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While melatonin is best known for regulating sleep, its most important work happens quietly and continuously across the body. Acting as both a direct antioxidant and a powerful signalling molecule, melatonin supports mitochondrial function, moderates immune responses, reduces inflammation, and protects vulnerable tissues like the brain and gut lining. Sleep is simply the most visible expression of a hormone whose real role is cellular protection and long-term resilience.
Dermatologist Aaron Lerner initially isolated the famous hormone from a bovine pineal gland in 1958. He was disappointed to learn it would be useless to treat vitiligo, contrary to his original intention. Lerner couldn't have predicted that 62 years later, the powerful antiviral properties of this compound would bring a wave of renewed interest.
Since Lemer's discovery, and after many peer-reviewed studies, we can say that melatonin is far more than a sleep hormone.
We have only known of melatonin's existence for about half a century. Still, its actual lifespan is astonishing: the compound has remained completely unchanged for over 3 billion years, during which time it has been a ubiquitous mainstay of plant, bacterial, and animal life. Even fungi, yeast, and algae make their melatonin.
Millions and millions of years ago, the master antioxidant melatonin was profoundly instrumental in protecting plant and bacterial life from the growing pressure of an increasingly oxygen-rich atmosphere. For life on earth, learning to live aerobically had huge benefits and set the stage for the evolutionary emergence of complex organisms like humans much later.
But it also had new challenges. Picture a sliced apple turning brown or a cast-iron pan left in open weather for a whole season, rusted beyond recognition. Such is the danger of oxygen, specifically reactive oxygen species better known as free radicals.
Like that apple or that skillet, the cells of our body are prone to oxidative damage from free radicals. Oxidative stress essentially disrupts biological function by altering molecular structures so they can't continue operating normally. Melatonin prevents that damage by mopping up loose electrons before they can bind to anything else that might get affected.
However, the special secret to melatonin's unique antioxidant power lies in its structure. After it binds to dangerous reactive oxygen species, the resulting byproducts of the confrontation aggressively scavenge even more free radicals.
But melatonin doesn't stop there: it goes a step further, activating a critical signalling chain called Nrf2. The Nrf2 pathway is responsible for creating a whole host of powerful antioxidant enzymes such as glutathione-s-transferase and glutathione reductase. So when melatonin isn't on the front lines of cellular defence personally fighting the good fight, it's activating a vast and complex network of other homemade free radical quenchers.
It turns out, that its role as a direct and indirect cellular protector is likely the reason virtually all forms of life have relied on melatonin since the dawn of time. Its role in circadian rhythms and sleep came much, much later.
In 2017 researchers confirmed that melatonin doesn't just collect in the mitochondria; it is also produced there. Mitochondria are like tiny furnaces harnessing cellular energy from controlled oxidation reactions. This makes them easily prone to free radical damage.
Another fascinating ramification of this discovery was that it lent a new dimension to the well-accepted endosymbiosis theory. The idea is that in the primordial soup of early life on earth before mitochondria were cellular components in plants and mammals, they were independent purple bacteria called Rhodospirillum Rubrum.
Endosymbiosis theory holds that developing complex organisms incorporate simpler life forms for various metabolic benefits. They were entirely separate creatures that our evolutionary predecessors engulfed, appropriated, and put to work. The theory would also explain why mitochondria still, to this day, have DNA unrelated to ours.
Where there are mitochondria, there is melatonin. An exceptionally dense concentration of mitochondria is needed to power the highly specialized neurons that make up our brain and nervous system. Each brain cell contains an estimated 2 million mitochondria.
We can think of melatonin as a nightly housekeeping hormone. While we experience deep, rejuvenating sleep, it actively supports the highly specialized glymphatic system that detoxifies harmful neurodegenerative proteins from our brain.
Melatonin is a powerful brain protector thanks to its status as an antioxidant powerhouse and its role in constantly defending the all-important mitochondria. It prevents the death of neurons, keeps synaptic signals firing optimally, and staves off cognitive impairment.
