key: cord-0792845-rpzqcw9w
authors: Cross, Kristina M.; Landis, Dylan M.; Sehgal, Laveena; Payne, J. Drew
title: Melatonin in Early Treatment for COVID-19: A Narrative Review of Current Evidence and Possible Efficacy
date: 2021-06-10
journal: Endocr Pract
DOI: 10.1016/j.eprac.2021.06.001
sha: 7769fae4b712d28cac4d91e08fc45dc1d4924b1d
doc_id: 792845
cord_uid: rpzqcw9w

OBJECTIVE: To date, there are no FDA approved medications for treatment of early COVID-19 infection. Recently, use of melatonin, a naturally occurring tryptophan-derivative synthesized in the pineal gland and immune cells, has been suggested as an early treatment option for COVID-19. Melatonin has known anti-inflammatory, immunomodulatory, and protective antioxidant mechanisms that may attenuate the severity of COVID-19 symptoms. The objective of the present narrative review is to discuss the use of melatonin as an early treatment option on the first day of diagnosis for COVID-19. METHODS: The MeSH terms “COVID-19” and “viral diseases” were manually searched on PubMed and relevant articles were included. RESULTS: Results showed that melatonin acts to reduce reactive-oxygen-species mediated damage, cytokine-induced inflammation, and lymphopenia in viral diseases similar to COVID-19. CONCLUSIONS: These conclusions provide evidence for potential benefits in melatonin use for COVID-19 treatment as early as the day of diagnosis.

As COVID-19 surged to a world-wide pandemic with more than 28 million people testing positive worldwide and over half a million deaths in the United State alone, scientists and physicians have been searching for early interventions upon diagnosis.

COVID-19 develops as the SARS-CoV-2 virus attaches to ACE2 receptors in airway epithelial cells, triggering a pro-inflammatory response that often results in a cytokine storm and potential onset of Acute Respiratory Distress Syndrome (ARDS) (1, 2) . An additional prooxidant response leads to ROS-mediated damage to the alveoli (3) . To avoid severe cases, treatment for COVID-19 should be started upon diagnosis. Compounds that would ameliorate excess inflammation and oxidative damage could lessen morbidity and mortality of infection (4) .

The use of melatonin, a naturally occurring tryptophan derivative synthesized in the pineal gland and immune cells (5) , is a potential treatment option to reduce the severity of COVID-19 symptoms due to its known anti-inflammatory, immunomodulatory, and protective antioxidant mechanisms (6) . As a powerful hydroxyl radical scavenger and stimulator of antioxidative enzymes such as glutathione peroxidase and superoxide dismutase, melatonin also provides significant protection against cellular oxidative damage. Although melatonin is discussed as a treatment for COVID-19 in later stages for disease progression, this review, using mechanistic evidence, aims to present the novel use of melatonin as an early treatment option starting the first day of diagnosis.

To review the extensive evidence about melatonin as a therapeutic modality for COVID- 19 , authors attempted to answer the following key questions. First, has melatonin provided J o u r n a l P r e -p r o o f benefit in use with other viral diseases? Second, would melatonin provide benefits with COVID-19? Third, should melatonin be used as an early intervention in COVID-19 disease?

We manually searched an electronic database, PubMed, for English-language titles and abstracts using the MeSH search terms "COVID-19" and "viral diseases." (113 publications).

Articles were included if they provided relevant information on key questions. Selected articles included peer reviewed laboratory-based studies on viruses, observational studies, and review articles. Reviewers critically assessed each of the included articles. Any paper that did not discuss melatonin as a treatment, use melatonin as a treatment, or discuss viral infections that cause disease in humans was removed from our study. The remaining were manually organized into publications related to COVID-19 (22 publications) or other viral diseases (43 publications).

