Melatonin

Melatonin

1. Identity and Chemical Characterization

Common name: Melatonin
Chemical/IUPAC name: N-acetyl-5-methoxytryptamine
Molecular formula: C₁₃H₁₆N₂O₂

Melatonin, also known by its chemical name N-acetyl-5-methoxytryptamine, is a natural hormone synthesized mainly by the pineal gland of vertebrates, and, secondarily, by other tissues and organs as well. From a physicochemical point of view, pure melatonin resembles an off-white powder with a molecular weight of 232.28 g/mol and a density of 1.175 g/cm³. The melting point ranges between 116.5 °C and 118 °C; the boiling point is 512.8 °C. From a chemical point of view, melatonin is identified by the chemical formula C₁₃H₁₆N₂O₂. The indole chemical scaffold is functionalized with a 3-amide group and a 5-alkoxy group.

Melatonin is an omnipresent molecule that has been observed to be present in almost every living being, from bacteria to humans. Research conducted up to 2024 has reported the presence of melatonin in a wide variety of plants and bacteria as well.

Regulatory Status

In the United States, melatonin is considered a dietary supplement. Although not officially approved for any indication by the U.S. Food and Drug Administration (FDA), exogenously supplied melatonin, available as a synthetic dietary supplement, mimics the regulatory functions of endogenous melatonin. However, melatonin receptor agonists such as ramelteon and tasimelteon are available on the market and are FDA-approved for the treatment of insomnia.

2. Natural Sources and Biosynthetic Origin

Endogenous Biosynthesis in Animals

The biosynthesis of melatonin in animals involves a sequence of enzymatic reactions starting with L-tryptophan, which can be synthesized through the shikimate pathway from chorismate, found in plants, or obtained from protein catabolism. Its biosynthesis from tryptophan involves four well-defined intracellular steps catalyzed by tryptophan hydroxylase, aromatic amino acid decarboxylase, arylalkylamine-N-acetyltransferase, and hydroxyindole-O-methyltransferase. Specifically: the first step is hydroxylation of the tryptophan indole ring at the 5-position to afford 5-hydroxytryptophan — a rate-limiting step in serotonin production catalyzed by tryptophan hydroxylase. The second step leading to serotonin (5-hydroxytryptamine) is catalyzed by aromatic amino acid decarboxylase. The conversion of serotonin to N-acetylserotonin, the immediate precursor of melatonin, is highly regulated in the pineal and is catalyzed by serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT).

Melatonin is a hormone produced by the pineal gland in the brain, mainly during the night, that helps regulate circadian rhythms. Its levels decrease with age. Compared to pineal melatonin, which has a well-established circadian rhythm, the melatonin secreted at the extrapineal level is not released into the blood, acting only locally at the level of the tissues and organs that produce it, and does not have a circadian secretion pattern. An estimated 99% of the melatonin in vertebrates is likely not produced in the pineal gland and is never released into the circulation. The discovery of melatonin in mitochondria, where it likely functions as a direct free radical scavenger and as an indirect antioxidant, means that the total quantity of melatonin synthesized in vertebrates is much greater than originally envisioned.

Phytomelatonin — Plant Sources

Plant cells generally have higher levels of melatonin than animal cells; this likely relates to the fact that plant cells have two sources of melatonin (mitochondria and chloroplasts) while animal cells have a single source. In vertebrates, melatonin is referred to as the chemical expression of darkness (based only on pineal and blood levels); in general, in plants a day/night rhythm is less common, although not totally absent in some species.

Many commonly consumed foods contain measurable quantities of phytomelatonin. Grapes, cherries, and strawberries were the most popular fruits studied for melatonin content, and they also showed differences between cultivars. The highest melatonin in these three fruits was reported in the range of 8.9–158.9 ng/g DW in the skin of grapes (Vitis vinifera L. cv. Malbec), 13.46 ± 1.10 ng/g FW in tart cherries (Prunus cerasus L. cv. Balaton), and 11.26 ± 0.13 ng/g FW in strawberry (Fragaria ananassa L. cv. Festival). Among fruits, tart cherries, particularly the Montmorency variety, are widely studied sources of dietary melatonin. An 8-ounce serving of tart cherry juice concentrate can contain a measurable amount of melatonin, sometimes exceeding 1 milligram.

