Traumatic brain injury (TBI) causes neuroinflammation, oxidative stress, impaired neuroplasticity, neurotransmitter imbalances, and cell death, leading to neurological and psychiatric disorders. The serotonergic psychedelics psilocybin and 5-MeO-DMT may help treat TBI by promoting neuroplasticity, reducing inflammation, and protecting neurons. Psilocybin acts through 5-HT1A, 5-HT2A, and neurotrophic TrkB receptors, while 5-MeO-DMT targets sigma-1 receptors with neuroprotective properties. Preclinical and clinical research suggests these compounds can alleviate cognitive and affective dysfunction and neuroinflammation after TBI. The review critically examines safety, dosing, and clinical challenges, highlighting the potential of these psychedelics as adjunctive treatments in neurorehabilitation.
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.
Repeated mild traumatic brain injury in rats produced lasting deficits in mood, social behavior, and pain sensitivity. Delayed treatment with psilocybin (1 mg/kg) reversed several of these effects, including antidepressant-like effects, increased social behavior, and raised pain thresholds. Psilocybin also reduced injury-related increases in microglial density and increased the number and complexity of newborn neurons in the dentate gyrus, suggesting enhanced neuroplasticity. The findings indicate psilocybin may be a promising intervention for persistent symptoms after repeated mild traumatic brain injury.