INTRODUCTION: Psychedelics are increasingly studied for their psychoactive properties, yet their direct cellular effects on neuroinflammation and neuroprotection remain poorly understood. These compounds are known to activate serotonin 5-HT₂A and/or Sigma-1 receptors, which play key roles in regulating neuronal survival, neuroplasticity and inflammatory signaling pathways. However, their potential involvement in promoting myelination or protecting against inflammation-induced demyelination has not been explored. Similarly, their effects on modulating blood–brain barrier (BBB) under normal and inflammatory conditions have yet to be investigated.

AIM(S): This project aims to determine whether psychedelics can protect against demyelination and neuron damage by activating anti-inflammatory signaling via 5-HT₂A and Sigma-1 receptors. In parallel, we will assess their effects on BBB integrity and permeability.

METHOD(S): Organotypic cerebellar slices were subjected to chemical demyelination and co-treated with DMT, either alone or in combination with selective antagonists: ketanserin (5-HT₂A receptor antagonist) and BD-1063 (Sigma-1 receptor antagonist). The release of pro- inflammatory cytokines and changes in gene expression were assessed by ELISAs and RT-qPCR. Human tri-cell BBB model was treated with psychedelics with or without a cocktail of pro-inflammatory cytokines IL17/TNFα and the antagonists (ketanserin or BD). Gene expression changes were assessed by RT-qPCR, including pro-inflammatory transcription factors, BBB components and the expression of 5-HT₂A and Sigma-1 receptors.

RESULTS: Treatment with psychedelics attenuated pro-inflammatory signaling in our ex vivo and in vitro models. The psychedelics-mediated anti-inflammatory effects were inhibited with receptor antagonists indicating 5-HT₂A and Sigma-1 receptors mediated effects.

CONCLUSIONS: This project and future findings may offer a cellular basis for exploring psychedelics as potential therapies in neuroimmune and neurodegenerative disorders.

FINANCIAL SUPPORT: NO.