Melatonin has also been referred to as “nature’s most versatile biological signal” (1) since its clinical application surpasses sleep. The classification of melatonin has been wide-ranging, from pineal hormone to amphiphilic antioxidant. It is a ubiquitous molecule, an indoleamine, produced endogenously in animals and plants. As a result, humans continually either ingest it from exogenous dietary sources or produce it endogenously. In humans, it is largely produced from the amino acid tryptophan by the pineal gland and in the gut-residing enterochromaffin cells. Even though the pineal gland receives much attention for its melatonin production, there is 400 times more melatonin in the gut mucosa (2).
Image Credit: Kvetnoy I, Ivanov D, Mironova E, Evsyukova I, Nasyrov R, Kvetnaia T, Polyakova V. Melatonin as the Cornerstone of Neuroimmunoendocrinology. Int J Mol Sci. 2022 Feb 6;23(3):1835. doi: 10.3390/ijms23031835. PMID: 35163757; PMCID: PMC8836571. CC-BY 4.0
Thus, it might be loosely implied that vitamin D deficiency indicates a “sunlight deficiency”
in perhaps the same manner that melatonin secretion could be affected by a “darkness deficiency,”
where there is overexposure to artificial, blue light at night, disabling the signal to the pineal gland
to produce it for initiating sleep.
On average, the pineal gland produces between 0.1 and 0.9 mg of melatonin per day (1,3). Melatonin production and circadian rhythms do not develop in babies until around three months (4). Breastfed babies have the benefit of melatonin from their mother’s milk (5). Levels from infancy to adolescence increase and plateau in association with Tanner stages of puberty and then slowly decline with age starting in the late twenties (6,7). Children typically produce more melatonin than adults, which may infer that their need for dietary supplementation may require further scrutiny and be limited to specific disease states (1,8). Production gradually declines as people age, starting in the late twenties to the fifties, with production leveling at approximately 30 pg/mL (8,9).
Aside from aging, production of melatonin can be influenced by illness (10), diet (1), environmental factors like bright light at night (11), medication use (12), and lifestyle (13). Of interest, research has indicated that the sheer amplitude of plasma melatonin may not have as much to do with chronological age but more with the degree of pineal calcification and associated melatonin secretion (14). However, that perspective begs the question of why the pineal gland becomes calcified and how it may be decalcified (14). In our modern era, perhaps the largest contributor to melatonin imbalance would be those subject to jet lag, shift work, overuse of artificial light at night (e.g., from cell phones, computers, and fluorescent/LED light), or challenges to their circadian rhythm due to environmental or seasonal changes.
Melatonin and Vitamin D
Melatonin is colloquially referred to as the “hormone of darkness” since it is produced in response to darkness, as perceived by the eye’s retina (1). Its synthesis is reduced by exposure to light, with artificial light reducing a person’s melatonin production and increasing disease risk (1,3). From a practical and even clinical perspective, vitamin D and melatonin may act as biochemical sensors to meet requirements for both light and darkness, respectively.
There may even be levels of crosstalk and overlap between them that have not yet been fully elucidated but might have clinical relevance. For example, it has been demonstrated that melatonin can bind several target proteins, including enzymes, receptors, pores, and transporters (15). Most relevant is that it can bind the vitamin D receptor (VDR), resulting in an enhancement of vitamin D’s signaling effects and subsequent cellular activities (16).
Like vitamin D, melatonin is found throughout the body. Melatonin has been found in many tissues other than the pineal gland and gut mucosa, including the brain, retina, lens, cochlea, trachea, skin, liver, kidney, thyroid, pancreas, thymus, spleen, and reproductive tissues . It is present in nearly all bodily fluids: cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, urine, feces, semen, and breast milk (14,17,18). Specifically, vitamin D and melatonin may work synergistically in the skin. Ultraviolet (UV)-B radiation is required to convert 7-dehydrocholesterol in the skin to vitamin D3. At the same time, melatonin is an antioxidant in the skin to ward off the damaging effects of UV light (19). In the future, there may be more skincare innovations that involve both vitamin D and melatonin due to the activities they share in the skin (20).
Image Credit: Kvetnoy I, Ivanov D, Mironova E, Evsyukova I, Nasyrov R, Kvetnaia T, Polyakova V. Melatonin as the Cornerstone of Neuroimmunoendocrinology. Int J Mol Sci. 2022 Feb 6;23(3):1835. doi: 10.3390/ijms23031835. PMID: 35163757; PMCID: PMC8836571.
As an adjunct to its well-known role in sleep, melatonin has been seen as a prominent cellular guard against oxidative stress, specifically linked to the redox status of cells and tissues. In fact, it has been suggested to be one of the most potent antioxidants because of its ability to scavenge up to 10 reactive oxygen (ROS) and nitrogen species (RNS) with its metabolites compared with most antioxidants, which may only be able to quench a few ROS (14,21,22). Finally, melatonin is involved with multiple activities that include mitochondrial homeostasis, genomic regulation, modulation of inflammatory and immune cytokines, directly impacting both systemic and acute anti-inflammatory properties as well as indications around its potential role in phase separation (23,24). It has been proposed that both vitamin D and melatonin orchestrate many of their functions, especially related to redox status, at the level of the mitochondria (25). Concurrent with the age-related depletions in levels of vitamin D and melatonin, there is mitochondrial dysfunction, which has implications in a variety of clinical conditions that present differently through the seasons with changing light exposure (25).
Hormone; Antioxidant; Anti-inflammatory compound; Mitochondrial regulator
Relationship with light
Darkness is needed for synthesis.
Synthesized in the skin and many other tissues; Produced by pineal gland and gut (enterochromaffin cells)
Crosses blood–brain barrier
Greater risk of insufficiency and/or deficiency with increasing age
Obtained from dietary sources
Biological need may change depending on lifestyle
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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