Melatonin is a hormone secreted by the pineal gland in the brain. It helps regulate other hormones and maintains the body’s circadian rhythm. The circadian rhythm is an internal 24-hour “clock” that plays a critical role in when we fall asleep and when we wake up. When it is dark, your body produces more melatonin. When it is light, the production of melatonin drops. Being exposed to bright lights in the evening, or too little light during the day can disrupt the body’s normal melatonin cycles. For example, jet lag, shift work, and poor vision can disrupt melatonin cycles.
Melatonin also helps control the timing and release of female reproductive hormones. It helps determine when a woman starts to menstruate, the frequency and duration of menstrual cycles, and when a woman stops menstruating (menopause). Preliminary research suggests low levels of melatonin help identify women at risk of a pregnancy complication called pre-eclampsia.
Melatonin is a member of the class of acetamides that is acetamide in which one of the hydrogens attached to the nitrogen atom is replaced by a 2-(5-methoxy-1H-indol-3-yl)ethyl group. It is a hormone secreted by the pineal gland in humans. It has a role as a hormone, an anticonvulsant, an immunological adjuvant, a radical scavenger, a central nervous system depressant, a human metabolite, a mouse metabolite and a geroprotector. It is a member of acetamides and a member of tryptamines. It derives from tryptamine. Melatonin has strong antioxidant effects. Preliminary evidence suggests that it may help strengthen the immune system.
Melatonin is a hormone normally produced in the pineal gland and released into the blood. The essential amino acid L-tryptophan is a precursor in the synthesis of melatonin. It helps regulate sleep-wake cycles or the circadian rhythm. Production of melatonin is stimulated by darkness and inhibited by light. High levels of melatonin induce sleep and so consumption of the drug can be used to combat insomnia and jet lag. MT1 and MT2 receptors may be a target for the treatment of circadian and non-circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24-hour cycle which regulates many different body functions ranging from sleep to immune functions
Mechanism of Action
Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cyclase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but also activates phospholipase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signaling cascades have various effects on the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types. The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area, and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin, and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary, and aortic tissue, myometrium and granulosa cells, immune cells, duodenum, and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of nonactivation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorylation of cAMP-responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels, and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.
Uses/ Indications
Therapeutic Melatonin is a therapeutic chemically synthesized form of pineal indole melatonin with antioxidant properties. The pineal synthesis and secretion of melatonin, a serotonin-derived neurohormone, is dependent on beta-adrenergic receptor function. Melatonin is involved in numerous biological functions including circadian rhythm, sleep, stress response, aging, and immunity.
Melatonin is synthesized at night in the human pineal gland and released into the blood and cerebrospinal fluid. It acts on the brains of humans to promote sleep, and also influences the phasing of sleep and various other circadian rhythms. During the day, plasma melatonin levels are low; at night, they rise 10 to 100-fold or more in young adults, but by considerably less in older people- who often may have frequent nocturnal awakenings as a consequence
Insomnia
- Melatonin drugs and supplements have use in treating insomnia, sleep disorders and jet lag; treatment for reducing pain of “cluster headaches; some evidence that melatonin might improve the effectiveness of cancer drugs used to fight tumors in the breast, lung, kidney, liver, pancreas, stomach and colon.
- Studies suggest that melatonin supplements may help people with disrupted circadian rhythms (such as people with jet lag or those who work the night shift), and those with low melatonin levels (such as some seniors and people with schizophrenia) to sleep better. A review of the scientific literature suggests that melatonin supplements may help prevent jet lag, particularly in people who cross 5 or more time zones.
- A few clinical studies suggest that, when taken for short periods of time (days to weeks), melatonin is more effective than a placebo in reducing the time it takes to fall asleep, increasing the number of sleeping hours, and boosting daytime alertness. It is not clear how well melatonin works, however. Some studies suggest that it only reduces the amount of time to fall asleep by a few minutes.
- Several human studies have measured the effects of melatonin supplements on sleep in healthy people. A wide range of doses has been used, often taken by mouth 30 to 60 minutes prior to sleep time. Results have been mixed. Some evidence suggests that melatonin may work best for people over 55 who have insomnia. One study of 334 people aged 55 and older found that sustained-release melatonin seemed to help people with primary insomnia fall asleep faster, sleep better, be more alert in the morning, and improve quality of life in people with primary insomnia.
Heart Disease
- Several studies show melatonin has cardioprotective properties, including antioxidant and anti-inflammatory effects. Research also suggests that melatonin may help lower blood pressure levels and improve cholesterol profiles. More research is needed.
Menopause
- Melatonin supplements may improve sleep problems associated with menopause. Other studies suggest it may help restore quality of life and prevent bone loss among perimenopausal women. However, it does not appear to relieve other symptoms of menopause, such as hot flashes. Peri- or postmenopausal women who use melatonin supplements should do so only for a short period of time since long-term effects are not known.
