MDMA and Psilocybin Regulate Oligodendrocyte-Lineage Cell Numbers and Anxiety-Like Behaviors in a Rat Model of Fear

Psilocybin and MDMA produce rapid, enduring therapeutic effects in posttraumatic stress disorder (PTSD); however, the underlying cellular mechanisms remain incompletely understood. In this study, we 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, intraperitoneally [i.p.], for 4 days) or MDMA (0.1 mg/kg/day, i.p., for 4 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 multiomic signatures of myelin-related remodeling; however, mean g-ratio measures of myelin thickness did not differ significantly between intact fear-conditioned animals with or without psychedelic treatment. Myelin disruption abolished these anxiolytic effects, and integrative multiomics 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-HT_2A 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 may be a viable strategy to augment or sustain the therapeutic effects of psychedelic-assisted treatments for PTSD and related disorders.