The sleep hormone melatonin is essential for regulating the circadian rhythm and making sure you fall asleep. Read about the latest research and its variety of potential benefits here.
What is Melatonin?
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 .
Melatonin is also made by many other organs in the body, especially in the stomach .
If sleep is interrupted by blue light exposure at night, melatonin levels decrease drastically. In addition, melatonin levels also decrease with age . However, darkness does not stimulate melatonin production. It simply permits melatonin production .
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 .
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 .
Sleep and Circadian Rhythm
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 .
Light from the environment influences the signals sent from the SCN .
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 .
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 . These mutant fish were equally easy to wake up and slept as deep as the control fish.
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 synthase) [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 . 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 .
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 .
A single molecule of melatonin may neutralize up to 10 molecules of ROSs and RNSs .
It also blocks an enzyme called nitric oxide synthase that produces reactive nitrogen species and causes inflammation .
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 .
Energy production by mitochondria leads to the creation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) . 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) .
Melatonin, therefore, helps with organs that are most critically dependent on the mitochondria, including the nervous system and the heart.
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 .
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), another toxin used to imitate Parkinson’s disease . 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 .
- 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 . 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 .
- 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 . Melatonin also protects the damage to mitochondrial DNA caused by potassium cyanide in mice and in culture .
Inflammation and Immune Function
Melatonin receptors are present in a wide variety of immune cells . It is immunomodulatory, which means that it reduces excessive immune function in inflammatory conditions and enhances immune function in immunocompromised people.
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 .
Benefits of Melatonin (Likely Effective)
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.
1) Delayed Sleep Phase Syndrome
Melatonin regulates the sleep-wake cycle .
In patients with insomnia, melatonin concentration is significantly lower compared to people with normal sleep .
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 .
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 .
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 .
In summary, 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.
Potential Benefits (Possibly Effective)
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 . Melatonin and melatonin supplements can shift the phase of the circadian rhythm in animals and humans [8, 30].
Surprisingly, melatonin has shown promise for reducing pain in endometriosis. In a study of 40 women of reproductive age, 10 mg of melatonin per day reduced pain scores and dysmenorrhea by almost 40% each. Women who took melatonin also used fewer painkillers .
4) Blood Pressure
Melatonin plays an important role in the regulation of blood pressure. Activation of its receptors, MT1 and MT2, widens blood vessels, which decreases blood pressure .
Like sleep, blood pressure has circadian rhythmicity. It increases in the morning and decreases at night. Melatonin rises at night and decreases in the morning. This indicates that there may be a connection between melatonin and blood pressure .
Certain types of hypertension (high blood pressure) are characterized by low melatonin .
In patients with type 2 diabetes, 5 mg of melatonin decreased blood pressure levels. However, there is not enough information about how melatonin reduces blood pressure to determine whether it is effective at lowering blood pressure. It may be used as a supporting therapy in hypertensive patients .
Topical gels or creams containing melatonin may prevent sunburn in people with highly sensitive skin. In multiple studies (a total of 83 volunteers), melatonin gels or creams significantly reduced skin reddening after UV exposure [34, 35, 36, 37].
The best formulation and concentration of melatonin gel or cream is unknown.
Thrombocytopenia, a blood disorder characterized by low platelet count, can result from cancer, cancer treatments, and other underlying conditions. In multiple studies, melatonin restored platelet count in patients with these conditions or undergoing chemotherapy [38, 39, 40, 41, 42, 43].
Despite this apparent wealth of promising results, melatonin is generally not used for this purpose because better-studied and more effective alternatives are readily available.
Other Potential Benefits with Insufficient Evidence
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.
Melatonin was 150 times more effective compared with other drugs that treat tinnitus at decreasing tinnitus symptoms .
In elderly patients with tinnitus, melatonin levels are very low. This may indicate that its levels are connected with normal ear activity .
8) Gut Health
Melatonin concentration in stomach tissues is 10 to 100 times higher than in the blood. Its concentrations are 400 times higher in the gut than in the brain .
Stomach melatonin is controlled differently from brain melatonin. Its concentration is the highest at midday, not at night .
In the stomach, it reacts mostly to incoming food .
Melatonin and its precursor L-tryptophan can help heal stomach ulcers in humans. They protected against lesions caused by aspirin and H. pylori infections. Administration of melatonin also accelerates healing of the ulcers .
Melatonin strengthens the intestinal barrier by reducing oxidative stress by up to 88% . It dose-dependently prevented stress-induced stomach damage and increased the efficiency of drugs that treat stomach ulcer, ranitidine and omeprazole. Melatonin reduced free radicals by 88% in rats.
Melatonin also helps prevent the death of stomach lining cells due to poisoning .
