There are currently no available effective pharmacological therapies for treating chronic cognitive deficits after traumatic brain injury (TBI). Psychoplastogens, including atypical psychedelics, classical serotonergic psychedelics, and neuroplastogens, are a class of small molecule drugs that can enhance neuroplasticity by inducing rapid and sustained effects on neuronal architecture and function, with the potential to have broad therapeutic effects. Ketamine, psilocybin, and dimethyltryptamine (DMT) have demonstrated therapeutic efficacy for treating multiple psychiatric conditions, and their ability to enhance neuroplasticity is hypothesized to be the primary mechanism. However, the administration of psychoplastogens for the treatment of cognitive impairments in TBI and other neurodegenerative diseases is nascent. In this review, we discuss the following: (1) relevant TBI pathologies and how neuroplasticity is impaired following TBI, (2) psychoplastogens and their use in neural repair models, and (3) the potential of psychoplastogens as treatments for TBI to alleviate various pathologies and improve cognitive behavioral outcomes. The underlying pathologies observed after TBI, including impaired neuroplasticity, synaptic dysfunction, neuronal atrophy, altered neurotransmission, and cellular dysfunction, are shared with several psychiatric disorders. Based on the multiple pathophysiological targets, there is a critical unmet need to investigate psychoplastogens as therapeutic interventions during the chronic phase of TBI for cognitive outcomes and underlying impact on neuroplasticity.
