Numerous clinical studies suggest otherwise, a look at their findings not related to sleep
Since its discovery in 1958, we have learned much about the diverse functions of melatonin in animals, where it serves not only as a circadian rhythm regulator, but also as an antioxidant, immunoregulatory and anti-inflammatory molecule, hormone, metal chelator, and much more.,,, However, there still are a great many questions about its use as a supplement, especially for applications beyond promoting sleep. Herein, we address many of these questions, and touch on the broad range of clinical research pertaining to melatonin – even at doses as high as 100 to 300 mg daily.
Concerns of Sedation: Well Founded, or Not?
Although most supplement users are familiar with the use of melatonin at bedtime to support a normal, healthy sleep cycle or for prevention of jet lag (uses that many clinical studies support),, many are uncertain of the research backing its use beyond this. Additionally, there often is hesitation to take higher doses due to the fear of excessive sedation. However, those in the field of melatonin research often implement dosing schemes far different from the use of melatonin that most are familiar with. As studies suggest that the dose of melatonin required for its antioxidant effects are particularly higher than those given to modulate the circadian rhythm, there has been considerable research investigating how supraphysiological doses of melatonin (up to as high as 3500 mg, acutely) impact the body symptomatically and biochemically.
Numerous clinical trials suggest that the potential sedative effects are not as profound as we tend to anticipate, and studies have looked even at the use of higher doses of melatonin (6 to 20 mg) immediately prior to athletic events, – quite contrary to how many would use this pineal gland hormone/antioxidant!
Numerous clinical trials suggest that the potential sedative effects are not as profound as we tend to anticipate, and studies have looked even at the use of higher doses of melatonin immediately prior to athletic events.
One particularly interesting randomized, double-blind clinical trial (RDBPCT) looked at the pharmacokinetics and sedation effects of intravenous doses of 10 and 100 mg of melatonin in healthy individuals, finding that even the dosage of 100 mg did not lead to sedation or other adverse effects (as assessed by symptom reporting and a simple reaction time test) at 120, 180, 300, and 420 minutes after administration. Another tolerability and pharmacokinetics study using 20, 30, 50, and 100 mg oral doses of melatonin found that although 75% of subjects experienced some drowsiness during the visit, there was no relationship to dosage, and subjects were fully recovered and able to go home six hours later. No effects on sleeping patterns or adverse effects were seen.
Long term use of high-dose melatonin has been studied for safety in limited settings, however in each of the studies mentioned herein, no significant adverse effects were seen. The highest dosage and longest term of use found in this review of such research was in a patient population having amyotrophic lateral sclerosis (ALS). In this population, 300 mg of melatonin (administered as a suppository to eliminate problems with swallowing difficulties, common in ALS) was taken at bedtime for a period of up to two years. Researchers found that after two months plasma melatonin levels stayed in the expected range, indicating there was not accumulation or increased metabolism. No adverse effects were reported or observed, including melatonin “hangover” or increased daytime fatigue. A positive outcome of this study was that a marker of oxidative stress in the ALS patients was restored to levels of healthy control individuals with melatonin supplementation.
Melatonin Research Highlights Beyond Sleep
Clinical studies in many different settings have shown that higher doses of melatonin may be useful for many purposes other than supporting sleep.
Athletes. Although some level of oxidative stress is necessary for the adaptive response and muscle hypertrophy that one seeks to achieve with athletic training, too much leads to fatigue and has detrimental effects on performance, the immune response, and other parameters.
In one RDBPCT of male resistance-trained athletes, supplementation with 100 mg of melatonin before bed for four weeks significantly increased oxygen radical absorption capacity and decreased levels of lipid peroxidation, advanced oxidation protein products, creatine kinase, lactate dehydrogenase, creatine, and total cholesterol levels compared to placebo, suggesting it may be of benefit in this setting. A shorter two-week study looked at the impact of melatonin, taken at a dose of 20 mg immediately before intense exercise, on similar parameters related to oxidative stress, finding that supplementation in this fashion significantly improved total antioxidant capacity and the glutathione peroxidase activity compared to placebo, with reduced DNA damage noted as well.
