INTRODUCTION: Psychedelics are emerging as modulators of neuroinflammation, yet their mechanisms remain poorly understood.

AIM(S): In our lab, we investigate five compounds—DMT, 5-MeO-DMT, LSD, ketamine and ibogaine—chosen for their activity at 5-HT2A and/or Sigma-1 receptors, key players in neuroimmune signalling. These molecules exhibit diverse receptor profiles, acting as agonists, partial agonists or antagonists across serotonergic, NMDA, adrenergic, opioid and sigma receptors, influencing processes such as cognition, neurogenesis and immune function.

METHOD(S): Here, we tested anti-inflammatory properties of selected psychedelics in the organotypic cerebellar slice model, primary oligodendrocyte progenitor cells (OPCs) and human blood-brain barrier model.

RESULTS: DMT reduced LPC-induced NF-κB signalling and cytokine release, protected against demyelination and inhibited inflammation-driven OPC activation in organotypic cerebellar slices. On endothelial cells, DMT counteracts VCAM1 induction and selectively modulates junctional gene expression.

CONCLUSIONS: DMT acts primarily as an immune regulator. These insights provide a foundation for understanding how psychedelics may shape neuroinflammatory pathways and guide future therapeutic strategies.