What Is Melatonin? | Everyday Health

Medically Reviewed

Can’t sleep? Melatonin supplements may help, but it’s important to understand how the hormone works and the potential side effects.Marc Tran/Stocksy

Can’t sleep? You’re not alone. The number of Americans who regularly use melatonin as a sleep aid has quadrupled over the past 20 years, according to a study published July 27, 2022, in JAMA.

Quality sleep is definitely a cornerstone of good health, and melatonin, a hormone produced by our bodies, has long been thought of as a natural way to get through a restless night. Like all supplements, however, synthetic melatonin, which comes in pills, gummies, and other forms and is even marketed toward children, is not regulated by the U.S. Food and Drug Administration (FDA). Sleep experts are wary of the increasing reliance on melatonin supplements as a sleep aid, especially given the lack of rigorous research on the hormone’s long-term side effects.

Read on to learn what is known about melatonin supplements, how they work, potential side effects, and more.

What Exactly Is Melatonin?

Melatonin is a natural hormone produced by the pineal gland, according to the book Physiology of the Pineal Gland and Melatonin. This gland is located near the middle of the brain, and for the most part, remains relatively inactive — until you’re ready to sleep. Melatonin is a unique hormone because it’s released only in the dark, to prepare your body for sleep. Typically, melatonin levels increase in the bloodstream about two hours before bed, according to Johns Hopkins Medicine. This causes a sleepy feeling, resulting in a restful night.

Common Questions & Answers

Is it safe to take melatonin?

Melatonin is generally considered safe for short-term use. But more research needs to be done on its long-term use. Dietary supplements like melatonin are regulated by the FDA.

Does melatonin cause side effects?

Possible side effects of melatonin include irritability, drowsiness, nausea, diarrhea, and headache. Melatonin has been known to worsen depressive symptoms.

Can you overdose on melatonin?

Yes, it is possible to overdose on melatonin. The symptoms of an overdose resemble common side effects, but may also include tremors, low body temperature, and low blood pressure.

How do you take melatonin?

Melatonin comes in different forms. Oral forms include gummies, pills, liquid, chewables, and capsules. You can also purchase melatonin sprays, powder, patches, and creams.

Do you need a prescription for melatonin?

No. Melatonin is available in the United States without a prescription. You can find melatonin supplements at grocery stores, pharmacies, and health food stores.

What Affects Melatonin Production?

Most people produce enough melatonin to fall asleep and stay asleep with no problem, according to Johns Hopkins Medicine. But some people don’t produce enough, and melatonin levels can change over time and for different reasons.

It is believed that melatonin levels decrease with age, even in otherwise healthy people, per the Mayo Clinic. In people with sleep disorders that affect their circadian rhythms and interfere with the timing of sleep (such as delayed sleep phase syndrome), melatonin production may play a role.

Some everyday habits can also affect melatonin production. Sleeping in less than complete darkness is one factor that contributes to sleep problems, says Carolyn Dean, ND, MD, the author of 365 Ways to Boost Your Brain Power: Tips, Exercise, Advice. Also, blue light emitted from your phone or TV too close to bedtime can interrupt your circadian rhythm and suppress your melatonin production, per the American Sleep Association (ASA).

It’s also important to make sure you get enough of what Dr. Dean calls “the sleep mineral,” magnesium. “Magnesium facilitates sleep-regulating melatonin production, and studies have shown that magnesium helps you get a deep and restful sleep,” she says. “Magnesium also relieves muscle tension that can prevent restful sleep.”

Some research supports these claims. Past research found that in a group of elderly adults with insomnia, those who took magnesium supplements showed a significant increase in melatonin levels compared with those who didn’t take a supplement. Other research has shown that magnesium blocks calcium (which makes muscles contract) to help muscles relax.

If your body doesn’t produce enough melatonin naturally, your doctor may recommend a supplement with synthetic melatonin.

What Are Melatonin Supplements?

Oral forms of synthetic melatonin include melatonin gummies, pills, liquids, chewables, and capsules. You can purchase the hormone in other forms, too, including melatonin sprays, powder, patches, and creams, all of which are available in grocery stores, pharmacies, and health food stores. Melatonin supplements are marketed to help with sleep and jet lag.

As pointed out by the JAMA study, many melatonin users regularly take doses higher than the maximum recommended 5 milligrams (mg) per night. This is particularly concerning in regard to children. A report published in June 2022 by the Centers for Disease Control and Prevention (CDC) examined data between the years 2012 and 2021 and found that poison control had fielded 260,435 calls about kids who had taken too much melatonin. Of those, two children under the age of 2 died, five were put on a ventilator, nearly 300 ended up in intensive care, and more than 4,000 were hospitalized.

Part of the problem may be that there is “no general consensus” regarding melatonin dosage, according to the aforementioned book. Recommended dosages vary by brand, and can range from 0.3 to 10 mg, per the The Sleep Doctor. Low doses (from 0.1 to 0.3 mg) may be used for circadian rhythm synchronization, while sleep disorders may require doses ranging from 0.6 to 5 mg.

It’s important to speak to a qualified healthcare provider about the correct dosage for yourself, or for a child who has sleep issues because of a developmental or neurological problem.

Does Melatonin Help You Go to Sleep?