In one study, starved rats experienced stomach stress. Melatonin treatment for one week improved stomach lining condition .
9) Acid Reflux (GERD)
Gastroesophageal reflux disease (GERD) is also known as acid reflux. It is a condition that develops when stomach acid and its contents come back up the esophagus (food pipe). Some symptoms include heartburn, nausea, chest pain, and regurgitation .
In a study of 36 GERD patients, melatonin supplementation was able to decrease GERD symptoms. Melatonin reduced esophageal pressure and prevented injury when used alone or in conjunction with omeprazole .
However, omeprazole, a drug that treats GERD, showed better results when administered alone than in combination with melatonin. So although melatonin may be able to treat GERD symptoms, it is not the best option to treat acid reflux .
In humans, melatonin levels decline with age .
Oxidative stress and damage contribute to the aging process. Melatonin’s antioxidant effects can help stop oxidative damage .
Melatonin protects against UV-induced skin aging in humans. Topical application helps the skin through melatonin’s antioxidant activity. The oral administration does not benefit the skin as much .
In old rats, dietary melatonin helped stop age-related bone loss. Supplementation increased bone volume and stiffness, which improved bone health .
Melatonin increased the lifespan of various animals, including water fleas, fruit flies, and male rodents .
However, even though melatonin is an anti-aging hormone, it does not delay aging .
A part of the eye called the macula tends to degenerate with age. In a study of 100 patients with macular degeneration, 3 mg of melatonin per day for 6 months maintained vision and tissue status roughly the same as at the beginning of the study. While there was no measurable improvement in this study, the time frame was long enough that the researchers expected further degeneration .
Unfortunately, the study did not include a placebo group, and additional research is required to determine whether melatonin has any real benefit.
Androgenic alopecia is a genetic hair loss condition. The topical application of melatonin helped prevent hair loss in men and women with alopecia .
Melatonin application improved hair condition and texture. In multiple studies, melatonin solution helped partially reduce hair loss. It also led to new hair growth in some cases. Although its mechanisms are unknown, melatonin could potentially delay hair loss .
In one study, oral administration of melatonin in humans reduced oxidative damage to oocytes and increased fertilization rates. However, since the study was very small and did not have a control group, this is not sufficient evidence for melatonin’s benefits .
Melatonin may improve overall movement of sperm cells upon direct exposure. It may also inhibit cell death in the sperm and improve overall sperm quality, therefore increasing the probability of successful fertilization .
Aging can lead to a decline in fertility. Melatonin treatment in female mice delayed age-associated infertility .
Melatonin administration (10 mg/kg over 6 and 12 months) in mice also increased the quantity and quality of oocytes (egg cells). This may be due to the suppression of oxidative stress by melatonin .
However, higher doses of melatonin can harm the oocyte and embryo cell cultures .
Reactive oxygen species and oxidative damage can negatively impact the success of infertility treatments. Melatonin’s antioxidant activity may help with in vitro fertilization results .
Melatonin administration can maintain female reproductive capacity in aging mice. However, there are not enough studies on humans to support these results. More trials are needed to confirm melatonin’s benefits on the postponement of childbearing .
Parkinson’s disease often disrupts sleep .
In the animal model of Parkinson’s, melatonin prevents cell death and brain damage .
Animal Research (Lacking Evidence)
No clinical evidence supports the use of melatonin for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.
14) Blood-Brain Barrier
Melatonin is being investigated for its potential to strengthen the barrier between the brain and the blood .
A leaky blood-brain barrier can cause cognitive dysfunction (brain fog), Alzheimer’s, and may also contribute to psychiatric disorders such as anxiety and depression. Read this post to learn more about the blood-brain barrier.
15) Recovery from Stroke
In mouse models of stroke, melatonin blocked the release of cytochrome C (a substance that would cause cell death if leaked from the mitochondria) from mitochondria, which effectively prevented cell death as a result of the injury .
In another rat model of a stroke, melatonin blocks the activity of inflammatory cytokines IL-1β and TNF-α, and cell death proteins BAD and BAX . These proteins initiate inflammation and nerve cell death after the artery leading to the brain gets blocked .
16) Traumatic Brain Injury
Melatonin is being researched in the context of brain trauma .
Treatment of rats with melatonin after brain injury helps reduce the subsequent swelling of various brain regions .
17) Amyotrophic Lateral Sclerosis (ALS)
In amyotrophic lateral sclerosis (ALS), the nerve cells responsible for movement die. In mouse models, melatonin relieved symptoms of ALS by preventing the death of those cells and slowing the disease progression .
18) Vision & Eye Health
The cells of the eye, especially the retina, make melatonin .
