Melatonin Use in Pediatrics: Evaluating the Discrepancy in Evidence Based on Country and Regulations Regarding Production

Melatonin is commonly used as a remedy for various sleep disorders; however, there is conflicting evidence about the efficacy and safety of melatonin for these indications.^1,2  Many factors must be considered when evaluating this evidence, including where the study was completed, whether melatonin is considered a prescription or dietary supplement in the country performing the research, type of sleep disorder, length of therapy, age of the study participants, and comorbid disease considerations.^1,2 

Melatonin is a hormone produced by the pineal gland. It is involved with the human body's circadian rhythm, otherwise known as the sleep-wake cycle.^1–3  The retina of the eye senses darkness and sends a trigger to the hypothalamus, stimulating melatonin secretion from the pineal gland.⁴  Melatonin is also involved in growth hormone secretion and sexual maturation.^4–7  Young adults typically secrete 5 to 25 mg of melatonin every evening.⁷  Information about the role of melatonin on pubertal development is limited, and further research is needed to address the use of melatonin as a sleep aid in younger populations, and how it may affect pubertal development.⁸ 

It is important to recognize that although melatonin is an endogenous hormone in the body, the melatonin available for purchase is a synthetically made compound. Researchers outline the concern of serotonin contamination as serotonin overdoses can occur with relatively low levels of serotonin.⁹  Studies evaluating purity of melatonin products determined contaminants such as tryptophan-related compounds as well as significant quantities of serotonin.^9,10  Detection of tryptophan in these supplements is concerning. Eosinophilia-myalgia syndrome, a disease that occurred in an epidemic outbreak, was linked to L-tryptophan containing dietary supplements.¹¹  This outbreak resulted in 1500 cases and 30 deaths.¹¹ 

In the United States, melatonin is regulated as a dietary supplement. Many dietary supplements marketed in the United States have been discovered by the FDA to be tainted with compounds that do not appear on the product label.^12–17  These compounds include medications that have been both banned and approved by the FDA, some of which have modified chemical structures with similar pharmacological activity.^12–17  Despite dietary supplements lacking safety and regulation, production of melatonin products claiming to provide sleep benefits for the pediatric population continues to increase.

Most children who experience difficulty sleeping are diagnosed with a variety of sleep disorders including, but not limited to, idiopathic chronic sleep onset insomnia (CSOI), delayed sleep phase syndrome (DSPS), or behavioral insomnia of childhood.^18,19  CSOI is defined as the chronic inability to fall asleep with slight variation in the definition based on the author. Table 1 provides the variety of definitions for CSOI. CSOI can develop alone or in combination with dim light melatonin onset.^22,23  Dim light melatonin onset is how the circadian pathway regulates itself to secrete melatonin at night, and some children experience a delayed secretion of melatonin, which may account for the inability to fall asleep.^22,23  DSPS is a circadian sleep disorder that entails an individual waking up later than usual due to a timing imbalance.²⁰  DSPS is likely derived from an underlying delayed sleep pattern, but does not affect sleep quality or duration.²⁴  Behavioral insomnia of childhood is defined by the inability to stay asleep or with difficulties falling asleep.²⁰  These sleep disorders have often prompted the use of melatonin; however, melatonin is becoming increasingly popular in the absence of the diagnosis of a sleep disorder.

Melatonin manufacturers have begun producing melatonin products specifically targeted for use in the pediatric population. This paper aims to critically evaluate the evidence available for the use of melatonin in children, taking into consideration where the clinical trials are performed, and the regulations regarding the production of melatonin in that country.

Search Strategy. PubMed was used with the following search terms: MeSH; Child + Melatonin (filter: selection of clinical trials), MeSH; Child, Preschool + Melatonin (filter: selection of clinical trials) and lastly the MeSH terms; Pediatrics + Melatonin (filter: selection of clinical trials). Inclusion criteria included the following terms: autism, attention-deficit/hyperactivity disorder (ADHD), atopic dermatitis, insomnias, neurodevelopmental disorders, and generally healthy individuals. Exclusion terms included the following: critically ill, surgical, migraine prophylaxis, anxiety/pain, Dravet/epilepsy, cancer, bipolar disorder, cystic fibrosis, Angelman syndrome, tuberous sclerosis complex alone, Smith-Magenis syndrome alone, Rett syndrome, and visually impaired. The exclusion criteria were created because the aim of this research is to evaluate the evidence for the generally healthy pediatric patient population that may be using OTC melatonin products. Critically ill patients and other exclusion conditions are patient populations that melatonin may be used for in an acute care setting or under the supervision of health care provider(s), which are outside the scope of this paper.

