Is Melatonin the "Next Vitamin D"?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements

Abstract

Melatonin has become a popular dietary supplement, most known as a chronobiotic, and for establishing healthy sleep. Research over the last decade into cancer, Alzheimer's disease, multiple sclerosis, fertility, PCOS, and many other conditions, combined with the COVID-19 pandemic, has led to greater awareness of melatonin because of its ability to act as a potent antioxidant, immune-active agent, and mitochondrial regulator. There are distinct similarities between melatonin and vitamin D in the depth and breadth of their impact on health. Both act as hormones, affect multiple systems through their immune-modulating, anti-inflammatory functions, are found in the skin, and are responsive to sunlight and darkness. In fact, there may be similarities between the widespread concern about vitamin D deficiency as a "sunlight deficiency" and reduced melatonin secretion as a result of "darkness deficiency" from overexposure to artificial blue light. The trend toward greater use of melatonin supplements has resulted in concern about its safety, especially higher doses, long-term use, and application in certain populations (e.g., children). This review aims to evaluate the recent data on melatonin's mechanisms, its clinical uses beyond sleep, safety concerns, and a thorough summary of therapeutic considerations concerning dietary supplementation, including the different formats available (animal, synthetic, and phytomelatonin), dosing, timing, contraindications, and nutrient combinations.

Keywords: antioxidant; blue light; chronobiotic; chrononutrition; circadian rhythm; darkness deficiency; melatonin; phytomelatonin; sleep; vitamin D.

Figure 1

Age-related decrease in melatonin in humans. Modified from [10].

Figure 2

Vitamin D and melatonin as light and dark sensors with shared functions. Graphic created using https://Canva.com accessed 27 July 2022.

Figure 3

Inhibition of inflammation by phytomelatonin (blue bar) and synthetic melatonin (gray bar). Data are expressed as a percentage of human recombinant COX-2 inhibition. Amounts used for each were 0.030 mL (5 mg/mL). Values are derived from the original data presented in [34].

Figure 4

Free Radical Scavenging Percentage (DPPH%) by phytomelatonin (blue bar) and three synthetic melatonins (gray bars). Data are expressed as mcg/mL. Values are derived from the original data presented in [34].

Figure 5

ROS fluorescence in human skin cell line by phytomelatonin (blue bars) and synthetic melatonin (gray bars). Data are expressed as ROS fluorescence using 50 mcg/mL for both phytomelatonin and synthetic melatonin. Values are derived from the original data presented in [34].

Figure 6

Chemical Structure of Melatonin (CAS: 73-31-4; Wikipedia, public domain) [254].

Figure 7

Nutritional characteristics of phytomelatonin. The phytomelatonin detailed below refers to the proprietary format utilized in [34]. Graphic created using Canva.com using images from pavelnaumov (chlorella, alfalfa), Victoria Sergeeva (rice), and Walrus_d’s (melatonin). https://Canva.com accessed 27 July 2022.

Figure 8

Oxygen radical absorbance capacity (ORAC) of two samples of phytomelatonin (blue bars) and three types of synthetic melatonin (gray bars) [271,272].

Figure 9

Melatonin production throughout the day. Modified from [10].

Figure 10

A comprehensive nutrition and lifestyle approach to optimizing melatonin. There are several aspects to ensuring healthy melatonin levels, including lifestyle modifications involving light exposure, selecting specific dietary patterns and foods, and, when required, targeted supplemental sources. Graphic created using https://Canva.com, accessed 27 July 2022.