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SAFETY OF MELATONIN

General Safety

 

Oral melatonin is considered a safe product that is well-tolerated for general use in adults and children, with adverse effects rarely reported in the literature (1–3).

 

Natural Medicines (formerly Natural Standards database), one of the most complete resources and collections of data regarding the safety of supplements and drug-herb interactions, report more than two dozen studies showing the safety of melatonin for general sleep and sleep disorders, immune health, gastrointestinal health, cancer, and hormone support. Due to the volume of data regarding safety, this database classifies melatonin as ‘likely safe’ (the highest safety rating in the database) for short-term use and is considered an appropriate recommendation for most people. Because less data is available, it earns a ‘possibly safe’ designation for long-term use. There are currently more than 40 studies on the use of melatonin in various health conditions showing the safety of up to 8-10 mg for 6 months to 2 years when used appropriately (2). Notably, a dose of 8-10 mg per day is higher than required for most clinical applications.

 

The American Academy of Sleep Medicine (4) and the National Center for Complimentary and Integrative Health (NIH) (5) suggest the use of melatonin is generally safe, with caveats that more studies are needed in long-term use and special populations. They also recommend that when melatonin is being used for sleep, implementation of general sleep behaviors (i.e., avoiding blue light, sleep schedule, dark room, etc.) should be the first line of therapy. 

 

Adverse Effects

In a recent systematic review of melatonin’s use across all sleep and mental health disorders, it was reported that only four individuals (three adults and one child) dropped out of the included 34 trials due to side effects, with headaches being the most commonly reported (6). Another narrative review highlighted that the most common adverse effects included daytime sleepiness, headaches, and dizziness. However, most studies found that these effects were not statistically different from placebo and were of “minor clinical significance given the mild nature of the reported symptoms.” (7) One study reported that 5 mg of melatonin increased the level of reactive aggression in healthy young men when they were provoked. Of note, the researchers included that a high degree of provocation was induced in the study and was in fact a limitation in the findings. It is unclear if the same type of aggression would occur without provocation or at a lower dose of supplemental melatonin (8). Rates of adverse events ranged from 0.008% to 2% of the populations studied, with an increased risk of these events occurring when melatonin is dosed 10 mg or higher (7).

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Lethal levels of melatonin have not been previously reported in adults, however, in 2023, one case report was published reporting a lethal concentration of over-the-counter (OTC) sleep aids. A 21-year-old female was found deceased after excessive consumption of diphenhydramine (DPH) and melatonin. It was reported that 8,000 mg of DPH and 480 mg of melatonin were missing from the bottles found at the site of death. Toxic levels of DPH have been established and were measured in this case. Melatonin levels were recorded as 3.9 mg/L in the iliac blood, 4.40 mg/L in cardiac blood, and 130 mg/L in gastric contents, all of which were indicated as “primary toxic agents”. Due to the multifactorial cause of death, melatonin alone could not be implicated as the sole contributing factor; however, the cause of death was noted as “suicide by acute combined DPH and melatonin toxicity.” (9).

 

Medication Interactions

As with all supplements, interactions with medications should always be cross-referenced. Due to isolated incidents and theoretical risks, general healthcare guidance is advised around the concomitant use of the following medications: (2,7)

  • Anticoagulant/antiplatelets  

  • Anticonvulsants

  • Antidiabetes drugs

  • Antihypertensive drugs

  • Caffeine

  • CNS depressants

  • Contraceptives

  • Cytochrome P540 Substrates

 

Melatonin may have a slight blood thinning effect so it may be additive with anticoagulants (2,7) and as a hypnotic, be additive with CNS depressants (7,10) while possibly reducing the effectiveness of anticonvulsants via similar hepatic clearance pathways (11).

 

Rather than avoiding melatonin supplementation, it is recommended that healthcare professionals check for interactions, use a low dose of melatonin (<1 mg per day at bedtime) when applicable, and routinely monitor the patient, including labs, when necessary.

