Melatonin as a medication and supplement

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 (where it reached phase 3 trials but was not approved). 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. Circadian rhythm sleep disorders Melatonin may be useful in the treatment of delayed sleep phase syndrome. 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. Some found that it was effective, Low doses of melatonin may be advantageous to high doses in the treatment of sleep-cycle disorders. 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. 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 (increased confusion and restlessness at night) 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 (AASM) says that the melatonin content in unregulated (without a USP verified mark) 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==

Contraindications 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 (Circadin) contains lactose and should not be used in people with the lactase deficiency or glucose–galactose malabsorption. Use of melatonin is also not recommended 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. ==Overdose==

Melatonin appears to be relatively safe in overdose. The most commonly reported adverse effect of melatonin overdose is somnolence. Upon melatonin overdose, drowsiness may be expected and the compound should be cleared within 12hours. No special treatment is needed for melatonin overdose. ==Interactions==

Melatonin is metabolized mainly by CYP1A enzymes. As such, inhibitors and inducers of CYP1A enzymes, such as CYP1A2, can modify melatonin metabolism and exposure. ==Pharmacology==

Pharmacodynamics Melatonin acts as an agonist of the melatonin MT1 and MT2 receptors, the biological targets of endogenous melatonin.) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening. Normal melatonin production is approximately 30μg (0.03mg) per day/night. In adults in temperate zones, the onset of melatonin secretion is around 21:00 to 22:00h, the peak is around 02:00 to 04:00h, and the offset is around 07:00 to 09:00h. There is marked variability (e.g., 10-fold) in melatonin secretion and levels between individuals. Doses of melatonin even above 300μg (0.3mg) have been shown to produce supraphysiological melatonin levels. Usual doses of exogenous melatonin of 1 to 12mg produce circulating melatonin concentrations that are 10 to 100times higher than endogenous peak levels, which remain elevated for 4 to 8hours. Melatonin levels with Circadin, an approved 4-mg controlled-release pharmaceutical drug, are also supraphysiological. Clinical studies have found melatonin to have maximal effectiveness and the fewest side effects at a once-nightly dose of 0.3mg. In elderly people, this dose resulted in similar melatonin spikes in magnitude and duration to those that occur in healthy young people. Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60minutes of administration, and is then eliminated. A single 0.5mg dose of melatonin achieved peak melatonin levels ranging between 2 and 395nmol/L between different individuals. Metabolism Melatonin is metabolized in the liver by cytochrome P450 enzyme CYP1A2 to 6-hydroxymelatonin. Metabolites are conjugated with sulfuric acid or glucuronic acid for excretion in the urine. Some of the metabolites formed via the reaction of melatonin with a free radical include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK). The half-life of prolonged-release melatonin (Circadin) is 3.5 to 4hours. ==Chemistry==

Melatonin, also known as N-acetyl-5-methoxytryptamine, is a substituted tryptamine and a derivative of serotonin (5-hydroxytryptamine). It is structurally related to N-acetylserotonin (normelatonin; N-acetyl-5-hydroxytryptamine), which is the chemical intermediate between serotonin and melatonin in the body. Synthetic melatonin receptor agonists used in medicine like ramelteon, tasimelteon, agomelatine, and piromelatine (still in clinical trials) are analogues of melatonin. Synthesis The chemical synthesis of melatonin has been described. ==History==

The first patent for its use in circadian rhythm disorders was granted in 1987 to Roger V Short and Stuart Armstrong at Monash University, and the first patent for its use as a low-dose sleep aid was granted to Richard Wurtman at MIT in 1995. Around the same time, the hormone got a lot of press as a possible treatment for many illnesses. The New England Journal of Medicine editorialized in 2000: "With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear." It was approved for medical use in the European Union in 2007. ==Society and culture==

Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada. though the FDA has found claims that it cures cancer to be false. As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin. According to Harriet Hall, caution is advisable, since quality control is a documented problem, particularly with respect to discrepancies between actual and label-stated dosage. To make matters worse, in one study, 8 out of 31 products were contaminated with the neurotransmitter serotonin. Formerly, melatonin was derived from animal (e.g., bovine) pineal tissue. It is now synthetic, which limits the risks of contamination and of transmitting infectious material. Melatonin is the most popular over-the-counter sleep remedy in the United States, with sales in excess of US$400 million during 2017. In 2022, it was the 217th most commonly prescribed medication in the United States, with more than 1million prescriptions. The FDA considered whether these food products could continue to be sold with the label "dietary supplements". On 13 January 2010, it issued a warning letter to Innovative Beverage, creators of several such products, stating that melatonin, while legal as a dietary supplement, was not approved as a food additive. Bebida Beverage Company received a warning letter in 2015 for selling a melatonin-containing beverage. ==Research==

Some research supports an antidepressant and anxiolytic effect of melatonin. It has also been used to aid in the treatment of manic episodes in bipolar disorder, although evidence for its effectiveness is still inconsistent. Other studies have shown that melatonin may help reduce some types of headaches, epigastric pain and heartburn. There have also been studies trying to prove the effectiveness of melatonin in relation to epilepsy, dysmenorrhea, delirium, and tinnitus, but little to no beneficial role has been found. Melatonin has also been tested as a treatment for cancer, but the National Cancer Institute found insufficient evidence for it. However, further research found it to slightly improve survival of patients and to alleviate chemotherapy-related side effects. Melatonin has been found to possess anti-inflammatory effects. It has been found to reduce levels of several pro-inflammatory cytokines in clinical studies, with large effect sizes. Melatonin might be useful in the treatment of inflammatory disorders. ==References==