The melatonin your body produces is instrumental in helping you fall asleep. Melatonin supplements are often seen as a more natural way than prescription medications to help you drift off.

Although melatonin supplements are widely used for that purpose, they do not function the same way sleeping pills do. If you take a sleeping pill, you may fall asleep within 8 to 20 minutes of ingesting the medicine, reports the Cleveland Clinic. Melatonin supplements send a signal to the brain that it’s time to sleep, and your brain then signals your body to prepare for sleep (which usually takes up to 40 minutes, the Cleveland Clinic says.

Keep in mind that chronic issues with sleep might be caused by something other than an inability to produce melatonin naturally, such as poor sleep hygiene, caffeine and alcohol consumption, night-shift work, and recent travel.

Learn More About Melatonin Supplements and Sleep

Potential Health Benefits of Melatonin

Melatonin’s main use is as a natural remedy for helping reset a disrupted sleep schedule. But it’s thought to be beneficial for issues other than sleeplessness. While more research is needed to understand the effects of the hormone, the supplement may help with the following conditions.

Cancer

A review published in May 2021 in Molecules found that melatonin had therapeutic anticancer effects against colorectal, breast, gastric, prostate, ovarian, lung, and oral cancers. It was found to mediate cell death, boost the immune system, and improve patient sleep and quality of life.

Alzheimer’s Disease

Alzheimer’s is characterized by the extracellular accumulation of amyloid-beta (Aβ) plaques and the formation of intracellular neurofibrillary tangles (NFT), and melatonin has been found to reduce both, along with reducing oxidative stress and neuroinflammation in both cell and animal studies, per review published in April 2022 in Frontiers in Neuroendocrinology. Additional research in humans is still needed.

Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s disease)

A retrospective analysis published in January 2021 in Muscle & Nerve that looked at ALS patients in a large database found an association of slower ALS progression in those who took melatonin. The study authors stated that the results are merely preliminary, and further research is needed before any causal relationships can be inferred.

Nighttime High Blood Pressure

Past research found that repeated bedtime melatonin intake significantly reduced sleep blood pressure rates in males with untreated hypertension.

Irritable Bowel Syndrome

Research says melatonin is likely useful in mediating pain thresholds in those with IBS, but more studies are warranted.

Reproductive Issues

A study published in September 2019 in Antioxidants found that melatonin supplementation slightly enhanced in vitro fertilization success rates in women with unexplained infertility. The study was very small, however, with just 40 participants, and the study authors stated that “before a definite recommendation is made on the use of melatonin in women with [unresolved infertility], larger clinical studies in populations with different backgrounds need to be performed.”

COVID-19

The authors of a study published in April 2020 in International Reviews of Immunology reported that melatonin may reduce the severity of COVID-19, as it can inhibit programmed cell death, decrease inflammation in the lungs, and improve sleep and anxiety and therefore immunity. It’s also known to prevent fibrosis, one of COVID-19’s most dangerous complications.

What Are the Possible Side Effects of Melatonin?

Melatonin is a dietary supplement, and dietary supplements are not regulated or approved by the FDA. The FDA is, however, aware that dietary supplements can contain ingredients that conflict with a prescription medicine or a medical condition you may have, which is why they recommend consulting a doctor before taking one. According to MedlinePlus, melatonin may produce a moderate reaction when taken with birth control pills, some prescription drugs used for diabetes, high blood pressure, certain sedatives, and more. Consult your healthcare provider before taking melatonin if you are on any prescription medications.

Melatonin on its own can also cause side effects if you’re sensitive to the supplement. According to National Capital Poison Center, side effects vary, but include:

• Irritability
• Drowsiness
• Nausea
• Diarrhea
• Headache

Side effects don’t always mean that you should stop taking melatonin. The decision to stop will depend on the severity of your side effects, and whether they improve or continue. If, for example, you take melatonin and repeatedly experience cramps or diarrhea the next day, you might be sensitive and want to consider other options for better sleep, perhaps chamomile tea or lavender oil, which has been shown to calm the nervous system.

To reduce the likelihood of side effects, it can help to start with a low dose of melatonin and increase your dose as needed. Consult your healthcare provider for information on exact dosages, and if you can, bring the specific supplement you will be taking because many brands of synthetic melatonin contain 5 to 10 mg per serving, which is more than what adults often need to regulate their sleep cycle.

“You should disclose all your medicines to your doctor or pharmacist prior to taking melatonin to assure there’s no potential interaction,” says Chrisoula Politis, MD, the director of sleep medicine at Mercy Medical Center in Rockville Centre, New York.

Learn More About the Potential Side Effects of Melatonin

Who Should Not Take Melatonin?

Generally speaking, melatonin supplements are safe for most adults, although its use should be avoided in anyone who is pregnant or breastfeeding, says Dr. Politis. The effects of melatonin in those instances are understudied, and although the limited available research has found no adverse effects, per the Drugs and Lactation Database, further research is needed.

Melatonin can also cause an inflammatory response in the body in certain patients, so the Mayo Clinic recommends that people who have certain autoimmune diseases not take it. Some newer studies do not support this claim, however, so it’s best to discuss it with your healthcare provider.

