Melatonin & Acetaminophen use in COVID19 cases

A neglected multi-purpose hormone and a simple painkiller in action

What does the “fall-asleep-fast” pill have to do with infections? Well, have you ever heard of off-label uses of medicines? Regulators (the FDA in the US) approve substances for the treatment of specific morbid conditions, and this is what shows on the label. This does not mean that there are no other potential uses, but these unfortunately pass into oblivion until someone bring them back to attention. Similar is the case with acetaminophen (alias paracetamol), well known in the US as Tylenol, whose label reads “anti-pyretic, analgesic”.

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Credit: https://www.melatonin-research.net/index.php/MR/about

Melatonin is a highly conserved molecule during evolution; a hormone with multiple physiological effects, including its all-important cross-reactivity with the endocannabinoid system.

In its anti-inflammatory capacity, melatonin decreases the TLR-mediated downstream gene expression in infected macrophages and the subsequent NF-kB-dependent gene expression, NLRP3 inflammasome activation and IL-1β production. Modulation of the inflammatory response, the reactive oxygen species production and the related oxidative stress represents a novel pharmacological approach to ameliorate the host reactions against viral infections and their long-term consequences. Melatonin reduces oxidative lung injury and inflammatory cell recruitment during viral infections. In fact, the age-related decline in melatonin production is one proposed mechanism to explain why children do not appear to have severe symptoms while the elderly do, as is the case in the COVID19 pandemic (Silvestri & Rossi, 2013, Peng et al, 2018).

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DC: Dendritic cell, IL-: Interleulin, TNF-: Tumor Necrosis Factor, CDx: Cluster of Differentiation (types of lymphcytes), FOXp3: A regulator of T-cells. Credit: S. H. Huang, https://doi.org/10.1016/j.jff.2019.04.062

Melatonin markedly reduces oxidative breakdown of lipids, especially in vivo, both directly and through its metabolites, thereby preserving membrane integrity and fluidity (Reiter et al, 2014). Lipid peroxidation of alveolar cell membranes, a degradative pathogenic process observed in some cases of SARS-CoV-2 induced acute respiratory distress syndrome (ARDS), may be generated by ferric (Fe+++) and ferryl (Fe++++) radicals, produced from cell-free heme degradation during sepsis. Melatonin, apart from acting as an antioxidant, can exert its protective effect by preventing the release of iron radicals from cell-free heme (Shaeib et al., 2015); it could be considered as a preventative of the above morbid mechanism in cases of ambulatory acute respiratory infections, at least for the elderly and the compromised; for patients already in the ICU, the addition of acetaminophene is a proven therapeutic measure against heme-induced lipid peroxidation in the lungs (Janz et al., 2015); no interactions have been reported between the two substances (Drugs.com).

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This is plain ol’ Tylenol, and it has a very important life-saving off-label use in some cases of acute respiratory distress syndrome due to viral infections of the lung.

Administration of melatonin to humans at pharmacological concentrations is essentially non-toxic; it is considered a safe supplement with few contraindications and precautions for its use: Pregnancy, certain autoimmune disorders and daytime administration. Its therapeutic window is also very wide, ranging from 0.1 to 100 mg/d, depending on the individual and the condition treated (Peres et al, 2006, Silvestri & Rossi, 2013).

I don’t believe in miracle molecules; I keep asking myself, though, why is the generally recognized as safe melatonin neglected in modern therapeutics. The evidence is there, and the study of Janz et al (2015) is a randomized controlled trial proving the efficacy of acetaminophene for its off-label use.

Selected bibliography

Silvestri & Rossi, 2013: https://link.springer.com/article/10.1186/1824-7288-39-61

Peng et al, 2018: https://pubmed.ncbi.nlm.nih.gov/29990691/

Reiter et al, 2014: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186275/

Shaeib et al, 2015: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120737

Janz et al., 2015: https://pubmed.ncbi.nlm.nih.gov/25474535/

Drugs.com: https://www.drugs.com/drug-interactions/melatonin-with-tylenol-1548-0-11-12.html

Peres et al, 2016: https://pubmed.ncbi.nlm.nih.gov/16548786/

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