Ayahuasca is a hallucinogenic decoction used as a traditional medicine in several Amazonian regions. The ritualistic use of ayahuasca has spread throughout many countries, making it necessary to study its risks and benefits. Two sub-studies were designed for this investigation. In sub-study 1, a psychiatric interview and a battery of questionnaires were administered to subjects (n = 40) before their first ayahuasca use. Two follow-ups were conducted at 1 and 6 months. In sub-study 2, the same interview and battery of questionnaires were administered to long-term ayahuasca users (n = 23) and their scores were compared with those of the ayahuasca-naïve group. In the first assessment, nearly half (45%) of the naïve users were found to meet the diagnostic criteria for a psychiatric disorder. After the ayahuasca use, more than 80% of those subjects showed clinical improvements that persisted at 6 months. The questionnaires showed significant reductions in depression and psychopathology. Regarding substudy 2, long-term users showed lower depression scores, and higher scores for self-transcendence and quality of life, as compared to their peers in sub-study 1. Further controlled and observational naturalistic studies assessing the eventual risks and potential benefits of ayahuasca are warranted.Ayahuasca is a psychoactive beverage that results from the decoction of Banisteriopsis caapi and Psychotria viridis, plants rich in β-carbolines (harmine or tetrahydroharmine, among others) and N,N-dimethyltryptamine (DMT), respectively. DMT is a partial agonist of serotonin (5-HT) receptors 1 , but it can interact with other receptors as well (for a review see Carbonaro & Gatch 2 ). The hallucinogenic effects are primarily caused by the combination of the monoamine-oxidase A (MAO-A) inhibiting properties of β-carbolines and DMT, which results in the oral bioavailability of the latter 3 .Ayahuasca has been traditionally used in several communities of the Amazonia, but in recent decades its use has spread throughout the world 4 , first to urban areas of Brazil, where syncretic religions such as Santo Daime, União do Vegetal and Barquinha were established 5 , and then to other contexts, including several countries of the world where ayahuasca retreat centers have been developed and/or neoshamanic groups exist 6,7 .Concurrent with this increased public interest in ayahuasca ceremonies, there has been major interest from the academic and biomedical fields regarding its potential health effects 8,9 . Data from observational studies suggest that ayahuasca and its active ingredient DMT may have anxiolytic properties 10,11 . Furthermore, it has not been associated with increased psychopathology or with impairments in neuropsychological functioning 12,13 . An open-label clinical study found significant therapeutic benefits among patients with treatment-resistant major depressive disorder (MDD) after the administration of a single dose of ayahuasca 14,15 . Additionally, one randomized, placebo-controlled clinical trial was recently publish...