In a rat model of recurrent intimate partner violence brain injury (daily mild traumatic brain injury plus non-fatal strangulation for five days followed by 16 weeks of recovery), a single dose of psilocybin (1 mg/kg) reversed injury-induced anxiety-like behavior in the elevated plus-maze, increased sucrose preference (indicating reduced anhedonia), and improved reversal learning in the water maze and spatial memory in the Y-maze. Psilocybin also prevented the increase in microglial cells in the dorsal hippocampal molecular layer and the loss of reelin-positive cells in the subgranular zone seen in saline-treated injured rats. Pre-treatment with a 5-HT2A receptor antagonist blocked psilocybin's behavioral effects, indicating these benefits depend on 5-HT2A receptor activation.
One year after a fluid-percussion traumatic brain injury, male rats showed persistent sensorimotor, learning, memory, and affective deficits; reduced serotonin 2A receptor binding; and microglial changes in the medial prefrontal cortex, including decreased process branching and enlarged soma size. A single dose of psilocybin (1 mg/kg) improved sensorimotor function, restored serotonin 2A receptor binding, and reduced microglial cell counts. These results suggest psilocybin has therapeutic potential for chronic traumatic brain injury and support further investigation of psychedelic treatments.