Melatonin

Origin and structure

Melatonin is not a peptide. It is a small indoleamine, N-acetyl-5-methoxytryptamine, built from serotonin rather than from a chain of amino acids, and it is made mainly by the pineal gland in the brain. Its release rises soon after dark, peaks between about 2 and 4 a.m. and falls again in the second half of the night, so the hormone works as the body's signal that it is night. Production declines with age, which is the reasoning behind the medicine for people aged 55 and over.

The melatonin in medicines and supplements is made synthetically and is chemically identical to the body's own. Taken by mouth it is absorbed, but the liver breaks down about 85% on the first pass, so only about 15% reaches the circulation, and its elimination half-life is about 40 minutes. To imitate the night-long release of the pineal gland, Circadin and Slenyto are prolonged-release tablets that release melatonin over several hours. Blood levels differ widely between people: peak levels in women are three to four times those in men, and older people break it down more slowly.

How it works

Melatonin acts mainly on two receptors, MT1 and MT2, which take part in regulating the body clock and sleep. It has two kinds of effect. It shifts the timing of the body clock and helps align it with the light-dark cycle, which is why timing matters: in the jet-lag trials it helped when given close to the target bedtime at the destination, while a dose at the wrong time, early in the day, can cause sleepiness and delay adaptation to local time. It also has a mild sleep-promoting effect, raising the tendency to fall asleep.

Its profile differs from that of classic sleeping pills: in a sleep-laboratory study Circadin shortened the time to fall asleep without changing the structure of sleep or the amount of REM sleep, and without impairing daytime functioning.

Is melatonin approved?

Yes, in the EU, as a prescription medicine for specific sleep problems, and in the Netherlands also as a self-care medicine for jet lag. In the US it is not an approved medicine.

In the Netherlands Circadin is available on prescription and is not reimbursed from basic health insurance. Tablets of 1, 3 and 5 mg for short-term treatment of jet lag in adults are registered as self-care medicines, sold without prescription in pharmacies and drugstores, and are not reimbursed either. Products with less than 0.3 mg a day are sold as food supplements; the section below explains that line.

Research-grade melatonin is none of these medicines. It has no marketing authorisation, is not made under a medicines licence and may not be used in people. The approvals below describe the licensed products only.

• EU: Circadin (2 mg prolonged-release tablets, Neurim) authorised on 29 June 2007 as monotherapy for short-term treatment of primary insomnia with poor sleep quality in people aged 55 and over. Slenyto (1 and 5 mg prolonged-release mini-tablets, Neurim) authorised on 20 September 2018 for insomnia in children and adolescents aged 2 to 18 with autism spectrum disorder and/or Smith-Magenis syndrome when sleep-hygiene measures are not enough. In August 2024 that indication was widened to neurogenetic disorders with abnormal daytime melatonin secretion or night waking, and in March 2025 insomnia in children aged 6 to 17 with ADHD was added.
• Netherlands: besides these EU-wide authorisations, 1, 3 and 5 mg tablets from several manufacturers are registered as medicines for short-term treatment of jet lag in adults and sold without prescription.
• US: no melatonin product is approved by the FDA. Melatonin is sold over the counter as a dietary supplement, which needs no government approval of its quality or strength before sale.

What the research shows

Melatonin has been tested in many placebo-controlled trials, most of them small and lasting weeks rather than months. The effects on sleep are real but modest, and larger in some groups than in others:

• Primary sleep disorders (meta-analysis, PLoS One 2013): across 19 trials with 1,683 people, participants on melatonin fell asleep 7 minutes faster (95% CI 4.4 to 9.8) and slept 8 minutes longer (95% CI 1.7 to 14.8) than on placebo, and rated their sleep quality slightly better. Longer trials and higher doses showed somewhat larger effects on falling asleep and total sleep.
• Circadin in adults aged 55 and over: in three main studies with 681 patients, 32% (86 of 265) reported a clear improvement in sleep quality and next-day functioning after three weeks, against 19% (51 of 272) on placebo. In a sleep-laboratory study it shortened the time to fall asleep by 9 minutes compared with placebo. A six-month trial in 600 people showed that the benefit held for three months but missed its main analysis at six months. The EMA's committee judged the effect small, in a relatively small number of patients, but the benefits greater than the risks.
• Jet lag (Cochrane review, 2002): in 9 of 10 randomised trials, melatonin taken close to the target bedtime at the destination reduced jet lag after flights across five or more time zones. Doses of 0.5 to 5 mg worked about equally well, although people fell asleep faster after 5 mg; doses above 5 mg were no better, and 2 mg slow-release worked less well. The number needed to treat was 2, with less benefit on westward flights.
• Children with autism (the Slenyto trial): 125 children aged 2 to 17 whose sleep had not improved with behavioural measures. After 13 weeks they slept 57.5 minutes longer on Slenyto against 9.1 minutes on placebo (adjusted difference 33 minutes) and fell asleep 39.6 against 12.5 minutes faster, without waking earlier. The gains were maintained in open-label follow-up, and the trial treated children for up to two years.
• Children with ADHD: in a Dutch trial (van der Heijden, 2007) of 105 medication-free children aged 6 to 12 with chronic trouble falling asleep, 3 or 6 mg for four weeks shortened the time to fall asleep by 21.3 minutes, against a 3-minute increase on placebo, and lengthened total sleep by 19.8 minutes, against a 13.6-minute loss; behaviour, cognitive performance and quality of life did not change. In the Slenyto trial the 36 children who also had ADHD improved as much as the others.
• Guidelines: the European Insomnia Guideline (2023) puts cognitive behavioural therapy first, allows prolonged-release melatonin for up to three months from age 55, and does not recommend fast-release melatonin for insomnia. The Dutch Farmacotherapeutisch Kompas advises against melatonin without a medical indication and supervision and states that it has no clinically relevant effect on insomnia.

