Poor Sleep in Neuroinflammatory Conditions: Understanding The Biology of Poor Sleep in Long COVID, ME/CFS, and Fibromyalgia

Getting a good night’s sleep is an important commitment everyone must make for optimal overall health. But not everyone can.

Patients suffering from neuroinflammatory conditions, especially Long COVID, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and Fibromyalgia, frequently suffer from sleep disorders. In addition to poor sleep, these conditions share other similarities such as post-exertional malaise (PEM), cognitive impairment, chronic pain, autonomic dysfunction, metabolic dysfunction, and often psychiatric conditions such as depression, anxiety, and mood disorders.

This sleep deep dive is aimed at helping patients with Long COVID, ME/CFS, Fibromyalgia (FM), and other neuroinflammatory and neurodegenerative conditions understand why they can’t seem to get a good night’s sleep and what they might do to correct it.

Without further ado, let’s dive in.

Poor Sleep Defined

Let’s first define what unusual sleep characteristics are experienced by a subset of patients with Long COVID, ME/CFS, FM, and other neuroinflammatory conditions. These sleep patterns are one or more of the following:

– insomnia
– sleep continuity disorders
– feeling of non-restorative sleep
– changes in the sleep-waking cycle

Prevalence of Disordered Sleep In Long COVID

While the real number of individuals with Long COVID suffering from sleep disorder, a recent meta-analysis of 27 studies with 15,362 total participants reported the prevalence to be 45% (95% CI: 37%—53%; I2 = 98.7%)(1). This association between Long COVID and sleep deprivation is so common that it is referred to as ‘coronasomnia’.

Prevalence of Disordered Sleep In ME/CFS and Fibromyalgia

The association between ME/CFS and poor sleep is even higher, as one study found that 55% experienced ‘severe unrefreshing sleep (2) while the prevalence of a sleep disorder in patients with fibromyalgia has been reported to be as high as 92.9% (3).

Putative Disordered Sleep Mechanisms

Many peer-reviewed scientific publications are attempting to understand why Long COVID and ME/CFS patients experience disordered sleep. Yet, the exact mechanism(s) remain poorly understood. We can speculate this is because the cause(s) of the disordered sleep is likely heterogeneous. The biological driver(s) of one person’s sleep difficulties might differ from another person who suffers from the same conditions. Let’s begin by understanding some pathophysiological similarities shared by ME/CFS, Long COVID, and Fibromyalgia patients.

ME/CFS and Long COVID Shared Molecular Features

Patients with Long COVID and ME/CFS have low cortisol, mitochondrial dysfunction, dysautonomia, neuroinflammation, endothelial cell damage, reduced cerebral blood flow, and Epstein-Barr Virus (EBV) and/or Human Herpes Virus 6 (HHV6) reactivation.

A subgroup of patients with ME/CFS and Long COVID might suffer from an inflamed pituitary gland resulting from chronic inflammation caused by the chronic reactivation of dormant viruses. This inflamed gland could cause a range of symptoms experienced by those with ME/CFS and Long COVID, due in part to a dysfunctional hypothalamic pituitary adrenal axis (HPA axis reviewed in a previous deep dive). An HPA axis that does not work properly would result in low cortisol levels, leading to chronic inflammation.

As you will learn in the following sections, the hypothalamus is not only important in regulating stress but also in metabolism, parts of the autonomic nervous system, and, you guessed it… sleep. In other words, most of the issues are experienced by those with Long COVID and ME/CFS.

High Intracranial Pressure

One hypothesis to explain the prevalence of poor sleep in a subset of ME/CFS and Long COVID patients is that the brain and brainstem are under an abnormally high amount of pressure inside the skull. The cause of this abnormal pressure is unknown, giving it the medical name, idiopathic intracranial hypertension. This increased pressure was recently discovered to be associated with obstructive sleep apnea (4). What might cause this?

The brain has a unique lymphatic vascular system called glymphatics, which is responsible for removing metabolic waste by flushing cerebral spinal fluid (CSF) from the brain. Could this glymphatic vascular system be broken in a subset of ME/CFS and Long COVID patients due to damaged lymphatic endothelial cells or glymphatic vessel blockage (occlusions) from a thrombus (clot) due to hypercoagulation (5)? More research is needed to understand how this occurs and how to alleviate the intracranial pressure.

Circadian Rhythm Disruptions

What Is Circadian Rhythm?

The human body’s circadian rhythm is a natural, internal clock influenced by light and temperature that regulates the sleep-wake cycle, repeating roughly every 24 hours. This rhythm is crucial for maintaining overall health as it affects sleep patterns, hormone release, eating habits, digestion, and body temperature. Disruptions to the circadian rhythm can lead to sleep disorders, metabolic issues, and other health problems.

Circadian Rhythm Disruptions in ME/CFS, Long COVID, and FM

Circadian rhythm disruptions have been observed in ME/CFS6 and fibromyalgia (FM)6,7, leaving scientists to speculate that these disturbances also occur in a subgroup of Long COVID patients8, contributing to the high rate of sleep disorders in both patient groups.

