Potential of melatonin as a treatment option for long COVID: A call for research

Abstract

The 21st century's most significant public health crisis is the COVID-19 pandemic. Patients and society face prolonged consequences related to COVID-19, which is generally known as long COVID. New treatments are still under development.¹ While the development of drugs can take over a decade, we should explore currently approved medications for patients in the meantime.

Melatonin is well known for governing sleep–wake cycles and has more than 50 years of safe use. Initially, it was described as a hormone product of the pineal gland. However, it is now realized to be synthesized and secreted from tissues that include the retina, bone marrow, gastrointestinal tract and the placenta.²

Long COVID shows a variety of symptoms, among which neuropsychiatric symptoms like brain fog, memory impairment, anxiety and insomnia are prevalent, for which neuroinflammation, oxidative stress and mitochondrial dysfunction are the fundamental mechanisms.³

Inflammation in long COVID is often associated with a cytokine storm that disrupts the blood–brain barrier. The latter allows proinflammatory cytokines, such as IL-6, to activate microglia in the brain, shifting towards a proinflammatory phenotype and exacerbating neuroinflammation. Melatonin may prevent it by decreasing the release of proinflammatory cytokines, including TNF-α, IL-1β and IL-6 while stimulating sirtuin-1-mediated production of the anti-inflammatory cytokine IL-10. Furthermore, by increasing the expression of nuclear factor erythroid 2-related factor 2 (NRF2) activity, melatonin helps restore the balance between reactive oxygen species (ROS) and antioxidants to manage oxidative stress. This modulation of inflammatory pathways could potentially reduce neuroinflammation and thus may reduce symptoms in the long COVID patients suffering from cognitive and mood disturbances. Mitochondrial dysfunction, often seen in chronic inflammatory states, can be relieved by melatonin by improving mitochondrial function, reducing oxidative damage and restoring energy production, which may help alleviate symptoms like fatigue and cognitive impairment.^{2, 4}

Some studies have assessed the impact of melatonin in patients with acute infection of COVID-19. A randomized control trial (RCT) demonstrated that 5mg oral melatonin improved the CRP and ESR.⁵ Similarly, a randomized double-masked clinical trial (3mg melatonin)⁶ and pilot study (6mg melatonin)⁷ found that melatonin significantly improved CRP levels.

Although many reports indicate melatonin's positive impact on COVID-19 patients, it is critical to conduct clinical trials explicitly focusing on the effect in long COVID. Some studies are already being conducted to determine its role in COVID-19. However, the optimal dosing and efficiency of melatonin for managing neuropsychiatric and cognitive symptoms of long COVID should be assessed. We urge the research community to explore melatonin's potential as a therapeutic option across various geographical settings.

Conceptualization: Urmisha U. Kakad and Priyanka S. Khopkar-Kale. Writing original draft: Urmisha U. Kakad. Data organization: Urmisha U. Kakad and Priyanka S. Khopkar-Kale. Formal analysis: Urmisha U. Kakad and Priyanka S. Khopkar-Kale. Supervision: Priyanka S. Khopkar-Kale, Srikanth P. Tripathy and Jitendra S. Bhawalkar. Writing—review and editing: Priyanka S. Khopkar-Kale, Srikanth P. Tripathy and Jitendra S. Bhawalkar. Submission: Priyanka S. Khopkar-Kale. Correspondance: Priyanka S. Khopkar-Kale.

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