Metabolic and Liver Disease. In recent years, there has been considerable research regarding the use of melatonin for a variety of metabolic diseases and their consequences., In addition to its antioxidant and anti-inflammatory principles, melatonin also is involved metabolism, affecting insulin signaling, cellular glucose uptake, the balance of white and brown adipose, and adipokine secretion among other things, which has prompted this research.
Clinical studies also have shown melatonin may help ameliorate metabolic issues associated with antipsychotic medication use and the inflammation and oxidative stress associated with obesity.
Benefits with melatonin supplementation have been seen in obese patients following a calorie-restricted diet, where compared to placebo, supplementation with 10 mg of melatonin at bedtime improved markers of oxidative stress, regulated adipokine (hormones secreted by adipose tissue) secretion, and supported weight loss. Other clinical studies also have shown melatonin may help ameliorate metabolic issues associated with antipsychotic medication use and the inflammation and oxidative stress associated with obesity.,,,
Liver disease also is often accompanied by oxidative stress, whether it is one of the initiating factors or a consequence of disease. At a cellular level, hepatic mitochondrial dysfunction, often caused by a high level of oxidative stress, is one contributor to fibrosis which melatonin has been shown in numerous animal models to improve.,,
In patient with histologically proven nonalcoholic steatohepatitis (NASH), supplementation with 5 mg of melatonin twice daily (in the AM and before bed) for 28 days significantly improved insulin resistance, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) levels compared to baseline. In this study, much like many of the others, despite morning dosing of melatonin, there were no reports of somnolence or other side effects. Longer studies in this population with the same protocol reinforced this finding, with significant decreases in AST and GGT being seen compared to placebo and baseline which were maintained through the longer treatment period, although 12 weeks after discontinuing treatment, AST levels returned close to that of baseline.,
One additional study pertaining to both metabolic and liver health looked at melatonin as a therapy for statin-induced liver enzyme elevation, finding that treatment with 5 mg of melatonin twice daily for six months significantly improved AST, ALT, and GGT compared to placebo.
Adjunctive Agent in Cancer Care. Numerous studies have looked at melatonin as an adjunctive agent for adults with malignancies. In addition to its antioxidant effects, melatonin has context-specific influences on apoptosis: in normal cells, melatonin has been demonstrated to have anti-apoptotic effects, however in cancer cells, melatonin is often pro-apoptotic. Research also suggests it has anti-angiogenesis effects, activates the immune response, stimulates cell differentiation, and inhibits telomerase activity, among many other things, each of which may help reduce the risk of malignancy.,
Studies suggest melatonin may be useful as an adjunctive agent with immunotherapy, chemotherapy, and other cytotoxic drugs, reducing adverse effects that commonly occur with their use.
Several studies suggest melatonin may be useful as an adjunctive agent with immunotherapy, chemotherapy, and other cytotoxic drugs, reducing adverse effects that commonly occur with their use. As an adjunctive agent for individuals receiving traditional care for malignancy, at a dosage of 20 mg/day or higher, melatonin has been shown in small studies to reduce cancer-related and chemotherapy-induced thrombocytopenia,, improve chemotherapy-related myelodysplastic syndrome, delay the onset of more severe oral mucositis and treatment interruptions due to it, reduce anxiety, severity of hair loss, and infections associated with radiotherapy, reduce anxiety associated with chemotherapy, and reduce chemotherapy-related asthenia, stomatitis, and cardio- and neurotoxicity. A growing volume of research also suggests melatonin may actually improve the response to chemotherapy and radiation treatment, simultaneously protecting the healthy normal tissue from damage associated with these forms of treatment.,, It is appropriate to note, however, that any such usage of melatonin with treatments for malignancy should be thoroughly discussed with one’s oncologist before initiating supplementation.
Although this review primarily focuses on the use of higher doses of melatonin, clinical studies have also shown supplementation with more customary doses of melatonin (ranging from 3 to 9 mg) may be beneficial for psychosomatic symptoms and irritable bowel syndrome in postmenopausal women;, reduction of chronic migraine frequency, duration, and severity; and improvement of mood, anxiety levels, quality of life, and cortisol balance in fibromyalgia patients. In the studies with morning dosing, melatonin was well tolerated, with minimal reports of daytime fatigue (seen primarily in the initial week of the study if it did occur). These, and many other preclinical and clinical studies not able to be highlighted here due to constraints of space, far broaden the potential scope of health conditions that may be positively impacted by melatonin.
