Glymphatic system dysfunction in alcohol use disorder: Current understanding and future directions

doi:10.5498/wjp.v15.i10.107936

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World Journal of Psychiatry

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2220-3206

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Psychiatry. Oct 19, 2025; 15(10): 107936
Published online Oct 19, 2025. doi: 10.5498/wjp.v15.i10.107936

Glymphatic system dysfunction in alcohol use disorder: Current understanding and future directions

Jia-Yu Lin, Hai-Bo Zhang, Ling Luo, Ren-Jie Li, Xiao-Guang Wang

Jia-Yu Lin, Ling Luo, Ren-Jie Li, Xiao-Guang Wang, Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China

Jia-Yu Lin, Basic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China

Hai-Bo Zhang, Department of Radiology, The Third Affiliated Hospital, Sun Yat-sen University, Zhongshan 528400, Guangdong Province, China

Xiao-Guang Wang, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China

Xiao-Guang Wang, Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China

Co-first authors: Jia-Yu Lin and Hai-Bo Zhang.

Author contributions: Lin JY and Zhang HB contributed to writing the original draft and made equal contributions as co-first authors; Lin JY, Zhang HB, Luo L, Li RJ, and Wang XG contributed to the review and editing; Wang XG contributed to conceptualization and supervision; All authors approved the final version to publish.

Conflict-of-interest statement: The authors have no conflicts of interest to declare.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Xiao-Guang Wang, MD, PhD, Associate Professor, Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan 2^nd Road, Guangzhou 510080, Guangdong Province, China. wxguang@mail.sysu.edu.cn

Received: April 2, 2025
Revised: May 7, 2025
Accepted: July 23, 2025
Published online: October 19, 2025
Processing time: 178 Days and 19.7 Hours

Abstract

The glymphatic system, a recently discovered cerebrospinal fluid-mediated pathway, plays a crucial role in fluid exchange and waste clearance in the brain. Its dysfunction has been implicated in various neurological disorders, including Alzheimer’s disease and traumatic brain injury. Recent studies suggest that alcohol intake has a biphasic effect on the glymphatic system: Low doses of alcohol enhance glymphatic function, whereas high doses lead to glymphatic suppression and cognitive decline, mirroring patterns seen in alcohol-related dementia, providing valuable insights into the dose-dependent effects of alcohol on glymphatic function, but significant gaps persist, particularly regarding the mechanistic understanding and the influence of confounding factors such as sex, age, blood pressure, and wakefulness. Here, we synthesize and critically evaluate the important research findings within this field to gauge its progress and identify new research opportunities. We discuss the specific mechanisms by which alcohol affects the glymphatic system, including how alcohol influences cerebrospinal fluid-interstitial fluid exchange and waste removal. We also discuss the potential of the glymphatic system as a new target, such as through pharmacological or lifestyle interventions aimed at enhancing glymphatic function to treat alcohol use disorder and other neurological disorders associated with glymphatic dysfunction.

Keywords: Alcohol use disorder; Glymphatic system; Aquaporin 4; Perivascular space; Mitochondrial dysfunction

Core Tip: The glymphatic system, a critical pathway for fluid exchange and waste clearance in the brain, is linked to neurological disorders when dysfunctional. Alcohol has a biphasic effect: Low doses enhance glymphatic function, while high doses suppress it and cause cognitive decline, mirroring alcohol-related dementia. Studies explore how alcohol affects cerebrospinal fluid-interstitial fluid exchange and waste removal. Despite progress, gaps remain in understanding mechanisms and confounding factors like sex, age, and blood pressure. The significance of this review lies in deepening the understanding of the relationship between alcohol and glymphatic system disorders and offering possible targets for developing new treatments.