Abstract
Entheogens have emerged in clinical research as an alternative pharmacological solution for Treatment-Resistant Depression (TRD) because they possess rapid and enduring antidepressant and anxiolytic effects and mitigate suicidal ideation. Furthermore, they induce positive emotions and elicit mystical or spiritual experiences, attributes that may contribute to their therapeutic efficacy, given the protective influence of mysticism and religiosity against depression. This narrative review aims to discuss the extant evidence concerning the utilization of entheogens in TRD, provide an up-to-date understanding of the research landscape and to elucidate the mechanisms of action of compounds such as psilocybin, DMT, LSD, ketamine, esketamine, and cannabinoids. The effectiveness of entheogens in the management of depression has been consistently validated in clinical trials. Nonetheless, it is imperative to recognize our limited understanding of potential adverse effects, particularly in the long term, despite data supporting its acute tolerability.
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