Composition of food supplements containing melatonin available in PortugalAbstract
Melatonin straddles the boundary between food supplements and medicine. In Portugal, its classification is contingent upon a critical dosage threshold of 2 mg. This study aimed to detail the composition of melatonin-containing food supplements, available in Portugal based on their labels, and report the number of potential intoxications. Data was collected from 44 food supplements, and the difference in active ingredients was revealed towards the 16 approved medicines. Data on melatonin intoxication cases from 2018 to 2022 were obtained from the Portuguese Poisons Information Center (CIAV). Melatonin supplements, available in tablets, capsules, gummies, powders, or sprays, exhibited a recommended daily dose ranging from 1 to 1.95 mg. Only 20% contained melatonin alone, while the majority included plant extracts and vitamins. The absence of clinical studies supporting the efficacy of melatonin combined with plant extracts in these formulations raises concerns about their evidence-based effectiveness. Medicines contain 2 to 3 mg of melatonin per tablet, either immediate or modified release. Melatonin intoxication occurs mainly in children, with a higher prevalence between the first year of life and the age of four. Food supplements containing melatonin and plant extracts should be more carefully studied, including the potential adverse effects.
Keywords:
Melatonin; N-acetyl-5-methoxytryptamine; Dietary supplement; Medicine; Intoxication
INTRODUCTION
Melatonin, N-acetyl-5-methoxytryptamine, is a widely recognized molecule and is commonly referred to as the “sleep hormone”. Chemically, it is an indolic compound, being a ubiquitous substance in nature an amphiphilic antioxidant with lipophilic properties, which allows it to enter cells, compartments, or body fluids (Minich et al., 2022; Samanta, 2022). Melatonin is known in vertebrates for its role in regulating circadian rhythms, particularly the sleep cycle in humans (Megha et al., 2024; Wurtman, 2020). Currently, it is recognized as a multifaceted molecule possessing an array of functions covering areas such as immune regulation, antioxidant, anti-inflammatory effects, anti-aging action, potential anti-cancer properties, as well as possible neuroprotective effects, among others (Gunata, Parlakpinar, Acet, 2020; Martin Gimenez et al., 2022; Minich et al., 2022; Rivara et al., 2015). Studies have shown that through its interaction with monoaminergic neurotransmitters, melatonin secretion and/or serum levels vary seasonally and chronologically, with a reduction in the hormone’s production being observed, particularly in childhood and advanced age, which is often associated with pathological conditions (Martin Gimenez et al., 2022; Ophoff et al., 2018). This decrease in production or reduced expression of melatonin receptors often emphasizes the need for dietary supplementation with the hormone, or its clinical use to restore appropriate physiological levels and optimize its physiological functions (Erland, Saxena, 2017).
Melatonin’s pharmacological effects are remarkable, particularly in the treatment of sleep disorders in humans, which has been widely documented. There is evidence to prove that the administration of exogenous melatonin anticipates the onset of sleep without altering its architecture, making it the first-line indication. The molecule exerts its action by inhibiting the chemical signals coming from the pathway that connects the retina to the pineal gland, thus stimulating the melatonin receptors (Megha et al., 2024; Meng et al., 2017; Rivara et al., 2015; Samanta, 2022). This process is triggered by the absence of light, predominantly at night, reaching its peak plasma concentration between 03:00 and 04:00 in the morning (Gunata, Parlakpinar, Acet, et al., 2020). In general, its effect on sleep is believed to be a consequence of mechanisms that include an increase in sleep propensity, increasing the amplitude of circadian clock oscillations via MT1 receptors, while at the same time synchronizing the circadian clock via MT2 receptors (Kostoglou-Athanassiou, 2013; Wurtman, 2020). Although most of melatonin’s actions are receptor-mediated, other functions can occur independently, with melatonin interacting directly with intra-or extracellular molecules (Rivara et al., 2015). However, despite the extensive research carried out to date, the results of clinical studies have been equivocal, making it a molecule of great controversy in the scientific community, remembering that melatonin is an active field of research, and discoveries are emerging all the time (Givler et al., 2023).