While it is generally agreed that melatonin supplements can be effective in the short-term, the National Center for Complementary and Integrative Health (NCCIH) says information on its long-term side effects and how long one can safely take it is lacking. Because of that lack of information and fears of long-term side effects, researchers behind the JAMA study recommend avoiding long-term sleep aid use before you try other approaches, like changing sleep hygiene, CBT for insomnia, and other stress management approaches.

If you have difficulty going to sleep or staying asleep and still want to try melatonin, one approach is to take melatonin for a couple of nights or weeks, and then stop taking the supplement for a few days to see if your sleep improves. If not, see your primary healthcare provider or a sleep specialist to rule out a disorder.

Can You Overdose on Melatonin?

Melatonin is generally safe when used responsibly, but it is possible to overdose. The symptoms of an overdose can mimic those of common side effects, including moderate to severe diarrhea, tremors, low body temperature, or low blood pressure, according to the National Capital Poison Center.

Research has found that taking too much melatonin may also put you at risk for rebound insomnia, which is essentially the inability to sleep without it. So instead of melatonin helping to reset your sleep cycle, too much in your system may actually make your sleep problems worse. Too much melatonin can also lead to increased sleep inertia, which is that groggy transitional phase between waking up and actually feeling awake, per a review published in October 2017 in Sleep Medicine Reviews. In a perfect world, you should be able to take melatonin at night, sleep through the night, and wake up feeling refreshed. The opposite can happen if you overdose. Instead of waking up alert, you may have a hungover feeling.

Be mindful that sleep inertia can also occur if you take melatonin too late at night. If you take the supplement, allow for at least seven hours of sleep and don’t operate heavy machinery until you know how you’re affected, says Politis. If you take too much, medical attention isn’t always necessary. You’ll feel uncomfortable, but symptoms should gradually improve as the amount of melatonin in your bloodstream decreases, per the National Capital Poison Center.

The exception is if you have more severe symptoms, like low blood pressure. This is a dangerous complication of too much melatonin. See a doctor immediately to stabilize your health. Signs of low blood pressure include lack of concentration, blurry vision, and fainting, per the Mayo Clinic.

Learn More About the Risks of Overdosing on Melatonin

Summary

Melatonin can be helpful when you have trouble going to sleep or staying asleep in the short term. Better sleep hygiene, like dimming the lights at night and avoiding stimulating activities before bed, can help your body produce melatonin naturally.

If these measures don’t work, oral melatonin supplements or another form of the hormone might provide the restful sleep you need with minimal side effects. Just make sure to speak to your healthcare provider about how much to take and any potential side effects before you use it long-term.

Additional reporting by Kayla Blanton.

Editorial Sources and Fact-Checking

• Kuehn B. Climbing Melatonin Use for Insomnia Raises Safety Concerns. JAMA. July 2022.
• Aulinas A. Physiology of the Pineal Gland and Melatonin. Endotext. 2000.
• Melatonin for Sleep: Does It Work? Johns Hopkins Medicine.
• Melatonin. Mayo Clinic. March 3, 2021.
• The Dangers of Blue Light. American Sleep Association.
• Djokic G, Vojvodić P, Korcok D, et al. The Effects of Magnesium – Melatonin – Vit B Complex Supplementation in Treatment of Insomnia. Open Access Macedonian Journal of Medical Sciences. August 2019.
• Potter JD, Robertson SP, Johnson JD. Magnesium and the Regulation of Muscle Contraction. Federation Proceedings. 1981.
• Lelak K, Vohra V, Neuman MI, et al. Pediatric Melatonin Ingestions — United States, 2012–2021. Centers for Disease Control and Prevention. June 2022.
• Melatonin: Dosage, Reviews & Safety. American Sleep Association.
• Sleeping Pills. Cleveland Clinic. April 27, 2021.
• Melatonin: How Much Should You Take? Cleveland Clinic. March 14, 2022.
• Talib WH, Alsayed AR, Abuawad A, et al. Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities. Molecules. May 2021.
• Roy J, YinWong K, Aquili L, et al. Role of Melatonin in Alzheimer’s Disease: From Preclinical Studies to Novel Melatonin-Based Therapies. Frontiers in Neuroendocrinology. April 2022.
• Bald EM, Nance CS, Schultz JL. Melatonin May Slow Disease Progression in Amyotrophic Lateral Sclerosis: Findings From the Pooled Resource Open-Access ALS Clinic Trials Database. Muscle & Nerve. January 2021.
• Scheer FAJL, Van Montfrans GA, Van Someren EJW, et al. Daily Nighttime Melatonin Reduces Blood Pressure in Male Patients With Essential Hypertension. AHA Journals. January 2004.
• Ho Siah KT, Min Wong RK, Yu Ho K. Melatonin for the Treatment of Irritable Bowel Syndrome. World Journal of Gastroenterology. March 2014.
• Espino J, Macedo M, Lozano G, et al. Impact of Melatonin Supplementation in Women With Unexplained Infertility Undergoing Fertility Treatment. Antioxidants. September 2019.
• Shneider A, Kudriavtsev A, Vakhrusheva A. Can Melatonin Reduce the Severity of COVID-19 Pandemic? International Reviews of Immunology. April 2020.
• Dietary Supplements. U.S. Food and Drug Administration.
• Melatonin Potential Uses and Benefits. National Capital Poison Center.
• Hossein Koulivand P, Khaleghi Ghadiri M, Gorji A. Lavender and the Nervous System. Evidence-Based Complementary and Alternative Medicine. March 2013.
• Melatonin. Drugs and Lactation Database. National Library of Medicine. July 18, 2022.
• Melatonin: What You Need to Know. National Center for Complementary and Integrative Health. July 2022.
• Roehrs T, Vogel G, Roth T. Rebound Insomnia: Its Determinants and Significance. American Journal of Medicine. March 1990.
• Trotti LM. Waking Up Is the Hardest Thing I Do All Day: Sleep Inertia and Sleep Drunkenness. Sleep Medicine Reviews. October 2018.
• Low Blood Pressure (Hypotension). Mayo Clinic.

