The Potential Role of Psilocybin in Traumatic Brain Injury Recovery: A Narrative Review

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The Potential Role of Psilocybin in Traumatic Brain Injury Recovery: A Narrative Review            

                                 by

Charles Palmer

¹,

Ally T. Ferber

² and

Brian D. Greenwald

^2,*

¹

Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA

²

Department of Physical Medicine and Rehabilitation, JFK Johnson Rehabilitation Institute at Hackensack Meridian Health, Edison, NJ 08820, USA

^*

Author to whom correspondence should be addressed.

Brain Sci. 2025, 15(6), 572; https://doi.org/10.3390/brainsci15060572

Submission received: 5 April 2025 / Revised: 16 May 2025 / Accepted: 22 May 2025 / Published: 26 May 2025

(This article belongs to the Section Neurorehabilitation)

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Abstract

Background: This narrative review explores psilocybin’s potential use as a therapeutic agent in patients with traumatic brain injury (TBI). 

Methods: We engaged in a search of PubMed, ScienceDirect, and Cochrane’s databases for information on the effects of psilocybin. We also reviewed articles where psilocybin was used in patients with TBI. Articles from 2000–2025 were included. 

Results: A total of 29 articles met our initial inclusion criteria. Additionally, 13 articles were obtained from reference lists and 3 more articles on the legality of psilocybin from public websites. 

Conclusions: Assisted psilocybin use may have benefits in TBI by reducing inflammation, promoting neuroplasticity and neuroregeneration, and alleviating associated mood disorders. Positive findings in related fields, like treatment for depression and addiction, highlight the necessity for more extensive clinical trials on psilocybin’s role in TBI recovery.

Keywords:

medical psilocybin; traumatic brain injury; addiction; psychedelic

1. Introduction

Approximately 69 million people worldwide suffer from traumatic brain injuries (TBIs) each year. The incidence was highest in North America, with rates reaching 1299 out of 100,000 people [1]. Progress in modern medicine has increased the survival rate of TBI patients [2]. However, there continues to be a need for new treatment solutions for TBI survivors because of their rising numbers, since these survivors experience extended physical, cognitive, and psychological difficulties.

TBI is the result of direct physical impact that leads to neuronal necrosis and tissue damage. The initial impact creates a primary injury, otherwise known as a contusion. The contusion can later expand, resulting in delayed neurodegeneration [3]. The area around the contusion, known as the pericontusion, can also expand due to edema or increasing pressure in the brain, increasing the risk of ischemia [3]. The impact is also followed by an immune response involving macrophages. Macrophages help clear cellular debris and support tissue repair, but their prolonged release of pro-inflammatory mediators can worsen neuronal death, increase neurovascular injury, and lead to long-term white matter loss [4]. Macrophages can polarize into either pro-inflammatory (M1) or anti-inflammatory (M2) states. Early after TBI, both M1 and M2 markers are present, but the expression of M2 quickly declines [4]. The M1 state is longer lasting, leading to the unopposed release of pro-inflammatory cytokines and resulting in neurodegeneration. A method that can address the neurodegeneration and inflammation found in TBI would be a crucial step forward in finding effective treatments for TBI patients.

A recent trend is the question of psychedelics’ role in the clinical setting. Because of their structural similarity to tryptophan, psychedelics can interact with serotonin receptors, functioning as agonists on the 5HT-2A receptor [5]. Psychedelics have shown promise in treating substance use disorders (SUDs) and mood disorders through interaction with the dopamine and serotonin pathways as well as the hypothalamic–pituitary–adrenal (HPA) axis [5]. This new trend, along with the increasing need for TBI treatments, prompted the question of if psychedelics have a potential role in TBI treatment, given the similar neurochemical disturbances found in patients after a traumatic brain injury. Previous explorations into this question have involved consideration of multiple psychedelics such as LSD, MDMA, ketamine, and psilocybin with positive indications yielded [6,7]. This paper aims to focus on psilocybin alone, creating a focused review. Psilocybin is a natural psychedelic alkaloid found in over 100 species of mushrooms in the Psilocybe genus [5]. When it comes to treatment with psilocybin, there is an initial concern of the legality. In the United States, nine states have already decriminalized it, and two states have legalized assisted medical use. During this time, there have been trials on its use for depression, anxiety, and substance use disorder, but there are no data as of yet on its direct application in TBI patients. This paper explores the therapeutic potential of psilocybin specifically, looking at examples of its anti-inflammatory and synaptogenesis-inducing properties and how these benefits could play a role in TBI treatment.

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