Ayahuasca is a psychoactive brew containing N,N-dimethyltryptamine (DMT) and β-carboline alkaloids that induces marked alterations in perception, emotion and self-referential processing. However, the multiscale biological organization linking peripheral metabolism, brain network dynamics, neurochemistry, and subjective experience in humans remains poorly understood. Here, we applied an integrative, within-subject, multiblock partial least squares framework to model coordinated changes across four complementary biological and phenotypic layers: plasma psychoactive alkaloids, targeted metabolomics, resting-state fMRI–derived functional connectomes, and multidimensional subjective experience assessed with the 5-Dimensional Altered States of Consciousness (5D-ASC) scale, in 20 experienced ceremonial ayahuasca users. Complementary ¹H-MRS data were used to examine associations between peripheral metabolism, posterior cingulate cortex neurochemistry, and default mode network (DMN)-related connectivity. Multilayer integration revealed that the experiential dimensions oceanic boundlessness, visionary restructuralization and auditory alterations covaried with circulating DMT and β-carbolines, alterations in lipid, amino acid and energy metabolisms and reconfiguration of dorsal attention- and DMN-related connectivity. Shared network features across experiential dimensions were most strongly associated with endocannabinoid-related N-acylethanolamines, acylglycerols, and ceramides, extending canonical serotonergic models toward downstream lipid-signalling and metabolic processes. Complementary rCCA analyses further showed structured covariation between peripheral metabolites, posterior cingulate cortex neurochemistry, and DMN-related connectivity. Together, these findings indicate that psychedelic states reflect coordinated, system-level interactions between peripheral metabolism and functional brain networks rather than isolated neurochemical or neural events. Framed within a brain–body integromics perspective, this work provides translationally relevant insight into metabolic pathways that may modulate brain function and subjective response, with potential implications for neuropsychiatric and pharmacometabolic research.
Madrid-Gambín et al. (Thu,) studied this question.