Nuts and seeds are another category with high concentrations of the hormone. Pistachios are a particularly rich source, containing significantly more melatonin than most other nuts. Walnuts are sources of several nutrients that can be helpful for sleep and brain health, like omega-3 fatty acids and tryptophan. The melatonin content is approximately 3.5 nanograms per gram. Melatonin is also found in grains, such as oats and rice, with whole grain and black rice varieties often containing concentrated amounts. However, the concentration of melatonin in foods is typically far below therapeutic supplement doses; consuming just 0.3 milligrams of melatonin from walnuts would require approximately 857 cups of shelled walnuts (over 500,000 kcal).

A 2014 study screened melatonin content in leaves of seven edible herbs used as sleeping aids in Thai traditional medicine. Melatonin was found in six of the seven herbs; one of these, Piper nigrum (black pepper), exhibited an encouragingly high amount of melatonin. Specifically, the highest melatonin content was from the P. nigrum extract (1092.7 ng/g of dry sample weight).

Several reports in the past decade have identified melatonin in different parts of plants, opening a new chapter in the field of plant-derived melatonin (phytomelatonin). The majority of herbs which contain high levels of melatonin have been used traditionally to treat neurological disorders or diseases associated with the generation of free radicals, which could be due to the presence of this potent antioxidant molecule.

Commercial Supplement Forms

Melatonin dietary supplements can be made from animals or microorganisms, but most often they are made synthetically. Melatonin is sold as an over-the-counter dietary supplement in a range of doses. Commercially available formulations include immediate-release tablets and capsules, sublingual tablets, liquid drops, chewable tablets, gummy preparations, transdermal patches, and prolonged-release oral preparations (the latter approved as a prescription medicine in the European Union under the brand name Circadin® for adults ≥55 years).

3. Discovery and Historical Context

Melatonin was first discovered in 1958 by a dermatologist named Aaron Lerner, and it has been researched extensively since the 1980s. Lerner was able to isolate a compound in a bovine pineal gland that had a strong bleaching effect on amphibian skin, which he gave the name melatonin. They named it melatonin after the Greek words "melas" (black) and "tonos" (stretch), as they observed that the hormone had a skin-lightening effect in amphibians.

It was also Lerner who began studying the effect of the hormone on sleep. After a self-experiment with 100 mg of melatonin, Lerner reported that he had no side effects except for drowsiness. In the 1960s, it was still assumed that the light-dark rhythm was important for mammals but not for humans. Not until 1981 did Alfred Lewy discover that bright light applied at night suppressed endogenous melatonin in humans. This discovery was a breakthrough for chronobiology and research on melatonin.

Melatonin was discovered in land plants about 25 years ago, where it functions as an antioxidant in a receptor-independent manner, as it does in animals. Although melatonin itself was not known as an entity in traditional herbalism, plants such as Tanacetum parthenium (feverfew), Tripleurospermum disciforme, and Viola odorata have a long history in Iranian traditional medicine for the treatment of migraine, cancer, and menstrual cramps, and have also been used as sedatives, antimicrobial and anti-inflammatory agents, and for problems related to stress — uses now understood to potentially reflect their melatonin content.

In Thai traditional medicine, melatonin content was screened in leaves of seven edible herbs used as sleeping aids. This investigation provides a scientific basis for the traditional ethnobotanical use of these plants to promote sleep, a function consistent with their melatonin content. The use of melatonin as a commercial dietary supplement began to grow substantially in the early 1990s following growing interest in its chronobiotic and antioxidant properties, and melatonin dietary supplement sales in the U.S. more than doubled to USD 821 million in 2020 compared with 2017.

4. Key Constituents and Active Compounds

Melatonin is a single well-defined molecule (N-acetyl-5-methoxytryptamine) rather than a multi-constituent botanical extract. Its biological activity derives from its interactions with specific receptor systems and its intrinsic chemical properties.

Receptor-Mediated Mechanisms

The rhythmic release of melatonin from the pineal gland and retina helps coordinate circadian rhythms and neuroendocrine processes via activation of two G protein-coupled receptors, termed MT1 and MT2. The circadian production of pineal melatonin is controlled by endogenous oscillators within the suprachiasmatic nucleus (SCN) and entrained by daily and seasonal changes in the environmental light-dark cycle.

