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

Serotonergic psychedelics are a class of drugs that act principally by binding and activating serotonin 5-HT2A receptors, which are widely expressed throughout the body including the gastrointestinal tract, platelets and the nervous system. Although there is growing evidence for therapeutic benefits of these compounds in psychiatric disorders, the neurobiological and pharmacological mechanisms remain incompletely understood. The authors note that about 95% of the body's serotonin (5-HT) is produced in the gut by enterochromaffin cells (ECs), that much of this peripheral 5-HT is taken up and carried by platelets, and that peripheral 5-HT has diverse signalling roles beyond classical synaptic neurotransmission — including effects on membrane properties and vascular permeability. P. and colleagues set out to present an integrative, multidisciplinary hypothesis that links gut-derived 5-HT, platelets, blood–brain barrier (BBB) permeability and nonsynaptic volume transmission to the central effects of serotonergic psychedelics. In brief, they propose that psychedelics transiently alter gut microbes and EC 5-HT production, increasing plasma 5-HT carried by platelets; this hormone-like signal can alter membrane and BBB permeability, permitting peripheral 5-HT to enter the central nervous system (CNS) where it is distributed by volume transmission and transiently perturbs excitatory–inhibitory balance and large-scale networks (notably the default mode network and amygdala), thereby facilitating emotional processing and neural plasticity distinct from conventional selective serotonin reuptake inhibitor (SSRI) mechanisms.

The authors develop a stepwise hypothesis that links several literatures. First, they argue that serotonergic psychedelics can modulate the gut microbiota and enteric nervous system, which in turn can increase 5-HT synthesis by intestinal enterochromaffin cells. Much of this gut-derived 5-HT is taken up into platelets and circulates systemically. Second, because 5-HT has strong lipid–membrane affinity and can influence membrane structure and signalling (including lipid-raft properties), raised plasma 5-HT could alter vascular endothelial permeability. Platelet-related mediators such as platelet-activating factor (PAF), platelet-derived extracellular vesicles (pEVs), and platelet activity more broadly are proposed as potential effectors that can transiently and reversibly increase microvessel and BBB permeability. Third, the authors propose multiple mechanisms by which peripheral 5-HT could enter or influence the CNS: bidirectional functioning of the serotonin transporter (SERT) in the BBB, transfer via pEVs or other extracellular vesicles, and, under some conditions, direct platelet interactions with CNS tissue. Once in the CNS extracellular space, gut-derived 5-HT could act via nonsynaptic volume transmission — a diffusion-based signalling mode the authors emphasise — to modulate excitatory and inhibitory circuits. They suggest that such modulation could produce transient disintegration or desegregation of large-scale networks (for example, the default mode network) and change amygdala responsivity, thereby permitting access to suppressed emotional material and supporting an emotional ‘‘reset’’. The authors link this network perturbation to observed psychedelic effects (acute network disintegration, post-acute reintegration, increases in dendritic spine number and size, epigenetic changes and long-lasting behavioural effects) and contrast this putative mechanism with the different action profile attributed to SSRIs. P. and colleagues marshal evidence from diverse experimental domains to support the plausibility of individual links in their chain: studies showing gut microbiota regulate EC 5-HT synthesis (including spore-forming bacteria and short-chain fatty-acid effects), work demonstrating platelet uptake and peripheral distribution of 5-HT and shared molecular machinery between platelets and neurons (SERT and 5-HT2A receptors), experiments indicating that elevated plasma 5-HT or platelet mediators can affect endothelial permeability, the presence of SERT in BBB endothelium, and literature on extracellular vesicles and volume transmission as routes for intercellular signalling. They also cite neuroimaging and animal work linking psychedelics to DMN modulation, amygdala effects, dendritic structural changes and experience resembling REM/dream states. The authors acknowledge substantial uncertainties. Many constituent findings derive from animal or cellular studies and may not translate directly to humans. The physiological role and mechanisms of volume transmission, the capacity and selectivity by which pEVs or SERT might permit peripheral 5-HT to enter the CNS, and the conditions under which platelets or their vesicles traverse or interact with the BBB are incompletely characterised. The authors acknowledge the theoretical risk that transiently increased BBB permeability could permit peripheral cytokines or toxic substances to access the brain; while they suggest selective entry mechanisms might exist, this is not established. They state that parts of the hypothesis are difficult to substantiate with current literature and call for further multidisciplinary research to test the proposed links. Overall, the authors present their hypothesis as a psychosomatic framework that could help reconcile gut–brain interactions, platelet-mediated peripheral 5-HT signalling, BBB dynamics and nonsynaptic transmission with the acute and lasting central effects of serotonergic psychedelics, and they contrast this putative mechanism with the action of SSRIs. They propose re-examining the common assumption that serotonin cannot cross the BBB and recommend empirical work to evaluate each step of their proposed chain of events.