Melatonin

• How It Works

  Melatonin has not been shown to treat cancer in humans. It may improve sleep quality in some patients.

  Melatonin is a hormone naturally produced by the brain in humans. The supplemental form is used to treat insomnia. Scientists believe that it controls circadian rhythms of sleep and wakefulness. Nighttime darkness causes increased production of melatonin, promoting sleep and causing a decrease in body temperature. Both elderly and depressed patients tend to have lower baseline levels of melatonin.

  Laboratory studies suggest that melatonin is an antioxidant that can stimulate some aspects of the immune system, but it is not known if this effect occurs in humans. Melatonin also inhibits the growth of certain cancer cells including breast cancer and melanoma when directly applied to these cells. Studies in humans, however, do not show an anticancer effect. When used at the same time as specific chemotherapy drugs, melatonin may increase survival time. Other studies indicate it may improve sleep quality in some patients, but whether it can be of benefit in depression or for easing withdrawal symptoms is unclear.

• Purported Uses
  • To prevent aging
    Clinical trials show that melatonin can help age-related sleep problems, but there is no evidence to support its use as an “anti-aging” supplement.
  • To treat cancer
    Clinical trials do not support this use, but a few studies found that a combination of melatonin with standard chemotherapy may increase survival time in cancer patients.
  • To reduce chemotherapy side effects
    An analysis of clinical trials suggests melatonin may help reduce the incidence of some chemotherapy side effects. Additional trials are needed to confirm this.
  • To treat depression
    Evidence for the use of melatonin in depression is unclear. Additional studies are needed.
  • To treat insomnia
    Several clinical trials support this use.
  • To prevent and manage jet lag
    A few studies suggest melatonin may be helpful for jet lag. 
  • To treat seasonal affective disorder (SAD)
    Clinical trials on melatonin for this use are lacking.
  • To ease withdrawal from benzodiazepines
    Evidence on whether melatonin can ease withdrawal symptoms is mixed. Additional studies are needed.
  • For migraine prevention
    A small study suggests melatonin can reduce frequency of migraine attacks.
• Patient Warnings
  • This product is regulated by the FDA as a dietary supplement. Unlike approved drugs, supplements are not required to be manufactured under specific standardized conditions. This product may not contain the labeled amount or may be contaminated. In addition, it may not have been tested for safety or effectiveness.
  • Melatonin may cause drowsiness. Patients should not drive or operate heavy machinery until familiar with its effects.
• Do Not Take If
  • You are taking nifedipine (Procardia®): Use of melatonin and nifedipine at the same time has resulted in elevations in blood pressure and heart rate.
  • You are taking fluvoxamine (Luvox®): Fluvoxamine may increase blood levels of melatonin, resulting in sedation.
  • You are taking blood thinners such as warfarin: Caution is warranted, as a single dose of melatonin was found to decrease clotting factors in the lab tests of healthy adults. Therefore, it may increase the chance of adverse effects when used with blood-thinning drugs.
  • You are taking Rhubarb: A study using human primary hepatocytes showed that concomitant use can cause metabolic disorder of melatonin.
• Side Effects
  • Headaches
  • Drowsiness
  • Alterations in sleep patterns
  • Trouble sleeping
  • Bad dreams
  • Altered mental status, disorientation
  • Fast heart rate
  • Flushing
  • Itching
  • Abdominal cramps
  • Abnormally low body temperature
• Scientific Name

  N-acetyl-methoxytryptamine

• Clinical Summary

  Melatonin is produced endogenously in humans by the pineal gland. Although the exact mechanism of action is unknown, it is thought to control the circadian pacemaker and promote sleep ⁽¹⁾. Small amounts of melatonin are found in fruits, nuts, olive oil, and wine. The supplemental form is used as a sleep-aid.