In 1926, thirty years before melatonin was isolated, scientists observed that feeding the pineal glands of bulls to kittens significantly enhanced their immune function. By 2005 it was clear that human immune cells make their own melatonin and bear receptors for it. Today we know even more about its essential role in the immune system.
We can describe melatonin as an immunomodulator. Innate and acquired immune functions are constantly engaged in complex communication, distribution, and activation. Melatonin works as a messenger to regulate the precise choreography of the cells in this network. It seems intuitive that poor sleeping habits make us more vulnerable to infection and illness. Still, we likely underestimate melatonin's specific role in the equation.
Melatonin and Inflammation, a large meta-analysis published in March 2021, reviewed 31 studies involving 1517 participants to examine melatonin's effects on inflammation. The researchers found that melatonin exhibits significant anti-inflammatory effects across various metabolic pathways.
As a powerful antioxidant, melatonin can neutralize highly toxic free radicals that cause oxidative stress and inflammatory tissue damage. Additionally, its modulation of immune function switches off cellular signalling pathways that produce inflammatory cytokines and otherwise delay healing.
Put it all together, and we can think of melatonin as a universal guardian hormone: it protects the integrity of tissues and organs all over the body through several separate and synergistic mechanisms. The essential antioxidant and anti-inflammatory qualities of melatonin probably go a long way in explaining why it appears in every part of the body.
Melatonin is associated with the pineal gland, that mysterious jewel in the center of the brain that Descartes described as the "seat of the soul." When the darkness of night reaches our eyes, a signal is sent to the cone-shaped pineal gland (hence its name), cueing it to secrete melatonin through the night for a deep and relaxing sleep. The practical takeaways from this are well known: any guide to the basics of sleep hygiene will recommend against exposure to light in the hours leading up to bedtime.
Less well-known is melatonin's actual headquarters in the intestine. Yes, there is about 400 times more melatonin in the gut than in the pineal gland at any time, night or day. Along the entire length of the small intestine and colon, melatonin is produced and used by local receptors 24 hours a day, independent of the circadian rhythms governing pineal production. Therefore, it is not surprising that it plays a role in protecting the mucosal barrier from damage, influencing gut motility, and even affecting the makeup of the microbiome.
One placebo-controlled study found that two weeks of melatonin supplementation significantly reduced abdominal pain in IBS sufferers, independent of any effects on sleep. That study was not alone- at least two others examining the use of melatonin on IBS symptoms had similar results.
To be clear, this does not mean that supplementing melatonin will fix all your tummy troubles, and it does not mean that if you have IBS, you should take melatonin. But it certainly goes to show that the melatonin-gut connection is significant.
Melatonin has been the subject of renewed scientific interest during the pandemic because of its well-established ability to support the immune system for a wide range of viral infections, including; Ebola, West Nile, RSV, HIV, viral hepatitis, viral myocarditis, and more.
In most cases, this action is indirect, adjusting immune responses like natural killer cell activity, macrophage activation, and controlled cell death (apoptosis). These changes make our body much less susceptible to viral infection and spread. In some cases, however, such as Ebola, melatonin seems to induce the activation of a specific enzyme that limits viral replication.
One of the main reasons melatonin research for infection prevention and recovery continues is that its supplementation is relatively safe.
The amount of science on melatonin in a wide variety of different contexts is beyond staggering. The long history of its life on Earth is also genuinely mind-boggling. Of course, most people never know or think about melatonin's prehistoric origins when they supplement it to get a good night's rest.
We should be thankful that we live in an incredible era for melatonin research. More ground-breaking discoveries in our lifetime will continue stretching our understanding that melatonin is so much more than a sleep hormone.
