Anthropologists have long speculated that ancient peoples of Mesoamerica 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. We 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). We demonstrate that the venom of B. alvarius, though 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 a hallucinogenic agent from the animal kingdom, and they provide clear evidence of a psychoactive toad that could have been employed by Precolumbiae peoples of the New World.