Beyond sleep and circadian rhythm, melatonin has many important health benefits because it is a potent antioxidant and anti-inflammatory hormone. Read this post to learn more about how melatonin is critical for brain health, gut health, and fertility, and may help treat and prevent.
Plus also why melatonin supplementation doesn’t help with sleep for many people.
Melatonin is derived from the amino acid tryptophan and the neurotransmitter serotonin (R).
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
A part of the brain, the pineal gland, 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 (R).
Melatonin is also made by many other organs in the body, especially in the stomach (R).
If sleep is interrupted by blue light exposure at night, melatonin levels decrease drastically. In addition, melatonin levels also decrease with age (R). However, darkness does not stimulate melatonin production. It simply permits melatonin production (R).
Melatonin acts through interacting with two receptor proteins, MT1 and MT2 (R).
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 (R).
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 (R).
How Melatonin Derives Its Health Benefits
Melatonin Influences 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 (R).
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 (R).
Light from the environment influences the signals sent from the SCN (R).
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 (R).
While most scientists believe that melatonin can shift the circadian rhythm phase and entrain the circadian rhythm, this property of melatonin is controversial (R, R2).
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 (R). These mutant fish were equally easy to wake up and slept as deep as the control fish.
Melatonin is a Potent Antioxidant
Several health benefits of melatonin are derived from its potent antioxidant properties, both directly and indirectly.
Administration of melatonin increases cellular production of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and γ-glutamylcysteine synthase) (R, R2, R3), 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 (R). This allows melatonin to protect several tissues and organ systems from oxidative damage. Tissues that produce melatonin and rely on melatonin for this purpose includes gut, ovary, testes, lens, bone marrow, and the brain (R).
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 (R).
A single molecule of melatonin may neutralize up to 10 molecules of ROSs and RNSs (R).
It also blocks an enzyme called nitric oxide synthase that produces reactive nitrogen species and causes inflammation (R).
Melatonin Protects the Mitochondria and Inhibits Programmed Cell Death
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 (R).
Energy production by mitochondria leads to the creation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (R). 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) (R).
Melatonin, therefore, helps with organs that are most critically dependent on the mitochondria, including the nervous system and the heart.
Melatonin Protects Against Mitochondria 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 (R).
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), another toxin used to imitate Parkinson’s disease (R). 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 (R).
- 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 (R). 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 (R).
- Cyanide (R, R2), 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 (R). Melatonin also protects the damage to mitochondrial DNA caused by potassium cyanide in mice and in culture (R).
- Melatonin Reduces Inflammation and Promotes Healthy Immune Function
- Melatonin receptors are present in a wide variety of immune cells (R). 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 (R).
In addition, by reducing free radicals in the microglial (immune cells that are specific to the brain), melatonin can reduce brain inflammation through reducing NF-kB (R).
In humans and rodents, melatonin can promote healthy immune responses, and reverse suppression of the immune system due to aging, steroid medications, lead and chemical exposures (R).
Melatonin and Sleep
1) Melatonin Helps Improves Sleep Quality
Melatonin controls the sleep-awake cycle (R).
In patients with insomnia, melatonin concentration is significantly lower compared to people with normal sleep (R).
Melatonin induces sleep through two melatonin receptors, MT1, and MT2 (R).
Melatonin helps patients to go to sleep quicker, sleep longer, and deeper (R).
Some studies suggest that melatonin itself is not effective in some types of sleep disorders, though it does improve sleep quality (R).
It helps patients discontinue therapy with benzodiazepines, a class of drugs usually prescribed for anxiety and insomnia. Benzodiazepines have potential side effects, resulting in addiction. Also, withdrawal of such therapy is hard for the patient, leading to sleep deprivation and anxiety (R).
Melatonin supplementation helps patients reduce their dependence on drugs, without major side effects (R).
Melatonin is also a safe option for children with autism disorders and ADHD. In the case of ADHD, administration of melatonin has helped children to go to sleep an hour earlier in average (R).
When Melatonin May Not Be an Effective Sleep Aid
Nattha’s experience: Consistently, I observe that melatonin doesn’t appear to be helpful in cases of stress-related insomnia among my clients. In these cases, stress management, meditation, sleep hygiene, and other sedating substances such as theanine, passionflower and lemon balm tend to be more effective.
Exogenous (supplemental) melatonin has very subtle (2 – 3%) sleep-enhancing effects in humans comparing to prescription sleep medications (R, R2), which might explain why some people don’t find melatonin beneficial as a sleep aid.
A meta-analysis found no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders that are secondary to other health problems, jet lag, and shift work (R).
For other ways to address insomnia and other sleep disorders that we have found to be more effective than melatonin, check out our new book Biohacking Insomnia.
2) Melatonin Helps with 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 (R). Melatonin and melatonin supplements can shift the phase of the circadian rhythm in animals and humans (R, R).
