Possible Interactions Between 5-HT2A Receptors and the Endocannabinoid System in Humans: Preliminary Evidence of Interactive Effects of Ayahuasca and Endocannabinoids in a Healthy Human Subject

Introduction

Ayahuasca is a traditional Amazonian psychoactive decoction that combines Banisteriopsis caapi, which contains reversible monoamine oxidase A (MAO-A) inhibitors (β-carbolines), with Psychotria viridis, which supplies N,N-dimethyltryptamine (DMT), a 5-HT1A/2A/2C agonist. Because the β-carbolines inhibit peripheral MAO-A, orally administered DMT can reach the brain; earlier clinical work has reported rapid antidepressant effects after a single ayahuasca dose in patients with treatment-resistant depression. Basic pharmacology indicates that activation of cortical 5-HT2A receptors can trigger formation and release of endocannabinoids (ECs), particularly 2-arachidonoylglycerol (2-AG), and both the 5-HT2A receptor and the endocannabinoid system (ECS) are coexpressed in brain regions implicated in emotional processing, suggesting a plausible interaction that could contribute to ayahuasca’s effects on mood and anxiety. Romanos and colleagues set out to probe whether acute 5-HT2A agonism via ayahuasca alters peripheral EC levels in humans and to relate any changes to subjective and physiological responses. The study used an open-label, single-subject design in a healthy volunteer to obtain preliminary evidence of interactive effects between ayahuasca and the ECS and to assess tolerability and subjective mood/anxiety changes over the acute time course of the drug’s action.