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While for many people sleep can seem elusive,¹ it is essential to many physiological functions. One of those essential functions may be the clearance of toxins from the brain. Glymphatic flow is part of the brain’s natural detoxification and repair system, and both human and animal studies suggest that the glymphatic system is a paravascular network primarily active and enhanced during sleep that promotes the removal of toxic proteins and waste metabolites from the brain through cerebrospinal fluid (CSF) movement and interstitial fluid interactions.^2-4

Research studies continue to investigate the glymphatic system not only for its potential role in various disease pathologies, such as neurodegenerative diseases,^5,6 sleep disorders, and migraine,⁷ but also for those health conditions such as metabolic syndrome and other vascular risk factors that may adversely affect its toxin clearing functions.⁸ What is the latest human research regarding the glymphatic system and the mechanisms involved? How does sleep quality benefit this waste removal system and ultimately brain health?

The Importance of Sleep & Mechanisms of Action in Glymphatic Flow

The word glymphatic is a portmanteau of “glial” and “lymphatic,” highlighting the role that glial cells are theorized to play in helping rid the brain of waste, in a manner similar to the lymphatic system. While a full understanding of the fluid dynamics has not yet been reached and not all researchers agree with the mechanisms proposed thus far,^4,9 research into the glymphatic system (first documented in rodents)¹⁰ highlights the role of sleep in the clearance of many neurotoxins.

During sleep, the extracellular space of the brain expands, neurotoxins are exchanged from CSF into interstitial fluid, and harmful proteins and waste are transported out of the brain.^9,10 As an example, amyloid beta, buildup of which is heavily implicated in Alzheimer’s disease, is transported out of the brain via this pathway in rodents,¹⁰ and studies have confirmed similar findings of amyloid beta accumulation during sleep deprivation in humans.⁹

A 2022 systematic review of 190 articles (n=19,129 total participants) investigated the relationship between sleep, CSF-related, and glymphatic system–related components among healthy individuals and those with a pathology such as autoimmune, neurodegenerative, and sleep-related conditions.¹¹ While there were relationship differences noted across pathologies, several associations were found between sleep problems and both increased CSF metabolite concentrations (e.g., amyloid beta and tau proteins) and CSF volumes.¹¹ Clearance of both amyloid beta and tau has been shown to be reduced in patients with Alzheimer’s when compared to healthy controls.⁹ Glymphatic flow may also be impaired in patients with metabolic syndrome and hyperglycemia, which may contribute to diabetes-induced dementia.¹²

Non-Paravascular Mechanisms for Brain Toxin Clearance

The glymphatic system is not the only toxin clearance system in the brain. Another route by which metabolic byproducts and toxins are expelled from the brain is through the olfactory nerve to the cervical lymphatic vessels.⁹ In addition, the meningeal lymphatic vessels also interact closely with the glymphatic system and play a role in the drainage of interstitial fluid, CSF, molecules, and immune cells.¹³ As an important component of the brain waste removal system, a decrease in the function of meningeal lymphatic vessels has been associated with neurodegenerative diseases, intracranial hemorrhages, brain tumors, and trauma.¹⁴ Research continues to explore how the expanding knowledge regarding the meningeal lymphatic vessels may inform therapies for brain disease treatments as well as for neuroprotection.¹⁴

Clinical Applications

Research studies are continuing to investigate how sleep time, quality, and efficiency impact health outcomes associated with the glymphatic system; however, contradictory findings have been found.¹⁵ A 2023 systematic review of 51 studies that included healthy adults indicated that the outcomes of the glymphatic system may be influenced by changes in sleep.¹⁵ Yet the results were inconsistent, and the various sleep assessment methods used in individual studies influenced the findings. In addition, researchers noted that the sleep-glymphatic system interaction in humans is notably more complex than what has been observed in animals, and additional study is warranted.¹⁵

For many patients, supporting strong sleep habits in general may increase overall health.¹⁶ Poor sleep quality has been associated with a higher rate of depressive symptoms and an increased odds of mental distress in healthy subjects.^17,18 In addition, chronic sleep deprivation has been associated with an increased risk of cardiovascular events and all-cause mortality, as well as impaired glucose metabolism.^19,20

Engaging in lifestyle-based routines such as exercise may help to improve sleep.²¹ A close working relationship between clinician and patient can help identify sleep troubles and develop a personalized treatment intervention that implements effective behavioral and lifestyle therapies for improved sleep. Learn more about tools and strategies to help patients achieve sustainable lifestyle change and improve their well-being through IFM’s new course Lifestyle: The Foundations of Functional Medicine.

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