MDMA and psilocybin regulate oligodendrocyte-lineage cell numbers and anxiety-like behaviors in a rat model of fear.
Biological psychiatry – February 03, 2026
Source: PubMed
Summary
Psilocybin and MDMA significantly reduce fear-related behaviors, acting through brain changes. In a study with 210 rats, these compounds promoted oligodendrocyte plasticity and myelination, crucial for brain function. Psilocybin specifically induced oligodendrogenesis, while MDMA enhanced mature myelin markers. Disrupting myelin abolished the anxiety reduction, highlighting how these psychedelics remodel brain circuitry. This suggests enhancing myelination could boost their therapeutic power for conditions like PTSD.
Abstract
Psilocybin and 3,4-methylenedioxymethamphetamine (MDMA) produce rapid, enduring therapeutic effects in post-traumatic stress disorder (PTSD); however, the underlying cellular mechanisms remain incompletely understood. This study investigated whether adult myelin plasticity contributes to the therapeutic actions of psilocybin and MDMA in a rat model of contextual fear conditioning. Adult male Wistar rats (n = 210) received repeated low doses of psilocybin (0.5 mg/kg, i.p., for four days) or MDMA (0.1 mg/kg/day, i.p., for four days). Behavioral tests assessed anxiety-like behaviors and spatial memory. Following local and global manipulations of myelin integrity, we assessed the drugs' effects on myelination by quantifying myelin sheath thickness, oligodendrocyte-lineage cell densities, and transcriptomic, proteomic, and metabolomic profiles in the dentate gyrus. Both compounds reduced anxiety-like behaviors. These improvements coincided with oligodendroglial changes and multi-omic signatures of myelin-related remodeling; mean g-ratio measures of myelin thickness, however, did not differ significantly between intact fear-conditioned animals with or without psychedelic treatment. Myelin disruption abolished these anxiolytic effects, and integrative multi-omics revealed convergent upregulation of myelin-related proteins following administration of psilocybin or MDMA. Psilocybin preferentially induced early oligodendroglial gene programs, while MDMA enhanced markers of mature myelin. Notably, 5-HT2A receptor blockade completely abolished the myelin and behavioral enhancements induced by both psilocybin and MDMA. Psilocybin and MDMA promote adult oligodendrocyte and myelin plasticity. Enhancing myelination might be a viable strategy to augment or sustain the therapeutic effects of psychedelic-assisted treatments for PTSD and related disorders.