Ethnopharmacological and Pharmacological Insights into Ayahuasca: Experimental Evidence, Toxicological Perspectives, and Emerging Biomedical Applications

Ayahuasca (AYA), a sacred Amazonian decoction made from Banisteriopsis caapi and Psychotria viridis , has long been used in Indigenous healing rituals. Its primary bioactive constituents, β-carboline alkaloids and N,N-dimethyltryptamine (DMT), are the focus of growing biomedical interest due to their neuroactive, antioxidant, and immunomodulatory properties. This review integrates preclinical and clinical evidence on the pharmacological and toxicological actions of AYA and its major compounds, highlighting their therapeutic potential in neuropsychiatric, oncological, and inflammatory conditions, as well as emerging opportunities in nanomedicine. A comprehensive literature search was performed across PubMed, ScienceDirect, Scopus, and Google Scholar (2014–2025) in accordance with PRISMA guidelines. Eligible studies included original in vitro, in vivo, and clinical research assessing the pharmacological or toxicological effects of AYA, its extracts, or isolated compounds. Harmine, harmaline, tetrahydroharmine, and DMT demonstrated neuroprotective, antioxidant, and anti-inflammatory effects in models of depression, cerebral ischemia, sepsis, neurodegeneration, and cancer. DMT modulated key pathways through interactions with 5-HT₂A and sigma-1 receptors. Emerging nanotechnological approaches suggest that AYA-derived alkaloids and phytochemicals may be explored as candidates for green nanomaterial synthesis and nanocarrier functionalization; however, direct evidence remains limited and requires experimental validation. High-dose and prolonged exposures raised concerns regarding reproductive and cardiovascular toxicity. Further progress will require rigorous phytochemical standardization, dose-response toxicity studies, systematic evaluation of nanomaterial synthesis and characterization, and translational validation to establish the safety and therapeutic potential of AYA-derived compounds.