PSYCHEDELICS DOWNREGULATE INFLAMMATORY SIGNALLING SUPPORTING BLOOD–BRAIN BARRIER INTEGRITY VIA 5-HT₂A AND SIGMA-1 RECEPTORS

Psychedelics such as N,N‑Dimethyltryptamine (DMT) are widely studied for their psychoactive properties, yet their direct effects on neuroinflammation and blood–brain barrier (BBB) function remain incompletely understood.
Amis: The aim of this study was to determine whether DMT modulates inflammatory signalling and endothelial properties relevant and to identify the receptor mechanisms underlying these effects.
Methods: Organotypic cerebellar slice cultures were exposed to lysophosphatidylcholine-induced demyelination and treated with DMT, a dual 5-HT₂A or Sigma-1 receptor agonist, in the presence or absence of receptor specific antagonists. NF-κB signalling and cytokine release were analysed and BBB-related gene expression was quantified. In parallel, a human tri-cell BBB model was exposed to inflammatory cytokines in the presence of DMT and antagonists.
Results: DMT attenuated NF-κB signalling and reduced pro-inflammatory cytokine release in the cerebellar slices. In the same model, DMT reversed LPC-induced VCAM1 induction, did not rescue Occludin expression but further enhanced VE-cadherin indicating anti-inflammatory effects on the endothelium. In the human BBB model, DMT also exerted anti-inflammatory effects while differentially modulating junctional proteins. The observed effects were largely abolished by 5-HT₂A or Sigma-1 receptor antagonists, supporting receptor-specific mechanisms.
Conclusions: Together, these findings demonstrate that DMT exerts anti-inflammatory and immunomodulatory effects in the vascular compartment, contributing to the preservation of BBB integrity via 5-HT₂A and Sigma-1 signalling. Our results provide mechanistic insight into the cellular actions of psychedelics and suggest potential relevance for neuroimmune and neurodegenerative disease contexts.