Melatonin regulates circadian rhythms by reducing neuronal firing of the SCN. This occurs at night via its binding to the G-protein-coupled receptor MT1, to activate G-protein-coupled inwardly rectifying potassium (GIRK) channels. Melatonin can also bind to another G-protein-coupled receptor, MT2, to inhibit cyclic guanine monophosphate (cGMP) formation and stimulate protein kinase C, a neurotransmitter regulator.

Melatonin activates two high-affinity G protein-coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Many of melatonin's actions are mediated through interaction with the G-protein coupled membrane-bound melatonin receptors type 1 and type 2 (MT1 and MT2), or indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined as the MT3 receptor.

Administration of typical levels of melatonin results in the removal of MT2 receptors from the membrane (internalization) and a decrease in the sensitivity of the receptor to melatonin. These responses help the MT2 receptor accomplish its role in phase-shifting the circadian clock by adjusting the sensitivity and availability of the population of MT2 receptors.

Receptor-Independent Mechanisms

In addition to MT1 and MT2, melatonin may act on the quinone reductase QR2 and might be involved in mediating its antioxidant effects. Due to its lipophilic nature, melatonin passes the cell membrane and might interact directly with intracellular proteins. Thus, receptor-independent responses may also play a role in melatonin-dependent mechanisms. Antioxidant and mitochondrial-protecting effects are receptor-independent effects of melatonin.

The discovery of melatonin in mitochondria, where it likely functions as a direct free radical scavenger and as an indirect antioxidant, means that the total quantity of melatonin synthesized in vertebrates is much greater than originally envisioned. In addition to functioning as a scavenger at the site at which it is produced (mitochondria), melatonin generated at the subcellular level may be locally released to function as a paracrine or autocrine agent.

5. Body Systems and Health Areas

While its role in sleep promotion is its most well known, melatonin has involvement in a wide range of biological processes. In addition to sleep promotion, melatonin also regulates hormone secretion, rhythms in reproductive activity, immune functionality, and circadian rhythms. Further, melatonin functions as a neuroprotective, pain-reducer, tumor suppressor, reproduction stimulant, and antioxidant.

• Circadian rhythm and sleep-wake regulation
• Immune system modulation
• Antioxidant and free radical scavenging activity
• Cardiovascular function and blood pressure
• Oncology / cancer biology
• Neurological and neurodevelopmental conditions
• Reproductive endocrinology
• Metabolic regulation (including glucose and insulin signaling)

6. Scientific Evidence by Area of Use

6.1 Insomnia and General Sleep Quality

Research on the efficacy of melatonin supplementation for treating insomnia has shown varied results. However, a meta-analysis conducted by Ferracioli-Oda et al. concluded that individuals who used melatonin experienced an average reduction in sleep onset latency of approximately 7 minutes.

One systematic review and meta-analysis found that melatonin led to a moderate increase in total sleep time by 30.33 minutes (95% CI 18.96–41.70, 4 studies, I² = 0%) and a moderate reduction in sleep latency by 18.03 minutes (95% CI −26.61 to −9.44, 3 studies, I² = 0%). A dose-response meta-analysis of 26 randomized controlled trials (RCTs) published between 1987 and 2020, encompassing 1,689 observations, found that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day. Previous studies reported inconsistent results about exogenous melatonin's sleep-promoting effects, with a possible explanation relying on the heterogeneity in administration schedule and dose.

A network meta-analysis including 40 studies with 36 entered into the quantitative analysis found that findings support effectiveness of melatonin in improving sleep-onset difficulties. Nevertheless, results also suggest that even after optimizing the administration schedule, the degree of melatonin efficacy in insomnia treatment is limited compared to other therapeutic approaches such as cognitive behavioral therapy (CBT). CBT has been shown to reduce sleep onset latency in insomnia patients by 19.03 minutes with respect to inactive comparators, more than twice the highest effect size predicted by the melatonin models.

The Rapid Evidence Assessment of the Literature (REAL) process, drawing on 35 RCTs, concluded that according to GRADE methodology, weak recommendations were made for preventing phase shifts from jet lag, for improving insomnia in both healthy volunteers and individuals with a history of insomnia, and for initiating sleep and/or improving sleep efficacy.

Evidence assessment: Overall evidence for melatonin in primary insomnia is moderate in quantity but modest in effect size. Reductions in sleep onset latency are consistently reported but are numerically small. Effect sizes are meaningfully lower than those seen with CBT-I.