Alghamdi B. S. (2018). The neuroprotective role of melatonin in neurological disorders. Journal of neuroscience research, 96(7), 1136–1149. https://doi.org/10.1002/jnr.24220
Bahrampour Juybari, K., Pourhanifeh, M. H., Hosseinzadeh, A., Hemati, K., & Mehrzadi, S. (2020). Melatonin potentials against viral infections including COVID-19: Current evidence and new findings. Virus research, 287, 198108. https://doi.org/10.1016/j.virusres.2020.198108
Cardinali D. P. (2019). Melatonin: Clinical Perspectives in Neurodegeneration. Frontiers in endocrinology, 10, 480. https://doi.org/10.3389/fendo.2019.00480
Carrillo-Vico, A., Calvo, J. R., Abreu, P., Lardone, P. J., García-Mauriño, S., Reiter, R. J., & Guerrero, J. M. (2004). Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 18(3), 537–539. https://doi.org/10.1096/fj.03-0694fje
Carrillo-Vico, A., Guerrero, J. M., Lardone, P. J., & Reiter, R. J. (2005). A review of the multiple actions of melatonin on the immune system. Endocrine, 27(2), 189–200. https://doi.org/10.1385/ENDO:27:2:189
Carrillo-Vico, A., Lardone, P. J., Alvarez-Sánchez, N., Rodríguez-Rodríguez, A., & Guerrero, J. M. (2013). Melatonin: buffering the immune system. International journal of molecular sciences, 14(4), 8638–8683. https://doi.org/10.3390/ijms14048638
Chen, C. Q., Fichna, J., Bashashati, M., Li, Y. Y., & Storr, M. (2011). Distribution, function and physiological role of melatonin in the lower gut. World journal of gastroenterology, 17(34), 3888–3898. https://doi.org/10.3748/wjg.v17.i34.3888
Cho, J. H., Bhutani, S., Kim, C. H., & Irwin, M. R. (2021, February 10). Anti-inflammatory effects of Melatonin: A systematic review and meta-analysis of clinical trials. Science Direct. Retrieved February 27, 2023, from https://www.sciencedirect.com/science/article/abs/pii/S0889159121000386
DiNicolantonio, J. J., McCarty, M., & Barroso-Aranda, J. (2021, March 1). Melatonin may decrease risk for and aid treatment of COVID-19 and other RNA viral infections. BMJ Journal. Retrieved February 27, 2023, from https://openheart.bmj.com/content/8/1/e001568.abstract
Durán, N., Alonso, J. C. C., & Favaro, W. (2021, February 18). Melatonin: What do we know so far about the activity of this hormone against COVID-19? SSRN. Retrieved February 27, 2023, from https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3783206
Farnoosh, G., Akbariqomi, M., Badri, T., Bagheri, M., Izadi, M., Saeedi-Boroujeni, A., Rezaie, E., Ghaleh, H. E. G., Aghamollaei, H., Fasihi-ramandi, M., Hassanpour, K., & Alishiri, G. H. (2021, June 27). Efficacy of a low dose of melatonin as an adjunctive therapy in hospitalized patients with COVID-19: A randomized, double-blind clinical trial. Authorea. Retrieved February 27, 2023, from https://www.authorea.com/users/381612/articles/497517-efficacy-of-a-low-dose-of-melatonin-as-an-adjunctive-therapy-in-hospitalized-patients-with-covid-19-a-randomized-double-blind-clinical-trial
Gardener, A. (2023, January 31). Activating the Nrf2 pathway: Nutrients and latest science. Gene Food. Retrieved February 27, 2023, from https://www.mygenefood.com/blog/activating-nrf2-pathway-nutrition-need-know/
Hardeland, R., & Poeggeler, B. (n.d.). Non-vertebrate melatonin. Journal of pineal research. Retrieved February 27, 2023, from https://pubmed.ncbi.nlm.nih.gov/12662344/
Lu, W. Z., Gwee, K. A., Moochhalla, S., & Ho, K. Y. (2005). Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Alimentary pharmacology & therapeutics, 22(10), 927–934. https://doi.org/10.1111/j.1365-2036.2005.02673.x