Due to its ROS-scavenging and anti-inflammatory properties, melatonin has been both proposed and explored as a treatment for various viral infections with mechanisms that cause an excessive immunoinflammatory response (5, (7) (8) (9) . As a powerful hydroxyl radical scavenger and stimulator of antioxidative enzymes such as glutathione peroxidase and superoxide dismutase, melatonin also provides significant protection against cellular oxidative damage (10, 11). Many viruses, including ones that cause a cytokine storm, tend to decrease melatonin synthesis which J o u r n a l P r e -p r o o f negatively effects the host's immune system (12) . The viral diseases discussed in this review have been found to target host melatonin synthesis in order to evade destruction and begin proliferating inside of the host (3). Viral pathogens work to decrease the anti-inflammatory effect of melatonin by suppressing gene expression of many melatonin-synthesizing enzymes and depleting tryptophan, a melatonin precursor (3). These melatonin-depleting effects result in increased severity of many viral diseases (3).

Melatonin has been used to treat respiratory syncytial virus (RSV), a well-studied lower respiratory tract disease, that causes damage to the bronchial epithelial cells via analogous mechanisms of inflammatory cell infiltration and ROS overproduction. RSV causes a signal cascade by the activation of toll-like receptor-3 (TLR3), which induces NF-kB activity, a transcription factor that upregulates production of pro-inflammatory cytokines. Similarly, influenza A virus is one of the most common causes of respiratory disease due to extensive tissue injury. These injuries stem from excessive production of ROS such as superoxide during phagocytosis by macrophages and neutrophils employed by the host to contain the virus. There is mass infiltration of the lung parenchyma in both of these diseases by lymphocytes, neutrophils, and macrophages, resulting in proinflammatory and non-specific oxidative stress related damage (10) . Melatonin plays a key role in prohibiting NF-kB activity, thus reducing the hyperinflammatory response to these respiratory viruses (13) . RSV-infected macrophages have been found to have decreased TLR3-mediated downstream gene expression when treated with melatonin (10) . Influenza A infected mice treated with melatonin were found to have decreased TNF-α producing CD8 cells in both the spleen and lungs, which can significantly reduce the severity of lung injury (14) . High dose melatonin treatment has also been found to increase the production of anti-inflammatory cytokines such as IL-10, which can further attenuate the J o u r n a l P r e -p r o o f inflammatory response produced by lung infection with these viruses. Additionally, RSVinfected mice treated with melatonin were found to have a reduction in acute lung oxidative injury due to suppressed production of malondialdehyde, nitric oxide, and hydroxyl production along with increased lung levels of antioxidants glutathione peroxidase and superoxide dismutase.

Data from murine models suggests that melatonin also has protective effects against Ebola virus which causes severe vascular endothelial damage resulting in multi-organ hemorrhage. These dangerous effects are due to a large increase in inflammatory chemokines and cytokines such as TNF-α, IFN-α, IL-6, IL-8, tissue factor, and MCP-1 that cause coagulation irregularities and fibrinolysis (7) . Melatonin attenuates this cytokine storm and neutralizes ROS associated with viral infection, while increasing natural killer cell activity, IFN gamma response, and TH1 produced cytokines (5) to combat the viral mechanism of Ebola.

Furthermore, melatonin interferes with Ebola replication ability via the induction of the antiinflammatory enzyme heme oxygenase-1 (5) . As a result, melatonin decreases pro-inflammatory processes, induces endogenous antioxidants, neutralizes ROS associated with viral infection, and improves mitochondrial functioning thus preventing damage to endothelial barriers that lead to septic shock and disseminated intravascular coagulation (5, 15, 16) . Data from patients with similar hemorrhagic fevers show that patients had significantly decreased plasma melatonin levels than the control group, suggesting that melatonin plays a protective role in these diseases (17) (18) (19) (20) .

