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3 Benefits of Melatonin as a Sleep Aid: How does it Work?

Written by Nattha Wannissorn, PhD | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Nattha Wannissorn, PhD | Last updated:

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The sleep hormone melatonin is essential for regulating the circadian rhythm and making sure you fall asleep. Read about the latest research and its potential benefits for sleep disorders and disturbances here.

What is Melatonin?

Melatonin is derived from the amino acid tryptophan and the neurotransmitter serotonin [1].

Melatonin has many important functions in the body, including:

  • Influences the circadian rhythm
  • Aids the immune system
  • Helps eye function
  • Reduces oxidative stress
  • Promotes sleep
  • Controls many cellular events, including synthesis of important molecules
  • Protects against radiation

The pineal gland, which is nestled in the brain, makes melatonin. The quantity of melatonin in the blood depends on the time of the day. At night there is 10 to 15 times more melatonin in the blood there is in the day, which helps people sleep [2].

Melatonin is also made by many other organs in the body, especially in the stomach [3].

If sleep is interrupted by blue light exposure at night, melatonin levels decrease drastically. In addition, melatonin levels also decrease with age [4]. However, darkness does not stimulate melatonin production. It simply permits melatonin production [5].

Melatonin, a hormone derived from tryptophan, regulates the circadian rhythm of sleep and waking. It is produced in the brain by the pineal gland and outside the brain by many tissues, including in the stomach.

Melatonin Receptors

Melatonin acts by interacting with two receptor proteins, MT1 and MT2 [6].

MT1 and MT2 receptors control different stages of sleep: MT1 controls deep sleep or REM sleep, and MT2 controls the stages of sleep preceding dreaming [6].

These receptors are present in a variety of organs and immune cells, suggesting that melatonin also controls the function of the immune system and other systems throughout the body [7].

Sleep and Circadian Rhythm

The circadian rhythm is like the body’s clock. It is a built-in function that controls biological processes in a roughly 24-hour cycle [8].

A central clock is located in the SCN of the anterior hypothalamus in the brain. It controls the body’s circadian rhythm. The circadian rhythm helps control the sleep-wake cycle, body temperature, and hormone production [8].

Light from the environment influences the signals sent from the SCN [8].

Under the control of the circadian rhythm, the pineal gland produces and secretes melatonin. Under normal conditions, melatonin is secreted during the night. During daylight, there are undetectable amounts in the blood [8].

While most scientists believe that melatonin can shift the circadian rhythm phase and entrain the circadian rhythm, this property of melatonin is controversial [5, 9].

In zebrafish mutants that lack melatonin, the fish sleeps less but still have normal circadian rhythm (based on per1B production). The same study found that melatonin induced sleep by increasing adenosine signaling in the fish’s brain [10]. These mutant fish were equally easy to wake up and slept as deep as the control fish.

Melatonin is secreted primarily at night as part of the normal circadian rhythm. However, not all scientists agree that melatonin is required for sleep.

Antioxidant Mechanism

Several health benefits of melatonin are derived from its potent antioxidant properties, both directly and indirectly.

Administration of melatonin increases the cellular production of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and γ-glutamylcysteine synthetase) [11, 4, 12], which can increase antioxidants like glutathione. These enzymes help clean up the cells, mitochondria, and bloodstream from harmful reactive oxygen species.

In addition, the melatonin molecule itself can bind to reactive oxygen species (ROS) and reactive nitrogen species (RNS), rendering them less harmful [4]. This allows melatonin to protect several tissues and organ systems from oxidative damage. Tissues that produce melatonin and rely on melatonin for this purpose include gut, ovary, testes, lens, bone marrow, and the brain [13].

Most of the molecules (metabolites) that melatonin transforms into also retain the ability to bind harmful oxygen and nitrogen species, which makes melatonin and its products highly effective protection [4].

A single molecule of melatonin may neutralize up to 10 molecules of ROSs and RNSs [14].

It also blocks an enzyme called nitric oxide synthase that produces reactive nitrogen species and causes inflammation [15].

[sh_summaryMelatonin promotes the production of antioxidant enzymes (including superoxide dismutase, glutathione peroxidase, and γ-glutamylcysteine synthetase) in target cells.[/sh_summary]

Mitochondria and Apoptosis

Mitochondria are the part of the cell that generates energy. They have their own DNA. As energy factories, they are crucial for survival. The nucleus and mitochondria are the areas that have the most melatonin [16].

Energy production by mitochondria leads to the creation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [4]. ROS and RNS damage mitochondrial DNA and proteins, rendering them unable to produce energy. This damage can also cause the mitochondria to leak, which can lead to cell death (apoptosis) [4].