6.2 Jet Lag and Circadian Phase Disruption

Melatonin supplements may help with jet lag. Jet lag affects people when they travel by air across multiple time zones and may cause disturbed sleep, daytime tiredness, impaired functioning, and digestive problems. Research suggests that melatonin supplements may help with jet lag, based on medium-sized reviews from 2010 and 2014.

However, findings are not uniform across all studies. One systematic review found that while two earlier systematic reviews concluded that melatonin is effective in alleviating the symptoms of jet lag, a more recent review showed that melatonin does not affect either sleep onset latency or sleep efficiency in people with jet lag or shiftwork disorder. That review did not determine the effect of melatonin on measures of daytime fatigue.

The effects of melatonin, including sleep-promoting, phase-shifting, and entrainment effects, were investigated on jet lag symptoms, adaptation of shift workers, and entrainment in non-24-hour sleep-wake rhythm disorder. Despite conflicting findings, several studies suggested potential effects on correcting and stabilizing circadian rhythm sleep-wake cycles.

Evidence assessment: The evidence for jet lag is mixed. Some well-designed systematic reviews report modest benefit, particularly for subjective jet lag symptoms, while others find no significant effect on objective sleep parameters. Evidence is stronger for eastward travel (phase advance scenarios).

6.3 Delayed Sleep-Wake Phase Disorder (DSWPD)

Delayed sleep-wake phase disorder (DSPD) is the most frequently occurring intrinsic circadian rhythm sleep-wake disorder, with the highest prevalence in adolescence. It is characterized by difficulty in falling asleep and waking in the morning, while sleep duration and quality are usually normal. In DSPD, the endogenous melatonin rhythm is delayed, and is no longer in alignment with the desired sleep time. Melatonin has been shown to advance the timing of sleep in delayed sleep-wake phase disorder (DSWPD).

Evidence supports that melatonin is an efficacious and safe chronobiotic drug for the treatment of DSPD in children, provided that it is administered at the correct time (3–5 hours before endogenous melatonin starts to rise in dim light), and in the correct (minimal effective) dose.

Evidence assessment: Stronger and more consistent evidence base than for primary insomnia, particularly when melatonin is administered with attention to circadian timing.

6.4 Sleep Disorders in Children with Neurodevelopmental Conditions (ASD and ADHD)

Sleep disorders co-occur in approximately half of the patients with autism spectrum disorder (ASD). Various potential mechanisms, including delayed melatonin peak and reduced rhythm amplitude, have been hypothesized as causes of sleep problems in ASD.

In systematic review analysis, the mean difference in children's sleep disorder showed statistically significant improvement in sleep duration and sleep latency onset compared to placebo. Overall, a high response rate was observed in the melatonin group compared to placebo in treating sleep problems in children. One double-blind RCT including 66 children (age 4–10 years) with ASD found that patients on both CBT and melatonin improved significantly compared to those in the melatonin-only group in terms of reduction in sleep onset latency, wakefulness after sleep onset, and total sleep duration.

Regarding long-term use, one study including 95 children and adolescents with ASD and neurogenetic disorders with or without ADHD comorbidity found that long-term treatment with 5 or 10 mg controlled-release melatonin over 39–52 weeks was both safe and efficacious.

In ADHD specifically, sleep disturbances are profound: insomnia and sleep disturbances affect up to 80% of adults with ADHD and similarly up to 82% of children with ADHD, delayed sleep-wake timing occurs in up to 78%, and dim-light melatonin onset (DLMO) is delayed by approximately 45 minutes in children and 90 minutes in adults. Melatonin and bright light therapy have advanced DLMO in both children and adults with ADHD.

To date, melatonin (in a controlled-release formulation) is only authorized for the treatment of insomnia in children with autism or Smith-Magenis syndrome. Concerns have been raised with respect to the safety and efficacy of melatonin for more general use in children, as melatonin has not undergone the formal safety testing required for a new drug, especially long-term safety in children.

Evidence assessment: Moderate-to-good evidence for sleep improvement in ASD; however, controlled-release formulations are specifically authorized for this population in some jurisdictions, and long-term safety data remain limited.

6.5 Cardiovascular Function and Blood Pressure

Prescription of exogenous melatonin has been demonstrated to decrease nocturnal hypertension, the pulsatility index of the internal carotid artery, platelet aggregation, and catecholamine levels. Melatonin attenuates blood pressure, vascular reactivity, and circulating catecholamine versus placebo in healthy individuals. A double-blind, placebo-controlled study in 2004 demonstrated that oral daily melatonin therapy with 2.5 mg for 3 weeks significantly decreased systolic and diastolic blood pressure in 16 male hypertensive patients.

