{"doi":"10.3389/fresc.2025.1648002","title":"A novel multimodal pharmacologic approach using guanfacine, N-acetylcysteine, and donepezil in severe TBI: a case series","abstract":"<jats:p>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.</jats:p>","journal":"Frontiers in Rehabilitation Sciences","year":2025,"id":631975,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1637994,"name":"Timothy Belliveau","orcid":null,"position":1,"is_corresponding":false},{"id":649714,"name":"Robert H. Pietrzak","orcid":"0000-0002-5561-6414","position":2,"is_corresponding":false},{"id":412445,"name":"Amy Arnsten","orcid":null,"position":3,"is_corresponding":false},{"id":1637993,"name":"Arman Fesharaki-Zadeh","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"A novel multimodal pharmacologic approach using guanfacine, N-acetylcysteine, and donepezil in severe TBI: a case series","abstract":"<jats:p>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.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41211476","pmcid":"PMC12592045","openalex_id":"https://openalex.org/W4415494771","authors":[],"funders":[],"total_grants":0,"fwci":0.0,"citation_percentile":0.36410179,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://public-pages-files-2025.frontiersin.org/journals/rehabilitation-sciences/articles/10.3389/fresc.2025.1648002/pdf","host_type":"journal"},{"url":"https://public-pages-files-2025.frontiersin.org/journals/rehabilitation-sciences/articles/10.3389/fresc.2025.1648002/pdf","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fresc.2025.1648002/full","host_type":"publisher"},{"url":"https://doi.org/10.3389/fresc.2025.1648002","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41211476","host_type":"repository"},{"url":"https://doaj.org/article/71451da1b85a4143a494135afa0ad657","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12592045","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12592045","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12592045?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Traumatic Brain Injury and Neurovascular Disturbances","Nicotinic Acetylcholine Receptors Study","Epilepsy research and treatment"],"mesh_terms":[],"keywords":["Donepezil","Neurocognitive","Cognition","Prefrontal cortex","Neurochemical","Executive functions","Neuroprotection","Neuropsychology","Traumatic brain injury","N-acetylcysteine","Guanfacine","Tbi","Severe Tbi"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T01:16:38.646393Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}