Molecular Pathways of the Therapeutic Effects of Ayahuasca, a Botanical Psychedelic and Potential Rapid-Acting Antidepressant

Ayahuasca, a psychoactive brew used in South American rituals, contains DMT from Psychotria viridis and MAO-inhibiting β-carbolines from Banisteriopsis caapi. Preclinical and clinical evidence suggests its antidepressant effects involve complex modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems, along with interactions with VMAT, TAAR1, and sigma-1 receptors. The brew also appears to beneficially modulate inflammatory and neurotrophic factors, leading to neuroprotective and neuroplastic effects. This review summarizes current knowledge of these molecular interactions and their relation to ayahuasca's potential antidepressant properties.

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Abstract

Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for β-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca’s therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca’s components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce.