Psilocybin, the prodrug found in over 200 species of psychedelic mushrooms, was first identified and synthesized in 1957. Clinical observations from the 1950s and 1960s suggested potential therapeutic effects for depressive symptoms, anxiety, and conversion disorder, despite scientific design limitations. After being classified as a Schedule I substance in 1970, renewed scientific interest since the 1990s has produced further evidence supporting its therapeutic use for psychiatric disorders including pathological anxiety, mood depressive disorder, and addiction.
The gut microbiome may influence how individuals respond to psychedelic substances used in therapy. This review examines the gut–brain axis and its effects on mood, cognition, and behavior, and discusses how microbiome variations could affect the metabolism and bioavailability of psychedelics. It also considers microbiome-targeted interventions as a potential way to enhance psychedelic therapy's effectiveness. By integrating psychopharmacology, microbiology, and neuroscience, the authors aim to advance understanding of the microbiome-psychedelic relationship and optimize mental health outcomes in the current psychedelic renaissance.