Effects of psilocybin and related compounds on cerebroprotection during ischemic stroke (Stage 1 Registered Report)

Psilocybin and related tryptamine compounds may protect brain cells after stroke by engaging serotonin receptor pathways. In this registered report, the authors plan to test these compounds using living brain slices from mice and human surgical tissue exposed to low oxygen and glucose to mimic stroke. They will measure cell survival and use single-nucleus RNA sequencing to identify which neuronal and glial cell types respond and which biological pathways are involved. The work aims to clarify the molecular and cellular mechanisms underlying potential cerebroprotection and may inform future psilocybin-based therapies for stroke.

Study at a glance

Abstract

Stroke remains a leading cause of death and long-term disability and stroke patients have only limited treatment options.Recent preclinical evidence suggests that psychedelics such as psilocybin may confer cerebroprotection by engaging serotonin (5-HT) receptor pathways, yet their cellular targets and translational potential remain poorly understood.Here, we propose to systematically evaluate psilocybin and related tryptamine analogs for cerebroprotective effects in ischemic mouse and human brain tissue.Using an ex vivo oxygen-glucose deprivation (OGD) model combined with automated imaging and single-nucleus RNA sequencing, we will quantify compound-specific protection, identify responsive neuronal and glial subtypes, and map conserved signaling networks in mice and human.This study will dissect the molecular and cellular pathways through which psilocybin and related tryptamines may promote cerebroprotection in stroke.Additionally, these findings may support the development of future psilocybin-related therapies. Lay summary:In this registered report we plan to test whether psilocybin-like compounds can protect brain cells after stroke.We use living brain slices from mice and from human surgical tissue, place them under low oxygen and glucose to mimic stroke, and then measure how many cells survive after treatment.We then use single nucleus RNA sequencing to determine which cell types respond and which biological pathways are involved.