In the evolving world of skincare science, antioxidants play a central role in combating skin aging by neutralizing free radicals and supporting cellular health [1,2]. Traditional antioxidants like vitamin C, vitamin A (retinol), niacinamide, and green tea have long been mainstays of skincare.
An unexpected contender, methylene blue, originally a dye and the first fully man-made medicine [3], has received attention for its potent antioxidant activity, unique mitochondrial action, and promising data in skin model research [3-5].
This article delves into how methylene blue compares to other established antioxidants, exploring its mechanisms, scientific evidence, potential benefits, safety considerations, and real-world observations. We previously discussed methylene blue's benefits in skin health here; check it out if you want to learn more about its applications in anti-aging, regeneration, and more!
How Does Methylene Blue Work and What Does It Mean for Skincare?
Methylene blue is a small phenothiazine dye that cycles between an oxidized (blue) and reduced (colorless) state. Unlike traditional “scavenger” antioxidants that neutralize reactive oxygen species (ROS) after they form, methylene blue can act as a mitochondrial redox cycler. This means it accepts electrons from upstream parts of the electron transport chain and donates them to cytochrome c (or complex IV), effectively bypassing dysfunctional complex I/III and reducing mitochondrial superoxide production [3].
Mitochondrial targeting is important for skin because mitochondria are a major intracellular source of ROS, and mitochondrial dysfunction is a recognized driver of cellular aging in dermal fibroblasts and epidermal cells.
The actions of methylene blue, for instance, improved mitochondrial respiration, lowered mitochondrial ROS, and altered expression of extracellular-matrix genes, are the major reasons that researchers have explored its use as a topical “anti-aging” candidate [3,4].
In a widely accessed study from 2017, methylene blue was compared to several other antioxidants (N-acetylcysteine/NAC, MitoQ, and MitoTEMPO) in primary human skin fibroblasts and 3D skin models [4].
Methylene blue at nanomolar concentrations reduced mitochondrial ROS and promoted fibroblast proliferation more effectively than the comparators, and improved markers of the dermal extracellular matrix in reconstructed skin. The authors concluded that methylene blue was the most potent of the tested antioxidants in their analysis.
Since then, reviews and mechanistic papers have positioned methylene blue as an antioxidant with potential applications for skin aging, wound healing, and protection from oxidative insults such as ultraviolet radiation [6-8]. However, these data are preclinical, and despite demonstrating promising future uses, human randomized topical clinical trials for routine cosmetic anti-aging applications are still lacking.
How Does Methylene Blue Compare with Common Skincare Antioxidants?
Vitamin C (ascorbic acid) is a direct electron donor and free-radical scavenger that is also important for collagen synthesis and photoprotection [9,10]. It is unstable (oxidizes readily) and requires low pH or stabilized derivatives for good skin penetration and shelf life. Topical vitamin C has broad human clinical evidence for photoprotection, brightening, and collagen support when well formulated.
Compared to methylene blue, vitamin C acts mainly by scavenging ROS and supporting collagen biosynthesis, whereas methylene blue acts at the mitochondrial level to reduce ROS production.
Vitamin E (tocopherols) is a lipid-soluble chain-breaking antioxidant that protects membranes from lipid peroxidation [11]. It is often paired with vitamin C for synergistic photoprotection. Compared to methylene blue, vitamin E acts primarily in membranes and oils, whereas methylene blue is water-soluble and intracellular.
Coenzyme Q10 (CoQ10) is a native electron carrier in mitochondria and works as an antioxidant, and MitoQ is a mitochondria-targeted CoQ derivative [12-14]. Topical CoQ10 can penetrate skin and reduce oxidative markers, while MitoQ is designed to concentrate in mitochondria. Methylene blue’s redox potential and the way it bypasses complex I/III is mechanistically different from CoQ/MitoQ. In comparative research, methylene blue outperformed MitoQ and other mitochondrial antioxidants in reducing mitochondrial ROS and promoting fibroblast proliferation. This result is promising but limited to preclinical models [4].
Formulation, Stability, Safety, and Practical Aspects
In cell platforms, methylene blue has activity at nanomolar concentrations. Overconcentration risks skin staining and potential photosensitization effects [15]. It is water-soluble and will likely behave differently in serums vs. oil-based creams, and formulators must control pH and its interactions with other dyes and active ingredients [4].
Most evidence for methylene blue applications on skin comes from cell culture, reconstructed skin models, animal studies, and case series for wound/PDT uses. The 2017 work presented earlier showed improved dermal markers in 3D skin models and low irritation in reconstructed skin models, yet there is a substantial gap between this evidence and human randomized clinical trials.
Methylene blue can cause staining and, on rare occasions, skin necrosis or allergic reactions in the context of injections or surgical use. Systemic methylene blue (through IV) has well-described systemic side effects, such as serotonin syndrome risk with serotonergic drugs and hemolysis in G6PD deficiency. Topical use appears better tolerated in low doses, but case reports from surgical dye use and other studies show skin complications can occur [16-18], so safety testing and patch testing are advisable for cosmetic usage in future years.
Conclusions
Methylene blue offers an unconventional and scientifically intriguing perspective on oxidative stress in the skin. Instead of only scavenging free radicals, it can reduce ROS production by altering mitochondrial electron flow. Preclinical data indicate that methylene blue can outperform several antioxidants in cell and reconstructed-skin models. However, human topical clinical evidence is currently limited, and formulation/safety issues exist (e.g., staining, photoreactivity, and rare adverse events) that require careful attention.