3) Melatonin Helps with Sleep in Anxiety, Depression and Bipolar Disorders
Melatonin can help treat anxiety and depression, and the co-occurring sleep disturbances.
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 (R).
Abnormal day-and-night concentrations of melatonin are markers of severe depression (R).
Melatonin helps with sleep regulation and depression in patients with delayed sleep phase syndrome (R).
In rats, melatonin alleviates depression induced by chronic stress and significantly changes the brain dynamics these animals (R).
Treatment with melatonin in breast cancer patients reduces the risk of depression (R).
Melatonin synthesis is also disrupted in 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 (R).
As bipolar disorder is also associated with sleep and mood deregulation, melatonin improves the condition in patients with this problem (R).
Melatonin Protects the Brain
Melatonin not only helps reduce oxidative stress and inflammation inside the brain, but also increase BDNF and strengthen the blood-brain barrier. It has been proposed as a treatment for several brain and neurological diseases.
It also protects nerve cells. Melatonin demonstrated an antioxidant effect in the brain, spinal cord, optic nerve, and spinal cord white matter (R).
4) Melatonin Helps with Brain Regeneration and Neuroplasticity
Melatonin activates brain-derived neurotrophic factor (BDNF), a protein responsible for nerve cells’ well-being and regeneration (R).
5) Melatonin Strengthens the Blood-Brain Barrier
Melatonin strengthens the barrier between brain and the blood (R).
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.
6) Melatonin Helps with Recovery from Stroke
In mouse models of stroke, melatonin was able to block 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 (R).
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 (R). These proteins initiate inflammation and nerve cell death after the artery leading to the brain gets blocked (R).
7) Melatonin Helps with Traumatic Brain Injury
Melatonin helps with brain trauma (R).
Treatment of rats with melatonin after brain injury helps reduce the subsequent swelling of various brain regions (R).
8) Melatonin Helps with Alzheimer’s
Melatonin helps alleviate symptoms similar to Alzheimer′s and Parkinson′s disease in mice and rats (R). 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 (R).
In humans, both MT1 and MT2 levels are low in elderly patients with Alzheimer’s (R).
In mouse nerve cells, melatonin prevents cell death caused by amyloid beta25-35, a substance that causes a condition similar to Alzheimer’s disease (R).
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 (R).
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 (R).
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 (R).
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 (R).
9) Melatonin Helps with Parkinson’s
The development of Parkinson’s disease also disrupts sleep (R).
There are several studies that show melatonin to improve sleep in patients with this condition, but it does not improve other associated symptoms (R, R2).
In the animal model of Parkinson’s, melatonin prevents cell death and brain damage (R).
10) Melatonin Helps with Amyotrophic Lateral Sclerosis (ALS)
In amyotrophic lateral sclerosis (ALS), the nerve cells responsible for movement die. In mouse models, melatonin helps relieve symptoms of ALS by preventing the death of those cells and slowing the disease progression in mice (R).
11) Melatonin Is Important for Eye Health and Vision
The cells of the eye, especially the retina, make melatonin (R).
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 produce (R).
Disruption of MT receptors leads to the death of cone cells, the cells in the eye that help the eye to discern color (R).
Melatonin is also important for normal eye development. For example, mice that lacked one of the melatonin receptors – MT1 – had a decrease in specific nerve cells crucial for vision (R).
It was also shown to protect human cells that make eye pigment from cell death (R).
12) Melatonin Help with Glaucoma
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 (R).
The disturbances in melatonin function may be one of the causes of glaucoma (R).
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 (R).
13) Melatonin Protects Nerve Cells in the Eyes from Damage from Free Radicals
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 (R).
Also, it is beneficial in refractory central serous chorioretinopathy, a condition that affects the eyes of diabetic patients (R).
Supplementation with melatonin drops in infancy and in the elderly is potentially beneficial for eye protection (R).
14) Melatonin Relieves Noises in the Ear (Tinnitus)
Tinnitus is the unexplained noise in the ears that affects many people: the elderly, those with a hearing disability, or those affected as a result of certain drugs (R, R2).
Melatonin was 150 times more effective compared with other drugs that treat tinnitus at decreasing tinnitus symptoms (R).
In elderly patients with tinnitus, melatonin levels are very low. This may indicate that its levels are connected with normal ear activity (R).
Other Health Benefits of Melatonin
With its potent antioxidant and anti-inflammatory effects, melatonin has several other health benefits throughout the body. Melatonin also controls the levels of other hormones, such as insulin.
15) Melatonin May Help Prevent and Treat Cancer
Melatonin may play a role in the prevention and treatment of various cancers. Breast, prostate, and colorectal cancer patients had reduced melatonin levels compared to healthy patients (R).
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 the cancer to grow (R).
Melatonin treatment of cells increases the production of tumor suppressor protein E-cadherin. It also decreases the levels of OCT4 and N-cadherin, which help the tumor cells to survive and invade other organs (R).
