Interest in psychoactive ethnobotanicals such as ayahuasca or Psilocybe mushrooms for clinical uses has increased over the last two decades. While clinical and experimental approaches have focused on using isolated compounds of interest (such as psilocybin), an emerging trend in drug discovery involves a more comprehensive approach. The polypharmacology paradigm, as it has been named, suggests that promiscuous drugs could be safer and more effective than highly selective ones. This is especially relevant with regards to complex diseases, like most mental health problems and neurodegenerative diseases, and for natural products, including psychoactive ethnobotanicals. Natural products not only show a multi-target profile, but they also contain several compounds capable of interacting with one another and producing synergistic effects. In this chapter, the use of whole natural products instead of isolated compounds is suggested in support of combining two recent paradigms: psychedelic-assisted therapy on the one side and polypharmacology on the other. Keywords: Natural products, Polypharmacology, Psychedelics, Synergy.