Melatonin & Other Antioxidants
Can melatonin be taken in conjunction with other antioxidants?
When combined, antioxidants have been shown to display a synergistic effect (1,2). For example, vitamin C works with vitamin E by recycling tocopheryl radical to tocopherol (1). Vitamin C recycles melatonin, enhancing melatonin’s antioxidant capacity (1,2). However, antioxidants such as vitamin C, vitamin E, and glutathione have pro-oxidant effects when interacting with metal ions, such as iron and copper (1,3). In contrast, melatonin has been shown not to exhibit pro-oxidative activity (1).
Among the antioxidants, it is described that ascorbic acid is depleted first when the body is under stress, followed by glutathione and vitamin E, leaving melatonin as the “last line of defense against oxidative damage.” (4)
“Since the melatonin is sacrificed and does not participate in redox cycling after scavenging free radicals, not only does melatonin not consume the basic cellular reductive force, glutathione, but it also preserves or even increases the content of glutathione in tissues” (1)
In one cell study, melatonin and vitamin C combined showed a more significant reduction in reactive oxygen species production (5). Another cell assay found that phytomelatonin was more effective than synthetic melatonin in its free radical scavenging activity, which was further enhanced when combined with vitamin C (6), though the clinical application cannot be inferred from this study.
Image: Percentage of radical scavenging inhibition for ascorbic acid (vitamin C), phytomelatonin (PHT-MLT) and phytomelatonin plus vitamin C (PHT-MLT+Vit C).
Image credit: 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
Melatonin, when combined with vitamin C, vitamin E, or glutathione has been observed to have synergistic effects in both animal and human studies, including the protective effects against iron-induced lipid peroxidation (1,2).
Animal Studies
In animal studies, the synergistic effect of melatonin and ascorbic acid has reduced inflammatory markers and cellular damage caused by sepsis-induced heart, kidney, and liver damage (7,8). Of note, melatonin, as a stand-alone agent, has also shown positive outcomes in severe sepsis in humans. In mice, ascorbyl palmitate (a derivative of ascorbic acid) combined with melatonin exhibited greater antitumor activity than melatonin alone (9).
The combination of melatonin with vitamins C and E, demonstrated a more significant reduction in chlorpyrifos-ethyl (an organophosphate pesticide)-induced lung toxicity in mice (10). Melatonin and vitamin C performed better than melatonin alone to combat the adverse effects of acrylamide, the toxic compound formed by cooking foods at high temperatures (i.e., grilling) (11). Melatonin and vitamin E showed the best antioxidant effects in rats for protection against liver and kidney damage caused by exposure to lead (12).
Human Studies
In humans a combination of 2 mg of melatonin plus 60 mg of vitamin C for females or 75 mg of vitamin C for males resulted in significant improvement in postoperative outcomes of periodontal disease at 6 months compared to 3 months and the non-treated group (2). Of note, some studies have not demonstrated that vitamin C alone impacted the outcomes of periodontal disease, further highlighting a synergistic effect (2). On the contrary, topical melatonin, as a stand-alone treatment, has decreased inflammatory markers and improved gingival index and pocket depth (13).
The combination of vitamins C, E, and melatonin (topical) provided better protection from ultraviolet-induced erythema than applied alone (14).
At present, there is limited data on the use of combining melatonin and other antioxidants in human studies.
Author: Kim Ross, DCN
Reviewer: Deanna Minich, Ph.D
Last updated: August 28, 2023
References
1. Gitto E, Tan DX, Reiter RJ, Karbownik M, Manchester LC, Cuzzocrea S, et al. Individual and synergistic antioxidative actions of melatonin: studies with vitamin E, vitamin C, glutathione and desferrrioxamine (desferoxamine) in rat liver homogenates. Journal of Pharmacy and Pharmacology. 2010 Feb 18;53(10):1393–401.
2. Chitsazi M, Faramarzie M, Sadighi M, Shirmohammadi A, Hashemzadeh A. Effects of adjective use of melatonin and vitamin C in the treatment of chronic periodontitis: A randomized clinical trial. J Dent Res Dent Clin Dent Prospects. 2017;11(4).
3. Kaźmierczak-Barańska J, Boguszewska K, Adamus-Grabicka A, Karwowski BT. Two faces of vitamin c—antioxidative and pro-oxidative agent. Vol. 12, Nutrients. 2020.
4. Johns JR, Platts JA. Theoretical insight into the antioxidant properties of melatonin and derivatives. Org Biomol Chem. 2014;12(39):7820–7.
5. Lee HJ, Lee HJ, Sohn EJ, Lee EO, Kim JH, Lee MH, et al. Inhibition of Connexin 26/43 and Extracellular-Regulated Kinase Protein Plays a Critical Role in Melatonin Facilitated Gap Junctional Intercellular Communication in Hydrogen Peroxide-Treated HaCaT Keratinocyte Cells. Evidence-Based Complementary and Alternative Medicine. 2012;2012:1–9.
6. 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;
7. Üstündağ H, Doğanay S, Huyut MT, Kurt N, Demir Ö, Özgeriş FB, et al. A new treatment approach: Melatonin and ascorbic acid synergy shields against sepsis-induced heart and kidney damage in male rats. Life Sci. 2023;
8. Üstündağ H, Demir Ö, Çiçek B, Huyut MT, Yüce N, Tavacı T. Protective effect of melatonin and ascorbic acid combination on sepsis‐induced lung injury: An Experimental study. Clin Exp Pharmacol Physiol. 2023 Aug 18;50(8):634–46.
9. El-Far M, Essam A, El-Senduny FF, Abd El-Azim AO, Yahia S, El-Sherbiny IM. Synergistic Anticancer Effect of Melatonin and Ascorbyl Palmitate Nanoformulation: A Promising Combination for Cancer Therapy. Biointerface Res Appl Chem. 2023;13(6).
10. Karaoz E, Gultekin F, Akdogan M, Oncu M, Gokcimen A. Protective role of melatonin and a combination of vitamin C and vitamin E on lung toxicity induced by chlorpyrifos-ethyl in rats. Experimental and Toxicologic Pathology. 2002;54(2).
11. Alwan N & Ghadhban R. Melatonin and Vitamin C Administration Alone or as a Combination Ameliorative Role on Acrylamide Hematotoxicity Effects in Wistar Male Rats. Egyptian Journal of Veterinary Sciences. 2021;52(2).
12. Aziz FM. Effects of melatonin, vitamin Cand E alone or in combination on lead-induced injury in liver and kidney organs of rats. IOSR Journal of Pharmacy (IOSRPHR). 2012;2(5).
13. Cutando A, Montero J, Diego RG de, Ferrera MJ, Lopez-Valverde A. Effect of topical application of melatonin on serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in patients with type 1 or type 2 diabetes and periodontal disease. J Clin Exp Dent. 2015;7(5).
14. Dreher, Gabard, Schwindt, Maibach. Topical melatonin in combination with vitamins E and C protects skin from ultraviolet-induced erythema: a human study in vivo. British Journal of Dermatology. 1998 Aug;139(2):332–9.