Benzodiazepine Withdrawal
- Some research suggests that melatonin may help elderly people with insomnia who are tapering off or stopping benzodiazepines such as diazepam (Valium), alprazolam (Xanax), or lorazepam (Ativan). Taking controlled-release melatonin improved sleep quality in those stopping benzodiazepine use. More research is needed. You should never combine melatonin with sedative medications unless you are under the strict supervision of a health care provider.
Breast Cancer
- Several studies suggest that low melatonin levels may be associated with breast cancer risk. For example, women with breast cancer tend to have lower levels of melatonin than those without the disease. Laboratory experiments have found that low levels of melatonin stimulate the growth of certain types of breast cancer cells, while adding melatonin to these cells slows their growth. Preliminary evidence also suggests that melatonin may strengthen the effects of some chemotherapy drugs used to treat breast cancer. In a study that included a small number of women with breast cancer, melatonin (given 7 days before beginning chemotherapy) prevented the lowering of platelets in the blood. This is a common complication of chemotherapy that can lead to bleeding.
- In another small study of women who were taking tamoxifen for breast cancer but seeing no improvement, adding melatonin caused tumors to modestly shrink in more than 28% of the women. Women with breast cancer should ask their doctors before taking melatonin.
Prostate Cancer
- Studies show that men with prostate cancer have lower melatonin levels than men without the disease. In test tube studies, melatonin blocks the growth of prostate cancer cells. In one small-scale study, melatonin, combined with conventional medical treatment, improved survival rates in 9 out of 14 men with metastatic prostate cancer. Interestingly, since meditation may cause melatonin levels to rise it appears to be a valuable addition to the treatment of prostate cancer. More research is needed before doctors can make recommendations in this area. Men with prostate cancer should talk to their doctor before taking medication.
Attention Deficit Hyperactivity Disorder (ADHD) and Autism
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Some evidence suggests that melatonin may help promote sleep in children with ADHD or autism, although it does not seem to improve the behavioral symptoms of ADHD or autism.
Fibromyalgia and Chronic Pain
- A randomized, placebo-controlled study found that people with fibromyalgia experienced a significant reduction in their symptoms when they took a melatonin supplement either alone or in conjunction with fluoxetine (Prozac). Other studies suggest that melatonin may play a role in other painful conditions, such as migraines. People with chronic pain should speak to their physicians before using melatonin as it can interact with some medications.
Other Uses
- Sunburn. Preliminary studies suggest that gels, lotions, or ointments containing melatonin may protect against sunburn and other skin damage. Studies examined using melatonin alone or combined with topical vitamin E prior to UV light exposure from the sun.
- Irritable Bowel Syndrome (IBS). Preliminary research suggests that people with IBS who take melatonin reduce some symptoms, such as abdominal pain. Results are mixed as to whether melatonin may help improve other symptoms, such as bloating and frequency of bowel movements.
- Epilepsy. Some studies suggest melatonin may reduce the frequency and duration of seizures in children with epilepsy, but other studies suggest melatonin may increase the frequency of seizures. DO NOT take melatonin for epilepsy, or give it to a child, without talking to your doctor first.
- Sarcoidosis. Some researchers suggest that melatonin may be effective in the treatment of pulmonary sarcoidosis. Talk to your doctor.
- Assisted Reproduction. Interestingly, preliminary studies suggest melatonin supplementation in the eggs of women with polycystic ovarian syndrome could improve egg maturation and pregnancy rates.
- Other Uses. Preliminary evidence suggests that melatonin may play a role in pain modulation and digestive function. More research is needed.
Dosage
Melatonin is available as tablets, capsules, cream, and lozenges that dissolve under the tongue.
How to Take It
There is currently no recommended dose for melatonin supplements. Different people will have different responses to its effects. Lower doses appear to work better in people who are especially sensitive. Higher doses may cause anxiety and irritability.
The best approach for any condition is to begin with very low doses of melatonin. Keep the dose close to the amount that our bodies normally produce (< 0.3 mg per day). You should only use the lowest amount possible to achieve the desired effect. Your doctor can help you determine the most appropriate dose for your situation, including how to increase the amount, if needed.
Pediatric
- Always ask your child’s doctor before giving melatonin to a child. In fact, doses between 1 to 5 mg may cause seizures in this age group.
Adult
- You should work with your doctor to find the safest and most effective dose for you. The right dose for you should produce restful sleep with no daytime irritability or fatigue.
- Jet lag: 0.5 to 5 mg of melatonin 1 hour prior to bedtime at final destination has been used in several studies. Another approach that has been used is 1 to 5 mg 1 hour before bedtime for 2 days prior to departure and for 2 to 3 days upon arrival at final destination.
Side Effects
- Because of the potential for side effects and interactions with medications, people should take dietary supplements only under the supervision of a knowledgeable health care provider.
- Some people may have vivid dreams or nightmares when they take melatonin. Taking too much melatonin may disrupt circadian rhythms (your “body clock”).
- Melatonin can cause drowsiness if taken during the day. If you are drowsy the morning after taking melatonin, try taking a lower dose.
