Melatonin as a medication and supplement
is a naturally occurring hormone produced in the brain that is also used as a dietary supplement and medication. As a hormone, melatonin is released by the pineal gland and is involved in sleep–wake cycles. As a supplement and medication, it is often used for the short-term treatment of disrupted sleep patterns such as from jet lag or shift work, and is typically taken orally.
Side effects from melatonin supplements are minimal at low doses for short durations. Side effects of melatonin are rare but may occur in 1 to 10 patients out of 1,000. They may include somnolence, headaches, nausea, diarrhea, abnormal dreams, irritability, restlessness, insomnia, anxiety, migraine, lethargy, hyperactivity, dizziness, hypertension, abdominal pain, heartburn, mouth ulcers, dry mouth, hyperbilirubinaemia, dermatitis, night sweats, pruritus, rash, dry skin, pain in the extremities, symptoms of menopause, chest pain, glycosuria, proteinuria, abnormal liver function tests, weight gain, mood swings, aggression, and grogginess after awakening. Its use is not recommended during pregnancy or breastfeeding or for those with liver disease.
Melatonin acts as an agonist of the melatonin MT1 and MT2 receptors, the biological targets of endogenous melatonin. It is thought to activate these receptors in the suprachiasmatic nucleus of the hypothalamus in the brain to regulate the circadian clock and sleep–wake cycles. Immediate-release melatonin has a short elimination half-life of about 20 to 50minutes. Prolonged-release melatonin used as a medication has a half-life of 3.5 to 4hours.
Melatonin was discovered in 1958. It is sold over-the-counter in Canada and the United States; in the United Kingdom, it is a prescription-only medication. In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54. Slenyto is a prolonged-release melatonin medicine used in the E.U. to treat insomnia in children and adolescents with autism spectrum disorder, neurogenetic disorders, or ADHD. The U.S. Food and Drug Administration treats melatonin as a dietary supplement and, as such, has not approved it for any medical uses. It was approved for medical use in the European Union in 2007. Besides melatonin, certain synthetic melatonin receptor agonists like ramelteon, tasimelteon, and agomelatine are also used in medicine. In 2023, it was the 164th most commonly prescribed medication in the United States, with more than 3million prescriptions.
Medical uses
Insomnia
An extended-release pharmaceutical formulation of melatonin is approved under the brand name Circadin for the treatment of insomnia in certain settings, such as in people over 55years of age. It is approved in the European Union, Israel, Australia, and countries in Asia and elsewhere in the world, but not in the United States. The medication has been licensed since 2007. Slenyto is a prolonged-release melatonin medicine used in the E.U. to treat insomnia in children and adolescents with autism spectrum disorder, neurogenetic disorders, or ADHD.The 2023 European Insomnia Guideline recommended use of prolonged-release melatonin for treatment of insomnia in people age 55 or older for up to 3months. It recommended against fast-release or over-the-counter melatonin for treatment of insomnia. These recommendations were based on several meta-analyses published in 2022 and 2023.
The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of melatonin in the treatment of insomnia due to poor effectiveness and very low quality of evidence.
Circadian rhythm sleep disorders
Melatonin may be useful in the treatment of delayed sleep phase syndrome.Melatonin is known to reduce jet lag, especially in eastward travel. However, if it is not taken at the correct time, it can instead delay adaptation.
Melatonin appears to have limited use against the sleep problems of people who work shift work. Tentative evidence suggests that it increases the length of time people are able to sleep.
Meta-analyses, published between 2005 and 2017, appear to show different results as to whether melatonin is effective for circadian rhythm sleep disorders or not. Some found that it was effective, while others found no evidence of effectiveness. Meta-analyses of melatonin for delayed sleep phase syndrome that found it effective have reported that it improves time to sleep onset by about 40minutes and advances onset of endogenous melatonin secretion by about 1.2hours. One meta-analysis found that melatonin was notably more effective in improving sleep onset latency in people with delayed sleep phase syndrome than in people with insomnia. One meta-analysis found that melatonin was probably effective for jet lag syndrome.
Low doses of melatonin may be advantageous to high doses in the treatment of sleep-cycle disorders.
REM sleep behavior disorder
Melatonin is a safer alternative than clonazepam in the treatment of REM sleep behavior disorder – a condition associated with the synucleinopathies like Parkinson's disease and dementia with Lewy bodies. However, clonazepam may be more effective. In any case, the quality of evidence for both treatments is very low and it is unclear whether either is definitely effective.Dementia
A 2020 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer's disease. A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer's disease it has little to no effect. Melatonin may, however, help with sundowning in people with dementia.Available forms
A prolonged-release 2mg oral formulation of melatonin sold under the brand name Circadin is approved for use in the European Union in the short-term treatment of insomnia in people age 55 and older.Melatonin is also available as an over-the-counter dietary supplement in many countries. It is available in both immediate-release and less commonly prolonged-release forms. The compound is available in supplements at doses ranging from 0.3mg to 10mg or more. It is also possible to buy raw melatonin powder by weight. Immediate-release formulations of melatonin cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, oral films, or as a liquid. It is also available for use sublingually, or as transdermal patches. Several inhalation-based melatonin products with a wide range of doses are available but their safety remains to be evaluated.
The American Academy of Sleep Medicine says that the melatonin content in unregulated supplements can diverge widely from the claimed amount; a study found that the melatonin content ranged from one half to four times the stated dose.
Contraindications
s to the use of melatonin include hypersensitivity reactions among others. It is not recommended in people with autoimmune diseases due to lack of data in these individuals. Prolonged-release pharmaceutical melatonin contains lactose and should not be used in people with the lactase deficiency or glucose–galactose malabsorption. Use of melatonin is also not recommend in women who are pregnant or breastfeeding or in people with liver disease.Adverse effects
Melatonin appears to cause very few side effects as tested in the short term, up to three months, at low doses. Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials, and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and placebo. Prolonged-release melatonin is safe with long-term use of up to 12 months. Although not recommended for long-term use beyond this, low-dose melatonin is generally safer, and a better alternative, than many prescription and over-the-counter sleep aids if a sleeping medication must be used for an extended period of time. Low doses of melatonin are usually sufficient to produce a hypnotic effect in most people. Higher doses do not appear to result in a stronger effect but instead appear to cause drowsiness for a longer period of time.There is emerging evidence that the timing of taking exogenous melatonin in relation to food is also an important factor. Specifically, taking exogenous melatonin shortly after a meal is correlated with impaired glucose tolerance. Therefore, Rubio-Sastre and colleagues recommend waiting at least 2 hours after the last meal before taking a melatonin supplement.
Melatonin can cause nausea, next-day grogginess, and irritability. In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.
Melatonin can lower follicle-stimulating hormone levels. Melatonin's effects on human reproduction remain unclear.
Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin increased REM sleep time and dream activity in people both with and without narcolepsy.
Increased use of melatonin in the 21st century has significantly increased reports of melatonin overdose, calls to poison control centers, and related emergency department visits for children. The number of children who unintentionally ingested melatonin supplements in the US has increased 530% from 2012 to 2021. Over 4,000 reported ingestions required a hospital stay, and 287 children required intensive care. The American Academy of Sleep Medicine says there is little evidence that melatonin supplementation is effective in treating insomnia in healthy children.