, are plant defensive chemicals. Hence, children, and to a lesser extent adult women, should have evolved to avoid consuming them to protect their, or their fetuses' and nursing infants', developing nervous systems, respectively. Analyses of national and cross-national data find virtually no substance use among children, a switch-like transition to substance use in adolescence, and a nearly universal male bias in substance use. They also find that various reproductive indices, such as total fertility rate and age of the youngest child, are negatively associated with women's substance use, even after controlling for indices of women’s social, economic, and educational status. These results suggest that fetal protection helps explain female drug use decisions. The onset of substance use in adolescents of both sexes might be explained by the diminishing developmental costs of toxin exposure vs. its increasing benefits in ancestral environments, such as self-medication against macroparasites.