Light influences melatonin production, while the cells that react to light produce melatonin. The more light there is, the less melatonin the cells in the eye produces .
Disruption of MT receptors leads to the death of cone cells, the cells in the eye that help the eye to discern color .
Melatonin is also important for normal eye development. Mice that lacked one of the melatonin receptors – MT1 – had a decrease in specific nerve cells crucial for vision .
Melanin also protected human cells that make eye pigment from cell death .
Additionally, it decreases elevated pressure in the eye in humans. Moreover, removal of MT1 in mice results in an increase in the pressure inside the eye and death of nerve cells .
The disturbances in melatonin function may be one of the causes of glaucoma .
Melatonin and 5-MCA-NAT (a molecule similar to melatonin) are promising agents for treating glaucoma, which is an eye condition caused by elevated pressure .
Nerve Cells in the Eyes
Melatonin also prevents the death of nerve cells in an experimental model of optic neuritis in rats. Optic neuritis is a disease that causes the death of optic nerve cells responsible for vision .
Also, it is beneficial in refractory central serous chorioretinopathy, a condition that affects the eyes of diabetic patients .
In patients with type 2 diabetes, the concentrations of melatonin both during the day and night are lower compared to healthy subjects. However, the effect of melatonin supplements on type 2 diabetes is unclear .
Melatonin is part of the internal clock that changes insulin levels according to the time of the day . It is very important for insulin balance, as a disruption of this system may cause an inability of the cells to react to insulin and glucose .
In rats with diabetes, chronic treatment with melatonin improves diabetes outcomes in muscle, liver, and fat tissues .
In a cell-based study, melatonin protected muscle cells from a poison that causes insulin resistance and improved glucose transport into the cell .
Melatonin also helped improve the condition of the liver and its activity in diabetic overweight rats .
Additionally, it protects insulin-producing cells in the pancreas from cell death. It also restores their function .
Drugs that correct melatonin levels (namely Epifamin and Melaxen) can improve diabetes in rats .
Agomelatine, an antidepressant that targets the melatonin receptors, improves chronic pain associated with diabetes. Agomelatine also counteracts depression in patients with diabetes, as well as help to control blood sugar levels [93, 94].
20) Heart Health
Melatonin also showed protective effects in the heart in animal and cell models. Its antioxidant activity protected against strokes and heart attacks in mice, but very little is known about melatonin and the human cardiovascular system .
21) Organ Transplant Complications
Melatonin’s antioxidant and anti-inflammatory effects may be useful during organ transplantation. It could help reduce graft failure during heart, bone, liver, and other organ transplants. However, not enough human studies have been done to support these claims .
Melatonin supplementation improved some markers of health in prostate and colorectal cancer patients. It reduced the spread of tumors and increased cancer cell death .
Researchers are currently looking into the potential role of melatonin in the prevention and treatment of various cancers. Breast, prostate, and colorectal cancer patients have been observed to have reduced melatonin levels compared to healthy patients .
In cell studies, melatonin has mainly been investigated for its activity against breast cancer: in artificial spheres made from breast cells and cancer cells, adding melatonin blocked cancer-like growth. This was caused when melatonin blocked an estrogen receptor that caused cancer to grow .
The main function of regulatory T cells is to block the activity of other types of immune cells. Tumors support T regulatory cells as they protect the cancer cells from being killed by the immune system. Melatonin blocks T cells, which can lead to cancer cell death .
In cell cultures, melatonin interferes with cancer cells’ energy processes. Through this effect, it blocks cancer cell growth and limits their ability to invade .
However, melatonin injections could stimulate tumor growth if given at the wrong time of day. Much more research is required to understand the potential role of melatonin in cancer therapies; talk to your doctor before adding this supplement to your regimen .
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 .
Abnormal day-and-night concentrations of melatonin are markers of severe depression .
In rats, melatonin alleviates depression induced by chronic stress and significantly changes the brain dynamics of these animals .
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 .
As bipolar disorder is also associated with sleep and mood deregulation, melatonin improves the condition in patients with this problem .
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 [105, 106].
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 [107, 108, 109].
Additional human studies will be required to determine the role of melatonin in mental health.
Melatonin in Alzheimer’s & Dementia
Melatonin helps alleviate symptoms similar to Alzheimer′s and Parkinson′s disease in mice and rats . 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 .
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 .
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 .
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 .
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 .
Melatonin supplementation has also been linked with worsening mood, according to the ratings given by the patients’ caretakers .
Melatonin 3-Part Series
Part 2 & 3 Links
- Melatonin Part 2: Surprising Roles of Melatonin in Controlling Inflammation and Preventing Autoimmune Diseases
- Melatonin Part 3: Factors That Increase and Decrease Melatonin + Synergies
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