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Can’t sleep and looking for a nonhabit-forming sleep aid?

It’s not unusual to deal with insomnia from time to time. You may have difficulty falling asleep. Or if you’re able to fall asleep quickly, you may wake up after two or three hours. This can cause daytime sleepiness, irritability, and decreased productivity.

One night of bad sleep might not wreak too much havoc on your body. But when the problem goes on for days, weeks, or months, supplementing with melatonin can get your sleep back on track.

Melatonin is a hormone that your body makes naturally. Your melatonin level increases a couple of hours before bedtime, which signals your body to prepare for rest. (1) It’s important to note, however, that melatonin isn’t a sleep initiator but rather a sleep regulator, explains Carolyn Dean, MD, a sleep expert and author of 365 Ways to Boost Your Brain Power: Tips, Exercise, Advice.

Some people, however, don’t produce enough melatonin. And as a result, sleep doesn’t come easily. But while melatonin is a natural hormone that can help reset your circadian clock, oral melatonin isn’t right for everyone. (2)

What Are Melatonin Side Effects?

Melatonin needs vary from person to person. On average, most people need less than 3 milligrams (mg) per night to sleep better. Yet some people take more. (3)

Melatonin is generally safe for short-term use of one to two months in most healthy adults. But some people are more sensitive to the oral hormone and experience side effects. Adverse effects tend to occur with long-term use or when a person takes too much. (2,4)

Possible side effects of oral melatonin include: (1,3,5)

• Headache A mild to moderate headache can indicate that you’ve taken too much or that your body is sensitive to oral melatonin.
• Stomach Problems Melatonin also causes stomach discomfort in some people. This may include cramps, nausea, and diarrhea.
• Dizziness Some people who take melatonin also report mild dizziness, lightheadedness, or vertigo.
• Irritability Too much melatonin can also affect mood. You may feel cranky, anxious, or have periods of depression.
• Drowsiness Even though melatonin doesn’t usually cause a “hangover effect,” some people do experience daytime drowsiness. This can reduce alertness and make it difficult to drive or operate machinery. If you take melatonin, wait at least five hours before operating machinery. Keep in mind that some medication may intensify drowsiness, such as depressants and selective serotonin reuptake inhibitors. (1)
• Low Blood Pressure Sometimes, melatonin causes abnormally low blood pressure. Melatonin side effects are usually mild. (6) However, untreated low blood pressure can lead to life-threatening complications. Low blood pressure means that your body can’t carry enough oxygen to your organs. This can affect heart and brain function. Symptoms of low blood pressure include dizziness, fainting, blurry vision, confusion, and fatigue. (7)

If you experience mild side effects of oral melatonin, reduce your dosage to see if symptoms improve. Talk with your doctor about your dosage if your symptoms persist or worsen. Everyone’s body is different. So while one person may be able to tolerate 3 mg of melatonin a night, another person may be able to tolerate only 1 mg.

Melatonin for Children

Adults aren’t the only ones with acute or chronic sleep problems. Melatonin is also safe for children who have difficulty sleeping due to insomnia, circadian rhythm disorders, attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD), autism, and other neurological disorders.

Dosing for children varies. Some children may need only 1 to 3 mg a night, whereas a child with ADHD or autism may need 3 to 6 mg per night. But because oral melatonin is a supplement and is not regulated by the U. S. Food and Drug Administration, experts caution that parents should consult with a doctor before allowing children and adolescents to try melatonin. (10,11)

Your doctor can help you understand whether melatonin is right for your child and review the risk of side effects. “Side effects reported for children include nausea, diarrhea, headaches, changes in mood, sleepiness the next day, and bed-wetting,” notes Dr. Dean.

Who Shouldn’t Take Melatonin?

Some herbal and dietary supplements can interact negatively with prescription medication, and melatonin is no exception.

Before you take this supplement to improve the quality of your sleep, speak with your doctor.

Melatonin doesn’t interact with every prescription drug, but it can make some medicines less effective, like blood pressure and seizure medication. It can also boost blood sugar and is therefore not recommended for people with diabetes, warns Dean.

The supplement can also interact with blood-thinning medication, immunosuppressants, and corticosteroids. There’s also the risk of increased drowsiness when taken with birth control pills, depressants, or selective serotonin reuptake inhibitors. (1)

If you have chronic pain due to an inflammatory disease, melatonin might seem like a safe solution for better sleep. But this supplement isn’t recommended for people who have an autoimmune disease like lupus or arthritis. (12)

Melatonin can stimulate the immune system, triggering an inflammatory response and worsening these diseases.