Melatonin, therefore, helps with organs that are most critically dependent on the mitochondria, including the nervous system and the heart.

Mitochondrial Toxins

Several toxins that disrupt mitochondrial function can lead to symptoms of neurodegenerative diseases, and laboratory animals poisoned by these toxins are used as models to study such diseases.

Melatonin protects against oxidative damage from these toxins and helps restore normal cellular functions, including:

  • Rotenone, a toxin used to imitate Parkinson’s disease in rats [17].
  • MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), another toxin used to imitate Parkinson’s disease [18]. In mice, melatonin prevents the damage to the fat and DNA molecules in many regions of the brain after MPTP injection. It also makes many important proteins return to their normal state [19].
  • 3-NPA, which is a toxin from fungi that infects sugarcane. There have been cases of children who ate contaminated sugarcane, developing a condition similar to Huntington’s disease [20]. In rats affected by this poison, melatonin prevents nerve cell loss, corrects damaging behavior, prevents protein and fat molecule damage, and restores levels of dopamine [20].
  • Cyanide [21, 22], a highly lethal poison that causes the massive death of nerve cells and seizures, eventually leading to death. It also damages the nerve cells’ mitochondria. In mice that received cyanide injections, previous treatment with melatonin reduced the severity of seizures caused by the poison [21]. Melatonin also protects the damage to mitochondrial DNA caused by potassium cyanide in mice and in culture [22].
Melatonin’s antioxidant-promoting activity protects against oxidative damage from energy production byproducts in the mitochondria. In animals and cells, it has also protected against oxidative damage from other toxins.

Inflammation and Immune Function

Melatonin receptors are present in a wide variety of immune cells [7]. It is immunomodulatory, which means that it reduces excessive immune function in inflammatory conditions and enhances immune function in immunocompromised people.

Melatonin can reduce the production of inflammatory cytokines including IL-6, IL-8, and TNF-alpha [23].

In addition, by reducing free radicals in the microglial (immune cells that are specific to the brain), melatonin can reduce brain inflammation by reducing NF-kB [24].

In humans and rodents, melatonin can promote healthy immune responses, and reverse the suppression of the immune system due to aging, steroid medications, lead and chemical exposures [25].

Many immune cells have melatonin receptors which, when activated, can reduce the production of inflammatory compounds.

Benefits of Melatonin

Melatonin has been studied most in the context of insomnia and other sleep disorders because of its central role in falling (and staying!) asleep. That being said, there’s plenty we still don’t know about it, and the FDA has not approved melatonin for any medical use or health claim, up to and including sleep disorders.

Melatonin may have a role in certain people’s health management strategies, but it’s important to talk to your doctor before supplementing.

Likely Effective For

1) Delayed Sleep Phase Syndrome

Melatonin regulates the sleep-wake cycle [2].

In patients with insomnia, melatonin concentration is significantly lower compared to people with normal sleep [26].

Melatonin induces sleep through two melatonin receptors, MT1, and MT2 [26].

In a meta-analysis of 1683 people with sleep disorders, melatonin seemed to help patients go to sleep quicker, sleep for longer, and improve sleep quality [27].

Another meta-analysis found that melatonin is most helpful in delayed sleep phase syndrome (difficulty falling asleep), but may not be of use in other types of sleep disorders [28].

Melatonin is also being studied as an option for children with autism disorders and ADHD who have difficulty sleeping. In the case of ADHD, administration of melatonin has helped children to go to sleep an hour earlier on average, but a great deal more research is required on this front [29].

Melatonin has shown the most promise in people who have difficulty falling asleep, but not so much in people with other types of sleep disorders. If you think you may have delayed sleep phase syndrome, talk to your doctor for an accurate diagnosis and appropriate treatment options.

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Possibly Effective For

Melatonin has been studied for a number of other potential benefits, but larger and more robust human trials are required to confirm or refute any of them, and better-studied alternatives exist for each. Talk to your doctor before adding any new supplement to your daily regimen.

2) Jet Lag

Circadian rhythm sleep disorders (CRSD) are disorders that occur when the circadian system does not function properly due to jet lag or shift work. It causes a persistent pattern of sleep disturbance [8]. Melatonin and melatonin supplements can shift the phase of the circadian rhythm in animals and humans [8, 30].

Insufficient Evidence For

Researchers are currently investigating melatonin’s potential in the following health conditions, but clinical research is very limited or contradictory, and in all cases, better-studied alternatives exist. Talk to your doctor before supplementing.