Melatonin levels are decreased in pathological conditions including hypertension with no dipper pattern, congestive heart failure (CHF), ischemic heart disease, acute myocardial infarction, and coronary artery disease.

Studies have also examined the use of melatonin supplements for reducing blood pressure.

Evidence assessment: Preliminary evidence is encouraging, but trials are small and short-term. The cardiovascular effects of melatonin warrant larger, longer-duration RCTs before clinical recommendations can be made.

6.6 Immune Modulation

Laboratory and animal studies suggest that melatonin enhances immune response by increasing the proliferation and maturation of natural killer cells, T and B cells, granulocytes, and monocytes. Melatonin also appears to have anti-inflammatory and antioxidant effects.

Research over the last decade into cancer, Alzheimer's disease, multiple sclerosis, fertility, PCOS, and many other conditions, combined with the COVID-19 pandemic, has led to greater awareness of melatonin because of its ability to act as a potent antioxidant, immune-active agent, and mitochondrial regulator.

A few studies have found that people with COVID-19 who received melatonin in addition to standard care had milder symptoms than those who received just standard care. However, these studies were small and did not have a placebo group.

Evidence assessment: The immune-modulating effects of melatonin are robustly demonstrated in preclinical (animal and in vitro) models, but human clinical evidence remains preliminary, mostly from small, uncontrolled studies. This is an active area of research.

6.7 Oncology (Cancer)

Numerous experimental studies have indicated an oncostatic role of melatonin in various cancers, such as breast, ovarian, prostate, oral, gastric, and colorectal cancers. The underlying mechanisms include several molecular pathways associated with antioxidant activity, modulation of melatonin receptors MT1 and MT2, regulation of apoptosis, pro-survival signaling and tumor metabolism, inhibition of angiogenesis, invasion, and metastasis.

Results have shown the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials have revealed that melatonin is an effective adjuvant drug to all conventional therapies.

A review of ClinicalTrials.gov found 46 clinical trials registered up to January 17, 2024, all focused around the utilization of melatonin in cancer treatment. A commonly studied combination involved melatonin with metformin, particularly in trials investigating breast cancer and oral squamous cell carcinoma. Radiotherapy was another frequent therapeutic modality used alongside melatonin, particularly in head and neck cancer and lung cancer trials, with melatonin's potential to reduce radiation-induced toxicity and improve quality of life as a key outcome. None of the reviewed cancer trials had received approval for marketing.

Epidemiological studies concerning the association between body circadian melatonin levels and cancer incidence have led to controversial conclusions, either showing significant association or no association at all.

Despite promising insights, several unresolved questions remain. The context-dependent effects of melatonin across different tumor types, stages, and immune microenvironments require further clarification. Optimal dosing regimens, chronobiological considerations, and potential synergies between melatonin and immunotherapies warrant systematic investigation.

Evidence assessment: The preclinical oncostatic evidence is substantial and multi-mechanistic. Clinical evidence is emerging and shows promise, particularly as an adjuvant therapy, but the field lacks large, phase III RCTs. No regulatory body has approved melatonin as a cancer treatment.

6.8 Neurological Conditions and Neuroprotection

Promoting effects of melatonin on adult neurogenesis, such as antioxidative activity and enhanced expression of neurotrophic factors, have been suggested. The MT2 receptor plays an important role for the beneficial action of chronic melatonin treatment on long-term object recognition memory, while the MT1 may mediate the effects of melatonin on object location memory.

Melatonin has been prescribed for sleep disturbance in individuals with Alzheimer's disease (AD), although there is a lack of national guidelines for pharmacological care for this presentation. Prolonged sleep disturbances for individuals with AD tend to lead to poor quality of life, behavioral challenges, and carer exhaustion.

Evidence assessment: Evidence for neuroprotection in humans remains largely indirect and preliminary. Most data come from animal and in vitro models, with observational associations in human cohorts. Adequately powered clinical trials in conditions such as Alzheimer's disease are ongoing.

7. Dosage Forms and Dosages Reported in Studies

Melatonin appears to be safe for short-term use at typical doses of 1 to 10 mg/day, depending on age.