There is no definitive research on the safety of using melatonin during pregnancy or while breastfeeding, so experts recommend talking to your doctor if that’s something you want to consider. (13)

Melatonin is preferred by some because it’s nonhabit-forming and a natural sleep aid. But the supplement isn’t right for everyone, and side effects can occur if not taken properly.

If you experience side effects, reduce the amount you take. If symptoms continue, stop taking oral melatonin. Also, don’t forget to consult your doctor before combining melatonin with a prescription medication.

For the most part, melatonin should be used only as a short-term remedy. See your doctor or a sleep specialist if sleep problems worsen or don’t improve after a few months.

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Melatonin for COVID-19: Helping Treat the Virus

March 1, 2020 LifeSciences Journal Volume 244 Ruy Zheng, Huebing Wang, Leng Ni, Xiao Di, Baitao Ma, Ruai Niu, Changwei Liu, Russell J. Reiter

9003 3 1.Introduction

Coronaviruses (CoV) are RNA viruses that infect both human and animal; this infection affects the respiratory, gastrointestinal tract and central nervous system [1].

Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are infectious and deadly and have caused thousands of deaths over the past two decades.

Coronavirus outbreak recently occurred in Wuhan, China; this highly contagious disease has spread throughout China and other countries [2]. Although antiviral therapy, corticosteroid therapy, and mechanical respiratory support have been used, there is no specific treatment for COVID-19[2].

Melatonin ( N-acetyl-5-methoxytryptamine ) is a biologically active molecule with a number of health benefits; Melatonin has been successfully used to treat sleep disorders, delusions, atherosclerosis, respiratory diseases, and viral infections [3]. Previous studies have documented the positive effects of melatonin in relieving acute respiratory stress caused by virus, bacteria, radiation, etc. [[4], [5], [6]]. Here we review the evidence indicating that melatonin will help in the treatment of pneumonia caused by the COVID-19 coronavirus., acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) .

2. COVID-19 pathogenesis and rationale for the use of melatonin in coronavirus

Patients with COVID-19 (who have been infected with SARS-CoV-2) have been reported to have symptoms such as: fever, dry cough, myalgia, fatigue and diarrhea, etc. Patients’ symptoms vary somewhat according to their age. In some cases, severe disease progression leads to ALI/ARDS, respiratory failure, heart failure, sepsis, and sudden cardiac arrest within days [2,7]. Pathogenic examination of lung specimens in patients with mild COVID-19(who were retrospectively found to have COVID-19 during lung cancer surgery) showed edema, protein exudate with globules, focal inflammatory cell infiltrates, and moderate hyaline membrane formation [8]. In a post-mortem evaluation of a COVID-19 patient with severe ARDS, infected lung samples demonstrated bilateral diffuse alveolar injury with edema, pneumocyte desquamation, and hyaline membrane formation [9].

Although these pathological conditions have only been reported in a small number of cases, the results do indeed resemble the pathological features found in SARS and MERS pneumonia [10]. SARS-CoV, MERS-CoV and SARS-CoV-2 are classified as members of the betacoronavirus family [11]. Recent published studies show that SARS-CoV-2 has 790% nucleotide identity with SARS-CoV and 51.8% identity with MERS-CoV [12], indicating high genetic homology among SARS-CoV-2, MERS-CoV and SARS-CoV. In an animal model infected with SARS-CoV and MERS-CoV, pronounced inflammatory and immune responses can activate the “cytokine storm” and apoptosis of epithelial cells and endothelial cells; subsequently, exudation, abnormal responses of T cells and macrophages occur, which cause ALI/ARDS or even death [13].

Based on genetic homology and pathological features of the infected lung, we predicted that patients with COVID-19cytokine storm also predominates. In the blood of patients with COVID-19, there was a marked increase in interleukin 1β (IL-1β), interferon γ (IFN-γ), interferon-inducible protein 10 (IP-10), and monocyte chemoattractant protein 1 (MCP-1), as well as IL -4 and IL-10 compared with patients with SARS. This suggests some potential difference from SARS and MERS in coronavirus pathogenesis [2]. There is also potential suppressed immune function in COVID-19 patients with hypoalbuminemia, lymphopenia, neutropenia, and a reduced percentage of CD8+ T cells [2,7]. Recent reports suggest that some patients with COVID-19although their viral nucleic acid tests are negative, high levels of inflammation are still occasionally present. A clinical trial using certolizumab pegol (a TNF blocker) along with other antiviral therapies may benefit patients with COVID-19. Taken together, the findings indicate that inflammation is a core feature of COVID-19 patients. Thus, we hypothesize that excessive inflammation, a suppressed immune system, and an activated cytokine storm contribute significantly to the pathogenesis of COVID-19..

In the early stages of coronavirus infection, dendritic cells and epithelial cells are activated and express a cluster of pro-inflammatory cytokines and chemokines including IL-1β, IL-2, IL-6, IL-8, both IFN-α/β, tumor necrosis factor (TNF ), CC motif of chemokine 3 (CCL3), CCL5, CCL2, IP-10, etc. They are under the control of the immune system. Thus, overproduction of these cytokines and chemokines contributes to the development of the disease [[14], [15], [16]].