In the European Union “Supplements” and “Medicines” obey different legislation. “Supplements” include Food Supplements regulated by Directive 2002/46/ EC and are classified as food. There is no centralized pre-market authorization for these supplements, and the EU Member States can notify the placing of a food supplement on the market, with specific guidelines dictated by the regulatory authority of the country of origin (Thakkar et al., 2020; Tuft et al., 2023). Melatonin falls into this category, becoming a borderline product between food supplements and medicines, and is widely marketed in both forms. Food legislation allows the use of pharmaceutical drugs as ingredients in food supplements, which can occasionally make product categorization difficult. As a result, it is possible to find both a medicine and a food supplement on the market containing the same main substances, but falling into different categories, which subjects them to different requirements and obligations before the authorities. In the EU, melatonin can be marketed as an over-the-counter product if used in doses lower than 2 mg for immediate-release formulations. However, this is not the situation in several EU countries, such as Denmark, the Czech Republic, Slovenia, and in a non-EU country Switzerland, where the selling of melatonin as a food supplement requires a prescription (Skrzelowski et al., 2021).
Melatonin is normally intended to be administered orally but undergoes an extensive first-pass metabolism. The drug displays a poor and variable bioavailability with studies reporting a range from 3% to 56% (Tordjman et al., 2017; Vasey et al., 2021). Alternative administration routes, other than oral with higher bioavailability, have been studied including transdermal and intranasal (Zetner, Andersen, Rosenberg, 2016). Following oral absorption peak plasma concentrations are reached after 60 minutes, and the half-life after intravenous administration was determined to be lower than 6 minutes (Esposito et al., 2019; Tordjman et al., 2017). 6-sulfatoxymelatonin (6-SM), is the main metabolite, is inactive and excreted via the urinary route (Tordjman et al., 2017).
Considering all these factors, the study aimed to describe the composition of food supplements available in Portugal along with approved medications, in order to reveal the difference in their composition of active ingredients. Moreover, we detailed the number of potential intoxications notified to the Portuguese Poisons Information Center (from the Portuguese “Centro de Informação Antivenenos -CIAV”) involving melatonin, from 2018 to 2022, and evaluated the potential risk of melatonin products.
Methods
A survey of food supplements containing melatonin available on the Portuguese market sought out at local points of sale, including websites, food supplements consisting of melatonin, or its synonym N-acetyl-5-methoxytryptamine. The research carried out between September 2022 and March 2023, resulted in a total of 44 supplements, the information contained in the supplement was thoroughly analyzed and grouped by consulting websites, as well as physical points of sale, such as parapharmacies and pharmacies including other places selling supplements. Following this data collection, we detailed the composition of active ingredients contained in food supplements by analyzing the labels.
Medicines containing melatonin that are currently approved in Portugal were also researched. It was also carried a brief analysis of data on sales of melatonin-containing medicines in Portugal over the last 10 years, according to the National Authority of Medicines and Health Products (from the Portuguese “Autoridade Nacional do Medicamento e Produtos de Saúde, I.P”- INFARMED).
To determine the number of potential instances involving melatonin intoxication, an analysis of cases reported to CIAV from 2018 to 2022 was conducted.
RESULTS
Medicines containing melatonin approved in Portugal
Currently, according to the INFARMED website, there are 16 medicines containing melatonin approved in Portugal. These are listed in Table I, as well as the daily dose recommended for insomnia treatment. In the European Union, prescription drugs containing melatonin include Circadin® (Neurim Pharmaceuticals) and Slenyto® (Neurim Pharmaceuticals). Circadin® was the first melatonin receptor agonist medicine approved in the European Union by the European Medicines Agency (EMA) in 2007. Its therapeutic indication is monotherapy, for the short-term treatment of primary insomnia characterized by poor sleep quality in patients aged 55 and over. Slenyto® is formulated as prolonged-release tablets containing 1 and 5 mg of melatonin and is indicated for the treatment of insomnia in patients aged 2 to 18 with autism spectrum disorder and/or Smith-Magenis syndrome. Of note, some approved medicines are not being sold in Portugal. Medicines containing melatonin are presented as immediate and prolonged-release pharmaceutical forms.
Sales of melatonin-containing Medicines in Portugal 2012-2022
We collected the data from prescribed medicines dispensed in community pharmacies in Portugal from 2012 to 2022, according to data supplied by INFARMED Table II. There is a clear upward trend in both melatonin sales and DDD consumption over time, with notable annual fluctuations that reflect the dynamics in consumer preferences. The data revealed that sales vary from a low of 4 packs of melatonin (2012) to a high of 30 packs (2016). A similar pattern observed in DDD consumption agrees with a low use of these medicines that require a prescription.
Food supplements containing melatonin available in Portugal
Research into the melatonin-containing food supplements in the Portuguese market led us to compile information on 44 different products Table III. The products revealed a diverse and complex panorama, where various associations between ingredients were identified. The melatonin in the food supplements is in a recommended daily dose that varies between a minimum of 1 mg and a maximum of 1.95 mg, thus not exceeding the limit allowed in food supplements. Available in a variety of pharmaceutical formulations, including tablets, capsules, gummies, powders, or sprays, most supplements are designed in tablet form.