One study found that the severity of COVID-19 was positively correlated with an increased probability of developing symptoms of circadian rhythm disruption, including disrupted sleep patterns and decreased motor activity (9)

The Hypothalamus Influences Sleep

The hypothalamus plays a crucial role in sleep regulation, as it contains specialized neurons that produce orexin (also known as hypocretin), a neuropeptide that helps maintain the balance between sleep and wakefulness. Specifically, low levels of orexin initiate sleep while high levels of orexin initiate attention, energy homeostasis, neurogenesis (growth of neurons), and cognition. (10)

Disruptions in the hypothalamus, such as those caused by infections or inflammation, can lead to sleep disturbances and other health issues. This makes the hypothalamus a vital component in maintaining healthy sleep patterns and overall well-being.

Orexin Production in the Hypothalamus

Research suggests that SARS-CoV-2 may enter the brain through nerve fibers in the nose (olfactory bulb), reaching the hypothalamus and frontal cortex before spreading to other areas of the brain (11). Insomnia, fatigue, brain fog, and weight gain are likely manifestations of hypothalamic dysfunction caused by COVID-19 (11). That’s because, in addition to regulating our sleep, the hypothalamus controls our stress response (HPA axis) (12), metabolism (13), and autonomic functions like heart rate and blood pressure (14).

Studies have shown that COVID-19 viral particles are found in the brain, particularly affecting nerve cells in the hypothalamus that produce orexin, a neuropeptide involved in the sleep-wake cycle.15 These nerve cells are sensitive to infection and can be damaged during a viral attack, leading to sleep disturbances (11).

Orexin Levels in the Inflamed Brain

Neuroinflammatory and neurodegenerative diseases have been found to reduce orexin levels (10). Extreme reductions in orexin levels are associated with:

– Narcolepsy: a chronic sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks. People with narcolepsy often experience cataplexy, which is a sudden loss of muscle tone triggered by strong emotions (16).

– Fragmented Sleep: Individuals may have difficulty maintaining continuous sleep, leading to frequent awakenings during the night (17).

– REM Sleep Dysregulation: Reduced orexin levels can disrupt the normal regulation of REM (rapid eye movement) sleep, leading to abnormalities such as vivid dreams or sleep paralysis (18).

Neuroprotective Actions of Orexin

Loss of orexin is associated with neurodegeneration, memory and cognitive deficits, and neuroinflammation (19). In contrast, studies have determined that orexin A plays a neuroprotective role in the brain by reducing neuroinflammation and cell death (20-22).

Injecting mice with orexin-A was shown to reduce neurodegeneration and neuroinflammation in a mouse model of multiple sclerosis (23). Another mouse model of neuroinflammation found that administering orexin A in the nose of mice improved the outcome of sepsis-associated encephalopathy (SAE) by reducing the permeability of the blood-brain barrier (BBB) (24). Another study found that intranasal administration of orexin-A to rats similarly reduced neuroinflammation following resuscitation from cardiac arrest (25).

Orexin Receptor Autoantibodies

Autoantibody profiling of 172 patients with COVID-19 revealed autoantibodies that bind to an orexin receptor in 10 COVID-19 patients (26).

Restoration of Orexin - A Therapeutic Avenue

While intranasal administration of orexin in humans to reduce neuroinflammation and restore sleep has not been performed, scientists speculate that it might one day represent a viable treatment for sleep disorders observed in those with Long COVID.

Mitochondrial Dysfunction in Sleep Disorders

Experts suggest that brain damage, combined with changes in the body and other brain regions after a COVID-19 infection, may contribute to chronic insomnia, chronic fatigue, and other Long COVID symptoms.

Research indicates that patients with Long COVID and ME/CFS experience oxidative stress due to dysfunctional mitochondria, the energy factories inside our cells (27). SARS-CoV-2 can alter mitochondrial function to replicate, reducing the energy available to cells (28). Typically, mitochondria shut down energy production temporarily during infections, but some infections, including SARS-CoV-2, cause prolonged dysfunction, preventing mitochondria from recovering.28 This energy drop can deactivate the hypothalamic sleep center (29).

Nerve cells, especially those in the hypothalamus, require significant energy due to their constant activity (30). Mitochondria use oxygen in the process of producing ATP, a molecule that is used to power chemical reactions. Lower oxygen levels in the brains of Long COVID patients further hinder mitochondrial function (31).

These findings highlight the complex interplay between COVID-19, mitochondrial dysfunction, and the resulting impact on sleep and overall health.

Sleep Hormone Changes During Neuroinflammation

In the context of neuroinflammatory conditions, various hormones involved in the sleep-wake cycle can experience significant changes. The table below outlines these hormones and how their levels are affected by neuroinflammation.