IL-10 produced by T-helper-2 (Th3) is antiviral, with infection by coronaviruses resulting in a marked decrease in this agent [17,18]. Interestingly, patients with COVID-19sometimes have significantly elevated levels of IL-10 [2]. Whether this is a sign of COVID-19 infection or the result of treatment is unknown. An increase in the inflammatory response will promote cellular apoptosis or necrosis of the affected cells, which will stimulate inflammation, accompanied by an increase in blood vessel permeability and aberrant accumulation of inflammatory monocytes, macrophages and neutrophils in the lung alveoli [19]. This vicious circle will make matters worse as the regulation of the immune response is lost and the cytokine storm is activated, with dire consequences.

This putative “cytokine storm” pathology associated with coronaviruses is also supported by experimental models of SARS-CoV, one of which showed that the severity of ALI was accompanied by increased expression of genes associated with inflammation, rather than increased virus titers. In another case, removal of the IFN-α/β-receptor or depletion of inflammatory monocytes/macrophages caused a marked increase in the survival of cells with coronavirus without changing the viral load [19,20]. Both situations suggest a potential amplifying mechanism involved in co-induced ALI/ARDS regardless of viral load. If a similar pathology also exists in COVID-19, attenuating the cytokine storm by targeting a few key steps in the process can lead to improved outcomes.

Melatonin does not have antiviral activity, but has indirect antiviral activity [3] due to its anti-inflammatory, antioxidant and immunostimulatory properties [[21], [22], [23], [24]]. There are situations in which melatonin suppresses the symptoms of viral infections. In mice whose central nervous system is infected with a virus (eg, encephalitis), melatonin use caused less viremia, decreased paralysis and death, and reduced viral load [25]. In previous models of respiratory syncytial virus, melatonin caused the suppression of acute oxidative lung injury, the release of pro-inflammatory cytokines, and the return of inflammatory cells to control. These results, as well as those recently summarized by Reiter et al. [3], substantiate the use of tablets with this hormone in viral diseases. In addition, the anti-inflammatory, antioxidant, immune-boosting effects of melatonin support its potential to attenuate COVID-19 infection.(Fig. 1).

Fig. 1. COVID-19 pathogenesis and potential adjuvant use of melatonin in coronavirus. We postulated that lungs infected with SARS-CoV-2 and suppressed immune response, increased inflammation and excessive oxidative stress proceed unabated, leading to the activation of a cytokine storm. ALI/ARDS can occur with a range of complications, the outcomes of which vary depending on the severity of the disease. Melatonin may play an adjuvant drug role in the regulation of the immune system, inflammation and oxidative stress and provide support to patients with ALI/ARDS and related complications. ALI: Acute lung injury; ARDS: acute respiratory distress syndrome.

3. Melatonin and anti-inflammatory effects

Melatonin exerts anti-inflammatory effects in various ways. Sirtuin-1 (SIRT1) can mediate the anti-inflammatory action of this hormone by inhibiting the high motility group 1 protein (HMGB1) and thus suppressing macrophage polarization towards the pro-inflammatory type [26]. In sepsis-induced ALI, proper regulation of SIRT1 attenuates lung injury and inflammation, in which the use of this drug may be beneficial [27].

Nuclear factor kappa-B (NF-κB) is closely associated with pro-inflammatory and pro-oxidant responses, being an inflammatory mediator in ALI. The anti-inflammatory action of melatonin includes suppression of NF-κB activation in ARDS [28, 29]. This drug is reported to suppress NF-κB activation in T cells and lung tissues [30,31]. Stimulation of NF-E2-related factor 2 (Nrf2) is critical for protecting the lungs from injury. In related studies, melatonin induces Nrf2 activation with therapeutic effects in hepatoprotection, cardioprotection, etc. [32]. The involvement of Nrf2 in CoI-induced ALI remains unknown, but the close interaction of SIRT1, NF-κB, and Nrf2 suggests their involvement in CoV-induced ALI/ARDS. Thus, the data support the potential anti-inflammatory effects of melatonin. Inflammation is usually associated with increased production of cytokines and chemokines, while this hormone causes a decrease in pro-inflammatory cytokines. TNF-α, IL-1β, IL-6 and IL-8, as well as increased levels of the anti-inflammatory cytokine IL-10 [33,34]. However, there may be some concern regarding the potential pro-inflammatory effects of this hormone when used at very high doses or in immunosuppressed conditions where it may cause an increase in the production of pro-inflammatory cytokines, IL-1, IL-2, IL-6, IL-12, TNF- α and IFN-γ [35]. Conversely, in models of ALI infection, melatonin has anti-inflammatory and protective effects [6].

