Psychedelics in neuroinflammation: Mechanisms and therapeutic potential

Psychedelics like psilocybin, LSD, and DMT show promise for reducing neuroinflammation linked to Alzheimer's, Parkinson's, and major depressive disorder. They act mainly through serotonin 5-HT2A receptors, lowering pro-inflammatory cytokines, regulating microglial activity, and shifting metabolite balance toward neuroprotection. They also influence NF-κB, PI3K/Akt, and mTOR pathways, promoting neuroplasticity and anti-inflammatory effects. Other neurotransmitter systems—glutamatergic, dopaminergic, noradrenergic, GABAergic, and cholinergic—contribute to these effects. The review highlights psychedelics as potential treatments for neuroinflammatory and neuropsychiatric disorders.

Study at a glance

Abstract

Neuroinflammation is a critical factor in the pathogenesis of various neurodegenerative and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, and major depressive disorder. Psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT), have demonstrated promising therapeutic effects on neuroinflammation, primarily through interactions with serotonin (5-HT) receptors, particularly the 5-HT2A receptor. Activation of these receptors by psychedelics modulates the production of pro-inflammatory cytokines, regulates microglial activity, and shifts the balance between neurotoxic and neuroprotective metabolites. Additionally, psychedelics affect critical signaling pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and mechanistic target of rapamycin (mTOR) pathways, promoting neuroplasticity and exerting anti-inflammatory effects. Beyond the serotonergic system, other neurotransmitter systems-including the glutamatergic, dopaminergic, noradrenergic, gamma-aminobutyric acid (GABAergic), and cholinergic systems-also play significant roles in mediating the effects of psychedelics. This review examines the intricate mechanisms by which psychedelics modulate neuroinflammation and underscores their potential as innovative therapeutic agents for treating neuroinflammatory and neuropsychiatric disorders.