Camelia Dascalu 1 *, Raluca Cezara Popa 1, 2, Laura Dumea 1, 2, Constantin Roman 1, 3, 4, Andrei Szilagyi 1, 5, Daniela Nicolescu 6, Gabriela Ruja 6, Bogdan-Ionel Tamba 1
1 Prof. Ostin C. Mungiu Advanced Research and Development Center for Experimental Medicine – CEMEX, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania
2 Department of Pharmacology, Clinical Pharmacology and Algesiology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania
3 Faculty of Computer Science, Alexandru Ioan Cuza University of Iasi, Iasi, Romania
4 Faculty of Veterinary Medicine, Ion Ionescu de la Brad Iasi University of Life Sciences, Iasi, Romania
5 Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, Iasi, Romania
6 Media Kompass SRL, Bucharest, Romania
* Correspondence to: Camelia Dascalu, Prof. Ostin C. Mungiu Advanced Research and Development Center for Experimental Medicine – CEMEX, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115, Iasi, Romania. E-mail: camelia-enascut@email.umfiasi.ro
Abstract
Methylene blue (MB) is among the oldest synthetic molecules to retain clinical relevance in contemporary medicine. Synthesized in 1876 during the rapid expansion of the organic dye industry, the compound was initially developed as a textile colorant. However, it subsequently contributed to the emergence of modern microbiology and became the first synthetic antimalarial agent successfully used in humans. Over the past two decades, scientific interest in methylene blue has been renewed by its unique redox properties and its ability to modulate multiple biological processes, including mitochondrial bioenergetics, nitric oxide-dependent signaling, and neuronal metabolism. Beyond its established indication in the treatment of acquired methemoglobinemia, methylene blue is currently being investigated as an adjunctive therapy in refractory vasoplegia and as a potential modulator of mitochondrial dysfunction in neurodegenerative diseases, with emerging applications in oncology, infectious diseases, and neuropsychiatry. This comprehensive review synthesizes current evidence regarding the historical development, physicochemical and pharmacokinetic properties, molecular mechanisms of action, safety profile, and clinical applications of methylene blue across medical, dietary supplement, veterinary, food-related, and industrial domains. By distinguishing robust evidence supporting approved indications from the methodological limitations of exploratory studies, this review identifies the knowledge gaps that currently restrict therapeutic expansion. Ultimately, methylene blue should be regarded not merely as a single-purpose compound, but as a multi-regime substance whose safety, efficacy, and clinical relevance depend on intended use, product quality, and regulatory context.