4.Melatonin and antioxidant effect

The antioxidant effect of melatonin interacts with its anti-inflammatory action by increasing antioxidant enzymes (eg superoxide dismutase), inhibiting pro-oxidant enzymes (eg nitric oxide synthase), and it can also interact directly with free radicals , acting as a free radical scavenger [3,4]. Viral infections and their reproduction constantly generate oxidation products. In a SARS-induced model of ALI, oxidized low-density lipoprotein production activates the innate immune response by overproduction of alveolar macrophages IL-6 via Toll-like receptor 4 (TLR4)/NF-kB signaling, thereby leading to ALI [36]. TLR4 is an innate immune system receptor and also a therapeutic target for melatonin. In models of cerebral ischemia, gastritis, and periodontitis, this hormone has a documented anti-inflammatory effect through TLR4 signaling [[37], [38], [39]]. The antioxidant effect of melatonin has also been confirmed in ILP caused by radiation, sepsis, and ischemia-reperfusion [4,40,41]. In patients with ALI/ARDS, especially when their disease progresses, and in patients treated in intensive care units (ICUs), with severe inflammation, hypoxemia on mechanical ventilation using high concentrations of oxygen, the production of oxidants locally and systemically inevitably increases [42 .43]. Accordingly, we hypothesize that excessive oxidation may also be associated with COVID-19.. Extensive research by Gitto et al. [44,45], who used tablets with this hormone to treat neonates with respiratory distress, documented the antioxidant and anti-inflammatory effects of melatonin in the lungs. Thus, it is likely that the use of melatonin will be beneficial in controlling inflammation and oxidation in subjects infected with the coronavirus.

5. Melatonin and immunomodulation

When a virus is inhaled and infects respiratory epithelial cells, dendritic cells phagocytize the virus and present antigens to T cells. Effector T cells function by killing infected epithelial cells, while cytotoxic CD8+ T cells produce and release pro-inflammatory cytokines that induce cell apoptosis [46]. Both the pathogen (CoV) and cell apoptosis trigger and enhance the immune response. Exacerbated cytokine production, over-recruitment of immune cells, and uncontrolled epithelial damage creates a vicious circle for infection associated with ALI/ARDS [47]. Clinical characteristics of the coronavirus COVID-19indicate a decrease in the level of neutrophils, lymphocytes and CD8 + T-cells in the peripheral blood [7,48]. Melatonin has a regulatory effect on the immune system and directly enhances the immune response by improving the proliferation and maturation of natural killer cells, T and B lymphocytes, granulocytes and monocytes both in the bone marrow and in other tissues [49]. In macrophages, antigen presentation is also enhanced after melatonin administration, where activation of the accessory receptor 3 antigen, MHC class I and class II was found, and where CD4 antigens were found [50].

Inflammasome NOD-like receptor 3 (NLRP3) is part of the innate immune response to lung infection. A pathogen, including a virus (CoVs has not yet been tested), triggers NLRP3 activation to increase inflammation. There is probably a balance of protective and damaging effects of NLRP3 in the lungs. Thus, in an experiment on mice, inhibition of NLRP3 at an early stage of infection increased mortality, while suppression of NLRP3 at the peak of infection caused a protective effect [51]. This supports the use of melatonin in ALI/ARDS when inflammation is most severe. The NLRP3 inflammasome has been correlated with infection-induced lung diseases, including influenza A virus, syncytial virus, and bacteria [[51], [52], [53]]. The efficacy of melatonin in regulating NLRP3 has been proven in radiation-induced lung injury, allergic airway inflammation, and oxygen-induced ALI and LPS-induced models of ALI, in which melatonin reduced macrophage and neutrophil infiltration into the lungs in ALI due to inhibition of the NLRP3 inflasomm [ 4,28,54,55].

6. Effect of melatonin on cytokine levels in humans

Although there are apparently no reports of melatonin use in patients with COVID-19, in patients with other diseases and increased levels of inflammation, the use of melatonin has shown promising results in in relation to the decrease in the level of circulating cytokines. In a randomized controlled trial, 8-week oral administration of 6 mg/day of this drug in the form of tablets caused a significant decrease in serum levels of IL-6, TNF-α and hs-C-reactive protein (hs-CRP) in patients with diabetes mellitus and periodontitis [ 56]. In another study of patients with severe multiple sclerosis, oral administration of such a hormone at a dose of 25 mg/day for 6 months also contributed to a significant decrease in serum concentrations of TNF-α, IL-6, IL-1β and lipoperoxides [57]. In the acute phase of inflammation, including during surgical stress [58], brain reperfusion [59] and coronary artery reperfusion [60], taking melatonin at a dose of 10 mg/day, 6 mg/day and 5 mg/day induced a decrease in the level of pro-inflammatory cytokines in less than 5 days. A recent meta-analysis of a total of 22 randomized controlled trials found that melatonin supplementation was associated with significant reductions in TNF-α and IL-6 levels [61]. These clinical data suggest that the use of melatonin as a supplement can effectively reduce circulating cytokine levels and could potentially also reduce pro-inflammatory cytokine levels in COVID-19 patients..

7. Melatonin and other ancillary effects

The integrity of the vascular endothelial barrier is critical for immunoregulation in the alveoli. Severe inflammation and immune responses induce apoptosis of epithelial and endothelial cells, as well as increase the production of VEGF (vascular endothelial growth factor), which increases edema and extravasation of immune cells from blood vessels. Experimental evidence suggests that melatonin mediates the suppression of VEGF in vascular endothelial cells [62]. Based on clinical reports of COVID-19, patients with severe ALI/ARDS may also be at increased risk of sepsis and cardiac arrest [2]. Published reports indicate that the use of these tablets can attenuate septic shock during NLRP3 activation [63]. In particular, melatonin may have a preventive effect against sepsis caused by kidney damage, septic cardiomyopathy and liver damage [[64], [65], [66]]. It has also been reported that taking melatonin gives good results for patients with myocardial infarction, cardiomyopathy, hypertensive heart disease, and pulmonary hypertension. This effect is probably achieved through an increase in the TLR4 activating factor [67]. In addition, this hormone provides neurological protection by reducing the inflammatory response of the brain, cerebral edema, and blood-brain barrier permeability under a number of experimental conditions [68]. In the intensive care unit, deep sedation increases mortality for a long period of time, and the use of this drug reduces the use of sedatives and the incidence of pain, agitation, anxiety [69.70]. In addition, a recent meta-analysis showed that melatonin improves the quality of sleep in patients in the intensive care unit [71]. Thus, the rationale for the use of melatonin in patients with COVID-19 is not only aimed at ameliorating the respiratory distress caused by the infection, but also overall improving and preventing patient well-being and possible complications.

