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Part 1: Melatonin, Immune Function, and Inflammation

A look at the physiological role of melatonin beyond its sleep-supportive and antioxidant effects.

Melatonin and Respiratory Health

Melatonin has been shown to improve various markers of lung function and/or reduce pulmonary inflammation in numerous settings not having a primary infectious etiology. Although we typically think of melatonin as a regulator of the circadian rhythm and our most primitive protective antioxidant,[1],[2] the role it plays in the body is far more encompassing than this. In addition to regulating the sleep cycle, melatonin impacts reproductive function,[3] physical growth,[4] bone formation,[5] brain health,[6] metabolism,[7],[8] oral health,[9] and of greatest relevance to the discussion here, our immune system function.[10]

Much like other key hormones and signaling molecules, melatonin has multiple receptors that are found in nearly every system of the body including the cells of the immune system.[11],[12] Although melatonin is primarily produced by the pineal gland, research suggests it is also produced in the bone marrow,[13] thymus,[14] lymphocytes,[15],[16] and various cells of the gastrointestinal tract – each of which influence immune function.[17],[18]

melatonin and immune function

Well-established by numerous studies are the declining levels and altered rhythms of melatonin with increasing age.[19],[20] Age-related decreases in melatonin as well as other critical antioxidants including CoQ10 and glutathione are factors leading to the declining function of our cells, organs, and systems overall, and contribute to numerous diseases we see with increasing age.[21],[22],[23] Although each of these antioxidants are important for normal healthy immune function,[24],[25],[26] melatonin comes to the forefront as a critical factor that affects our susceptibility and response to infections.

Herein, we step through the mechanisms by which melatonin may impact immune function and inflammation, while in Part 2 we take a look at its impact on respiratory health in general and its anti-infective effects.

The Circadian Rhythm and the Immune Response

Melatonin is one of many hormones that have a circadian variation in the human body. Opposite to it, cortisol and dehydroepiandrosterone (DHEA) oscillate cyclically in a 24-hour period.[27],[28] Although we tend to think of these three hormones the most when it comes to the day-to-day cyclic variation, nearly every hormone in the body varies diurnally,[29] with each of them influencing each other as well.

melatonin and immune function

Levels of nearly all immunocyte populations and their related cytokines have a circadian variation, influenced by sleep.[30] Nocturnal sleep is associated with an acute lowering of monocytes, natural killer cells, and all lymphocyte subsets, followed by a rebound to daytime levels the following afternoon and evening.[31] When the normal nocturnal sleep period is absent, both the dip and rise of many of these lymphocytes is attenuated. Pro-inflammatory cytokines and undifferentiated naïve T cells peak during early nocturnal sleep while levels of anti-inflammatory cytokines and cytotoxic natural killer cells peak during daytime wakefulness.[32] Prolonged sleep disruption has been established by several human studies to promote a pro-inflammatory state.[33],[34],[35]

Melatonin influences the circadian variation of the immune response and levels of inflammatory mediators.[36],[37],[38] Conversely, inflammatory cytokines such as tumor necrosis factor (TNF)‐α influence nocturnal melatonin production as well.[39],[40] In severe illness such as sepsis, melatonin secretion is impaired,[41] while in other critical care settings, it often is dysregulated.[42],[43] Certain viral infections have also been shown to disrupt the circadian rhythm, which can additionally lead to increased viral replication.[44],[45] Animal studies have shown melatonin supplementation helps attenuate the proinflammatory effects of sleep deprivation and inflammatory response to triggers such as lipopolysaccharide (LPS), also reducing immunocyte infiltration and tissue damage in the lungs.[46],[47]

Studies suggest that sleep and/or melatonin administration enhances interactions between antigen-presenting cells and T helper cells,[48] promoting immunological memory much like it does for neurobehavioral memory.[49] Melatonin also has been observed to increase natural killer cell production and activity as well as antibody-dependent cellular cytotoxicity.[50],[51],[52] Melatonin not only opposes the wakefulness actions of cortisol, it also antagonizes its immunosuppressive effects.[53]

