Psychedelic therapy, combining psychedelic drugs with psychological support, shows promise for treating disorders marked by rigid and unhealthy patterns of emotion, thought, and behavior, including depression, treatment-resistant depression, addiction, and potentially anxiety, OCD, PTSD, and eating disorders. This review examines preclinical and clinical evidence through the Research Domain Criteria (RDoC) framework, mapping the drugs' effects across molecular, cellular, and network levels to RDoC constructs like negative and positive valence, arousal, social processing, cognition, and sensorimotor systems. The goal is to clarify the specific clinical dimensions psychedelics affect and their underlying neurobiology, aiming toward a mechanistic understanding and personalized psychedelic therapy.
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.