It was found that only nine (20%) supplements were characterized by the presence of melatonin alone, namely supplements 4, 6, 7, 8, 9, 10, 26, 38, and 41. Most supplements are made up of plant extracts, with Valerian, California Poppy, and Passionflower being the most frequent ingredients associated with melatonin in their formulations. According to the therapeutic indications on the label of these supplements, the dosage amount is defined according to the claimed effect. The information provided below is taken directly from the labels of the supplements analyzed, following the authorized health claims for Melatonin, as described in Commission Regulation (EU) No. 432/2012 dated May 16, 2012. According to these labels, the therapeutic indications for using melatonin include the relief of subjective symptoms of time difference, with a recommended minimum dose of 0.5 mg before bedtime on the first day of travel and in subsequent days after arrival at the destination. On the other hand, by taking 1 mg of the hormone right before bed, melatonin is also said to assist shorten the amount of time it takes to fall asleep.
In addition to the nutritional information on the label or in the description on websites, some food supplements sometimes contain the following warnings: “Food supplements should not be used as a substitute for a varied, balanced diet and a healthy lifestyle”, “Do not exceed the recommended daily intake”, “Keep out of reach and sight of children”, “Medical or nutritional advice is recommended”, and “Pregnant women, infants, and children are not recommended to use this product”. Including warnings on the label plays a crucial role in making consumers aware of the appropriate use of the product, thus enabling informed decision-making, and should be complemented by advice from health professionals, especially pharmacists.
Melatonin-related poisonings reported to the Portuguese Poisons Information Center
The number of reported intoxications suspected to involve melatonin are summarized in Table IV. The data shows that melatonin poisoning occurs mainly in children, with a higher prevalence between the first year of life and the age of four. Also, it is noticeable that the number of reports increased dramatically from 2020 onwards. The overwhelming majority of cases occur accidentally owing to easy access to the drug, mainly due to children’s propensity for more attractive galenic forms such as gummies. Some cases occur due to medication errors, such as dosage or time of administration. In addition, there are some cases, albeit rare, of intentional ingestion, mainly among the 10-17 age group. In general, intoxications are of low severity, and referral to the hospital is only necessary for unusual circumstances, particularly in smaller children, to keep them under medical monitoring until symptoms resolve.
DISCUSSION
The data on medicines sales, that require a prescription, reveal a low number of medicines sold. Overall, the observation of low use of melatonin-containing medicines suggests the possibility that consumers predominantly opt for food supplements not regulated by INFARMED, which can be acquired without the need for a prescription. Empirically, this clearly shows a growing preference for dietary supplements over prescription drugs. Regretfully, we do not possess supplement sales statistics, nor are we aware of any possibility of obtaining solely melatonin supplement sales in Portugal. The correlation between medicine sales and consumer preferences highlights the direct influence of consumer choices, which underscores the importance of understanding the motivations behind this behavior. Importantly, we cannot assume that consumers only are acquiring melatonin-containing food supplements for sleep disorders, as there are many other potential uses including the important antioxidant properties (Bonomini et al., 2018; Minich et al., 2022). Therefore, correlating medicines sales, which are only approved for sleep disorders, with those of dietary supplements may have limitations. However, it is crucial to recognize that the Portuguese market is part of a broader regulatory framework in the European Union, sharing common standards and guidelines. In this context, the local preference for food supplements raises pertinent questions about indiscriminate access and safety, considering the high heterogeneity in over-the-counter melatonin-containing formulations in Portugal, which may reflect similar trends in other EU countries (Skrzelowski et al., 2021).