Search Criteria. Regulation of melatonin was dependent upon the country of origin. The US regulations were found using the PubMed search terms: Dietary Supplement + Pharmaceutical Preparations + United States Food and Drug Administration (filter: 5 years) with supplemental information found at the US FDA website. Canadian regulations were extracted from the government's website under the Departments and Agencies Health Canada subsection. The safety review of melatonin guides the use of melatonin in the Canadian territory, and supplemental information pertaining to drug monographs was also obtained from the Health Canada website. Regulations for use of melatonin in the European Union (EU) were located in the European Medicines Agency (EMA) governmental website. Specific guidelines pertinent to each country were found utilizing each country's government website. The United Kingdom falls congruent with the European guidelines, with supplemental information from the National Institute for Health and Care Excellence (NICE) guidelines. Regulations for Taiwan were found under the Taiwan Food and Drug Administration (TFDA) governmental website.

Regulation. Medication regulations and specific guidelines are dictated by the regulating authority of the country of origin. Melatonin, as seen in Table 2, falls under different regulations dependent on which country is using the medication. Melatonin is classified as non-prescription in both the United States and Canada; however, it is regulated differently between the 2 countries. Melatonin is a prescription in most European countries, with the exception of a few countries, such as Poland.

United States. Melatonin is regulated as a dietary supplement in the United States. This differs dramatically from non-prescription and prescription medications. Dietary supplements are considered safe until proven unsafe and thus are permitted to market prior to any efficacy or safety analysis.^15,28  Thus, all melatonin products marketed in the United States, which are available as dietary supplements, have not been evaluated for safety or efficacy in a clinical trial. Guidelines are currently limited for OTC products; however, the American Academy of Sleep Medicine has a weak recommendation to not use melatonin to treat sleep onset or sleep maintenance insomnia in adults with no current recommendations for children.²⁹ 

Canada. Melatonin in Canada is licensed to be sold as an OTC medication with use beginning in 2005. For OTC medications to be sold legally in Canada, each OTC natural product must contain a natural product number or a drug identification number-homeopathic medicine number.^30,31  Identification numbers indicate that each individual product has met specific requirements and is reviewed under Health Canada. These requirements include evaluating the safety, efficacy, and quality of all medications available prior to and after introduction to the market. Evidenced-based claims must include data analyzed via a risk-based approach to support the efficacy and safety of each individual product.³²  Both prescription and non-prescription medications are reviewed by experts in the Health Products and Food Branch of Health Canada.^33,34  The Health Products and Food Branch is the governmental agency that focuses on ensuring all medications, including that of natural health products, are safe and follow nutritional standards. It is the major contributor to the investigation of safety issues.²⁵ 

Vitamins and supplements with therapeutic claims are further regulated under the Natural Health Products Regulations.^31,34  For natural health products to be brought to market, these supplements must have safety and efficacy evidence and are only allowed to be used under good manufacturing practices. Use of melatonin in the adult population is not recommended for more than a 4-week course and is not authorized to be used in children ages 11 and younger.²⁵  Due to the results of international reports of conflicting evidence of neurological side effects, Health Canada requests parents of children and adolescents consult a health care provider prior to using melatonin.²⁵ 

European Union. Melatonin in the EU is available as a prescription. Melatonin prescription products in the EU are Circadin (Neurim Pharmaceuticals, Tel Aviv-Yafo, Israel) and Slenyto (Neurim Pharmaceuticals). Circadin is indicated for individuals aged 55 years and older for the short-term treatment (13 weeks) of primary sleep disorders.³⁵  Circadin is available in 2 mg prolonged-release form.³⁵  Slenyto is available in 1 and 5 mg melatonin prolonged-release form, and is authorized for the treatment of insomnia in patients aged 2 to 18 years with autism spectrum disorder and/or Smith-Magenis syndrome.³⁶  Smith-Magenis syndrome is a disease that affects many parts of the body with features that include sleep disturbances and mild to moderate intellectual disability.