 

Safety During Pregnancy and Lactation

Melatonin’s use in pregnancy and lactation has been less studied, though research is emerging for this population. Some clinical trials report safety and no adverse effects with doses of 8-30 mg per day. These are levels higher than standard physiological doses typically recommended, especially for sleep concerns, which are commonly reported in pregnant women (12).

 

Historically, it was contraindicated in pregnancy because of the role melatonin has in uterine contractions; however, more recent literature suggests many positive aspects of melatonin, likely due to its antioxidant and anti-inflammatory properties. Some benefits include reducing preeclampsia risk, hyperglycemia, uterine growth retardation, and neonatal complications (12,13).

 

Less data is available on lactation, though based on current data, melatonin is reported to be safe during lactation. Despite that fact, clinical caution should be exercised (12).

 

At present, melatonin use during pregnancy and lactation is “probably safe” (12). Based on the current data, the low physiological dose for the shortest duration of time in this population can be considered, with careful monitoring of the patient. Pharmacological doses should be avoided due to the potential for uterine contractions.

 

Safety in the Older Population

The safety of melatonin in older adults (>65 years old) for sleep disorders has been explored. Based on current literature, melatonin is considered a safe therapy for the older population, with additional care taken for medication interactions and regular patient monitoring especially when other health conditions are present (7). 

 

More details on the literature available for this population can be explored in our Latest Publications.

 

Safety in the Pediatric Population

In this special population studies (14) show melatonin is safe for short-term use, and the Natural Medicines Database lists pediatric use of melatonin as ‘possibly safe’, due to lack of long-term studies, inconsistent dosing used, and most importantly, due to its limited use for select medical conditions (2). Melatonin is not suggested as a first line of therapy for sleep in the pediatric population. Most studies focus on short-term, low-dose use for pediatrics, with a maximum dose of 3 mg for children and 5 mg for adolescents for select medical conditions (15). In a literature review conducted in 2020, multiple studies on long-term use (up to 2 years) in children and adolescents showed safety (14). 

 

There is a very low side effect profile in pediatric populations, similar to adults, though occasional increased nighttime enuresis and morning grogginess have been reported that resolve with adjusted dosing. In rare instances, reports of headache, dizziness, and diarrhea have been reported with use and resolved upon discontinuation. One safety hesitation in children is due to the findings of three small, observational studies showing that melatonin supplementation may delay pubertal onset by downregulating the pituitary-gonadal axis. However, these studies had incomplete follow-up and poor measures of pubertal onset that have not been repeated subsequently (16). Among the studies that refute this point is a longer-term study showing no pubertal delay and safety in use at an average of 2.69 mg daily for three years (17).

 

The American Academy of Sleep Medicine (18) and American Academy of Pediatrics (19) have issued health advisories and guidance on melatonin in children, given the variability in need, formulation concerns, and suggest sleep hygiene as a primary treatment for childhood sleep issues, both state that melatonin may be used judiciously and recommend practitioner guidance (4).

 

Melatonin has been studied extensively in children with Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD), as well as with children with Autism Spectrum Disorders (ASD). These groups have been shown to have decreased production of melatonin and are known to have many circadian rhythm and sleep disorders that likely contribute to daytime behavioral symptoms (20-22). Melatonin has been shown to be useful in this population in multiple studies. At present, the British Society of Psychopharmacology has recommended the use of melatonin in pediatric patients with ASD (23) Similarly, the American Academy of Pediatrics and the Society of Developmental and Behavioral Pediatrics Developed in partnership with Health Resources and Services Administration Maternal and Child Health Bureau and Centers for Disease Control have put together anticipatory guidance for ASD that also support melatonin’s use in ASD, after lifestyle intervention, due to its being ‘relatively safe, well-tolerated, and readily available’ (24). One retrospective cohort study published in 2023 that involved children with autism reported that no safety concerns arose when melatonin was used for up to 88 months (25). A recent study in 2023 found that 3 mg of melatonin administered nightly (30-60 minutes before bed) was also safe and effective for children with infantile epileptic spasms syndrome (26).