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 Wurtman RJ. Melatonin as a hormone in humans: a history. Yale J Biol Med. 1985 Nov-Dec;58(6):547-52.
 Manchester LC, et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J. Pineal Res. 2015;59:403-19.
 Yu K, et al. Melatonin Regulates the Synthesis of Steroid Hormones on Male Reproduction: A Review. Molecules. 2018 Feb 17;23(2).
 Calvo JR, et al. The role of melatonin in the cells of the innate immunity: a review. J Pineal Res. 2013; 55:103–9.
 Reiter RJ, et al. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016 Oct;61(3):253-78.
 Brzezinski A, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev. 2005 Feb;9(1):41-50.
 Paul MA, et al. Melatonin treatment for eastward and westward travel preparation. Psychopharmacology (Berl). 2010 Feb;208(3):377-86.
 Nickkholgh A, et al. The use of high-dose melatonin in liver resection is safe: first clinical experience. J Pineal Res. 2011 May;50(4):381-8.
 Maldonado MD, et al. Melatonin administrated immediately before an intense exercise reverses oxidative stress, improves immunological defenses and lipid metabolism in football players. Physiol Behav. 2012 Mar 20;105(5):1099-103.
 Ortiz-Franco M, et al. Effect of melatonin supplementation on antioxidant status and DNA damage in high intensity trained athletes. Int J Sports Med. 2017 Dec;38(14):1117-25.
 Andersen LP, et al. Pharmacokinetics of high-dose intravenous melatonin in humans. J Clin Pharmacol. 2016 Mar;56(3):324-9.
 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.
 Andersen LP, et al. The Safety of Melatonin in Humans. Clin Drug Investig. 2016 Mar;36(3):169-75.
 Weishaupt JH, et al. Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res. 2006 Nov;41(4):313-23.
 Schoenfeld BJ. Potential mechanisms for a role of metabolic stress in hypertrophic adaptations to resistance training. Sports Med. 2013 Mar;43(3):179-94.
 Powers SK, et al. Exercise-induced oxidative stress in humans: cause and consequences. Free Radic Biol Med. 2011 Sep 1;51(5):942-50.
 Gleeson M, Bishop NC. Special feature for the Olympics: effects of exercise on the immune system: modification of immune responses to exercise by carbohydrate, glutamine and anti-oxidant supplements. Immunol Cell Biol. 2000 Oct;78(5):554-61.
 Leonardo-Mendonça RC, et al. The benefit of a supplement with the antioxidant melatonin on redox status and muscle damage in resistance-trained athletes. Appl Physiol Nutr Metab. 2017 Jul;42(7):700-707.
 Ortiz-Franco M, et al. Effect of melatonin supplementation on antioxidant status and DNA damage in high intensity trained athletes. Int J Sports Med. 2017 Dec;38(14):1117-25.
 Cardinali DP, Hardeland R. Inflammaging, Metabolic Syndrome and Melatonin: A Call for Treatment Studies. Neuroendocrinology. 2017;104(4):382-397.
 Cardinali DP, Vigo DE. Melatonin, mitochondria, and the metabolic syndrome. Cell Mol Life Sci. 2017 Nov;74(21):3941-3954.
 Cipolla-Neto J, et al. Melatonin, energy metabolism, and obesity: a review. J Pineal Res. 2014 May;56(4):371-81.
 Zanuto R, et al. Melatonin improves insulin sensitivity independently of weight loss in old obese rats. J Pineal Res. 2013 Sep;55(2):156-65.
 Jiménez-Aranda A, et al. Melatonin induces browning of inguinal white adipose tissue in Zucker diabetic fatty rats. J Pineal Res. 2013 Nov;55(4):416-23.
 Szewczyk-Golec K, et al. Melatonin Supplementation Lowers Oxidative Stress and Regulates Adipokines in Obese Patients on a Calorie-Restricted Diet. Oxid Med Cell Longev. 2017;2017:8494107.
 Modabbernia A, et al. Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: randomized double-blind placebo-controlled study. J Psychiatr Res. 2014 Jun;53:133-40.
 Mostafavi A, et al. Melatonin decreases olanzapine induced metabolic side-effects in adolescents with bipolar disorder: a randomized double-blind placebo-controlled trial. Acta Med Iran. 2014;52(10):734-9.
