Psilocybin restores behavior and 5-HT2A signaling while reducing microglial density after chronic traumatic brain injury in rats.
Josh Allen, Bianca Jupp, Tamara L Baker, Mohammad B Haskali, Robert Brkljača, Zoe Plummer, Mujun Sun, Justin Brand, Brian R Christie, Chantel T Debert, Stuart J Mcdonald, Terence J O'Brien, Pablo M Casillas-Espinosa, Sandy R Shultz
Cell reports. Medicine June 12, 2026 DOI: 10.1016/j.xcrm.2026.102867 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Male rats |
| Intervention | Psilocybin |
| Dose | 1 mg/kg |
| Duration | Single injection, behavioral testing began 24 hours later, positron emission tomography after two weeks |
| Topics | Psilocybin |
| Keywords | Iba1 PET Concussion Fluid-percussion injury Microglia Positron emission tomography Psychedelic Serotonin receptor |
| Key findings | A single psilocybin dose improved sensorimotor function, restored serotonin 2A receptor binding, and reduced microglial cell counts in rats one year after fluid-percussion traumatic brain injury. |
Abstract
Traumatic brain injury (TBI) causes persistent neurobehavioral deficits and increases the risk of psychiatric disorders, including depression, anxiety, and cognitive dysfunction linked to disrupted neuroplasticity, neuroinflammation, and serotonergic (5-HT) signaling. No effective pharmacotherapies exist for chronic TBI. Psilocybin, a psychedelic 5-HT2A receptor agonist, shows promise due to its neuroplasticity-enhancing, anti-inflammatory, and antidepressant effects. Here, male rats received fluid-percussion or sham injury, followed one year later by a single psilocybin (1 mg/kg) or saline injection. Behavioral testing began 24 h later, and positron emission tomography assessed 5-HT2A binding after two weeks. TBI produced persistent sensorimotor, learning and memory, and affective deficits; reduced 5-HT2A binding; and microglial alterations in the medial prefrontal cortex characterized by decreased process branching and enlarged soma size. Psilocybin treatment could improve sensorimotor function, restore 5-HT2A binding, and reduce microglial cell counts. These findings highlight psilocybin's therapeutic potential in chronic TBI and support further investigation of psychedelic treatments.