8. Melatonin and safety

When considering the use of melatonin for the treatment of COVID-19the safety of taking this drug is of paramount importance. As noted earlier, short-term use of melatonin is safe even when given at high doses, and reported side effects are limited to occasional dizziness, headache, nausea, and drowsiness; in general, taking this hormone is quite safe for humans [72]. In clinical trials, oral doses of 3 mg, 6 mg and 10 mg of this drug in patients in intensive care units showed satisfactory safety compared with placebo [70,73,74]. In addition, even when melatonin was given to humans at a dose of 1 g/day for a month, there were no adverse reports of effects at such doses [75]. Finally, no side effects have been reported following the use of this agent in animal studies with ALI/ARDS [3,4,28]. Although the safety of melatonin has been confirmed in many human studies, its effect when administered to patients with COVID-19should be carefully monitored despite the very high safety profile of melatonin.

9. Conclusion

The possible beneficial effects of melatonin as adjuvant use in COVID-19 in anti-inflammatory and antioxidant regulation, in the regulation of the immune response, have been repeatedly demonstrated in models of respiratory disorders caused by infections and related complications. Melatonin has a high safety profile. Although the results of the use of melatonin in patients with coronavirus COVID-19while unclear, its use in animal models and human studies has consistently documented its efficacy and safety, and its use in patients with COVID-19 is expected to be highly beneficial.

Authors of the article

Ryui Zheng: resources, writing the original version of the article.

Huebing Wang: writing the original version of the article.

Leng Ni: article writing, reviewing and editing.

Xiao Di: visualization.

Baitao Ma: writing, reviewing and editing.

Ruai Niu: resources.

Changwei Liu: conceptualization.

Russell J. Reuter: writing, reviewing and editing.

Thank you

We thank all the doctors, nurses and researchers who are fighting the virus on the front lines of the 2019 coronavirus epidemic-nCoV. We thank everyone who has provided great and selfless support in the fight against this deadly infection. This study did not receive a specific grant from funding agencies in the public, commercial, or non-profit sectors.

Used literature

Glycine + Melatonin Evalar sublingual tab. 33 Vkusvill

The melatonin in these sublingual tablets is fortified with glycine, which additionally: – soothes, – relieves daytime stress, – promotes deeper sleep. The combination of melatonin and glycine potentiates (strengthens) their joint action1, which provides a more vivid and pronounced effect than when taking each of these components separately. The drug is easy to take: if regular melatonin needs to be taken 40 minutes before bedtime, then Glycine + Melatonin Evalar 3 mg is taken immediately before bedtime: just put the pill under the tongue, and you don’t need to plan your bedtime in advance. And when you wake up at night, it is convenient to take the medicine without getting out of bed, because it does not require drinking. Lozenges are more environmentally friendly than regular lozenges, as they do not contain any auxiliary components that are required for the coating shell. Lozenges are available without a shell. Due to the fact that melatonin and glycine are physiological for the human body, this medicine is well tolerated, does not cause addiction and the “withdrawal” syndrome. For its production of tablets, raw materials of premium quality made in Italy are used. The quality is guaranteed by the GMP3 international quality standard. Indications for use Sleep disorders. Violation of the circadian rhythm of sleep and wakefulness associated with the change of time zones; in case of violation of the light regime, including among people engaged in shift or rotational work.

Glycine + Melatonin Evalar tab. sublingual 100mg + 3mg №20 / Pharmacy

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Description

The melatonin in these sublingual tablets is fortified with glycine, which additionally: – soothes, – relieves daytime stress, – promotes deeper sleep. The combination of melatonin and glycine potentiates (strengthens) their joint action1, which provides a more vivid and pronounced effect than when taking each of these components separately. The drug is easy to take: if regular melatonin needs to be taken 40 minutes before bedtime, then Glycine + Melatonin Evalar 3 mg is taken immediately before bedtime: just put the pill under the tongue, and you don’t need to plan your bedtime in advance. And when you wake up at night, it is convenient to take the medicine without getting out of bed, because it does not require drinking. Lozenges are more environmentally friendly than regular lozenges, as they do not contain any auxiliary components that are required for the coating shell. Lozenges are available without a shell. Due to the fact that melatonin and glycine are physiological for the human body, this medicine is well tolerated, does not cause addiction and the “withdrawal” syndrome. For its production of tablets, raw materials of premium quality made in Italy are used. The quality is guaranteed by the GMP3 international quality standard. Indications for use Sleep disorders. Violation of the circadian rhythm of sleep and wakefulness associated with the change of time zones; in case of violation of the light regime, including among people engaged in shift or rotational work.