 Romo-Nava F, et al. Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord. 2014 Jun;16(4):410-21.
 Mesri Alamdari N, et al. A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Horm Metab Res. 2015 Jun;47(7):504-8.
 Mantena SK, et al. Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic Biol Med. 2008 Apr 1;44(7):1259-72.
 Agil A, et al. Melatonin reduces hepatic mitochondrial dysfunction in diabetic obese rats. J Pineal Res. 2015 Aug;59(1):70-9.
 Cheshchevik V, et al. Corrections by melatonin of liver mitochondrial disorders under diabetes and acute intoxication in rats. Cell Biochem Funct. 2011 Aug;29(6):481-8.
 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.
 Gonciarz M, et al. The pilot study of 3-month course of melatonin treatment of patients with nonalcoholic steatohepatitis: effect on plasma levels of liver enzymes, lipids and melatonin. J Physiol Pharmacol. 2010 Dec;61(6):705-10.
 Gonciarz M, et al. The effects of long-term melatonin treatment on plasma liver enzymes levels and plasma concentrations of lipids and melatonin in patients with nonalcoholic steatohepatitis: a pilot study. J Physiol Pharmacol. 2012 Feb;63(1):35-40.
 Chojnacki C, et al. The Effects of Melatonin on Elevated Liver Enzymes during Statin Treatment. Biomed Res Int. 2017;2017:3204504.
 Bizzarri M, et al. Molecular mechanisms of the pro‐apoptotic actions of melatonin in cancer cells. Cell Mol Life Sci. 2013; 70:39–57.
 Lissoni P, et al. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro Endocrinol Lett. 2001;22(1):45-7.
 Su SC, et al. Cancer metastasis: Mechanisms of inhibition by melatonin. J Pineal Res. 2017 Jan;62(1).
 Panzer A, Viljoen M. The validity of melatonin as an oncostatic agent. J Pineal Res. 1997 May;22(4):184-202.
 Lissoni P, et al. Chemoneuroendocrine therapy of metastatic breast cancer with persistent thrombocytopenia with weekly low-dose epirubicin plus melatonin: a phase II study. J Pineal Res. 1999 Apr;26(3):169-73.
 Lissoni P, et al. A biological study on the efficacy of low-dose subcutaneous interleukin-2 plus melatonin in the treatment of cancer-related thrombocytopenia. Oncology. 1995 Sep-Oct;52(5):360-2.
 Viviani S, et al. Preliminary studies on melatonin in the treatment of myelodysplastic syndromes following cancer chemotherapy. J Pineal Res. 1990;8(4):347-54.
 Onseng K, et al. Beneficial Effects of Adjuvant Melatonin in Minimizing Oral Mucositis Complications in Head and Neck Cancer Patients Receiving Concurrent Chemoradiation. J Altern Complement Med. 2017 Dec;23(12):957-963.
 Lissoni P, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology. 1996 Jan-Feb;53(1):43-6.
 Lissoni P, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer. 1995 Apr;71(4):854-6.
 Lissoni P. Is there a role for melatonin in supportive care? Support Care Cancer. 2002 Mar;10(2):110-6.
 Asghari MH, et al. Does the use of melatonin overcome drug resistance in cancer chemotherapy? Life Sci. 2018 Mar 1;196:143-155.
 Farhood B, et al. Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization. Clin Transl Oncol. 2019 Mar;21(3):268-279.
 Mihandoost E, et al. Can melatonin help us in radiation oncology treatments? Biomed Res Int. 2014;2014:578137.
 Chojnacki C, et al. The effect of long-term melatonin supplementation on psychosomatic disorders in postmenopausal women. J Physiol Pharmacol. 2018 Apr;69(2).
 Chojnacki C, et al. Influence of melatonin on symptoms of irritable bowel syndrome in postmenopausal women. Endokrynol Pol. 2013;64(2):114-20.
 Ebrahimi-Monfared M, et al. Use of melatonin versus valproic acid in prophylaxis of migraine patients: A double-blind randomized clinical trial. Restor Neurol Neurosci. 2017;35(4):385-393.
 Castaño MY, et al. Melatonin improves mood status and quality of life and decreases cortisol levels in fibromyalgia. Biol Res Nurs. 2018 Nov 11:1099800418811634.