Sleep and the Glymphatic System: Exploring the Brain’s Nighttime Cleansing Process
For much of my life, I viewed sleep as a passive, routine part of the day—something that simply happened without much thought or effort. That perspective shifted dramatically after a period of illness, during which certain medications disrupted my sleep patterns. Since the onset of COVID-19, I’ve experienced persistent nighttime wakefulness and, at times, a heightened state of daytime arousal followed by an inability to fall or stay asleep. It reminded me of a period nearly 30 years ago, particularly when I was taking certain antidepressants.
The sleep disturbance soon evolved into something more profound. In addition to physical discomfort, I began experiencing persistent cognitive fog. I struggled to concentrate, had frequent lapses in short-term memory, and found it increasingly difficult to process new information. Multitasking was no longer possible, and even basic conversations became mentally exhausting. These changes left me questioning: Could this be the early onset of dementia or Alzheimer’s disease?
In search of answers, I began researching the science of sleep. What I discovered fundamentally shifted my understanding of how the brain functions—and just how essential restorative sleep is to long-term cognitive health.
The Glymphatic System: A Newly Discovered Brain Function
One of the most compelling findings I encountered was the discovery of the glymphatic system—a brain-wide waste clearance mechanism first described in 2013. This system operates primarily during sleep and plays a vital role in maintaining the brain’s internal environment.
The glymphatic system works by allowing cerebrospinal fluid to flow through expanded interstitial spaces between brain cells, helping to flush out metabolic waste products, including beta amyloid and tau proteins—both of which are associated with Alzheimer’s disease. Without regular, restorative sleep, this clearance process becomes impaired, and potentially harmful substances can accumulate in the brain over time.
Insights from Dr. Andrew Varga
At the 2025 SLEEP meeting, Dr. Andrew Varga, a neurologist and sleep specialist at the Mount Sinai Integrative Sleep Center, presented compelling evidence about the glymphatic system’s role in cognitive health. He emphasized that sleep is not simply about rest—it is a period of intense neurological housekeeping.
Dr. Varga’s research, which drew on data from the Alzheimer’s Disease Neuroimaging Initiative, showed that individuals with untreated sleep apnea developed mild cognitive impairment over a decade earlier than those without apnea or those who received proper treatment. This highlights the direct connection between disrupted sleep and accelerated cognitive decline.
He also pointed out that while some medications can aid sleep, they may interfere with glymphatic clearance. For instance, zolpidem (Ambien), a commonly prescribed hypnotic, may inhibit the system’s function, although the data is still preliminary.
Dr. Varga’s key recommendation: prioritize consistent, high-quality sleep with regular sleep-wake schedules, and address any underlying conditions—such as sleep apnea or chronic insomnia—that may compromise restorative sleep.
For additional context, neuroscientist Dr. Jarred Younger offers an accessible explanation of the glymphatic system in his presentation titled “The Brain's Hidden System,” available on YouTube.
https://www.youtube.com/watch?v=-3r0_24Qb5A
Hormonal Activity That Interferes with Sleep
Beyond structural and functional processes like the glymphatic system, sleep is heavily regulated by hormones and neurotransmitters. When these are imbalanced, even the most sleep-conducive environment may not result in rest.
The main disruptors are:
1. Cortisol – Often called the “stress hormone,” cortisol should be highest in the morning and lowest at night. Elevated nighttime cortisol—common in chronic stress or irregular schedules—can prevent sleep.
2. Adrenaline and Noradrenaline – These “fight-or-flight” chemicals promote wakefulness and are released during times of emotional or physical stress. Elevated levels can result in an overactive, racing mind at bedtime.
3. Orexin (Hypocretin) – This neuropeptide maintains wakefulness. Overactivity in this system has been linked to insomnia and disorders like narcolepsy.
4. Melatonin – A key sleep-promoting hormone. Suppressed melatonin production—often due to blue light exposure, caffeine, or irregular sleep timing—can delay or prevent sleep onset.
Maintaining hormonal balance is essential to establishing a healthy sleep-wake cycle.
Dopamine and Its Role in Sleep Deprivation
Another major neurotransmitter implicated in sleep regulation is dopamine, known for its role in reward, motivation, and alertness. Dopamine naturally rises in the morning and declines in the evening. However, when dopamine levels remain elevated at night—due to stimulants, screen exposure, or stress—it can disrupt sleep by increasing arousal and mental activity.
