Why researchers are looking at psilocybin for repeated mild head injuries

A three-day psilocybin regimen after repeated head impacts gave researchers a rare look at how the psychedelic may influence brain swelling, vascular function, neural networks, tau, and molecular pathways involved in recovery.

Study: Psilocybin as a treatment for repetitive mild head injury: evidence from neuroradiology and molecular biology. Image Credit: Deep Roots / Shutterstock

In a recent study published in the journal Communications Biology, researchers evaluated the therapeutic potential of psilocybin following repetitive mild traumatic brain injury (rmTBI).

The study specifically leveraged an awake, closed-skull momentum-exchange model (in adult female rats) to investigate whether administering psilocybin immediately after repeated head impacts could mitigate imaging, vascular, and molecular changes associated with rmTBI.

Experimental analyses demonstrated that three daily doses of psilocybin (3.0 milligrams per kilogram, mg/kg) were sufficient to significantly reduce acute imaging measures consistent with brain swelling and alter several injury-associated neurobiological biomarkers in rats.

Most notably, administration of the naturally occurring serotonergic psychedelic compound was shown to substantially mitigate the post-injury accumulation of soluble phosphorylated tau to levels comparable to uninjured rat controls, highlighting psilocybin’s potential relevance to tau-related neurodegenerative processes associated with Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), rather than demonstrating reduced disease risk.

Together, these findings underscore psilocybin as a multi-target therapeutic candidate that reduced vasogenic edema and phosphorylated tau, altered functional connectivity, increased BDNF and TrkB protein levels, and modulated glial and lipid markers, supporting future research in rmTBI, a class of injury for which no approved pharmacological treatments currently exist.

Background

Traumatic brain injury (TBI) is increasingly considered a prevalent and substantial public health problem, with data from the United States (US) Centers for Disease Control and Prevention (CDC) indicating that approximately 2.9 million Americans sustain a TBI annually (70-90% of which are categorized as ‘mild’).

Recent neurobiological research emphasizes that while the symptoms from an isolated ‘mild’ concussion can resolve quickly, repetitive mild traumatic brain injury (rmTBI) episodes (such as those frequently sustained in contact sports and military combat) can be associated with longer-lasting neuroinflammation, microvascular damage, and impaired fluid clearance.

Unfortunately, despite this knowledge, there are currently no approved medical treatments specifically for repetitive head impacts or rmTBI.

About the study

The present study aimed to address this persistent therapeutic limitation and inform future rmTBI research by investigating whether psilocybin could mitigate neurological and molecular changes following head trauma.

The study sample group comprised 9-month-old (‘middle-aged’) female Wistar rats, which were divided into three experimental cohorts: 1. Uninjured sham controls who were administered saline vehicle (Sham-VEH), 2. Head-impacted rats treated with vehicle (Hit-VEH), and 3. Head-impacted rats treated with psilocybin (3.0 mg/kg via intraperitoneal injection within 30 minutes of each impact; Hit-PSI).

Each experimental cohort comprised eight rats. Additionally, an exploratory aged pilot cohort comprised 12 Wistar and Sprague-Dawley rats aged 15-19 months, divided between injured vehicle and psilocybin groups without an age-matched sham control. To model the biomechanics of human sports-related concussion, the heads of fully awake Hit-cohort rats were exposed to a custom pneumatic momentum exchange apparatus.

The apparatus propelled a 50-gram impactor at 7.4 meters per second (delivering 1.37 Joules of kinetic energy). The experimental exposure was repeated once daily for three consecutive days.

Acute neuroimaging used diffusion-weighted imaging (DWI), which assesses water (fluid) mobility via the apparent diffusion coefficient (ADC). Fractional anisotropy (FA) was also assessed as a measure of tissue microstructure at 1 to 2 hours post-injury, with this acute imaging session conducted under isoflurane anesthesia.

Subsequently, awake functional magnetic resonance imaging (fMRI) was used to evaluate cerebrovascular reactivity (CVR) under a 5% carbon dioxide (CO2) challenge and resting-state functional connectivity three weeks post-injury.

Study findings

Acute neuroimaging analyses revealed that repeated head impacts triggered widespread changes consistent with vasogenic edema, as evidenced by a whole-brain surge in ADC and an inverse correlation with FA.

Psilocybin treatment significantly reduced rmTBI-associated ADC elevations across the prefrontal cortex, hippocampus, and basal ganglia, returning ADC values toward sham levels, with normalization observed in some regions. The authors cautioned that isoflurane anesthesia may have influenced the magnitude and spatial distribution of these acute ADC changes.

Psilocybin was also observed to markedly increase brain-wide functional connectivity following injury. The average whole-brain degree was 14.7 in sham controls and 9.1 in untreated injured rats, but rose to 35.5 after psilocybin, exceeding sham levels and indicating hyperconnectivity rather than simple restoration.

Behavioral effects were more limited: head-impacted rats showed reduced mobility regardless of treatment, while learning, memory, and motor outcomes were largely non-significant or showed only trends.

At the molecular level, untreated trauma led to a significant increase in soluble phosphorylated tau, which was significantly lower after psilocybin treatment, reaching levels near those of uninjured controls. However, the reduction in aggregated insoluble phosphorylated tau between the two injured groups was not statistically significant.

Psilocybin-treated rats also showed significantly higher BDNF and TrkB protein levels than sham controls, although the BDNF increase relative to untreated injured rats only approached statistical significance. GFAP and CD11b were also increased relative to sham controls, which the authors interpreted as a potentially protective glial response rather than evidence of reduced neuroinflammation.

Finally, plasma lipidomics showed that injury was associated with four significant decreases in circulating signaling lipids, whereas psilocybin treatment was associated with 18 significant increases in circulating signaling lipids. In the aged pilot cohort, psilocybin was also associated with an approximately two-fold increase in myelination in the corpus callosum and sensorimotor cortex relative to aged, injured, vehicle-treated rats, with increased MBP immunofluorescence in the corpus callosum.

Conclusions

The present study provides the first published experimental evidence that psilocybin may have therapeutic effects in a rat model of rmTBI, showing reductions in acute imaging measures consistent with vasogenic edema and phosphorylated tau, partial normalization of vascular hyperreactivity, and marked injury-dependent increases in resting-state functional connectivity.

Future research should aim to confirm the durability and mechanisms of these effects in further preclinical studies before testing safety and efficacy in controlled human cohorts, including whether reductions in early tau abnormalities translate into lower long-term neurodegenerative risk.

Among the study’s funding sources was Ekam Imaging Inc.; two authors reported partnership interests in the company, while another author reported consulting for BetterLife Pharma.