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References
[1] M.E. Rusu, I. Fizeșan, L. Vlase, D.-S. Popa, Antioxidants in Age-Related Diseases and Anti-Aging Strategies, Antioxidants 11 (2022) 1868. https://doi.org/10.3390/antiox11101868.
[2] N. Tranchida, F. Molinari, G.A. Franco, M. Cordaro, R. Di Paola, Potential Role of Dietary Antioxidants During Skin Aging, Food Science & Nutrition 13 (2025) e70231. https://doi.org/10.1002/fsn3.70231.
[3] H. Xue, A. Thaivalappil, K. Cao, The Potentials of Methylene Blue as an Anti-Aging Drug, Cells 10 (2021) 3379. https://doi.org/10.3390/cells10123379.
[4] Z.-M. Xiong, M. O’Donovan, L. Sun, J.Y. Choi, M. Ren, K. Cao, Anti-Aging Potentials of Methylene Blue for Human Skin Longevity, Sci Rep 7 (2017) 2475. https://doi.org/10.1038/s41598-017-02419-3.
[5] Z. Xiong, J.Y. Choi, K. Wang, H. Zhang, Z. Tariq, D. Wu, E. Ko, C. LaDana, H. Sesaki, K. Cao, Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria, Aging Cell 15 (2016) 279–290. https://doi.org/10.1111/acel.12434.
[6] Z.-M. Xiong, X. Mao, M. Trappio, C. Arya, J.E. Kordi, K. Cao, Ultraviolet radiation protection potentials of Methylene Blue for human skin and coral reef health, Sci Rep 11 (2021) 10871. https://doi.org/10.1038/s41598-021-89970-2.
[7] M.J. Rosique, R.G. Rosique, F.M. Faria, C.C. Oliveira, J.A. Farina, P.R.B. Évora, Methylene blue reduces progression of burn and increases skin survival in an experimental rat model, Burns 43 (2017) 1702–1708. https://doi.org/10.1016/j.burns.2017.04.021.
[8] Y. Gao, Z. Jiang, B. Xu, R. Mo, S. Li, Y. Jiang, D. Zhao, W. Cao, B. Chen, M. Tian, Q. Tan, Evaluation of topical methylene blue nanoemulsion for wound healing in diabetic mice, Pharmaceutical Biology 61 (2023) 1462–1473. https://doi.org/10.1080/13880209.2023.2254341.
[9] H. Goldenberg, H. Landertshamer, H. Laggner, Functions of Vitamin C as a Mediator of Transmembrane Electron Transport in Blood Cells and Related Cell Culture Models, Antioxidants & Redox Signaling 2 (2000) 189–196. https://doi.org/10.1089/ars.2000.2.2-189.
[10] P.K. Farris, Topical Vitamin C: A Useful Agent for Treating Photoaging and Other Dermatologic Conditions, Dermatologic Surgery 31 (2005) 814–818. https://doi.org/10.1111/j.1524-4725.2005.31725.
[11] E. Niki, Evidence for beneficial effects of vitamin E, Korean J Intern Med 30 (2015) 571–579. https://doi.org/10.3904/kjim.2015.30.5.571.
[12] J.M. Suárez-Rivero, C.J. Pastor-Maldonado, S. Povea-Cabello, M. Álvarez-Córdoba, I. Villalón-García, M. Munuera-Cabeza, A. Suárez-Carrillo, M. Talaverón-Rey, J.A. Sánchez-Alcázar, Coenzyme Q10 Analogues: Benefits and Challenges for Therapeutics, Antioxidants 10 (2021) 236. https://doi.org/10.3390/antiox10020236.
[13] A.O. Oyewole, M. Wilmot, M. Fowler, M.A. Birch‐Machin, Comparing the effects of mitochondrial targeted and localized antioxidants with cellular antioxidants in human skin cells exposed to UVA and hydrogen peroxide, FASEB j. 28 (2014) 485–494. https://doi.org/10.1096/fj.13-237008.
[14] Y. Zhao, R. Xiong, S. Jin, Y. Li, T. Dong, W. Wang, X. Song, C. Guan, MitoQ alleviates H2O2-induced mitochondrial dysfunction in keratinocytes through the Nrf2/PINK1 pathway, Biochemical Pharmacology 234 (2025) 116811. https://doi.org/10.1016/j.bcp.2025.116811.
[15] R. Porat, S. Gilbert, D. Magilner, Methylene blue-induced phototoxicity: an unrecognized complication, Pediatrics 97 (1996) 717–721.
[16] B. Stradling, G. Aranha, S. Gabram, Adverse skin lesions after methylene blue injections for sentinel lymph node localization, The American Journal of Surgery 184 (2002) 350–352. https://doi.org/10.1016/S0002-9610(02)00945-5.
[17] P. Borgstein, S. Meijer, R. Pijpers, Intradermal blue dye to identify sentinel lymphnode in breast cancer, The Lancet 349 (1997) 1668–1669. https://doi.org/10.1016/S0140-6736(05)62634-7.
[18] C. Durão, F. Pedrosa, R.J. Dinis-Oliveira, Greenish-blue discoloration of the brain and heart after treatment with methylene blue, Forensic Sci Med Pathol 17 (2021) 148–151. https://doi.org/10.1007/s12024-020-00316-2.
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