Furthermore, melatonin has been tested as a treatment of encephalitis-causing viral diseases of animal models such as rabbit hemorrhagic disease virus (21) (10, (26) (27) (28) (29) . Melatonin was found to significantly decrease blood viral load, reduce mortality rate, and decrease disease severity (10) . Diminished anti-inflammatory response is likely due to melatonin-induced downregulation of CNS TNF-a (30) . TNF-a alters blood brain barrier permeability, increases intercellular adhesion molecules, and augments lymphocyte recruitment to the CNS. Increased levels of the cytokine IL-1B is also thought to be a key player in the protective role of melatonin against the CNS infiltrating viruses (25, 31) . Possible protective mechanisms include increased neuronal support and nerve growth factor secretion by astrocytes. Melatonin administration not only reduced the mortality rate from these viruses, but also significantly postponed onset of disease (10), providing further evidence of melatonin use as treatment in a number of viral diseases. There is some research concerning the effects of melatonin on retroviruses such as HIV and murine model retroviruses such as LP-BM5 and Ts1, though these do not seem to have many pertinent similarities to COVID-19 (32) (33) (34) (35) .

Viral infection with SARS-CoV-2 can cause severe inflammatory responses and oxidative stress; the use of melatonin may be able to attenuate some of these reactions. SARS-CoV-2 enters alveolar epithelial cells via ACE2, facilitated by the S1 and S2 subunits of the S spike protein on the virus (36) . S1 allows attachment to ACE 2, while S2 mediates fusion of the virus with the cell membrane (37) . Calmodulin regulates the surface expression and retention of ACE2 in the plasma membrane. Melatonin indirectly inhibits coupling of ACE2 with SARS-CoV-2 during viral particle fusion through its inhibition of calmodulin (38) . Viral RNA released into the cytosol results in translation of the viral genome and production of new viral particles.

Cleavage of the viral polyproteins is facilitated by the main SARS-CoV-2 protease, known as chymotrypsin-like-protease, which is inhibited by melatonin. (38) .

There are thought to be "two hits" to the renin-angiotensin-aldosterone system that drive COVID-19 progression. Binding of SARS-CoV-2 to ACE2 results in formation of angiotensin II and blunts protective effects of Angiotensin 1-7. Angiotensin 1-7 is a vasodilatory peptide that normally provides anti-inflammatory, antioxidant, and anti-fibrotic effects. Angiotensin II binds to AT1R, which leads to downstream activation of NF-kB signaling, widespread vasoconstriction, and IL-6 production (39). The combined effects of increased angiotensin II and It is thought that SARS-CoV-2 causes severe lung pathology by inducing pyroptosis, which is a highly inflammatory form of programmed cell death (6) . Pyroptosis of lymphocytes leads to lymphopenia, thus blocking an effective immune response to the virus. Additionally, SARS-CoV-2 triggers the innate immune system receptor known as the 'inflammasome', and causes inflammation (41) . A viral protein created by SARS-CoV-2 directly interacts with inflammasome NLRP3 at the peak of infection, resulting in disruption of the host cell membrane and the inflammatory release of cell content (6) . Activation of NLPR3 also induces proinflammatory cytokines such as IL-1B and IL-18. Melatonin acts as an inhibitor of the NLRP3 inflammasome, inhibiting pyroptosis, and ultimately exerting an anti-inflammatory effect (6).

SARS-CoV-2 infection involves induction of a "cytokine storm," in which IL-1B, IL-6, IL-17, CRP, and TNF-a are upregulated due to an increase in the activation of neutrophils, macrophages, and mast cells (42, 43) . Melatonin has been shown to inhibit NF-kB signaling, J o u r n a l P r e -p r o o f downregulate iNOS and COX-2, and inhibit TLR4 activation; this inactivation of TLR4 leads to decreased levels of IL-1b, IL-6, IL-8, and TNF-a (44) . Hyperinflammatory monocytes and macrophages gather in the respiratory tract during the infection, playing a large role in exacerbating the disease. They reprogram their metabolism from mitochondrial oxidative phosphorylation to cytosolic anaerobic glycolysis for ATP production (36) , resulting in increased cytokine production, T cell destruction, and ultimately destruction of alveolar cells lining the respiratory epithelium (38) . Melatonin exerts anti-inflammatory effects through reduction of proinflammatory cytokines, inhibition of NF-kB, and elevation in anti-inflammatory cytokines such as IL-10. It also converts the hyperinflammatory glycolytic macrophages mentioned above to anti-inflammatory macrophages that undergo oxidative phosphorylation, further downregulating cytokine production. Additionally, melatonin activates the sirtuin-1 protein, which inhibits production of hyperinflammatory macrophages (38) .