It also acts against cancer stem cells, which are the type of cells that divide uncontrollably and make cancer more resistant to treatment. Melatonin reduces the aggressiveness and viability of cancer cells (R).
Melatonin’s anti-cancer effect is also due to its ability to improve immune function (R). It stimulates several types of immune cells, such as Th2 cells and natural killers (R, R).
Also, in mice with stomach cancer, melatonin treatment suppresses the activity of regulatory T cells (R).
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 (R).
Constant melatonin treatment reduced the incidence and size of breast tumors in patients (R).
Melatonin supplementation stabilized lung and colorectal cancer patients’ health. It reduced the spread of tumors and increased cancer cell death (R).
In cell cultures, melatonin interferes with cancer cells’ energy processes. Through this effect, it blocks cancer cell growth and limits their ability to invade (R).
However, melatonin injections can stimulate tumor growth if given in the morning. You have to be careful with the timing of melatonin administration (R).
16) Melatonin Helps Protect Against Diabetes
Melatonin acts as a clock and changes the insulin levels according to the time of the day (R). Melatonin is very important for insulin balance, as a disruption in this system may cause an inability of the cells to react to insulin and glucose (R).
In patients and rats with type 2 diabetes, the concentrations of melatonin both during day and night are lower compared to healthy subjects (R).
Even one sleepless night may cause insulin resistance). It can also disrupt metabolism. The disruption of melatonin balance has the ability to cause all of these problems (R, R, R).
In rats with diabetes, chronic treatment with melatonin improves diabetes outcomes in muscle, liver, and fat tissues (R).
In a cell-based study, melatonin protected muscle cells from a poison that causes insulin resistance and improved glucose transport into the cell (R).
Melatonin also helped improve the condition of the liver and its activity in diabetic overweight rats (R).
Additionally, it protects insulin-producing cells in the pancreas from cell death. It also restores their function (R).
Drugs that correct melatonin levels (namely Epifamin and Melaxen) can improve diabetes in rats (R).
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 (R, R).
17) Melatonin Reduces 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 (R).
Like sleep, blood pressure has a 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 (R).
There is a proven melatonin deficiency in certain types of hypertension (high blood pressure) (R).
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 (R).
18) Melatonin Protects the Heart
Melatonin also showed protective effects in the heart. Its antioxidant activity protected against strokes and heart attacks (R).
19) Melatonin Protects the Stomach
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 (R).
Stomach melatonin is controlled differently from brain melatonin. Its concentration is the highest at midday, not at night (R).
In the stomach, it reacts mostly to incoming food (R).
Stomach melatonin also controls the behavior of gut bacteria (R).
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 (R).
Melatonin strengthens the intestinal barrier by reducing oxidative stress by up to 88% (R). 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.
Its antioxidant properties can help stop inflammation in the stomach. These effects can help protect against disorders like colitis, irritable bowel syndrome, and even various cancers (R).
Melatonin also helps prevent the death of stomach lining cells due to poisoning (R)
In one study, starved rats experienced stomach stress. Melatonin treatment for one week improved stomach lining condition (R).
Also, it significantly reduced stomach pain in IBS patients (R).
20) Melatonin Helps Treat 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 (R).
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 (R).
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 (R).
21) Melatonin Helps with Aging
In humans, melatonin levels decline with age (R).
Oxidative stress and damage contribute to the aging process. Melatonin’s antioxidant effects can help stop oxidative damage (R).
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 (R).
In old rats, dietary melatonin helped stop age-related bone loss. Supplementation increased bone volume and stiffness, which improved bone health (R).
Melatonin increased the life span of various animals, including water fleas, fruit flies, and male rodents (R).
However, even though melatonin is an anti-aging hormone, it does not delay aging (R).
22) Melatonin Supplementation May Help with Fertility
Melatonin can improve overall movement of sperm cells. It can also inhibit cell death in the sperm. It improves overall sperm quality, therefore increasing the probability of successful fertilization (R).
Reactive oxygen species can inhibit oocyte (egg cells) maturation. In one review, oral administration of melatonin in humans reduced oxidative damage to oocytes and increased fertilization rates. However, since the study did not have a control group, this is not sufficient evidence for melatonin’s benefits (R).
Aging can lead to a decline in fertility. Melatonin treatment in female mice delayed age-associated infertility (R).
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 (R).
However, higher doses of melatonin can harm oocyte and embryo cell cultures (R).
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 (R).
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 (R).
23) Melatonin Helps Stop Hair Loss
Androgenetic alopecia is a genetic hair loss condition. Topical application of melatonin can help prevent hair loss in men and women with alopecia (R).
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 may be a new solution to delaying and treating hair loss (R).
24) Melatonin Prevents 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 (R).
Melatonin Part 2
Melatonin Part 2: Ways to Increase and Decrease Melatonin, Food/Drug/Supplement Interactions and Side Effects of Melatonin
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