Common causes of high nighttime dopamine include:
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Caffeine and nicotine
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ADHD medications (e.g., Adderall, Ritalin)
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High screen time before bed
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Engaging in stimulating or addictive behaviors late at night
Excess dopamine is also associated with restless legs syndrome and delayed sleep phase disorder, both of which can interfere with sleep quality.
Do Antidepressants Raise Dopamine?
Effexor (venlafaxine) is classified as a serotonin-norepinephrine reuptake inhibitor (SNRI), meaning it primarily increases the availability of serotonin and norepinephrine in the brain. While it may have some minor effects on dopamine—particularly at higher doses—this is not its primary mechanism of action.
Some individuals report feelings of increased alertness, restlessness, or difficulty sleeping when initiating treatment or adjusting their dosage. These effects are more commonly attributed to elevated norepinephrine activity, which can be stimulating, rather than a direct increase in dopamine.
Insomnia, vivid dreams, and fragmented sleep are documented side effects in a subset of users, especially during the early phases of treatment or at higher doses.
In summary, Effexor does not significantly raise dopamine levels for most individuals, but its activating effects, driven mainly by norepinephrine, can impact sleep quality and increase arousal in sensitive individuals.
Interventions: Medications and Supplements That Support Sleep
For those experiencing chronic or acute insomnia, several treatment options are available, ranging from prescription medications to natural supplements.
Prescription options include:
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Zolpidem (Ambien), Eszopiclone (Lunesta), and Zaleplon (Sonata): Short-acting hypnotics
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Temazepam (Restoril): A benzodiazepine
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Ramelteon (Rozerem): A melatonin receptor agonist
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Suvorexant (Belsomra), Lemborexant (Dayvigo): Orexin receptor antagonists
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Trazodone, Mirtazapine, and low-dose Doxepin: Sedating antidepressants often used off-label for sleep
Common natural and over-the-counter options:
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Melatonin – Regulates circadian rhythms; effective for jet lag and delayed sleep phase
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Magnesium – Promotes relaxation via GABA activity
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L-Theanine – A calming amino acid found in green tea
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Valerian root, glycine, and CBD – May help with stress-related or mild sleep disturbances
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Diphenhydramine (Benadryl), Ceterizine and Doxylamine (Unisom) – Antihistamines that induce drowsiness, though tolerance can develop quickly
Treatment should be aligned with the underlying cause of sleeplessness, whether it be stress, circadian rhythm disruption, chronic pain, or a neurological condition.
Substances and Medications That May Prevent Sleep
Just as there are treatments to support sleep, many commonly used substances can interfere with it. These include:
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Stimulant medications such as Adderall, Ritalin, and modafinil
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Caffeine and related compounds (found in coffee, energy drinks, pre-workout supplements)
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Activating antidepressants like bupropion, fluoxetine, and venlafaxine
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Corticosteroids (e.g., prednisone)
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Decongestants such as pseudoephedrine and phenylephrine
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Stimulant herbs and supplements including ginseng, Rhodiola rosea, and yohimbine
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Thyroid medications (e.g., levothyroxine) when dosed too high
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Recreational drugs and nicotine, which can elevate dopamine and delay sleep onset
Sleep disruption from these agents may go unnoticed until the consequences—daytime fatigue, cognitive issues, or mood instability—begin to interfere with daily life.
Does exercise improve glymphatic function?
Regular exercise not only improves circulation but also supports vital glymphatic system flow, thereby boosting waste removal and optimizing the glymphatic system.
The newly discovered glymphatic system: the missing link between physical exercise and brain health? https://pmc.ncbi.nlm.nih.gov/articles/PMC11058641/
What diseases are linked to glymphatic dysfunction?
Glymphatic system dysfunction has been documented to play a role in a
variety of neurological conditions, such as Alzheimer's disease, ischemic
strokes, traumatic brain injury, normal pressure hydrocephalus, Parkinson's
disease (PD), and multiple sclerosis6,7,8,9,10,11,12,13.
Glymphatic dysfunction evidenced by DTI-ALPS is related to obstructive sleep
apnea intensity in newly diagnosed Parkinson’s disease:
https://www.nature.com/articles/s41531-025-01018-8
Final Reflections
What began as a personal struggle with sleeplessness led to a deeper understanding of the complex interplay between sleep, brain function, and overall health. The glymphatic system in particular revealed that sleep is not simply restorative—it is essential for clearing toxic buildup in the brain and preserving long-term cognitive resilience.
Inadequate or poor-quality sleep isn’t just inconvenient—it may be neurologically harmful over time. For anyone experiencing persistent sleep issues, addressing the biological, hormonal, and behavioral factors behind sleep disruption is not just beneficial—it’s imperative.
© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9
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