ABOUT MELATONIN SUPPLEMENTS

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.

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