Produced by the pineal gland, melatonin is a hormone that is involved in the body’s circadian rhythm, or sleep-wake cycle. During the day, the hypothalamus blocks the pineal gland from secreting the hormone, promoting wakefulness. At night, when light exposure drops, production begins and melatonin is secreted into the bloodstream.
The development of synthetic melatonin in the 1950s opened the door to its commercial development, but its growing popularity has raised regulatory questions, particularly concerning its biological activity and whether it should be classified as a drug or supplement.
Across the EU, Member States have adopted different approaches to regulating melatonin. Denmark and Sweden do not permit its use in food supplements, while France, Spain and Italy allow it at certain doses. Hungary recently took a restrictive position, following longstanding warnings from its national health authorities that no minimum dose can be considered safe for regular, long-term use in over-the-counter (OTC) supplements.
Consequently, melatonin’s regulatory status varies considerably across Europe. It is also attracting increased global regulatory attention, including consideration under Article 8 of Regulation (ED) No 1925/2006, which provides a framework for restricting or prohibiting certain substances added to foods across the EU where potential risks to consumers has been identified.
1958: Discovery of melatonin
Melatonin was first isolated in 1958 by American physician Aaron B. Lerner and his colleagues at Yale University School of Medicine. Using more than 100 kg of bovine pineal glands, the team isolated and extracted the compound N-acetyl-5-methoxytryptamine.
It was named melatonin due to earlier research which found that when the compound was added to water, it caused the skin of tadpoles to lighten significantly. The researchers theorized that this occurred because melanin, the pigment responsible for skin color, clustered together with pigment-producing cells, making less pigment visible across the skin.
However, this production method yielded only 100 micrograms of natural melatonin, making it impractical for large-scale commercial production.
1959: Melatonin first synthesized
In 1959, Lerner’s team successfully synthesized melatonin in the lab using chemical precursors. The synthetic compound was tested side-by-side with extracted melatonin, proving to be identical across a series of chemical, physical and biological measures.
At the time, the researchers were unaware of melatonin’s role in sleep, with Lerner and colleagues noting in their 1960 paper that the physiological role of melatonin in animals was unknown. In the following decades, researchers began to explore its potential uses.
1965: The ‘melatonin hypothesis’
A few years later, Richard J. Wurtman, an academic at Massachusetts Institute of Technology (MIT) and Julius Axelrod of National Institutes of Health (NIH), further advanced understanding of melatonin’s role in the body. In 1965, they published a paper titled “The Pineal Gland” in Scientific American, outlining what became known as the melatonin hypothesis.
The hypothesis proposed that the pineal gland responds to changes changes in environmental light by increasing melatonin secretion in darkness and reducing it in the daylight. Through this mechanism, melatonin was thought to regulate biological rhythms and reproductive functions. These early findings laid the foundation for further research into melatonin’s role in sleep and the regulation of the sleep-wake cycle.
1970s-1980s: Research on melatonin’s properties begins
Over the following two decades, several studies provided further support for this theory. Among them was a paper by Antón-Tay and colleagues in 1971, which examined melatonin’s effects on human brain waves (EEG) and central nervous system activity, highlighting its potential calming and therapeutic effects.
In 1973, researchers from the University of Pittsburgh published a paper demonstrating for the first time that melatonin follows a 24-hour concentration cycle in human blood, directly linking it to nighttime states. Seven years later, researchers from the National Institute of Mental Health (NIMH, part of NIH) proved that bright light could suppress nocturnal melatonin production in humans. This discovery revolutionized the understanding of how environmental light affects human sleep-wake cycles and circadian rhythms.
By the 1990s, a growing body of clinical research had demonstrated that synthetic melatonin could improve certain aspects of sleep in healthy individuals. Other studies also began exploring its potential role in immune function, mood regulation and cancer.
1994: Melatonin classified as a supplement in the U.S.
In the United States, the 1994 enactment of the Dietary Supplement Health and Education Act (DSHEA) marked a turning point for melatonin’s commercial development by establishing a regulatory framework under which melatonin could be marketed as a dietary supplement. This allowed manufacturers to sell synthetic melatonin without the need for lengthy drug approvals, helping to accelerate the growth of the U.S. melatonin supplement market.
By 1995, health food stores all over the United States were selling melatonin supplements, and in September of that year, the U.S. Patent and Trademark Office published the Methods of Inducing Sleep Using Melatonin patent granted to the Massachusetts Institute of Technology (MIT), naming researcher Dr. Richard J. Wurtman as the inventor and overing the use of low doses of melatonin to promote sleep.