  Clinical studies suggest that melatonin may decrease sleep latency and improve sleep duration ^{(2) (3) (4)}, although randomized trials have produced mixed data ^{(27) (28) (29)}. A meta-analysis did not find any significant effects with melatonin on secondary sleep disorders associated with medical, neurological, or substance abuse disorders ⁽⁵⁾, but supplementation was reported to improve subjective sleep quality in patients with traumatic brain injury ⁽⁴⁴⁾. Additional studies show that melatonin may decrease surgery-associated anxiety and pain ⁽⁶⁾ as well as frequency of migraine attacks ⁽⁷⁾. Data also indicate that it can reduce perioperative anxiety ^(30) (56), but there is insufficient evidence for its use to improve sleep in ICU patients ⁽⁴⁶⁾, delirium in hospitalized patients ⁽⁵⁷⁾, to improve depression or depressive symptoms ⁽⁴⁷⁾, or for seasonal affective disorder (SAD) ⁽⁴⁸⁾. It also did not improve nocturia in a small study of multiple sclerosis patients ⁽⁵³⁾. A few studies suggest melatonin may be helpful for jet lag ^(51) (52). Studies on whether melatonin can help in benzodiazepine withdrawal are mixed ^(49) (50).

  In vitro and in vivo studies suggest that melatonin has antioxidant ^(38) (39) and antiproliferative properties, including against breast cancer cells ⁽⁴⁰⁾; synergistic effects with anticancer agents ^{(8) (9) (32)}; and protective effects against adriamycin-induced cardiotoxicity ⁽³³⁾.

  Clinical trials evaluating melatonin as a monotherapy or in combination with other agents and in patients with solid tumors suggest improvements in quality of life and survival time ^{(10) (11) (12) (13)}, but melatonin did not improve appetite, weight, or quality of life in cancer patients with cachexia ⁽³⁵⁾. In studies of postmenopausal breast cancer survivors, short-term supplementation did not influence estradiol levels ⁽³⁶⁾ but improved sleep quality ⁽³⁷⁾. Data also suggest that melatonin may help reduce incidence of chemotherapy side effects including thrombocytopenia, asthenia, and neurotoxicity ⁽⁵⁴⁾; and minimize radiotherapy-induced reduction in blood cell counts ⁽⁵⁸⁾.
  According to a case report, oral melatonin may delay menopause in pre-menopausal women by modulating levels of follicle stimulating hormone (FSH) and estrogen ⁽³¹⁾.

• Food Sources

  Small amounts of melatonin are found in fruits, nuts, olive oil and wine.

• Purported Uses
  • Antiaging
  • Cancer treatment
  • Chemotherapy side effects
  • Depression
  • Drug withdrawal symptoms
  • Insomnia
  • Jet lag
  • Migraine prophylaxis
  • Seasonal affective disorder (SAD)
• Mechanism of Action

  Melatonin is an endogenously produced indolamine hormone secreted by the pineal gland in humans. Nocturnal secretion is regulated by circadian rhythms and nighttime darkness ⁽¹⁷⁾, and melatonin is thought to control the circadian pacemaker and promote sleep. Ironically, it is associated with wakefulness and activity in nocturnal animals ⁽¹⁴⁾. As levels of melatonin increase, an associated drop in core body temperature occurs. Both elderly and depressed patients tend to have lower basal levels of melatonin ⁽²⁾.

  Melatonin is a free-radical scavenger ^(18) (38) and enhances antioxidative enzyme activities ⁽³⁹⁾, interacting with cytosolic calmodulin and stimulating IL-4 production in bone marrow T-lymphocytes ⁽¹⁾. In vitro and animal studies suggest that antitumor effects may occur through antimitotic or immunomodulatory activity. In vitro studies demonstrate antiproliferative effects on human breast cancer (HS578T) ⁽¹⁹⁾ and mouse melanoma (B16BL6, PG19) ⁽⁸⁾. Decreases in breast cancer metastasis may occur via modulation of Rho-associated kinase protein-1 expression ⁽⁴¹⁾. Melatonin reduces proliferation of PC-3 and LNCaP cells in mice, but has no effect on apoptosis ⁽⁹⁾. Its effect on tumor cell growth may be mediated in part by melatonin receptor signaling ^(20) (21). In endometrial cancer cells, it interferes with estrogen receptor expression ⁽²²⁾. Other laboratory studies suggest that melatonin behaves both as a selective estrogen receptor modulator (SERM) and as an aromatase inhibitor ^(42) (43). In a murine model, it modulated expression of genes crucial for DNA repair — Ogg1, Apex1, and Xrcc1 — in peripheral blood cells, to reduce X-ray-induced DNA damage  ⁽⁴⁵⁾.

