Traumatic Brain Injury and Neuroplasticity: The Promising Role of Psychedelics

Traumatic brain injury (TBI) is a serious condition that causes inflammation, neuron death, and cognitive and emotional difficulties. Recent research suggests that psychedelics such as psilocybin (found in some mushrooms) and 5-MeO-DMT (present in the venom of a type of frog and in certain plants) may aid recovery by stimulating brain plasticity and protecting brain cells from damage.

Traumatic brain injury, also called TBI, occurs when an external force strikes the head or body with enough intensity to alter brain function. This injury can cause physical, emotional, psychological, and cognitive changes that can last for a short time or become permanent.

Falls are the most common cause of this type of trauma. In addition to the immediate impact, the brain experiences significant mechanical stress, which can result in structural and functional changes.

The human brain has an impressive ability to adapt, called neuroplasticity. This means that when an injury occurs, the brain can create new connections between neurons or strengthen existing ones, helping to restore lost functions.

These processes include the remodeling of dendrites (the "branches" of neurons that receive signals), the creation of new dendritic spines (small connection points between neurons), and the reorganization of brain networks.

Researchers have attempted to develop various treatments for traumatic brain injury. In animal tests, substances called neuroprotectants have shown the ability to reduce inflammation and nerve cell death. However, when these treatments were tested in humans, they did not have the same effect. This "failure to translate" between animal studies and clinical trials is one of the major challenges in the field.

Faced with these difficulties, scientists began exploring the use of psychedelic substances, such as psilocybin (found in some mushrooms) and 5-MeO-DMT (present in the venom of a type of toad and in certain plants). Psilocybin, once ingested, transforms into an active substance called psilocin. 5-MeO-DMT can be administered in various ways: smoked, inhaled, orally, injected, or even through the skin.

In recent years, these compounds have gained prominence because, in clinical studies, they have shown efficacy in treating resistant depression and anxiety. This drew the attention of researchers to its possible use in brain injuries as well.

Both psilocybin and 5-MeO-DMT have chemical structures similar to serotonin, a neurotransmitter involved in mood, memory, and various brain functions. They primarily bind to 5-HT2A and 5-HT1A receptors, which are involved in regulating consciousness, perception, and emotional processes.

Furthermore, these compounds activate other receptors related to brain protection and regeneration, such as TrkB receptors (target of psilocybin) and sigma-1 receptors (target of 5-MeO-DMT). These receptors are linked to neuron survival, reduced inflammation, and increased brain plasticity.

After trauma, the brain suffers from inflammation, oxidative stress (damage caused by free radicals), overexcitation of neurons, and cell death. Psilocybin and 5-MeO-DMT act by reducing inflammatory factors and enhancing the action of anti-inflammatory substances, in addition to protecting neurons against premature death. Studies have shown that these effects also involve the regulation of microglia, defense cells found in the nervous system.

In experiments with mice, psilocybin lastingly increased the density of dendritic spines in the prefrontal cortex, an area important for memory and decision-making. This effect persisted for up to a month after administration. This suggests that the substance may facilitate brain recovery after injury.

Psilocybin and 5-MeO-DMT have good safety profiles. To date, there is no evidence that they cause dependence or long-term psychiatric illness. Their lethal doses are not yet known, but they are not expected to pose a high risk.

Psilocybin is typically ingested orally, while 5-MeO-DMT has several administration methods. The duration of action varies: psilocybin can last several hours, while 5-MeO-DMT tends to have shorter, more intense effects.

Traumatic brain injury is a serious and difficult-to-treat condition. So far, available therapies have not been very effective in clinical trials. Psychedelic compounds, such as psilocybin and 5-MeO-DMT, are emerging as promising new alternatives, as they have demonstrated the ability to reduce inflammation, protect neurons, and increase neuroplasticity.

Although the results are encouraging, further clinical studies are still needed to confirm their efficacy and safety in patients with traumatic brain injury.

READ MORE:

Examining the potential of psilocybin and 5-MeO-DMT as therapeutics for traumatic brain injury

Zoe Plummer, Josh Allen, Justin Brand, Leah M. Mayo, Sandy R. Shultz, and Brian R. Christie 

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 141, 30 August 2025, 111448

https://doi.org/10.1016/j.pnpbp.2025.111448

Abstract: 

Traumatic brain injury (TBI) is a significant global health challenge, with limited effective treatments for its acute and chronic consequences. TBI is characterized by neuroinflammation, oxidative stress, impaired neuroplasticity, imbalances in neurotransmission, and cell death - factors that contribute to the development of neurological and psychiatric disorders. Emerging evidence suggests that serotonergic psychedelics psilocybin and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) may hold promise as treatments for TBI. These compounds promote neuroplasticity, exert anti-inflammatory and neuroprotective effects, and have shown efficacy in treating psychiatric conditions that share pathophysiological features with TBI. 5-HT1A and 5-HT2A receptors are implicated in their effects, but psilocybin also targets neurotrophic TrkB receptors, whereas 5-MeO-DMT targets sigma-1 receptors, known to have neuroprotective properties. This review integrates current preclinical and clinical research, highlighting both the shared and distinct mechanistic pathways through which psilocybin and 5-MeO-DMT may alleviate TBI-related impairments, such as cognitive and affective dysfunction and neuroinflammation. Additionally, the safety profiles, dosing paradigms, and clinical challenges of these psychedelics are critically examined. By bridging insights from psychedelic science and neurotrauma research, this review underscores the innovative potential of psilocybin and 5-MeO-DMT as adjunctive treatments for TBI, paving the way for novel interventions in neurorehabilitation.