Depression is a disease that affects millions of people worldwide, current pharmacotherapeutic approaches remaining limited. Empirical evidence suggests that psilocybin has a great potential to be used as an antidepressant drug. Nevertheless, there is still a significant lack of information on psilocybin’s mechanisms of action and toxicity, in spite of these aspects being essential to understand the drug’s clinical effectiveness and safety. This project aims to elucidate the antidepressant potential and toxicity, namely damage of target organs and biochemical alterations, induced in rat, by the exposure to psilocybin, Psilocybe spp. mushrooms or their extracts. These novel data will advance the comprehension of the mechanisms implicated in psilocybin’s ability to improve depressive conditions, as well as eventual toxicity, especially if deviations from the profile of effects induced by psilocybin are observed when the other forms are administered (mushrooms and their extracts).