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

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.