• Warnings
  • Melatonin may cause drowsiness. Patients should not drive or operate heavy machinery until familiar with the effects of melatonin.
• Adverse Reactions

  Drowsiness, alterations in sleep patterns, altered mental status, disorientation, tachycardia, flushing, pruritus, abdominal cramps, headaches, trouble sleeping, bad dreams, hypothermia ^{(1) (2) (14) (15) (36)}

• Herb-Drug Interactions

  Nifedipine: Concomitant administration of melatonin and nifedipine has resulted in elevations in blood pressure and heart rate ⁽¹⁶⁾.
  CYP1A2 substrates: Melatonin inhibits CYP1A2 and may increase the bioavailability of substrate drugs, like fluvoxamine ^{(23) (26) (34)}.
  Anticoagulants: Oral melatonin intake is associated with lower plasma levels of factor VIII and fibrinogen ⁽²⁵⁾. Therefore, this may increase the risk of adverse effects when used with anticoagulant medications.
  Rhubarb: A study using human primary hepatocytes showed that concomitant use can cause metabolic disorder of melatonin ⁽⁵⁵⁾.

• Herb Lab Interactions

  May lower plasma levels of factor VIII and fibrinogen  ⁽²⁵⁾.

• References

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  2. Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med 1998:30:122-30.

  3. Riemersma-van der Lek RF, Swaab DF, Twisk J, et al. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA. Jun 11 2008;299(22):2642-2655.

  4. Wade AG, Ford I, Crawford G, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin. Oct 2007;23(10):2597-2605.

  5. Buscemi N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta analysis. BMJ 2006; 332: 385-88.

  6. Caumo W, Levandovski R, Hidalgo MP. Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy: a double-blind, randomized, placebo-controlled study. J Pain. 2009 Jan;10(1):100-8.

  7. Peres MF, et al. Melatonin, 3 mg, is effective for migraine prevention. Neurology. 2004 Aug 24;63(4):757.

  8. Cos S, Garcia-Bolado A, Sanchez-Barcelo EJ. Direct antiproliferative effects of melatonin on two metastatic cell sublines of mouse melanoma (B18BL6 and PG19). Melanoma Res 2001;11:197-201.

  9. Xi SC, et al. Inhibition of androgen-sensitive LNCaP prostate cancer growth in vivo by melatonin: association of antiproliferative action of the pineal hormone with mt1 receptor protein expression. Prostate 2001;46:52-61.

  10. Lissoni P, et al. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 1994;73:699-701.

  11. Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J Pineal Res. 2003 Aug;35(1):12-5.

  12. Lissoni P, et al. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients. Br J Cancer 1996:74:1466-8.

  13. Lissoni P, Brivio F, Fumagalli L, et al. Neuroimmunomodulation in medical oncology: application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors. Anticancer Res. Mar-Apr 2008;28(2B):1377-1381.

  14. Sack RL, Lewy AJ, Hughes RJ. Use of melatonin for sleep and circadian rhythm disorders. Ann Med 1998;30:115-21.

  15. Shamir E, et al. Melatonin treatment for tardive dyskinesia: A double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry 2001;58:1049-52.

  16. Lusordi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol 2000;49:423.

  17. Reppert SM, Weaver DR. Melatonin Madness. Cell 1995;83:1059-62.

  18. Karbownik M, Reiter RJ. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc Soc Exp Biol Med 2000;225:9-22.

  19. Blask E, Wilson ST, Zalatan F. Physiological melatonin inhibition of human breast cancer cell growth in vitro: evidence for a glutathione-mediated pathway. Cancer Res 1997;57:1909-14.

  20. Ram PT, Dai J, Yuan L, et al. Involvement of the mt1 melatonin receptor in human breast cancer.Cancer Lett. May 28 2002;179(2):141-150.

  21. Shiu SY, Law IC, Lau KW, et al. Melatonin slowed the early biochemical progression of hormone-refractory prostate cancer in a patient whose prostate tumor tissue expressed MT1 receptor subtype.J Pineal Res. Oct 2003;35(3):177-182.

  22. Watanabe M, Kobayashi Y, Takahashi N, et al. Expression of melatonin receptor (MT1) and interaction between melatonin and estrogen in endometrial cancer cell line. J Obstet Gynaecol Res. Aug 2008;34(4):567-573.