Melatonin and Inflammation

One mechanism by which melatonin may attenuate the severity of inflammation is through inhibition of the NLRP3 inflammasome. Activation of the NLRP3 inflammasome contributes to the pathology in numerous conditions associated with chronic, low-grade inflammation[54] including type 2 diabetes,[55] non-alcoholic steatohepatitis,[56] and Alzheimer’s disease;[57] each of which melatonin has been shown to help protect against.[58],[59],[60],[61] Although some level of NLRP3 activation is important for the normal, protective response to microbial invaders,[62] it also can be a mediator of excessive inflammation and the pathology that ensues.[63],[64]

Animal models of atherosclerosis,[65] subarachnoid hemorrhage,[66] osteoporosis,[67] diabetic cardiomyopathy,[68] radiation injury,[69] and more[70] show melatonin has protective effects via inhibition of NLRP3 inflammasome activation. Melatonin has also been shown in multiple studies to have anti-inflammatory effects by increasing levels of interleukin (IL)-10 and reducing TNF-α.[71],[72],[73] Cellular studies with human blood samples found that treatment with melatonin (at levels similar to what can be achieved physiologically) attenuated the mitochondrial dysfunction, oxidative stress, and cytokine response to LPS.[74] Melatonin also helps reduce the body’s overproduction of nitric oxide (NO).[75] Although NO helps mediate the body’s antiviral response, it also contributes to infection-related pathology.[76]

Multiple human studies have shown that in conditions associated with chronic inflammation such as type 2 diabetes, periodontitis, and multiple sclerosis, melatonin reduces levels of CRP and/or various pro-inflammatory cytokines.[77],[78],[79],[80] Acute application of melatonin as a therapy at doses ranging from three to 20 mg/day also has been shown to reduce markers of inflammation in surgical settings.[81],[82],[83] Results from a 2019 meta-analysis of randomized controlled trials also validates melatonin as an anti-inflammatory therapy, finding that supplementation with three to 25 mg of melatonin for four weeks or more significantly decreased TNF-α and IL-6 levels.[84]

Dr. Carrie Decker graduated with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Prior to becoming a naturopathic physician, Dr. Decker was an engineer, and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectively. Dr. Decker continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr. Decker supports Allergy Research Group as a member of their education and product development team.

For More See Part 2 on Melatonin and Respiratory Health


[1] Manchester LC, et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015 Nov;59(4):403-19.

[2] Reiter RJ, et al. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016 Oct;61(3):253-78.

[3] McGuire NL, et al. Effects of melatonin on peripheral reproductive function: regulation of testicular GnIH and testosterone. Endocrinology. 2011 Sep;152(9):3461-70.

[4] Motta-Teixeira LC, Machado-Nils AV, Battagello DS, Diniz GB, Andrade-Silva J, Silva S Jr, Matos RA, do Amaral FG, Xavier GF, et al. The absence of maternal pineal melatonin rhythm during pregnancy and lactation impairs offspring physical growth, neurodevelopment, and behavior. Horm Behav. 2018 Sep;105:146-156.

[5] Calvo-Guirado JL, et al. Melatonin stimulates the growth of new bone around implants in the tibia of rabbits. J Pineal Res. 2010 Nov;49(4):356-63.

[6] Srinivasan V, et al. Melatonin in Alzheimer’s disease and other neurodegenerative disorders. Behav Brain Funct. 2006 May 4;2:15.

[7] Ríos-Lugo MJ, et al. Melatonin effect on plasma adiponectin, leptin, insulin, glucose, triglycerides and cholesterol in normal and high fat-fed rats. J Pineal Res. 2010 Nov;49(4):342-8.

[8] Akbari M, et al. The effects of melatonin supplementation on inflammatory markers among patients with metabolic syndrome or related disorders: a systematic review and meta-analysis of randomized controlled trials. Inflammopharmacology. 2018 Aug;26(4):899-907.

[9] Cutando A, et al. A new perspective in oral health: potential importance and actions of melatonin receptors MT1, MT2, MT3, and RZR/ROR in the oral cavity. Arch Oral Biol. 2011 Oct;56(10):944-50.

[10] Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem. 2002 Feb;2(2):167-79.

