CASE REPORT article
Front. Rehabil. Sci.
Sec. Rehabilitation in Neurological Conditions
Volume 6 - 2025 | doi: 10.3389/fresc.2025.1648002
This article is part of the Research TopicAdvances in Neuropharmacological Therapies: From Molecular Discoveries to Personalized Clinical ApplicationsView all 3 articles
A Novel Multimodal Pharmacologic Strategy for Severe TBI: Case Series of Guanfacine, NAC, and Donepezil (GND) Therapy
Provisionally accepted
- 1Yale Medicine, New Haven, United States
- 2Yale School of Medicine, New Haven, United States
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Traumatic brain injury (TBI) remains a leading cause of long-term morbidity and disability worldwide. Individuals with moderate to severe TBI often experience persistent neurocognitive deficits, including short-term memory loss, executive dysfunction, and slowed cognitive processing for which there are currently no FDA-approved treatments. This case series investigates the synergistic use of guanfacine, N-acetylcysteine (NAC), and donepezil (GND) administered alongside ongoing cognitive rehabilitation, with treatment effects evaluated through pre-and post-intervention Montreal Cognitive Assessment (MoCA) scores. The guanfacine/NAC combination has previously been reported to improve working memory and executive function in individuals with mild TBI, suggesting its potential applicability to more severe TBI cases. Guanfacine, an alpha-2A agonist approved for ADHD, enhances prefrontal cortical function; Donepezil, a cholinesterase inhibitor, is widely used to treat cognitive symptoms in mild cognitive impairment and early dementia; and NAC, a potent antioxidant and glutamate modulator, has demonstrated neuroprotective effects across a range of clinical contexts, including TBI. Each of these agents has a well-established safety profile. The encouraging outcomes observed in this case series underscore the potential of the GND regimen as a multimodal pharmacologic approach to target the complex neurochemical disruptions following TBI. These preliminary findings warrant further investigation in larger, placebo-controlled trials in order to more rigorously assess the safety, efficacy, and translational potential of this intervention for mitigating chronic cognitive sequelae in individuals with moderate to severe TBI.
Keywords: TBI, Severe TBI, Guanfacine, N-acetylcysteine, donepezil
Received: 21 Jun 2025; Accepted: 07 Oct 2025.
Copyright: © 2025 Fesharaki-Zadeh, Belliveau, Pietrzak and Arnsten. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Arman Fesharaki-Zadeh, arman.fesharaki@yale.edu
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