To the best of our knowledge, there is no systematic description in the literature on how to handle psychological adverse reactions (PARs) in clinical trials with ayahuasca. Thus, this is the first scientific report detailing the management of PARs with ayahuasca in such context. Considering the increase in the number of clinical studies involving ayahuasca (and other classic hallucinogens), these cases aim to highlight the importance of discussing PARs in an experimental context and encourage further studies to report PAR management to formulate positive outcomes. The list of essential recommendations described is based on lived experiences of our group, and it is a first step to formulate a more structured protocol in the future for handling PARs using nonpharmacological management, keeping the use of more invasive measures to a minimum.