[11] Emet M, et al. A Review of Melatonin, Its Receptors and Drugs. Eurasian J Med. 2016 Jun;48(2):135-41.

[12] Kühlwein E, Irwin M. Melatonin modulation of lymphocyte proliferation and Th1/Th2 cytokine expression. J Neuroimmunol. 2001 Jul 2;117(1-2):51-7.

[13] Tan DX, et al. Identification of highly elevated levels of melatonin in bone marrow: its origin and significance. Biochim Biophys Acta. 1999 Oct 18;1472(1-2):206-14.

[14] Naranjo MC, et al. Melatonin biosynthesis in the thymus of humans and rats. Cell Mol Life Sci. 2007 Mar;64(6):781-90.

[15] Carrillo-Vico A, et al. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J. 2004 Mar;18(3):537-9.

[16] Carrillo-Vico A, et al. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J. 2004 Mar;18(3):537-9.

[17] Mukherjee S, Maitra SK. Gut Melatonin in Vertebrates: Chronobiology and Physiology. Front Endocrinol (Lausanne). 2015 Jul 22;6:112.

[18] Kvetnoy IM. Extrapineal melatonin: location and role within diffuse neuroendocrine system. Histochem J. 1999 Jan;31(1):1-12.

[19] Wu YH, Swaab DF. The human pineal gland and melatonin in aging and Alzheimer’s disease. J Pineal Res. 2005 Apr;38(3):145-52.

[20] Skene DJ, Swaab DF. Melatonin rhythmicity: effect of age and Alzheimer’s disease. Exp Gerontol. 2003 Jan-Feb;38(1-2):199-206.

[21] Karasek M. Melatonin, human aging, and age-related diseases. Exp Gerontol. 2004 Nov-Dec;39(11-12):1723-9.

[22] Gutierrez-Mariscal FM, et al. Coenzyme Q10: From bench to clinic in aging diseases, a translational review. Crit Rev Food Sci Nutr. 2019;59(14):2240-2257.

[23] Samiec PS, et al. Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes. Free Radic Biol Med. 1998 Mar 15;24(5):699-704.

[24] Furukawa T, et al. Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice. Mech Ageing Dev. 1987 Apr;38(2):107-17.

[25] Folkers K, Wolaniuk A. Research on coenzyme Q10 in clinical medicine and in immunomodulation. Drugs Exp Clin Res. 1985;11(8):539-45.

[26] Srinivasan V, et al. Melatonin, immune function and aging. Immun Ageing. 2005 Nov 29;2:17.

[27] Bhake RC, et al. Continuous Free Cortisol Profiles-Circadian Rhythms in Healthy Men. J Clin Endocrinol Metab. 2019 Dec 1;104(12):5935-5947.

[28] Al-Turk W, Al-Dujaili EA. Effect of age, gender and exercise on salivary dehydroepiandrosterone circadian rhythm profile in human volunteers. Steroids. 2016 Feb;106:19-25.

[29] Czeisler CA, Klerman EB. Circadian and sleep-dependent regulation of hormone release in humans. Recent Prog Horm Res. 1999;54:97-130; discussion 130-2.

[30] Lange T, et al. Effects of sleep and circadian rhythm on the human immune system. Ann N Y Acad Sci. 2010 Apr;1193:48-59.

[31] Born J, et al. Effects of sleep and circadian rhythm on human circulating immune cells. J Immunol. 1997 May 1;158(9):4454-64.

[32] Besedovsky L, et al. Sleep and immune function. Pflugers Arch. 2012 Jan;463(1):121-37.

[33] Meier-Ewert HK, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol. 2004 Feb 18;43(4):678-83.

[34] Haack M, et al. Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep. 2007 Sep;30(9):1145-52.

[35] Vgontzas AN, et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab. 2004 May;89(5):2119-26.

[36] Lopes C, et al. Circadian rhythm in experimental granulomatous inflammation is modulated by melatonin. J Pineal Res. 1997 Sep;23(2):72-8.

[37] Nelson RJ, Drazen DL. Melatonin mediates seasonal adjustments in immune function. Reprod Nutr Dev. 1999 May-Jun;39(3):383-98.

