MDMA and psilocybin regulate oligodendrocyte-lineage cell numbers and anxiety-like behaviors in a rat model of fear.
Mehmet Bostancıklıoğlu, Davut Sinan Kaplan, Ramazan Bal, Elif Yiğit, Hasan Ulusal, Ebru Temiz
Biological Psychiatry February 3, 2026 DOI: 10.1016/j.biopsych.2026.01.016 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study in an animal model Peer reviewed |
|---|---|
| Sample size | 210 |
| Population | Adult male Wistar rats |
| Interventions | Psilocybin MDMA |
| Dose | 0.5 mg/kg psilocybin or 0.1 mg/kg/day MDMA for four days |
| Duration | Four-day intervention |
| Topics | MDMA Psilocybin Anxiety |
| Keywords | Fear-related behaviors Myelination Oligodendrocyte plasticity Oligodendrogenesis |
| Key findings | Psilocybin and MDMA promote adult oligodendrocyte and myelin plasticity, and this myelin remodeling is necessary for their anxiolytic effects in a rat model of contextual fear conditioning. |
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.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Psilocybin and MDMA reduced anxiety-like behaviors in a rat model of contextual fear conditioning, and myelin disruption abolished these anxiolytic effects.
Synthesized
Comparable studies
Other preclinical and animal studies on MDMA for anxiety, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning Mice | 2015 | Preclinical experimental study | |
| Effects of acute social stress on the conditioned place preference induced by MDMA in adolescent and adult mice Adolescent (postnatal day 29-40) and adult (postnatal day 50-61) male mice | 2014 | Experimental study | |
| MDMA in Adolescent Male Rats Adolescent male rats (postnatal day 45) | 2006 | Controlled experiment | n = 12 |
| Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Rodents | 2024 | Review | |
| Differential behavioral outcomes of 3,4-methylenedioxymethamphetamine (MDMA-ecstasy) in anxiety-like responses in mice 2-month-old Balb/c male mice (25-35 g) | 2013 | Observational study | n = 70 |