Sleep disturbances have emerged as one of the most persistent and disruptive symptoms of Long COVID, affecting up to 40–76% of patients months after infection2. This article synthesizes 2025 peer-reviewed research to explore the mechanisms of sleep disruption, the role of circadian brain centers, and therapeutic strategies aimed at restoring healthy sleep architecture.
🧬 Mechanisms of Sleep Disruption in Long COVID
1. Neuroinflammation and Cytokine Imbalance
SARS-CoV-2 triggers prolonged neuroinflammation, elevating cytokines like IL-6, TNF-α, and IL-1β, which interfere with sleep regulation.
These cytokines disrupt hypothalamic signaling, delaying melatonin release and altering sleep-wake cycles.
2. Autonomic Nervous System Dysfunction
Long COVID patients show reduced parasympathetic tone and elevated nighttime heart rate variability, keeping the brain in a hyper-alert state.
This leads to insomnia, non-restorative sleep, and daytime fatigue.
3. Mitochondrial Dysfunction
Viral persistence impairs mitochondrial energy production, especially in hypothalamic neurons, which are highly energy-dependent.
This contributes to central fatigue and sleep fragmentation.
4. Cortisol Dysregulation
Salivary cortisol levels in long COVID patients peak later in the evening, disrupting circadian rhythm and sleep onset.
🧠Circadian Brain Centers Affected
🔹 Hypothalamus
The suprachiasmatic nucleus (SCN), the brain’s master clock, is disrupted by inflammation and spike protein persistence.
Orexin-producing neurons, crucial for wakefulness regulation, are damaged, leading to insomnia and hypersomnia.
🔹 Brainstem and Locus Coeruleus
These regions regulate norepinephrine and REM sleep. COVID-related inflammation impairs their function, contributing to sleep fragmentation.
🔹 Glymphatic System
Sleep-dependent clearance of neurotoxins via the glymphatic system is impaired due to microclots and endothelial damage, worsening brain fog and fatigue.