Furthermore, once inside the cell, SARS-CoV-2 begins damaging oxidative effects beginning with the recognition of its PAMPs by pattern recognition receptors located on host mitochondria and subsequent interaction with mitochondrial antiviral-signaling (MAVS) protein to initiate antiviral cascades resulting in excessive ROS production (3, 45) . The uncontrolled release of mitochondrial ROS leads to epithelial cell damage and induces neutrophils, macrophages, and monocytes to release their own ROS as part of the adaptive immune response (3) . Melatonin exerts its antioxidative properties against SARS-CoV-2 through direct scavenging of oxygen and nitrogen-based free radicals, suppression of pro-oxidant enzymes, maintenance of mitochondrial homeostasis, and stimulation of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GSH), and catalase (3, (46) (47) (48) (49) . Through its antioxidant properties, it has also been found to regulate endoplasmic reticulum stress, autophagy, and J o u r n a l P r e -p r o o f apoptosis (50) . Melatonin has been shown to reduce acute lung oxidative injury by suppression of ROS and restoration of GSH and SOD levels in the lungs of RSV infected mice (14, 51) .

The damaging consequences of ROS on the functions of both pulmonary and red blood cells (RBC) are a major contributor to the hypoxic respiratory failure that are seen in the most severe cases of SARS-CoV-2. Excessive ROS production may impact membrane lipids, integrins, and cytoplasmic proteins in circulating cells. One of the most prominent effects is on RBCs, which have a significant modification of their lipids that disturbs both the diffusion of gases and the RBC malleability in the capillary bed. These changes favor a thrombotic state, negatively influencing adequate oxygen transport and vasodilatation (52) . Melatonin counteracts ROS damage by stabilizing the inner mitochondrial membrane and activating the electron transport chain to improve mitochondrial respiration and ATP production, ultimately reducing electron leakage and ROS generation (46) .

The combination of the anti-inflammatory and antioxidative properties of melatonin provides a possible treatment for SARS-CoV-2 due to its effects on all stages of its life cycle including cell entry, viral replication, and deleterious downstream signaling cascades as shown in figure 1. Melatonin is evidenced to intervene at each level to support the host's immune system and suppress a harmful overreaction.

By inhibiting calmodulin and chymotrypsin-like protease, melatonin decreases viral entry and replication in the host (38) . Melatonin attenuates systemic inflammation and the onset of ARDS by increasing SIRT-1 activity, while inhibiting the NRLP3 inflammasome, TLR4 and subsequent NF-B signalling, and COX-2 and iNOS expression (6, 44) . Melatonin also acts to protect the lungs by inhibiting angiotensin II and facilitating angiotensin 1-7 activity (40) . To reduce J o u r n a l P r e -p r o o f oxidative stress caused by SARS-CoV-2, the compound can scavenge ROS and RNS while increasing SOD, GSH, and catalase activity (3, 46, 47) .

Given the information presented here, melatonin has plausible benefits of reducing inflammation and possibly curbing the cytokine storm caused by SARS-CoV-2. Melatonin recommended early in the course of infection could provide benefit at relatively low cost and a tolerable safety profile. Although melatonin acts to fight early viral replication, the use of melatonin in COVID-19 patients is not meant to be used as a cure, but instead as an agent that equips the body to better fight viral infection. This is demonstrated by the fact that in cases where the immune system is suppressed, melatonin has been found to stimulate the immune system, and in cases where there is inflammation, it has been found to show an immunosuppressive effect (53) . In the case of COVID-19, reduction of the long-lasting inflammatory and oxidative effects of the virus by melatonin allows the patient's own immune system to properly respond to infection and recover more efficiently with a reduced recovery time (54) .