[38] Hotchkiss AK, Nelson RJ. Melatonin and immune function: hype or hypothesis? Crit Rev Immunol. 2002;22(5-6):351-71.

[39] Pontes GN, et al. Pineal melatonin and the innate immune response: the TNF-alpha increase after cesarean section suppresses nocturnal melatonin production. J Pineal Res. 2007 Nov;43(4):365-71.

[40] Pontes GN, et al. Injury switches melatonin production source from endocrine (pineal) to paracrine (phagocytes) – melatonin in human colostrum and colostrum phagocytes. J Pineal Res. 2006 Sep;41(2):136-41.

[41] Mundigler G, et al. Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis. Crit Care Med. 2002 Mar;30(3):536-40.

[42] Billings ME, Watson NF. Circadian dysrhythmias in the intensive care unit. Crit Care Clin. 2015 Jul;31(3):393-402.

[43] Madrid-Navarro CJ, et al. Disruption of Circadian Rhythms and Delirium, Sleep Impairment and Sepsis in Critically ill Patients. Potential Therapeutic Implications for Increased Light-Dark Contrast and Melatonin Therapy in an ICU Environment. Curr Pharm Des. 2015;21(24):3453-68.

[44] Sundar IK, et al. Influenza A virus-dependent remodeling of pulmonary clock function in a mouse model of COPD. Sci Rep. 2015 Apr 29;4:9927.

[45] Edgar RS, et al. Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10085-90.

[46] Lee YD, et al. Melatonin attenuates lipopolysaccharide-induced acute lung inflammation in sleep-deprived mice. J Pineal Res. 2009 Jan;46(1):53-7.

[47] Kim JY, et al. Melatonin improves inflammatory cytokine profiles in lung inflammation associated with sleep deprivation. Mol Med Rep. 2012 May;5(5):1281-4.

[48] Pioli C, et al. Melatonin increases antigen presentation and amplifies specific and non specific signals for T-cell proliferation. Int J Immunopharmacol. 1993 May;15(4):463-8.

[49] Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010 Feb;11(2):114-26.

[50] Currier NL, et al. Exogenous melatonin: quantitative enhancement in vivo of cells mediating non-specific immunity. J Neuroimmunol. 2000 May 1;104(2):101-8.

[51] Giordano M, Palermo MS. Melatonin-induced enhancement of antibody-dependent cellular cytotoxicity. J Pineal Res. 1991 Apr;10(3):117-21.

[52] Szczepanik M. Melatonin and its influence on immune system. J Physiol Pharmacol. 2007 Dec;58 Suppl 6:115-24.

[53] Maestroni GJ, et al. Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. J Neuroimmunol. 1986 Nov;13(1):19-30.

[54] Ozaki E, et al. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives. J Inflamm Res. 2015 Jan 16;8:15-27.

[55] Lee HM, et al. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013 Jan;62(1):194-204.

[56] Wan X, et al. Role of NLRP3 Inflammasome in the Progression of NAFLD to NASH. Can J Gastroenterol Hepatol. 2016;2016:6489012.

[57] Tan MS, et al. The NLRP3 inflammasome in Alzheimer’s disease. Mol Neurobiol. 2013 Dec;48(3):875-82.

[58] Agahi M, et al. Effect of melatonin in reducing second-generation antipsychotic metabolic effects: A double blind controlled clinical trial. Diabetes Metab Syndr. 2018 Jan-Mar;12(1):9-15.

[59] Gonciarz M, et al. Plasma insulin, leptin, adiponectin, resistin, ghrelin, and melatonin in nonalcoholic steatohepatitis patients treated with melatonin. J Pineal Res. 2013 Mar;54(2):154-61.

[60] Vincent B. Protective roles of melatonin against the amyloid-dependent development of Alzheimer’s disease: A critical review. Pharmacol Res. 2018 Aug;134:223-237.

[61] McMullan CJ, et al. Melatonin secretion and the incidence of type 2 diabetes. JAMA. 2013 Apr 3;309(13):1388-96.

[62] Anand PK, et al. Role of the nlrp3 inflammasome in microbial infection. Front Microbiol. 2011 Feb 2;2:12.