 

The question of safety is a valid concern for parents and prescribers alike with the recent news of increased calls to U.S. Poison Control Centers. However, it is necessary to note that melatonin ingestion was 2.25% of all calls to the centers, and 84.4% of calls regarding melatonin were from ‘worried-well’ parents with asymptomatic children (27). Still, this is a serious matter that should make us all evaluate how we approach supplement safety, delivery (i.e., gummies versus capsule), and continued research. A 2023 study reported that the number of emergency room visits for unsupervised medication exposure among children increased by 421% (1,440 visits) due to melatonin exposure (28).

 

Melatonin is one of the most commonly sought-after supplements for pediatric sleep disorders due to its effectiveness and over-arching safety. However, it should be noted that children naturally produce melatonin at much higher levels than adults, and other courses of action, like sleep hygiene, daytime activity, reducing nighttime stimulation and structured routines should be utilized prior to using any sleep aid in this population, including melatonin.

 

Concluding Considerations

Despite its safety and low adverse effect profile, it is important to note the wide variability in product manufacturing. One study has shown some products contain up to five times the amount listed on the label (29). In this particular study, of 31 products tested, label claim variability was from 83% less to 478% more than what was listed on the label (29) This discrepancy underscores the importance of not just understanding melatonin’s safety for consumption but knowing, and trusting, the sourcing, manufacturing, and standards of production.

 

General recommendations to enhance safety:

  • Clinicians are advised to always check for drug-melatonin interactions before recommending this therapy.

  • Research supports the lowest physiological dose for the shortest duration of time.

 

Author: Mona Fahoum, ND

Reviewer(s): Deanna Minich, PhD & Kim Ross, DCN

Last Updated: November 14, 2023

 

References

 

1. Andersen LPH, Gögenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Vol. 36, Clinical Drug Investigation. 2016.

2. Natural Medicines [Internet]. 2023 [cited 2023 Jan 31]. Melatonin-Monograph. Available from: https://naturalmedicines-therapeuticresearch-com.scnmlib.idm.oclc.org/databases/food,-herbs-supplements/professional.aspx?productid=940

3.  Menczel Schrire Z, Phillips CL, Chapman JL, Duffy SL, Wong G, D’Rozario AL, et al. Safety of higher doses of melatonin in adults: A systematic review and meta-analysis. Vol. 72, Journal of Pineal Research. 2022.

4.  American Academy of Sleep Medicine [Internet]. 2022 [cited 2023 Jan 31]. Health Advisory: Melatonin Use in Children and Adolescents. Available from: https://aasm.org/advocacy/position-statements/melatonin-use-in-children-and-adolescents-health-advisory/

5.  National Center for Complementary and Integrative Health [Internet]. 2022 [cited 2023 Jan 31]. Melatonin: What You Need To Know. Available from: https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know

6.  Salanitro M, Wrigley T, Ghabra H, de Haan E, Hill CM, Solmi M, et al. Efficacy on sleep parameters and tolerability of melatonin in individuals with sleep or mental disorders: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2022 Aug;139:104723.

7.  Tuft C, Matar E, Menczel Schrire Z, Grunstein RR, Yee BJ, Hoyos CM. Current Insights into the Risks of Using Melatonin as a Treatment for Sleep Disorders in Older Adults. Clin Interv Aging. 2023 Jan;Volume 18:49–59.

8.  Liu J, Zhong R, Xiong W, Liu H, Eisenegger C, Zhou X. Melatonin increases reactive aggression in humans. Psychopharmacology (Berl). 2017;234(19).

9.  Zimmerman JT, Schreiber SJ, Huddle LN. Case Report of Lethal Concentrations of the Over-the-Counter Sleep Aids Diphenhydramine and Melatonin. American Journal of Forensic Medicine & Pathology. 2023 May 16;

10. Foster BC, Cvijovic K, Boon HS, Tam TW, Liu R, Murty M, et al. Melatonin interaction resulting in severe sedation. Journal of Pharmacy and Pharmaceutical Sciences. 2015;18(2).

11. Stewart LS. Endogenous melatonin and epileptogenesis: Facts and hypothesis. International Journal of Neuroscience. 2001;107(1–2).

