A Multidisciplinary Hypothesis about Serotonergic Psychedelics. Is it Possible that a Portion of Brain Serotonin Comes From the Gut?

A complex hypothesis proposes that serotonergic psychedelics act on gut microbes, prompting host enterochromaffin cells to temporarily increase production of 5-HT (serotonin). This 5-HT is taken up and distributed by platelets, potentially acting as a hormone-like signal that influences membrane permeability in organs and the brain. Elevated plasma 5-HT may transiently increase blood-brain barrier permeability, allowing 5-HT to enter the central nervous system via volume transmission. There, gut-derived 5-HT could modulate excitatory and inhibitory neurotransmission, causing network disintegration. This transient neural disruption may allow patients access to suppressed fear information and enable an emotional reset, with the amygdala playing a key role.

Study at a glance

Abstract

Here we present a complex hypothesis about the psychosomatic mechanism of serotonergic psychedelics. Serotonergic psychedelics affect gut microbes that produce a temporary increase of 5-HT by their host enterochromaffin cells (ECs). This increased 5-HT production—which is taken up and distributed by platelets—may work as a hormone-like regulatory signal that could influence membrane permeability in the host organs and tissues and in the brain. Increased plasma 5-HT levels could enhance permeability of 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. Next, this gut-derived 5-HT could modulate excitatory and inhibitory neurotransmission and produce special network disintegration in the CNS. This transient perturbation of the normal neural hierarchy allows patients access to suppressed fear information and perform an emotional reset, in which the amygdale may have a key role.