1995: MHRA classifies melatonin as a medicine
In contrast to the U.S. approach, the UK’s Medicines Control Agency (MCA), now the Medicines and Healthcare products Regulatory Agency (MHRA), determined that melatonin should be classified as a medicinal product rather than a food supplement. The decision was based on its significant pharmacological activity and its effects on human physiology. Under the applicable medicines legislation, substances used to restore, correct or modify physiological functions could fall within the definition of a medicinal product, meaning that melatonin-containing products required a marketing authorization before they could be legally sold.
1997: Melatonin deemed ‘not novel’
In May 1997, the EU introduced Regulation (EC) No 258/97 on Novel Food Ingredients. Under the regulation, foods and ingredients without a history of significant consumption in the EU before 15 May 1997 were generally subject to pre-market safety assessment and authorization. Because melatonin is a naturally occurring substance found in food, and that synthetic melatonin is bio-identical to what the body makes, it was not considered novel, meaning it remained available to purchase as a supplement and rigorous safety evaluations were not required.
2002: Regulations permitted to differ by Member State
The EU adopted Directive 2002/46/EC, establishing harmonized rules for vitamins and minerals in food supplements. However, other substances, like botanicals and their constituents, were excluded from its scope. This regulatory gap left Member States to determine their own approached to the classification of these substances, including melatonin, as either a food ingredient or medicinal product.
2007: First melatonin drug is approved
In 2007, the European Medicines Agency (EMA) recommended the first EU-wide marketing authorization for Circadin, a 2 mg prolonged-release melatonin tablet, as a prescription-only medicine. This decision set a an important regulatory precedent, reinforcing the classification that higher-dose, slow-release melatonin products were medicinal products rather than food supplements.
Immediate-release vs. prolonged-release melatonin
Immediate-release (IR) melatonin and prolonged-release (PR) melatonin differ primarily in how quickly they are absorbed and how long they stay active in the body. IR is absorbed rapidly and helps people to fall asleep, while PR releases the hormone gradually across 6 to 8 hours and is typically used when staying asleep is the primary issue.
These two types of melatonin are regulated differently in the EU. The European Medicines Agency (EMA) centrally licenses PR melatonin as a prescription-only drug, but IR melatonin is sometimes authorized in supplements, depending on the country.
2011: EU Member States begin imposing restrictions
In the early 2010s, EU member states increasingly began establishing their own national approaches to the classification and regulation of melatonin. In Germany, for example, the Federal Institute for Drugs and Medical Devices (BfArM) classified melatonin products at doses between 0.5 mg and 5 mg as medicinal products, effectively banning high-dose melatonin supplements. Regulations were later updated so that products containing up to 1 mg of melatonin could be sold as supplements.
In 2011, France added melatonin to its List II of poisonous substances leading to sale restrictions. However, restrictions were later lessened, permitting low-dose melatonin supplements.
2012: EFSA approves two health claims for low-dose melatonin
In May 2012, the European Commission officially adopted a new regulation (EU) No 432/2012, establishing a permitted list of health claims for use across the European Union. Two distinct health claims for melatonin—one for jet lag and one for sleep latency reduction—were approved but only in low-dose supplements of up to 1 mg per day.
2013: Italy reduces daily limit
In response to these new health claim laws, Italy’s Ministry of Health adjusted its national guidelines, lowering the maximum permitted dose of melatonin in food supplements to 1 mg per day to align with EFSA’s scientific opinion.
2018: Czech Republic enacts blanket ban
In 2018, the Czech Republic passed Decree No. 58/2018 Coll, adding melatonin to the list of prohibited substances in food and effectively requiring all melatonin-containing products to be regulated as prescription-only medicines, regardless of dose—an approach broadly consistent with the UK’s classification. In 2024, however, the country began permitting low-dose melatonin in supplements (up to 0.5 mg per day).
2018-2022: More melatonin drugs approved by EMA
The EMA approved two more centralized melatonin medications: Slenyto in 2018 (a prolonged-release, low-dose drug tailored for children) and Melatonin Neurim in 2022 (another slow-release prescription product for older adults).
2024: Melatonin comes under fire
In 2024, a working group representing the heads of European food safety agencies (HoA) identified melatonin—among 12 other substances—as a candidate for review under Article 8, primarily because supplement consumption can result in intakes substantially exceeding normal dietary exposure.
The assessment is currently on hold due to the divergent classifications of melatonin across across Member States, leading to a more complicated regulatory landscape compared to other botanical ingredients.
2026: Hungary bans melatonin in supplements
In August, Hungary enacted an outright ban on melatonin in food supplements due to a lack of long-term safety data and concerns about drug interactions.
There are now concerns that this ban could reactivate the dormant, EU-wide Article 8 safety review if Hungary requests a unified safety assessment from the European Food Safety Authority (EFSA).