Supplement or medicine: the Dutch 0.3 mg line

In the Netherlands the line between a food supplement and a medicine is drawn at 0.3 mg a day. The Health and Youth Care Inspectorate (IGJ) in principle does not treat products with a daily dose below 0.3 mg as medicines. From 0.3 mg a day it considers melatonin to have a significant pharmacological effect on the body, and a product can then be classed as a medicine if it also meets the other criteria set by the courts; it may then only be sold with a marketing authorisation from the CBG.

The IGJ and the food safety authority NVWA stepped up enforcement in 2019: in November and December that year they inspected ten manufacturers and wholesalers and sampled 84 unregistered melatonin products, and since 1 July 2020 selling unregistered melatonin medicines can lead to an administrative fine. Two companies contested the line in a case about the publication of inspection reports on them. On 1 April 2026 the Council of State, the highest general administrative court, ruled that there is sufficient factual basis for a significant pharmacological effect from a daily dose of 0.3 mg (ECLI:NL:RVS:2026:1846).

The rule is Dutch, not European. Under EU food law a supplement providing 1 mg may claim that melatonin shortens the time it takes to fall asleep, but according to the IGJ such a claim does not stop a product from being a medicine in the Netherlands. Label accuracy is a separate problem: in a 2023 test of 25 melatonin gummies sold in the US, 22 were inaccurately labelled; one contained no measurable melatonin, and the others held 74 to 347% of the amount on the label.

Side effects and warnings

In the Circadin trials (1,931 people on melatonin, 1,642 on placebo), adverse reactions were reported by 9.5% on melatonin against 7.4% on placebo; the most frequent events, headache, nasopharyngitis, back pain and joint pain, were common in both groups. Less common reactions included irritability, restlessness, abnormal dreams and nightmares, dizziness, migraine, sleepiness, raised blood pressure and stomach complaints. In children on Slenyto the common side effects were sleepiness, fatigue, mood swings, headache, irritability, aggression and a hangover feeling.

Melatonin causes drowsiness, which matters for driving. The labels advise against combining it with fluvoxamine, which raises melatonin exposure 17-fold, with alcohol, which reduces its effect on sleep, and with sleeping pills such as zolpidem, with which it impaired attention, memory and coordination more than zolpidem alone. Oestrogens, cimetidine and quinolone antibiotics raise melatonin levels; smoking, carbamazepine and rifampicin lower them. It is not recommended in pregnancy or during breastfeeding, with liver impairment, which slows its clearance, or with autoimmune disease, for lack of data. The Farmacotherapeutisch Kompas adds that it can affect blood-sugar control for a few hours, can counteract blood-pressure medicines and affect anticoagulant control, and calls for care in epilepsy. In overdose drowsiness is expected, and melatonin is cleared within about 12 hours.

Long-term safety is less well documented. A Dutch follow-up of 51 children who had used melatonin for a mean of 3.1 years found sleep, puberty stage and mental-health scores in line with Dutch children of the same age, but it was small and had no control group of its own. In November 2025 an observational study presented at the American Heart Association's meeting found that, in the health records of 130,828 adults with insomnia, heart failure was diagnosed within five years in 4.6% of those who had used melatonin for a year or more, against 2.7% of matched non-users. It has not been peer reviewed and cannot show cause and effect: insomnia severity and psychiatric illness were not known, and people taking melatonin as an over-the-counter supplement ended up in the comparison group.

Frequently asked questions

Is melatonin legal in the Netherlands?

Yes, within limits. Food supplements with less than 0.3 mg a day are sold freely. From 0.3 mg a day a product can count as a medicine and then needs a marketing authorisation: Circadin and Slenyto are prescription-only, and 1, 3 and 5 mg jet-lag tablets are sold without prescription in pharmacies and drugstores. In April 2026 the Council of State backed the 0.3 mg line. Research-grade melatonin is not a medicine and may not be used in people.

Why do Dutch melatonin supplements stay below 0.3 mg?

Because the IGJ considers 0.3 mg a day the dose from which melatonin has a significant pharmacological effect. A product at or above that dose can be classed as a medicine, and a medicine may only be sold with a marketing authorisation. The Council of State found that position sufficiently supported on 1 April 2026. The EU health claim about falling asleep faster applies to supplements with 1 mg per portion, but in the Netherlands such a product can still count as a medicine.

Does melatonin work for insomnia?

Only modestly. Across 19 placebo-controlled trials people fell asleep about 7 minutes faster and slept about 8 minutes longer. In adults aged 55 and over, Circadin helped 32% against 19% on placebo after three weeks. The European Insomnia Guideline puts cognitive behavioural therapy first, allows prolonged-release melatonin for up to three months from age 55 and does not recommend fast-release melatonin for insomnia. The effects are clearer for jet lag and for children with autism or ADHD.

Is melatonin safe for children?

In the approved uses the short-term side effects are mild to moderate. Slenyto is authorised from age 2 for autism and neurogenetic disorders and from age 6 for ADHD, only after sleep-hygiene measures have failed, and its trial followed children for up to two years. The Dutch jet-lag tablets are not for anyone under 18. Long-term effects, for example on puberty, have only been studied in small follow-ups, such as a Dutch study of 51 children after a mean of 3.1 years that found no differences from Dutch norms.

Is melatonin banned in sport?

No. Melatonin is not on the WADA Prohibited List for 2026, nor on the 2027 List that takes effect on 1 January 2027. Because it is an approved medicine, the S0 class for non-approved substances does not apply to it either.

Is melatonin a peptide?

No. Peptides are chains of amino acids; melatonin is a single small indoleamine molecule that the body makes from serotonin. It is a hormone and an authorised medicine, but not a peptide.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.