• Primary insomnia in adults: Dose-response meta-analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day.
• DSPD in children: Should be administered 3–5 hours before endogenous melatonin starts to rise in dim light, and in the correct minimal effective dose.
• ASD/ADHD (children and adolescents): Long-term treatment with 5 or 10 mg controlled-release melatonin over 39–52 weeks was studied and found to be both safe and efficacious.
• Hypertension (pilot study): A double-blind, placebo-controlled study used oral daily melatonin at 2.5 mg for 3 weeks in 16 male hypertensive patients.
• COVID-19 (small studies): In one study in patients with mild to moderate COVID-19, patients received 9 mg melatonin each day plus standard care.
• High-dose studies: Randomized controlled trials investigating high-dose melatonin (≥10 mg) in human adults over 30 years of age have been conducted across a large range of medical conditions.
• Circadian phase-shifting: For sleep phase effects, dosage varies between 0.3 mg and 5 mg, with no reported difference in effects on blood serum levels, phase shifting, or core body temperature with doses over 1 mg.

Note on formulations: Melatonin has a rapid half-life and fast clearance rate, with plasma half-life for doses up to 5 mg reported to be less than 1 hour from time of dosage. Negative side effects of daytime sleepiness or grogginess are usually reported following use of slow-release formulas.

8. Safety Considerations and Drug Interactions

General Safety Profile

A 2015 review on the safety of melatonin supplements indicated that only mild side effects were reported in various short-term studies involving adults, surgical patients, and critically ill patients. Some mild side effects reported in the studies included drowsiness, headache, and dizziness. The possible long-term side effects of melatonin use are unclear.

In a systematic review of high-dose melatonin (≥10 mg), only four studies met the pre-specified low risk of bias criteria for meta-analysis. In that small subset, melatonin did not cause a detectable increase in serious adverse events (Rate Ratio = 0.88 [0.52, 1.50], p = .64) or withdrawals due to adverse events (0.93 [0.24, 3.56], p = .92), but did appear to increase the risk of adverse events such as drowsiness, headache, and dizziness (1.40 [1.15, 1.69], p < .001). Overall, there has been limited adverse event reporting from high-dose melatonin studies. Based on this limited evidence, melatonin appears to have a good safety profile. Better safety reporting in future long-term trials is needed to confirm this, as confidence limits were very wide due to the paucity of suitable data.

In very rare cases, side effects of abdominal discomfort, mild anxiety, irritability, confusion, and short-lasting feelings of depression have been reported.

Older Adults

Melatonin may stay active in older people longer than in younger people and cause daytime drowsiness.

Drug Interactions

Melatonin supplements can interact with various medications, including blood-thinning medications (anticoagulants), medications that suppress the immune system (immunosuppressants), diabetes medications, and birth control pills.

Children and Pediatric Concerns

Concerns have been raised with respect to the safety and efficacy of melatonin for general use in children, as melatonin has not undergone the formal safety testing required for a new drug, especially for long-term safety. Melatonin is known to have profound effects on the reproductive systems of rodents, sheep, and primates, as well as effects on the cardiovascular, immune, and metabolic systems.

A 2023 study found that 22 out of 25 over-the-counter melatonin gummy products were inaccurately labeled. One product did not contain detectable levels of melatonin. In the remaining products, the melatonin levels ranged from 74 to 347 percent of the labeled quantity (i.e., up to almost 3.5 times more melatonin than reported on the label). Most had more than the label said, with the majority containing between 1.2 to 1.7 times more melatonin than the amount listed. Based on case surveillance data, a 2024 report by the U.S. Centers for Disease Control and Prevention (CDC) estimated that from 2019 to 2022, 11,000 emergency department visits were for unsupervised melatonin ingestion by children 5 years and younger.

As the status of circadian rhythmicity may change during long-term treatment, it is recommended to stop melatonin treatment at least once a year (preferably during the summer holidays).

Pregnancy and Lactation

Few studies have examined melatonin supplementation during pregnancy, and no data exist on the safety of melatonin supplementation during breastfeeding.

Dosage Accuracy and Product Quality

Even though the FDA regulates dietary supplements such as melatonin, the regulations for dietary supplements are different and less strict than those for prescription or over-the-counter drugs. The 2023 gummy product investigation noted above illustrates the potential for substantial discrepancies between labeled and actual melatonin content in commercially available products.

References

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