Visualization of the key aspects of our hypothesis. Serotonergic psychedelics could affect gut microbes that produce a transient increase of serotonin (5-HT) by host enterochromaffin cells (ECs). This increased gut 5-HT production—which is taken up and distributed by platelets—may work as a hormone-like regulatory signal that could influence membrane structure (that modifies membrane signaling processes) and membrane permeability in the host organs and tissues and in the brain. Increased plasma 5-HT levels could enhance permeability of microvessel endothelial cells and the blood-brain barrier (BBB). Transiently increased permeability of the BBB allows for plasma 5-HT to enter the central nervous system (CNS) and be distributed by the volume transmission (VT). Then, this gut-derived 5-HT could transiently modulate excitatory and inhibitory neurotransmission, produce special network disintegration in the CNS mainly within the default mode network (DMN), and promote structural and functional neural plasticity. This transient perturbation of the normal neural hierarchy (reduced connectivity between the frontal cortex and the lower brain areas, i.e., inhibition of top-down control) allows patients access to suppressed fear information and perform an emotional reset, in which the amygdala may have a key function.