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Melatonin has long been known to aid in sleep due to its role as a chronobiotic; however, there are a plethora of other benefits that supplementation may help support, including conditions with a high degree of inflammation and oxidative stress, such as in hypertension or metabolic syndrome (1–3).


In 2020, melatonin became one of the most sought-after dietary supplements for COVID-19 due to its role in immunomodulation and reducing the effects of the cytokine storm in conjunction with its use for sleep promotion (4,5). Not only are more people taking melatonin as a supplement, but they are taking it in higher doses, such as greater than 5 mg, which do not have a documented long history of safe use in the general population (6).


With the recent boost in sales and widespread availability in the retail market, concerns have been expressed based on an annual report (2020) by the nation’s poison centers indicating a large number of exposure cases to melatonin was in children ≤ five years old (7). Lelak et al.(8)  investigated further into unintentional melatonin use by children and potential consequences such as hospitalization. In this report, many questions were raised, including reasons for increased exposure (e.g., more children at home during the pandemic, more accessibility of melatonin supplements in chewable or other child-friendly formats), and even proposed causes of toxicity, whether related to overdose, variability in the amount of melatonin relative to label claim, or the variety of dosing protocols. Indeed, child-proof packaging, better scrutiny of dose, and whether children should be taking melatonin supplements must be addressed. Furthermore, there is more urgent concern about the significant overage and amounts reported in melatonin supplements. The melatonin content of the 31 over-the-counter melatonin products was found to be −83% to +478% of that listed on the label (9), with a recent lawsuit citing 165–274% of the label claim in a particular retail product (10).


The therapeutic and physiological dose of melatonin for various uses has been explored, as has the form used in supplements. As a dietary supplement in the retail channel, melatonin comes in various dosages, from as low as 0.3 mg to as high as 200 mg. The structure of the melatonin molecule is the same whether the source is from animals, plants, or synthetically produced.


Originally all melatonin was derived from the pineal gland of cows, sheep, or pigs. However, thirty years ago, with the development of chemically synthesized melatonin (“synthetic melatonin”), there was a dramatic shift to synthetic melatonin due to its cost-effectiveness and safety concerns over animal-derived melatonin, mainly because of the proteins or prions that could pass from cows and livestock to humans (11,12).


While plants naturally contain melatonin, it is at extremely low levels, making it difficult to obtain sufficient melatonin for therapeutic doses. While the terms “plant-based” and “natural” are prevalent for marketing melatonin supplements, it is important to highlight that nearly all melatonin involves industrial processing, employing potentially toxic substrates. The distinct difference between synthetic melatonin and pure phytomelatonin in the true sense would be that the phytomelatonin supplement would exclusively involve the plant material. Melatonin originating solely from the cells of plants, without the other industrial downsides, is highly uncommon. In fact, up until 2019, there was only one phytomelatonin supplement commercially available in the U.S. with therapeutic levels of melatonin with 1 mg of melatonin per 100 mg of herbal biomass (13).


Table 1. Considerations in the selection of a melatonin supplement.




● Animal (pineal gland)
● Chemical synthesis
● Phytomelatonin
● Microbial fermentation products (bioengineered)

General Comments

Synthetic melatonin is the most common form of melatonin on the market but can result in the use of potentially unwanted solvents and substrates in addition to it being environmentally undesirable (11). Plant-based melatonin presents challenges in concentrating to a viable dose of melatonin. Animal-based melatonin can involve the risk of viral infections. Microbial fermentation products are under development.




● Oral intake
● Oral, immediate release
● Oral, sustained, time-release
● Sublingual
● Intravenous
● Intramuscular
● Intranasal
● Transdermal
● Anal/Suppository
● Vaginal delivery

General Comments

There are a variety of formats available, and each needs to be individualized to the person’s needs. Several newer formats are being developed for optimizing delivery, although only oral administration is considered a dietary supplement in the U.S. (14,15).




● Capsule
● Tablet
● Chewable
● Gummies

General Comments

A trending format is that of gummies, which is a sweetened gelatinous-type delivery for greater palatability. While it may be the desired delivery form for consumers, there are concerns about the stability of melatonin in such a hygroscopic matrix, the resulting sugar content, the addition of dyes or flavoring agents, and the potential for an overdose of melatonin, especially in the case of children.




● As an isolated compound
● In combination with other actives
● In a plant matrix with other phytonutrients

General Comments

Often, dietary supplements of melatonin will include other nutritional or herbal actives with the intention of synergy or improved efficacy, although, on the whole, these types of preparations have not been effectively studied for interactions.




● Certified Good Manufacturing Practices (cGMP)
● Third-party testing for heavy metals, and contaminants
● Packaging integrity to ensure shelf-life and stability.

General Comments

Not all dietary supplements have the same quality. cGMP and third-party testing can be markers of objective quality measures.

Melatonin can degrade in the presence of air and light, so minimizing exposure (16) in oxygen-barrier blister packs would be preferential over open bottle format.




● Physiological dose (0.3-1.0 mg)
● Supraphysiological dose for occasional use (≥3 mg)
● Therapeutic dose prescribed by a qualified healthcare practitioner

General Comments

There is much debate about proper dose levels. Consider safety in addition to efficacy for the clinical condition it is being used for in a patient, as well as the duration of use, whether low dose, short term or high dose, long term.

Authors: Deanna Minich, Ph.D., Melanie Henning, ND, Catherine Darley, ND, Mona Fahoum, ND, Corey B. Schuler, DC, James Frame

Reviewer: Peer-review in Nutrients Journal

Last updated: September 22, 2022



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2. Navarro-Alarcón M, Ruiz-Ojeda FJ, Blanca-Herrera RM, A-Serrano MM, Acuña-Castroviejo D, Fernández-Vázquez G, et al. Melatonin and metabolic regulation: A review. Vol. 5, Food and Function. 2014.

3. Cardinali DP, Hardeland R. Inflammaging, Metabolic Syndrome and Melatonin: A Call for Treatment Studies. Vol. 104, Neuroendocrinology. 2017.

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9. 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;

10. Sabarese A. Lawsuits Filed Against Olly, P&G, Alleging Deceptive Advertising of Melatonin Supplements [Internet]. 2022 [cited 2022 Jul 30]. Available from:

11. Arnao MB, Hernández-Ruiz J. The potential of phytomelatonin as a nutraceutical. Molecules. 2018.

12. Kamalakar S, Javanthi T. Bovine spongiform encephalopathy (mad cow disease). Journal of Clinical and Scientific Research. 2015;4(1).

13. Kukula-Koch W, Szwajgier D, Gaweł-Bęben K, Strzępek-Gomółka M, Głowniak K, Meissner HO. Is phytomelatonin complex better than synthetic melatonin? The assessment of the antiradical and anti-inflammatory properties. Molecules. 2021;

14. Zetner D, Andersen LPK, Alder R, Jessen ML, Tolstrup A, Rosenberg J. Pharmacokinetics and Safety of Intravenous, Intravesical, Rectal, Transdermal, and Vaginal Melatonin in Healthy Female Volunteers: A Cross-Over Study. Pharmacology. 2021;106(3–4).

15. Zetner D, Andersen LPH, Rosenberg J. Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review. Vol. 66, Drug Research. 2016.

16. Pranil T, Moongngarm A, Loypimai P. Influence of pH, temperature, and light on the stability of melatonin in aqueous solutions and fruit juices. Heliyon. 2020;6(3).

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