[63] Ong JD, et al. Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection. J Leukoc Biol. 2017 Apr;101(4):863-874.

[64] Tate MD, Mansell A. An update on the NLRP3 inflammasome and influenza: the road to redemption or perdition? Curr Opin Immunol. 2018 Oct;54:80-85.

[65] Ma S, et al. Melatonin Ameliorates the Progression of Atherosclerosis via Mitophagy Activation and NLRP3 Inflammasome Inhibition. Oxid Med Cell Longev. 2018 Sep 4;2018:9286458.

[66] Cao S, et al. Melatonin-mediated mitophagy protects against early brain injury after subarachnoid hemorrhage through inhibition of NLRP3 inflammasome activation. Sci Rep. 2017 May 25;7(1):2417.

[67] Xu L, et al. Melatonin Suppresses Estrogen Deficiency-Induced Osteoporosis and Promotes Osteoblastogenesis by Inactivating the NLRP3 Inflammasome. Calcif Tissue Int. 2018 Oct;103(4):400-10.

[68] Che H, et al. Melatonin alleviates cardiac fibrosis via inhibiting lncRNA MALAT1/miR-141-mediated NLRP3 inflammasome and TGF-β1/Smads signaling in diabetic cardiomyopathy. FASEB J. 2020 Apr;34(4):5282-5298.

[69] Fernández-Gil B, et al. Melatonin protects rats from radiotherapy-induced small intestine toxicity. PLoS One. 2017 Apr 12;12(4):e0174474.

[70] Volt H, et al. Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. J Pineal Res. 2016 Mar;60(2):193-205.

[71] Lin GJ, et al. Melatonin prolongs islet graft survival in diabetic NOD mice. J Pineal Res. 2009 Oct;47(3):284-92.

[72] Shang Y, et al. Melatonin reduces acute lung injury in endotoxemic rats. Chin Med J (Engl). 2009 Jun 20;122(12):1388-93.

[73] Boga JA, et al. Beneficial actions of melatonin in the management of viral infections: a new use for this “molecular handyman”? Rev Med Virol. 2012 Sep;22(5):323-38.

[74] Galley HF, et al. Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis. J Pineal Res. 2014 May;56(4):427-38.

[75] Dong WG, et al. Effects of melatonin on the expression of iNOS and COX-2 in rat models of colitis. World J Gastroenterol. 2003 Jun;9(6):1307-11.

[76] Boga JA, et al. Beneficial actions of melatonin in the management of viral infections: a new use for this “molecular handyman”? Rev Med Virol. 2012 Sep;22(5):323-38.

[77] El-Sharkawy H, et al. Is dietary melatonin supplementation a viable adjunctive therapy for chronic periodontitis?-A randomized controlled clinical trial. J Periodontal Res. 2019 Apr;54(2):190-197.

[78] Sánchez-López AL, et al. Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis. Arch Med Res. 2018 Aug;49(6):391-398.

[79] Bazyar H, et al. The effects of melatonin supplementation in adjunct with non-surgical periodontal therapy on periodontal status, serum melatonin and inflammatory markers in type 2 diabetes mellitus patients with chronic periodontitis: a double-blind, placebo-controlled trial. Inflammopharmacology. 2019 Feb;27(1):67-76.

[80] Raygan F, et al. Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2019 Feb;38(1):191-196.

[81] Panah F, et al. The effect of oral melatonin on renal ischemia-reperfusion injury in transplant patients: A double-blind, randomized controlled trial. Transpl Immunol. 2019 Dec;57:101241

[82] Zhao Z, et al. The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: In vivo assessment and a randomized controlled trial. J Pineal Res. 2018 Nov;65(4):e12521.

[83] Shafiei E, et al. Effects of N-acetyl cysteine and melatonin on early reperfusion injury in patients undergoing coronary artery bypass grafting: A randomized, open-labeled, placebo-controlled trial. Medicine (Baltimore). 2018 Jul;97(30):e11383.

[84] Zarezadeh M, et al. Melatonin supplementation and pro-inflammatory mediators: a systematic review and meta-analysis of clinical trials. Eur J Nutr. 2019 Nov 2.


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