Anthropologists have long speculated that ancient peoples of Mesoameria used a toad, Bufo marinus, as a ritual intoxicant. This hypothesis rests on many iconographic and mythological representations of toads and on a number of speculative ethnographic reports. The authors reject B. marinus as a candidate for such use because of the toxicity of its venom. A more likely candidate is the Sonoran desert toad, Bufo alvarius, which secretes large amounts of the potent known hallucinogen, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). The authors demonstrate that the venom of B. alvarius, although known to be toxic when consumed orally, may be safely smoked and is powerfully psychoactive by that route of administration. These experiments are the first documentation of an hallucinogenic agent from the animal kingdom, and they provide clear evidence of a psychoactive toad that could have been employed by Precolumbian peoples of the New World.