CNSC-36. PSILOCYBIN INDUCES SUSTAINED GLIOMA GROWTH THROUGH SEROTONERGIC AND TRKB PATHWAYS

Abstract High-grade gliomas are the most aggressive form of brain tumors, and neuronal activity has emerged as a driver of glioma pathophysiology. Activity-dependent glioma growth results from paracrine factor signaling and bona fide neuron-to-glioma synapses that integrate glioma cells into brain-wide neuronal circuits. Here, we report how glioma cells integrate into serotonergic (5-HT) circuits and report that long-range dorsal raphe (DR) and median raphe (MR) projections promote a robust increase in calcium-mediated proliferation of glioma cells. Analysis of scRNA-seq datasets from human samples revealed that 5-HT2A is the most highly expressed serotonergic receptor in both glioblastoma and DMG. Psilocybin, a serotonergic psychedelic with high selectivity for 5-HT2A and additional activity at TrkB, is gaining interest for use in cancer patients; however, its effects on glioma cells remain unclear. We found that a single-dose administration of psilocybin significantly increased proliferation in both glioblastoma and DMG xenografts. Elevated proliferation rates persisted for at least two weeks following a single dose. Utilizing fiber photometry, we detected robust calcium transients in glioma cells as early as 30 minutes following psilocybin administration, which remained detectable for two weeks post-treatment. Glioma cells engineered to express a fluorescent indicator of 5-HT2A activation and xenografted to the mouse brain revealed receptor activation in vivo for at least 24 hours after a psilocybin dose. To delineate the receptor-specific contributions to psilocybin-induced glioma proliferation, we utilized DMG cell lines with genetic knockout of either 5-HT2A or TrkB. Knockout of 5-HT2A in glioma cells nearly abolished psilocybin-induced proliferation, while TrkB knockout partially reduced the effect. Together, these findings demonstrate that psilocybin promotes sustained elevations in glioma proliferation primarily through 5-HT2A activation, with a modulatory contribution from TrkB signaling. Clinical decision-making regarding the use of serotonergic psychedelics in patients with brain tumors should include consideration of possible growth-promoting effects.