Manchester, L. C., Coto-Montes, A., Boga, J. A., Andersen, L. P., Zhou, Z., Galano, A., Vriend, J., Tan, D. X., & Reiter, R. J. (2015). Melatonin: an ancient molecule that makes oxygen metabolically tolerable. Journal of pineal research, 59(4), 403–419. https://doi.org/10.1111/jpi.12267
Misgeld, T., & Schwarz, T. L. (2017). Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture. Neuron, 96(3), 651–666. https://doi.org/10.1016/j.neuron.2017.09.055
Reiter, R. J., Rosales-Corral, S., Tan, D. X., Jun, M. J., Galano, A., & Xu, B. (n.d.). Melatonin as a mitochondria-targeted antioxidant: One of evolution's best ideas. Cellular and molecular life sciences : CMLS. Retrieved February 27, 2023, from https://pubmed.ncbi.nlm.nih.gov/28864909/
Saha, L., Malhotra, S., Rana, S., Bhasin, D., & Pandhi, P. (2007). A preliminary study of melatonin in irritable bowel syndrome. Journal of clinical gastroenterology, 41(1), 29–32. https://doi.org/10.1097/MCG.0b013e31802df84c
Shneider, A., Kudriavtsev, A., & Vakhrusheva, A. (2020). Can melatonin reduce the severity of COVID-19 pandemic?. International reviews of immunology, 39(4), 153–162. https://doi.org/10.1080/08830185.2020.1756284
Song, G. H., Leng, P. H., Gwee, K. A., Moochhala, S. M., & Ho, K. Y. (2005). Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut, 54(10), 1402–1407. https://doi.org/10.1136/gut.2004.062034
Srinivasan, V., Mohamed, M., & Kato, H. (2012). Melatonin in bacterial and viral infections with focus on sepsis: a review. Recent patents on endocrine, metabolic & immune drug discovery, 6(1), 30–39. https://doi.org/10.2174/187221412799015317
Suofu, Y., Li, W., Jean-Alphonse, F. G., Jia, J., Khattar, N. K., Li, J., Baranov, S. V., Leronni, D., Mihalik, A. C., He, Y., Cecon, E., Wehbi, V. L., Kim, J., Heath, B. E., Baranova, O. V., Wang, X., Gable, M. J., Kretz, E. S., Di Benedetto, G., Lezon, T. R., … Friedlander, R. M. (2017). Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proceedings of the National Academy of Sciences of the United States of America, 114(38), E7997–E8006. https://doi.org/10.1073/pnas.1705768114
Tan, D. X., Manchester, L. C., Liu, X., Rosales-Corral, S. A., Acuna-Castroviejo, D., & Reiter, R. J. (2013). Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes. Journal of pineal research, 54(2), 127–138. https://doi.org/10.1111/jpi.12026
Tan, D. X., Manchester, L. C., Reiter, R. J., Qi, W. B., Karbownik, M., & Calvo, J. R. (n.d.). Significance of melatonin in Antioxidative defense system: Reactions and products. Biological signals and receptors. Retrieved February 27, 2023, from https://pubmed.ncbi.nlm.nih.gov/10899700/
Tesarik, J. (n.d.). Melatonin attenuates growth factor receptor signaling required for SARS-CoV-2 replication. Melatonin Research. Retrieved February 27, 2023, from https://www.melatonin-research.net/index.php/MR/article/view/116
U.S. National Library of Medicine. (n.d.). Mitochondrial DNA. MedlinePlus. Retrieved February 27, 2023, from https://medlineplus.gov/genetics/chromosome/mitochondrial-dna/
Wongprayoon, P., & Govitrapong, P. (2017). Melatonin as a mitochondrial protector in neurodegenerative diseases. Cellular and molecular life sciences : CMLS, 74(21), 3999–4014. https://doi.org/10.1007/s00018-017-2614-x
Wurtman, R. J. (1985). Melatonin as a Hormone in Humans: A History. The Yale Journal of Biology and Medicine, 58, 547–552.
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