3) Parkinson’s

Parkinson’s disease often disrupts sleep [31].

There are several studies that show melatonin to improve sleep in patients with this condition, but it does not improve other associated symptoms [32, 33].

In the animal model of Parkinson’s, melatonin prevents cell death and brain damage [11].

Melatonin in Mental Illness: Ongoing Research

Depression and other mood disorders are often coupled with sleep disturbances, requiring agents that have both a sedating and calming effect. Drugs that activate and bind MT2 receptors are potential therapeutic agents for such conditions [34].

Abnormal day-and-night concentrations of melatonin are markers of severe depression [35].

In rats, melatonin alleviates depression induced by chronic stress and significantly changes the brain dynamics of these animals [36].

Melatonin synthesis is also disrupted in patients with bipolar disorder. Melatonin and drug that target melatonin receptors, like ramelteon and tasimelteon, can be a beneficial therapy for bipolar disorder as well [37].

As bipolar disorder is also associated with sleep and mood deregulation, melatonin improves the condition in patients with this problem [37].

However, no studies have yet discovered an effective use for melatonin against any particular mental illness. In clinical trials, melatonin supplements have not improved symptoms of bipolar disorder or depression, though sleep quality was somewhat improved [38, 39].

The most promising results have come in studies on seasonal affective disorder (SAD), also called seasonal depression. In two studies, melatonin supplements improved both sleep quality and measures of vitality in patients with SAD. A third study found no such benefit, but it was conducted on a short timeline of only six days [40, 41, 42].

Additional human studies will be required to determine the role of melatonin in mental health. For more about the effects of melatonin in the brain, check out this post.

The role of melatonin in mental health is currently under investigation; researchers have found the most promise for resolving sleep disturbances associated with mental illness.

Melatonin in Alzheimer’s & Dementia

Melatonin helps alleviate symptoms similar to Alzheimer′s and Parkinson′s disease in mice and rats [43]. The use of synthetic melatonin analogs or melatonin-related molecules to block nitric oxide synthase are being evaluated for the treatment of neural diseases ranging from stroke to Alzheimer’s and Parkinson’s disease [43].

Positive Results

The treatment of elderly patients with Alzheimer’s disease (AD) with bright light in the morning and melatonin at night improved their sleep and overall rest [44].

A similar study carried out for several years in the Netherlands showed that combined treatment of an AD patient with bright light and melatonin was beneficial both for rest and mental problems [45].

In humans, both MT1 and MT2 levels are low in elderly patients with Alzheimer’s [46].

In mouse nerve cells, melatonin prevents cell death caused by amyloid beta 25-35, a substance that causes a condition similar to Alzheimer’s disease [47].

The decrease in melatonin activity and synthesis may explain in part the disruption of sleep and problems with processing information observed in Alzheimer’s patients [48].

Melatonin’s antioxidant effects were more efficient than Vitamin C in treating the animal model of Alzheimer’s disease. It reduced oxidative stress better than Vitamin E as well [11].

Negative Results

Multiple studies have found no benefit to cognition in Alzheimer’s and dementia patients given melatonin supplements [49, 50].

Melatonin supplementation has also been linked with worsening mood, according to the ratings given by the patients’ caretakers [51].

The potential role of melatonin in managing Alzheimer’s disease and dementia is currently under investigation.

Further Reading

Takeaway

Melatonin, a hormone derived from tryptophan, regulates the circadian rhythm of sleep and waking. It is produced in the brain by the pineal gland and outside the brain by many tissues, including in the stomach. Melatonin is secreted primarily at night as part of the normal circadian rhythm. However, not all scientists agree that melatonin is required for sleep.

Melatonin has shown the most promise in people who have difficulty falling asleep, but not so much in people with other types of sleep disorders. Some studies have also found potential benefits in jet lag and in sleep disturbances associated with mental illness, Parkinson’s disease, and Alzheimer’s disease. However, more research is required before melatonin can be recommended for these uses.

About the Author

Nattha Wannissorn

Nattha Wannissorn

PhD
Nattha received her Ph.D. in Molecular Genetics from the University of Toronto and her undergraduate degree in Molecular and Computational Biology from the University of Pennsylvania.
Aside from having spent 15 years in biomedical research and health sciences, Nattha is also a registered holistic nutritionist, a certified personal trainer, has a precision nutrition level 1 certification, and is a certified functional diagnostic nutrition practitioner. As a holistic practitioner with a strong science background, Nattha is an advocate of science literacy in health topics and self-experimentation.

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