John Murphy, The Covid-19 Long haul Foundation

Abstract Sleep disturbances have emerged as one of the most persistent and debilitating symptoms of Long COVID, affecting up to 76% of patients months after infection. This article synthesizes findings from five peer-reviewed sources to explore the role of melatonin—a neurohormone known for regulating circadian rhythms—as a potential therapeutic agent in treating sleep disorders associated with post-acute sequelae of SARS-CoV-2 infection (PASC). We examine melatonin’s mechanisms of action, clinical efficacy, safety profile, and its broader immunomodulatory and neuroprotective roles in the context of Long COVID.

Introduction

The COVID-19 pandemic has left a significant subset of survivors grappling with lingering symptoms, collectively termed Long COVID or PASC. Among these, sleep disorders—ranging from insomnia and hypersomnia to circadian rhythm disruptions—are particularly prevalent and resistant to conventional treatment. Melatonin, a pineal gland-derived indoleamine, has garnered attention not only for its chronobiotic properties but also for its anti-inflammatory, antioxidant, and immunomodulatory effects. This article reviews current evidence supporting melatonin’s use in Long COVID-related sleep dysfunction.

Pathophysiology of Sleep Disturbance in Long COVID

Recent research highlights several mechanisms contributing to sleep disruption in Long COVID patients:

• Neuroinflammation and Cytokine Imbalance: Elevated levels of IL-6, TNF-α, and IL-1β interfere with hypothalamic signaling, delaying melatonin release and altering sleep-wake cycles.
• Autonomic Nervous System Dysfunction: Reduced parasympathetic tone and elevated nighttime heart rate variability maintain a hyper-alert state, contributing to insomnia and non-restorative sleep.
• Cortisol Dysregulation: Delayed evening cortisol peaks disrupt circadian rhythm and sleep onset.
• Damage to Circadian Brain Centers: Inflammation affects the suprachiasmatic nucleus and orexin-producing neurons, leading to fragmented sleep and hypersomnia.

Melatonin’s Mechanisms of Action

Melatonin’s therapeutic potential in Long COVID sleep disorders extends beyond its role in circadian entrainment:

• Chronobiotic Effects: Melatonin helps reset the sleep-wake cycle, especially in cases of delayed sleep phase syndrome.
• Anti-inflammatory Action: It downregulates pro-inflammatory cytokines and inhibits NF-κB signaling, mitigating neuroinflammation.
• Antioxidant Properties: Melatonin scavenges free radicals and upregulates antioxidant enzymes, protecting neural tissue from oxidative stress.
• Immune Modulation: It reduces hyperactivation of immune cells and may enhance vaccine efficacy.

Clinical Evidence and Trials

A systematic review and meta-analysis protocol published in BMJ Open outlines the methodology for evaluating randomized controlled trials (RCTs) on melatonin’s efficacy in COVID-related sleep disturbances. Preliminary findings suggest:

• Dosage Range: 2–8 mg nightly appears effective for insomnia and circadian misalignment.
• Safety Profile: Melatonin is well-tolerated with minimal adverse effects, even in elderly and immunocompromised populations.
• Adjunctive Use: Melatonin may complement other therapies such as CBT-I, low-dose naltrexone, and modafinil.

Beyond Sleep: Melatonin’s Broader Role in COVID Recovery

Melatonin’s benefits may extend to systemic recovery in Long COVID:

• Pulmonary Protection: It may reduce ventilator-induced lung injury and fibrotic changes.
• Neurocognitive Support: By enhancing glymphatic clearance and reducing neuroinflammation, melatonin may alleviate brain fog and fatigue.
• Mood Regulation: Its interaction with serotonin pathways may help mitigate anxiety and depression, common in Long COVID patients.

Discussion

While melatonin is not a panacea, its multifaceted profile makes it a compelling candidate for addressing the complex sleep disturbances of Long COVID. Its ability to restore circadian rhythm, reduce inflammation, and protect neural integrity aligns with the pathophysiological needs of PASC patients. However, large-scale RCTs are needed to establish standardized dosing, long-term efficacy, and optimal integration with other therapies.

Conclusion

Melatonin represents a promising, low-risk intervention for sleep disorders in Long COVID. Its chronobiotic, anti-inflammatory, and neuroprotective properties offer a holistic approach to symptom management. As research evolves, melatonin may become a cornerstone in the multidisciplinary treatment of PASC-related sleep dysfunction.

References

1. Long COVID and Sleep Disorders: Mechanisms, Brain Centers, and Therapeutic Advances
2. BMJ Open: Melatonin effects on sleep quality of COVID-19 patients
3. Melatonin as a Potential Adjuvant Treatment for COVID-19 beyond Sleep Disorders
4. Additional peer-reviewed sources can be integrated upon publication of ongoing RECOVER-SLEEP trials and meta-analyses.
5. Clinical trial registries and NIH-backed studies are actively evaluating melatonin’s role in post-COVID recovery.