CNSC-36. PSILOCYBIN INDUCES SUSTAINED GLIOMA GROWTH THROUGH SEROTONERGIC AND TRKB PATHWAYS
Richard Drexler, Belgin Yalçın, Rebecca Mancusi, Abigail Rogers, Kiarash Shamardani, Pamelyn J. Woo, Alexandre Ravel, Yahaya A Yabo, Carlos Alberto Oliveira de Biagi-Junior, Costanza Lo Cascio, Robert C. Malenka, Boris D. Heifets, Mariella G. Filbin, Dieter Henrik Heiland, Karl Deisseroth, Michelle Monje
Neuro-Oncology November 1, 2025 DOI: 10.1093/neuonc/noaf201.0244 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study using xenograft mouse models and genetic knockout cell lines Peer reviewed |
|---|---|
| Population | Human glioblastoma and DMG xenografts in mice; DMG cell lines with 5-HT2A or TrkB knockout |
| Intervention | Psilocybin |
| Dose | single-dose administration |
| Duration | At least two weeks post-treatment |
| Topics | Serotonin Psilocybin |
| Keywords | Glioma Raphe nuclei Dorsal raphe nucleus Knockout mouse In vivo Paracrine signalling Angiogenesis Cancer research |
| Key findings | Psilocybin promotes sustained elevations in glioma proliferation primarily through 5-HT2A activation, with a modulatory contribution from TrkB signaling. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |