Introduction : Ayahuasca is a psychedelic brew originally used by indigenous tribes from the Amazon Rainforest and in religious rituals. Pre-clinical and observational studies have demonstrated its possible potential as an antidepressant, and open and placebo-controlled clinical trials corroborated these results. For it to become an approved treatment for depression, its safety and tolerability need to be assessed and documented. Areas covered : We have gathered data regarding occurrence of adverse events (AEs) in all reported randomized, placebo-controlled trials with healthy and clinical populations involving ayahuasca administration (n = 108 ayahuasca administrations). We systematically categorized these results, recorded their prevalence and discussed the possible mechanisms related to their emergence. Expert opinion : There were no reports of serious AEs, indicating a relative safety of ayahuasca administration in controlled settings. Most common AEs related to ayahuasca administration included nausea, vomiting, headaches and transient increases in cardiovascular measurements. Ayahuasca research is still in its infancy, especially concerning the absence of large and robust clinical trials to verify its antidepressant effects. Dose standardization, legal prohibition of the possession of its alkaloids and how traditional communities will be compensated if ayahuasca becomes an approved medicine are the biggest obstacles to overcome for its future use in the therapeutic context.