Hormone	Source	Role In Sleep	Neuroinflammation Effects
Melatonin	Pineal Gland	Regulates circadian rhythms and promotes sleep onset; rises in response to darkness.	Not reported
Cortisol	Adrenal Glands	Peaks in the morning for wakefulness; declines at night for sleep initiation.	Dysregulated during chronic inflammation; elevated levels can impair sleep cycles (32).
Adenosine	Brain (ATP Metabolism)	Builds up during wakefulness to induce sleep pressure; cleared during sleep.	Altered accumulation in neuroinflammation may affect sleep depth and quality (33).
GABA	Central Nervous System	Inhibits brain activity to promote relaxation and deep sleep.	Reduced GABA signaling in neuroinflammatory states contributing to poor sleep quality (34).
Orexin (Hypocretin)	Hypothalamus	Maintains wakefulness and prevents abrupt sleep transitions.	Decreased levels during neuroinflammation, especially in conditions like multiple sclerosis (10,19).
Serotonin	Brainstem (raphe nuclei)	Precursor to melatonin; stabilizes mood and aids sleep onset.	Not reported
Growth Hormone	Oituitary Gland	Released during deep sleep for tissue repair and metabolic regulation.	Not reported
Leptin	Fat Cells	Suppresses appetite; indirectly supports circadian rhythm and sleep regulation.	Increased systemic inflammation leads to metabolic disturbances that affect sleep (35).
Ghrelin	Stomach	Stimulates appetite; indirectly linked to disrupted sleep when levels are elevated.	Increased during inflammation; may interfere with sleep onset and maintenance (36).
Prolactin	Pituitary Gland	Peaks during REM sleep; supports immune regulation and sleep.	Not reported

Medications for Sleep Disturbances in Long COVID and ME/CFS

In the context of Long COVID and ME/CFS, managing sleep disturbances is crucial for improving overall quality of life. The table below lists medications that have been found to aid sleep in individuals with these conditions, detailing their effects and potential benefits.

Medication	Mechanisms of Action	Conditions Treated	Additional Notes
Trazodone	Serotonin antagonist and reuptake inhibitor (SARI); blocks histamine and alpha-1 adrenergic receptors.	Long COVID, FM, ME/CFS	Commonly used for insomnia; improves sleep maintenance and quality. Lower risk of dependence than benzodiazepines.
Gabapentin	Modulates calcium channels, reducing nerve excitability and promoting sleep by decreasing pain signals.	ME/CFS, FM	Beneficial for sleep issues associated with chronic pain (37).
Pregabalin	Similar to gabapentin, binds to voltage-gated calcium channels to reduce neuropathic pain and improve sleep.	ME/CFS, FM	Shown to enhance slow-wave sleep and reduce nighttime pain. It may also help with anxiety.38
Low-Dose Naltrexone (LDN)	Modulates microglial activation to reduce neuroinflammation and restore sleep architecture.	Long COVID, ME/CFS, FM	Not a sedative, but may improve sleep by addressing central inflammation and pain. Takes weeks to show the full effect. Has been reported to reduce fatigue (39).
Cyclobenzaprine	Muscle relaxant with sedative properties; reduces muscle tension and promotes sleep.	ME/CFS, FM	Structurally similar to tricyclic antidepressants. Might improve sleep and reduce pain.
Clonazepam	Benzodiazepine enhances GABA activity to promote relaxation and reduce REM-related disturbances.	ME/CFS, FM, POTS	Used for severe insomnia or restless leg syndrome (RLS). Risk of tolerance and dependence with prolonged use.
Hydroxyzine	Antihistamine blocks H1 receptors and has sedative properties.	Long COVID, FM, POTS	Helps with sleep initiation and anxiety. Non-addictive but can cause dry mouth and next-day drowsiness (40).
Doxepin	A tricyclic antidepressant that blocks histamine receptors at low doses to promote sleep maintenance.	Long COVID, FM, ME/CFS	Effective for sleep maintenance in insomnia. Minimal sedative hangover compared to other medications.
Mirtazapine	Tetracyclic antidepressant that blocks histamine, serotonin, and norepinephrine receptors; promotes sedation.	Long COVID, FM, ME/CFS	Effective for sleep onset and maintenance; also helps with mood and appetite.
Alpha-2 Agonists (e.g. Clonidine)	Modulate sympathetic nervous system activity; promote sedation by reducing norepinephrine release.	POTS, Long COVID	May help with insomnia and hyperadrenergic symptoms, but can cause hypotension or dizziness.

The Bottom Line

Sleep disturbances are a common and debilitating feature of neuroinflammatory conditions like Long COVID, ME/CFS, and Fibromyalgia, affecting 45–92.9% of patients with issues such as insomnia, non-restorative sleep, and disrupted circadian rhythms. These problems may stem from shared biological factors, including hypothalamic dysfunction, low orexin levels, mitochondrial impairment, and increased intracranial pressure.

Potential causes involve neuroinflammation, viral reactivation, and glymphatic system issues, though exact mechanisms remain unclear. Ongoing research is critical to unravel these complexities and develop effective treatments to improve sleep and quality of life for those affected.

Written By

Matthew Menendez, Ph.D.

Director of Science Communication, Brain Inflammation Collaborative

Dr. Menendez has a passion for empowering patients navigating complex chronic diseases. Through innovative educational strategies, he bridges the gap between cutting-edge research and real-world understanding, helping individuals advocate for better care and access to timely treatments.

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