Prescriptions undergo regulation by the European medicines regulatory network, a network consisting of the European Commission, the European Economic Area, and the EMA.²⁶  Inside of this network, experts are allocated to provide scientific guidance for the use of medications in allocated member states. Medications can be marketed for use in all member states, known as the centralized procedure, or for use in only a specific country, known as the decentralized procedure.²⁶  Regardless of the procedure, medications are subject to the same rules and regulations. A requirement for approval or refusal for marketing medications is that each medication must have a European Public Assessment Report.²⁶  The European Public Assessment Report must be published on the EMA website.²⁶  Although there is an overarching regulation on melatonin on behalf of the EU, there remains variations of what is permitted per country within the EU. For example, in 2011, melatonin become available as a supplement product in France at doses less than 2 mg. Doses at or exceeding 2 mg remain prescription.³⁷  The supplement products are still regulated in France by the General Directorate for Consumer Affairs, Competitions Policy and Fraud Control. This regulatory agency examines the composition of the dietary supplements and ensures products are labeled accurately.³⁸ 

Other countries within the EU such as Denmark, Czech Republic, Slovenia, and Switzerland do not permit melatonin at any dose to be available as a “food supplement” and are only available as a prescription.³⁷ 

United Kingdom. Medications in the United Kingdom are regulated by the Medicines and Healthcare Regulatory Agency, which requires medicine products to meet specific requirements for safety, efficacy, and quality.³⁹  The United Kingdom has only 1 licensed product of melatonin, Circadin. It is the same licensed product approved for the EU. Use of melatonin in other forms or for those who are younger than 18 years of age is considered unlicensed and off-labeled use, respectively.³⁹  Guidelines and recommendations for the use of medications fall under NICE.⁴⁰  The NICE guidelines follow the EU regulations with the recommendation that melatonin can be used in individuals over the age of 55 for the short-term treatment of primary insomnia. The NICE guidelines also support the use of unlicensed or off-label use of melatonin when clinically applicable and if the use of a licensed medication is not appropriate.⁴⁰ 

Taiwan. The regulating authority for medications in Taiwan falls under the Ministry of Health and Welfare.⁴¹  Under the Ministry of Health and Welfare, the TFDA focuses on regulating medications based on the safety and quality of medications and food, which must comply with the Pharmaceutical Affairs Act.⁴¹  Under the TFDA, the use of melatonin is not mentioned. Although current information on melatonin use is lacking, the medication appears to be considered a controlled substance since 1996 with consequences linked to the production or dispensing of this medication.^41,42  Patients who carry controlled medications into or out of the Republic of China must get a permit to do so.⁴¹ 

United States. In the United States, melatonin has become increasingly popular as an OTC dietary supplement. A National Health Interview Study was conducted between 2007 and 2012 in the United States evaluating complementary health approaches in children between the ages of 4 and 17 years of age.⁴³  Melatonin use in children increased from 0.1% in 2007 to 0.7% in 2012, and is considered 1 of the top 3 most used supplements by this population.^43,44  The number of melatonin products sold in the United States and indicated specifically for children are also increasing, with common products depicted in Table 3.

Melatonin products targeting use in the pediatric population in the United States contain directions recommending doses ranging from 0.5 to 6 mg per dose. Directions for use and age recommendations vary between each supplement. JoySpring melatonin products do not give a specific age to begin use, however, do recommend consulting a physician in patients younger than the age of 18. Other products give dosing recommendations beginning at 2, 3, and 4 years of age. Some similarities between the products exist in that most products recommend consulting a physician before use, and a few products recommend not using for more than 14 days. Only 1 product recommends avoiding in children with an endocrine or autoimmune condition. Directions for the timing of the supplement administration range between unspecific times before bed to 60 minutes before bed.

Other Country of Study. Current studies evaluating melatonin use in the pediatric population are detailed in Tables 4 through 8 and are arranged by country of origin and comorbidities of the patients in the studies. Five studies have been completed in the United States. Four of these studies were conducted in children with autism, and 1 in children with neurodevelopmental disorders. In Canada, 1 study has been conducted with children with ADHD, 1 with insomnia, and 2 studies with neurodevelopmental disorders.

Many of the studies included in this review used actigraphy as the primary method to determine sleep outcome with sleep logs/diaries being the alternative process. Actigraphy is measured through wrist bands that are worn overnight to record movements via specialized software.⁸²  A few studies used both processes to assess sleep outcomes.

Melatonin is regulated differently around the world with the least amount of regulation placed on OTC dietary supplements in the United States. A study conducted on US melatonin products discovered a variation of 0.3 to 5 mg/unit difference from the label content.¹⁰  One supplement had 15% less melatonin than the labeled amount. Varied amounts of melatonin in products sold in Canada have also been found, even under stronger regulations of OTC supplements.⁹  In a study conducted in Canada, the authors quantified the amount of melatonin in 30 commercial products with −83% to +478% of what was depicted on the label, not meeting a 10% margin of error.⁹  As evidenced by these studies, melatonin content in OTC dietary supplements can vary widely from what is listed on the bottle.