12. Vine T, Brown GM, Frey BN. Melatonin use during pregnancy and lactation: A scoping review of human studies. Vol. 44, Brazilian Journal of Psychiatry. 2022.

13. Verteramo R, Pierdomenico M, Greco P, Milano C. The Role of Melatonin in Pregnancy and the Health Benefits for the Newborn. Biomedicines. 2022 Dec 14;10(12):3252.

14. Rzepka-Migut B, Paprocka J. Efficacy and safety of melatonin treatment in children with autism spectrum disorder and attention-deficit/hyperactivity disorder-A review of the literature. Vol. 10, Brain Sciences. 2020.

15. Bruni O, Alonso-Alconada D, Besag F, Biran V, Braam W, Cortese S, et al. Current role of melatonin in pediatric neurology: Clinical recommendations. Vol. 19, European Journal of Paediatric Neurology. 2015.

16. Boafo A, Greenham S, Alenezi S, Robillard R, Pajer K, Tavakoli P, et al. Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician’s perspective. Nat Sci Sleep. 2019;11.

17. van Geijlswijk IM, Mol RH, Egberts TCG, Smits MG. Evaluation of sleep, puberty and mental health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia. Psychopharmacology (Berl). 2011;216(1).

18. American Academy of Sleep Medicine [Internet]. 2021 [cited 2023 Jan 31]. Missing the mark with melatonin: Finding the best treatment for insomnia. Available from: https://aasm.org/missing-the-mark-melatonin-finding-best-treatment-insomnia/

19. Whalen I. American Academy of Pediatrics. 2021 [cited 2023 Jan 31]. Thinking about melatonin to help kids sleep? Ask your pediatrician. Available from: https://publications.aap.org/aapnews/news/16325

20. Couturier JL, Speechley KN, Steele M, Norman R, Stringer B, Nicolson R. Parental perception of sleep problems in children of normal intelligence with pervasive developmental disorders: Prevalence, severity, and pattern. J Am Acad Child Adolesc Psychiatry. 2005;44(8).

21. Pagan C, Delorme R, Callebert J, Goubran-Botros H, Amsellem F, Drouot X, et al. The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders. Transl Psychiatry. 2014;4(11).

22. van der Heijden KB, Smits MG, van Someren EJW, Gunning WB. Idiopathic chronic sleep onset insomnia in attention-deficit/hyperactivity disorder: A circadian rhythm sleep disorder. Chronobiol Int. 2005;22(3).

23. Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. Vol. 32, Journal of Psychopharmacology. 2018.

24. Center for Disease Control (CDC) [Internet]. [cited 2023 Jan 31]. Autism Spectrum Disorder- Specific Anticipatory Guidance. Available from: https://www.cdc.gov/ncbddd/actearly/autism/curriculum/documents/autism-specific-anticipatory-guidance_508.pdf

25. Sadeh H, Meiri G, Zigdon D, Ilan M, Faroy M, Michaelovski A, et al. Adherence to treatment and parents’ perspective about effectiveness of melatonin in children with autism spectrum disorder and sleep disturbances. Child Adolesc Psychiatry Ment Health. 2023 Oct 27;17(1):123.

26. Sun Y, Chen J, Shi X, Li Z, Wan L, Yan H, et al. Safety and efficacy of melatonin supplementation as an add‐on treatment for infantile epileptic spasms syndrome: A randomized, placebo‐controlled, double‐blind trial. J Pineal Res. 2023 Nov;

27. Lelak K, Vohra V, Neuman MI, Toce MS SU. Pediatric Melatonin Ingestions - United States, 2012-2021. Morb Mortal Wkly Rep. 71(22):725–9.

28. Lovegrove MC, Weidle NJ, Geller AI, Lind JN, Rose KO, Goring SK, et al. Trends in Emergency Department Visits for Unsupervised Pediatric Medication Exposures. Am J Prev Med. 2023 Jun;64(6):834–43.

29. Erland LAE, Saxena PK. Melatonin Natural Health Products and Supplements: Presence of serotonin and significant variability of melatonin content. Journal of Clinical Sleep Medicine. 2017;

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