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Antioxidant Defense, Oxidative Stress Reduction, and Anti-inflammatory Properties

Numerous studies have identified melatonin as a powerful free-radical scavenger with potential protective properties against neurodegenerative disorders, epilepsy, and certain cancers. Recent in vitro and in vivo studies have continued to fortify the foundational aspects established over the past decades that would attest to melatonin’s roles in antioxidant defense, oxidative stress reduction, and anti-inflammatory processes (1,2). Notably, as stated above, it is a highly efficient antioxidant as one molecule of melatonin can scavenge multiple (~10) reactive oxygen and nitrogen species through a cascading mechanism related to its secondary, tertiary, and even quaternary metabolites (3,4). In addition, melatonin has the dual capability of targeting receptor-independent and receptor-dependent processes. These studies further report that melatonin has significant abilities to block pro-inflammatory processes acting on cyclooxygenase (COX-2) and enhance programmed cell death (apoptosis) in aberrant cells (1,5), which would theoretically make it a desirable therapeutic in diseases of aging (“inflammaging”), such as cancer. Melatonin’s dual actions can inhibit pro-oxidative enzymes (e.g., xanthine oxidase) while also acting to potentiate the critical antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase, and catalase, aiding in the body’s first line of immune defense and metabolic detoxification (4,5). Overall, age-related decreases in endogenous melatonin production are correlated with disease and dysfunction. In vitro and in vivo studies demonstrate melatonin’s protective ability against mitochondria-mediated injury with hypertension and obesity, suggesting that dietary supplementation with exogenous melatonin in later years may be an effective therapeutic intervention for such age-related conditions (6).


Kukula-Koch et al. (7) performed cellular assays to determine if superior effects in anti-radical, antioxidant, and anti-inflammatory activities exist in phytomelatonin compared to the synthetic form. Based on these in vitro results using human cell lines, they reported significant benefits with phytomelatonin compared to synthetic melatonin (7). Phytomelatonin was found to have 646% stronger COX-2 inhibition (see Figure 1), 267–470% more potent free-radical scavenging ability (see Figure 2), and 100% greater efficacy in reducing cellular ROS in a human skin cell line (see Figure 3) when compared to synthetic melatonin, most likely due to the other constituents found in phytomelatonin such as chlorophyll, beta-carotene, lutein, and other protective, antioxidant phytonutrients [values derived from the original data presented in (7).]

Figure 1. 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(5mg/L).

Figure 2. Free Radical Scavenging Percentage (DPPH%) by phytomelatonin (blue bar) and three synthetic melatonins (gray bars).  Data are expressed as mcg/mL.

Figure 3. 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. 

To learn more about the use of melatonin in conjunction with other antioxidants, such as vitamin C,

visit the 'Supplementation' menu option and choose the page called Melatonin & Other Antioxidants.

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




1. Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R. Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation. Vol. 2017, International Journal of Endocrinology. 2017.

2. D’Angelo G, Chimenz R, Reiter RJ, Gitto E. Use of melatonin in oxidative stress related neonatal diseases. Vol. 9, Antioxidants. 2020.

3. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? Vol. 42, Journal of Pineal Research. 2007.

4. Ighodaro OM, Akinloye OA. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid. Alexandria Journal of Medicine. 2018;54(4).

5. Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, et al. Melatonin’s impact on antioxidative and anti-inflammatory reprogramming in homeostasis and disease. Biomolecules. 2020;10(9).

6. Hardeland R. Aging, melatonin, and the pro-and anti-inflammatory networks. Vol. 20, International Journal of Molecular Sciences. 2019.

7. 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 Oct;26(19):6087.

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