- Additional side effects include stomach cramps, dizziness, headache, irritability, decreased libido, breast enlargement in men (called gynecomastia), and reduced sperm count.
- Pregnant or nursing women should not take melatonin because it could interfere with their fertility, or their pregnancy.
- Melatonin is a hormone so patients with a history of hormonal-related issues should only use melatonin under the supervision of their physicians.
- Some studies show that melatonin supplements worsened symptoms of depression. For this reason, people with depression should consult their doctor before using melatonin supplements.
- Although many researchers believe that melatonin levels go down with age, newer evidence has brought this theory into question. People older than 65 should ask their doctor before taking melatonin supplements, so blood levels of this hormone can be monitored.
Interactions
If you are taking prescription medications, you should not use melatonin without first discussing it with your health care provider. Below is a partial list of medications that may interact with melatonin.
- Antidepressant medications. In an animal study, melatonin supplements reduced the antidepressant effects of desipramine and fluoxetine (Prozac). More research is needed to know if the same thing would happen in people. In addition, fluoxetine (a member of a class of drugs called selective serotonin reuptake inhibitors, or SSRIs) can cause low levels of melatonin in people.
- Antipsychotic medications. A common side effect of antipsychotic medications used to treat schizophrenia is a condition called tardive dyskinesia, which causes involuntary movements. In a study of 22 people with schizophrenia and tardive dyskinesia caused by antipsychotic medications, those who took melatonin supplements had fewer symptoms compared to those who did not take the supplements.
- Benzodiazepines. The combination of melatonin and triazolam (Halcion) improved sleep quality in one study. In addition, a few reports have suggested that melatonin supplements may help people stop using long-term benzodiazepine therapy. (Benzodiazepines are habit forming.)
- Birth control pills. Birth control pills may increase the amount of melatonin your body makes. Taking additional melatonin could increase your levels of melatonin above the healthy range.
- Blood pressure medications. Melatonin may make blood pressure medications like methoxamine (Vasoxyl) and clonidine (Catopres) less effective. In addition, medications in a class called calcium channel blockers may lower melatonin levels. Calcium channel blockers include:
- Nifedipine (Procardia)
- Amlodipine (Norvasc)
- Verapamil (Calan, Isoptin)
- Diltiazem (Cardizem)
- Felodipine (Plendil)
- Nisoldipine (Sular)
- Bepridil (Vascor)
Beta-blockers. Use of beta-blockers may lower melatonin levels in the body. Beta-blockers include:
- Acebutolol (Sectral)
- Atenolol (Tenormin)
- Bisoprolol (Zebeta)
- Carteolol (Cartrol)
- Metoprolol (Lopressor, Toprol XL)
- Nadolol (Corgard)
- Propranolol (Inderal)
- Blood-thinning medications (anticoagulants). Melatonin may increase the risk of bleeding from anticoagulant medications such as warfarin (Coumadin).
- Interleukin-2. In one study of 80 cancer patients, use of melatonin along with interleukin-2 led to more tumor regression and better survival rates than treatment with interleukin-2 alone.
- Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs such as ibuprofen (Advil, Motrin) may lower levels of melatonin in the blood.
- Steroids and immunosuppressant medications. Melatonin may cause these medication to lose their effectiveness. DO NOT take melatonin with corticosteroids or other medications used to suppress the immune system.
- Tamoxifen. Preliminary research suggests that the combination of tamoxifen (a chemotherapy drug) and melatonin may benefit some people with breast and other cancers. More research is needed to confirm these results.
- Other. Caffeine, tobacco, and alcohol can all lower levels of melatonin in the body.
Pregnancy and Lactation
- Preliminary information indicates that canakinumab levels in milk are very low to undetectable. It is also likely to be partially destroyed in the infant’s gastrointestinal tract and absorption by the infant is minimal. A few infants have been breastfed without noticeable harm. Until more data become available, canakinumab injection should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. Topical or homeopathic preparations pose little risk to the nursing infant.
Drug Warnings
- Doses <8 mg have reportedly induced heavy head, headache, and transient depression. May aggravate depression in patients with psychiatric illness… Some studies suggest melatonin may deepen depression in those who have it or induce it in those susceptible to it.
- Melatonin in physiological doses causes vasoconstriction and also constricts cerebral arteries in rats.
- Dose-related increases in plasma melatonin levels were observed, the 0.3 mg dose causing peak levels in the range usually observed nocturnally among young adults. When subjects received a higher dose (3.0 mg) but not 0.3 mg, plasma melatonin levels remained significantly elevated during much of the following day and the subjects exhibited hypothermia.
- While high doses of melatonin (10-450 mg/kg body weight parenterally) have sometimes elicited antioxidant effects in experimental animals in vivo, neither their long-term safety nor their effects on the animals’ blood melatonin levels have been characterized. In humans- if not in nocturnally active lab rodents- such megadoses might ultimately impair sleep or various circadian rhythms, perhaps by downregulating melatonin receptors