Melatonin is best paired with an antiviral for an enhanced healing of a COVID-19 patient and may be best used as chronotherapy in COVID-19 patients (55) . Synergistic use of both melatonin and antivirals, such as Ribavirin (14) and Acyclovir (56) , was found to be more effective than treatment with only the antiviral . In addition, a single blind randomized study showed a higher percent of a complete regression of HSV-1 symptoms after melatonin treatment with antivirals compared to acyclovir alone (10) . Auxiliary treatment of melatonin with an antiviral has proven to be beneficial in other viruses and may be effective with COVID-19.

Furthermore, melatonin has been shown to provide protective functions when used with toxic J o u r n a l P r e -p r o o f pharmacological therapies (57) . Because of melatonin's ability to enhance drug efficacy and reduce toxicity, it seems apparent that it should be used alongside other treatments for COVID-

Currently, there are no published results from a clinical trial using melatonin as a treatment for COVID-19; however, our search provided two protocols for double blind, randomized clinical trials utilizing melatonin dosages of 5mg twice daily by oral capsule for 7 days (58) and 5mg per kg of bodyweight intravenous every 6 hours for 7 days (59). In addition, clinicaltrials.gov currently lists 6 ongoing studies (NCT04474483, NCT04784754, NCT04409522, NCT04530539, NCT04353128, NCT04470297) using melatonin as treatment in COVID-19 patients for both intensive care unit patients and outpatients (60) (61) (62) (63) (64) (65) . Although these studies will give insight into the effectiveness of melatonin in COVID-19, they do not focus on starting treatment as early as the day of diagnosis. In addition, an argument has been made that the treatment of COVID-19 with melatonin can be used before clinical trials have been conducted due to the urgency of the pandemic and the safety profile of melatonin (66) .

Melatonin is available over the counter with indications for jet lag, nicotine withdrawal, winter depression, tardive dyskinesia, chemo-related thrombocytopenia, and insomnia. The side effect profile remains relatively benign (67) . Most commonly reported side effects are defined as drowsiness and decreased alertness. Studies in both human and animals considered it safe for short term use even in extreme doses (68) and a dose of 3-10 mg/day demonstrated acceptable safety level in clinical trials (69) (70) (71) (72) . In adults, possible side effects of melatonin include transient dizziness, hypotension, nightmares, and abdominal pain. Administration for preterm infants, children, and adolescents in various diseases has shown no side effect except at high doses (73) . Caution should be given in patients on multiple medications due to potential J o u r n a l P r e -p r o o f unknown interactions (74) . Caution should also be made in patients taking a medication that can inhibit cytochrome P450, since it is mainly metabolized by this enzyme (75, 76) .

Those who are at highest risk for developing severe cases of COVID-19 should receive treatment as quickly as possible. The current paper argues that melatonin would be a cheap, safe, and effective first-line treatment for COVID-19, especially in higher-risk populations. The Centers for Disease Control and Prevention identifies patients with the following conditions as the most at risk for developing severe cases of COVID-19: cancer, chronic kidney disease, chronic obstructive pulmonary disease, heart conditions such as heart failure, coronary artery disease, cardiomyopathies, obesity, pregnancy, sickle cell disease, type 2 diabetes mellitus, a history of smoking, and a history of solid organ transplantation (77, 78) . For those at high risk, melatonin can be quickly and easily administered to reduce the severity of COVID-19 in these populations.

Our recommendation is to administer melatonin at 2.5mg-10mg nightly to all adults diagnosed with SARS-CoV-2 as early as the first day of diagnosis, especially for those at increased risk for morbidity or mortality. 

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