Research into the composition of dietary supplements containing melatonin reveals the significant heterogeneity in formulations across different brands, illustrating the wide variety and availability of these products on a global scale. Notably, this diversity raises concerns about consumer safety, particularly exacerbated by the significant challenge associated with food supplements in general, underscoring the lack of stringent regulation and, at times, inadequate scientific evidence to substantiate various claims made by these products (Bailey, 2020). The analysis further discloses that comprehensive warnings are incorporated into all packaging to safeguard the integrity of the product, ensuring both stability and safety. Recommendations for storage methods emphasize the importance of minimizing exposure, favoring blister packs with an oxygen barrier over the traditional bottle format (Pranil, Moongngarm, Loypimai, 2020). This precaution assumes particular significance due to melatonin’s susceptibility to degradation in the presence of air and light. The few, albeit rare, supplements that do not follow this pattern are mostly formulations intended for children or those who simply prefer alternative forms of intake. Apart from that, it is noteworthy that the recommended use of these supplements is specifically tailored to address sleep disorders, as explicitly indicated on their labels (Culnan, McCullough, Wyatt, 2019; Hartstein et al., 2024). There is a lack of studies evaluating the efficacy, quality, and safety of these products. Also, the complexity of the associations between components in the formulations, makes it sometimes challenging to study how they operate. FDA evaluation of dietary supplements occurs at incidence-based intervals, focusing on potential concerns or adverse effects associated to these products until they are proven unsafe (Bailey, 2020; Givler et al., 2023; Menczel Schrire et al., 2022). In addition, the absence of strict manufacturing guidelines contributes to variations in dosage and composition, including some supplements with added vitamins. This scenario implies that the effects of consumption are not exclusively attributable to melatonin, but to the complexity of the mixtures present in these supplements (Bonomini et al., 2018; Culnan, McCullough, Wyatt, 2019). These added components, predominantly plant extracts or parts of their roots, as observed in the supplements analyzed, are often incorporated due to their claimed hypnotic and sedative properties. It is known that the pharmacological effects are mainly mediated by the GABAergic system, which explains the promotion of these products as sleep aids. In this way, it is believed that the effects of the components present in the formulation, together with melatonin, are intended to be synergistic or have enhanced efficacy (Esposito et al., 2019; Lemoine, Bablon, Da Silva, 2019). Furthermore, contrary to what is observed with medicines, substantial efforts need to be made to determine the ideal dose of melatonin for long-term supplementation and to improve the forms of administration, thus considering alternative routes, or administration by different forms of preparation, as observed in the supplements analyzed (Meng et al., 2017; Zetner, Andersen, Rosenberg, 2016). The study on melatonin-containing medications revealed that immediate-release formulations are mainly used for sleep onset problems, while extended-release formulations are more effective for sleep maintenance problems. This distinction is attributed to the slower and more sustained absorption of extended-release melatonin, which delays and reduces the peak plasma concentration, unlike immediate-release formulations where melatonin is rapidly metabolized and eliminated (Skrzelowski et al., 2021). However, both maintain melatonin levels within physiological standards along the plasma concentration curve during the night. The dose generally ranges from 2 to 3 mg per tablet and is adjusted according to different needs, considering the person’s clinical history.
Overall, there was an increase in melatonin poisoning cases reported to the CIAV since 2020, coinciding with the year that the COVID-19 pandemic appeared (Beck et al., 2021). Growing evidence suggests that the significant changes in people’s daily routines due to the pandemic have contributed to the increase in sleep problems, also reflected in the increasing numbers of melatonin intoxications reported to the CIAV (Gasmi et al., 2024; Lelak et al., 2022). In particular, the substantial increase in poisonings, especially in children from 2020 to 2022, suggests a possible link with the significant increase in exposure, such as the presence of more children at home during the pandemic and the greater availability of melatonin supplements in chewable forms. This scenario highlights the importance of addressing issues related to the safety of childproof packaging and adjusting the dose of medicines and supplements, including melatonin (Bishop-Freeman et al., 2022; Minich et al., 2022). It is crucial to encourage consumers and healthcare professionals to report any adverse events related to melatonin products. Aggregating data from these reports can provide valuable insights into the need for implementing public health measures to raise awareness about the increase in pediatric melatonin intake (Esposito et al., 2019; Lelak et al., 2022).
Ultimately, when confronting the data on melatonin medicines sales with the notable increase in the number of intoxications, it would be expected an association between the increase in consumption and the subsequent increase in poisonings. However, it is not possible to estimate a causal relationship between the two factors as we lack data on sales of melatonin-containing supplements. This lack of correlation is exacerbated by the non-mandatory notification of supplements to regulatory bodies and the absence of monitoring requirements at the time of sale and after consumption, in contrast to the strict control observed for medicines.
CONCLUSION REMARKS
Consumers should be made aware by healthcare professionals of the various melatonin formulations available, their effective doses, and their potential adverse effects. In the case of supplements, several combinations with plant extracts have been identified, their mode of action is complex to understand and their therapeutic potential as well as adverse effects merit careful clinical studies.
ACKNOWLEDGMENTS
This research was funded by national funds from Fundação para a Ciência e a Tecnologia (FCT), I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences (UCIBIO) and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy-i4HB.
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Publication Dates
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Publication in this collection
20 Jan 2025 -
Date of issue
2025
History
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Received
23 Apr 2024 -
Accepted
17 July 2024
