A systems psychiatry approach recognizes complex interactions across biological levels and requires integrated treatment strategies. Serotonergic psychedelics primarily target cortical 5-HT2A receptors, but their therapeutic mechanisms span molecular, cellular, and network levels, influenced by biofeedback from the periphery and environment. The gut microbiome, through the gut-brain axis, regulates host neurophysiology via unconscious parallel processing systems. Although psychedelic and microbial signaling operate on different timescales, the microbiota-gut-brain axis may contribute to the preparatory, acute, and integration phases of psychedelic therapy. This review examines the gut microbiome and mycobiome, pathways of the MGB axis, and potential interactions with psychedelic therapy, discussing implications for precision medicine.
Human cognition depends not only on brain processes but also on bodily and environmental factors, a view known as the 4E perspective (embodied, embedded, enacted, extended). The human microbiome—the community of microorganisms living in and on the body—is a key mediator of this interaction, influencing brain function and mental health across a person's lifetime. This theoretical review presents a 4E approach to the microbiome, arguing that microbial networks from the gut, skin, and built environments shape mental processes. The authors review evidence for this framework and outline future research and clinical interventions that integrate biological, psychological, social, and environmental factors, particularly targeting the brain-gut-microbiome axis for low-cost, personalized mental health treatments.