Current clinical trials do not commit to using a specific brand or generic melatonin product, increasing the variability of products across all nations completing studies on pediatric melatonin use. For example, as seen in Table 4, the United States completed 6 clinical trials with the inclusion criteria mentioned earlier, but only 3 trials disclosed the melatonin product that was used in the study. Two of the manufacturers, Natrol (Chatsworth, CA) and Twinlab (Boca Raton, FL), produce only vitamins and supplements, whereas Regis Technologies (Morton Grover, IL) is a chemical supplier and manufacturer of active pharmaceutical ingredients.⁸³ 

In clinical trials conducted in Canada per Table 5, all 4 studies disclosed where the melatonin was obtained. All melatonin products were obtained abroad from a variety of different manufacturers and did not include the generic OTC melatonin that is available for use in Canada. One study used the EU product, Circadin, and the other 3 studies used Circa Dia BV (Amsterdam, Netherlands) that is based in the Netherlands.

Five of 12 clinical trials conducted in the EU, as seen in Table 6, used the following manufacturers: Neurim Pharmaceuticals, Pharma Nord (Vejle, Denmark), Duchefa Farma BV (Haarlem, Netherlands), and Helsinn Chemicals (Pazzallo, Switzerland). All of these manufacturers produce prescription regulated melatonin products. Melatonin use in the EU is approved for the medication Circadin, which, at this moment, is produced from a manufacturer with headquarters out of Israel, and a branch located in Switzerland. Pharma Nord falls under Danish pharmaceutical control, a member state of the EU. Duchefa Farma BV is also based in the Netherlands.

In the United Kingdom, 4 of 6 studies conducted in Table 7 disclosed the manufacturer of melatonin. The manufacturers include Penn Pharmaceutical (Tafarnaubach, United Kingdom), Alliance Pharma (Chippenham, United Kingdom), and DHP Pharma (Kent, United Kingdom). It is important to mention that although the status of melatonin use in Taiwan is unknown, melatonin is still studied in both the adult and pediatric populations, as seen in Table 8.

Melatonin supplements sold OTC are generally targeting overall healthy individuals, including some children who are having issues sleeping. Table 9 depicts the number of studies conducted in each location. As seen by the table, the studies with otherwise healthy individuals were mostly conducted in the EU, and no studies were conducted in the United States for children without other comorbidities such as autism and neurodevelopmental disorders. It is important to mention that products sold in the United States likely base their claims off studies conducted in other countries that have different regulations for the production of melatonin. This brings up the concern of the inappropriate extrapolation from studies conducted in other countries with different standards on the use of melatonin than here in the United States. Table 9 provides an overview of studies evaluating melatonin in pediatric populations respective to the country of origin and comorbidities, if applicable.

The majority of studies evaluating melatonin use in the pediatric population are conducted with children who have other comorbidities. The data supporting the use of melatonin in the otherwise healthy pediatric population are limited and/or non-existent (in the United States). There is growing evidence for the use of melatonin in patients with certain comorbidities including ADHD, autism, and neurodevelopmental disorders, but these data are extrapolated from variable settings based on the country and regulations in place for the production and use of melatonin. Based on the lack of efficacy and safety regulations in place in the United States, pediatricians, pharmacists, and caregivers/parents should consider the following when using melatonin in pediatric patients: 1) Document the initiation of product, and share with all providers and caregivers, including the product name, dose, and administration schedule (frequency); 2) Evaluate response to therapy, starting at the lowest dose and titrating based on response. Document any changes to therapy, including if dosing changes occur, or change of product; 3) Document any side effects/adverse effects and report adverse events associated with the melatonin product to the Safety Reporting Portal available at: https://www.safetyreporting.hhs.gov/fpsr/WorkflowLoginIO; 4) The Safety Reporting Portal is the only mechanism in place to ensure the safety of OTC dietary supplements in the United States. Share this portal information with caregivers and all providers of the pediatric patient to help support this ongoing effort to evaluate the supplement products in the United States; and 5) Studies evaluating the safety and efficacy of the specific OTC supplements available in the United States targeting pediatric patients is needed. As of now, safety and efficacy cannot be ensured by utilizing the products available in the United States for the pediatric population.

ADHD

attention-deficit/hyperactivity disorder

ASD

autism spectrum disorder

CBT

cognitive-behavioral therapy

CNS

central nervous system

CR

controlled release

CSOI

chronic sleep onset insomnia

DLMO

dim light melatonin onset

DSPS

delayed sleep phase syndrome

EHR

electronic health record

EMA

European Medicines Agency

ER

extended release

EU

European Union

FDA

US Food and Drug Administration

FR

fast release

IQ

intelligence quotient

IR

immediate release

NICE

National Institute for Health and Care Excellence

OTC

over the counter

PR

prolonged release

SR

sustained release

TFDA

Taiwan Food and Drug Administration