  23. Hartter S, et al. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther 2000;67:1-6.

  24. DeMuro RL, et al. The absolute bioavailability of oral melatonin. J Clin Pharmacol 2000;40:781-4.

  25. Wirtz PH, Spillmann M, Bartschi C, et al. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. J Pineal Res. Mar 2008;44(2):127-133.

  26. Von Bahr C, et al. Fluvoxamine but not citalopram increases serum melatonin in healthy subjects – an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin Pharmacol 2000;56:123-7.

  27. Gögenur I, Kücükakin B, Bisgaard T, et al. The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, placebo-controlled trial. Anesth Analg. 2009 Apr;108(4):1152-6.

  28. Garzón C, Guerrero JM, Aramburu O, et al. Effect of melatonin administration on sleep, behavioral disorders and hypnotic drug discontinuation in the elderly: a randomized, double-blind, placebo-controlled study. Aging Clin Exp Res. 2009 Feb;21(1):38-42.

  29. Gehrman PR, Connor DJ, Martin JL, et al. Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Am J Geriatr Psychiatry. 2009 Feb;17(2):166-9.

  30. Yousaf F, Seet E, Venkatraghavan L, Abrishami A, Chung F. Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials. Anesthesiology. 2010 Oct;113(4):968-76.

  31. Diaz BL, Llaneza PC. Endocrine regulation of the course of menopause by oral melatonin: first case report. Menopause. 2008 Mar-Apr;15(2):388-92.

  32. Ruiz-Rabelo J, Vázquez R, Arjona A, et al. Improvement of capecitabine antitumoral activity by melatonin in pancreatic cancer. Pancreas. 2011 Apr;40(3):410-4.

  33. Aydemir S, Ozdemir I, Kart A. Role of exogenous melatonin on adriamycin-induced changes in the rat heart. Eur Rev Med Pharmacol Sci. 2010 May;14(5):435-41.

  34. Chang TK, Chen J, Yang G, et al. Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin. J Pineal Res. 2010 Jan;48(1):55-64.

  35. Del Fabbro E, Dev R, Hui D, et al. Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. J Clin Oncol. 2013 Apr 1;31(10):1271-6.

  36. Schernhammer ES, Giobbie-Hurder A, Gantman K, et al. A randomized controlled trial of oral melatonin supplementation and breast cancer biomarkers. Cancer Causes Control. 2012 Apr;23(4):609-16.

  37. Chen WY, Giobbie-Hurder A, Gantman K, et al. A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes. Breast Cancer Res Treat. 2014 Jun;145(2):381-8.

  38. Reiter RJ, Tan DX, Manchester LC, et al. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem Biophys. 2001;34(2):237-256.

  39. Zwirska-Korczala K, Jochem J, Adamczyk-Sowa M, et al. Influence of melatonin on cell proliferation, antioxidative enzyme activities and lipid peroxidation in 3T3-L1 preadipocytes—an in vitro study. J Physiol Pharmacol. Dec 2005;56 Suppl 6:91-99.

  40. Squecco R, Tani A, Zecchi-Orlandini S, et al. Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium. Eur J Pharmacol. Jul 05 2015;758:40-52.

  41. Borin TF, Arbab AS, Gelaleti GB, et al. Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression. J Pineal Res. Jan 2016;60(1):3-15.

  42. Gonzalez A, Cos S, Martinez-Campa C, Alonso-Gonzalez C, et al. Selective estrogen enzyme modulator actions of melatonin in human breast cancer cells. J Pineal Res. 2008 Aug;45(1):86-92.

  43. Alvarez-García V González A, Martínez-Campa C. et al. Melatonin modulates aromatase activity and expression in endothelial cells. Oncol Rep. 2013 May;29(5):2058-64.

  44. Grima NA, Rajaratnam SMW, Mansfield D, Sletten TL, Spitz G, Ponsford JL. Efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial. BMC Med. 2018 Jan 19;16(1):8.

  45. Rezapoor S, Shirazi A, Abbasi S, et al. Modulation of Radiation-induced Base Excision Repair Pathway Gene Expression by Melatonin. J Med Phys. 2017 Oct-Dec;42(4):245-250.

  46. Lewis SR, Pritchard MW, Schofield-Robinson OJ, et al. Melatonin for the promotion of sleep in adults in the intensive care unit. Cochrane Database Syst Rev. May 10 2018;5:Cd012455.

  47. Hansen MV, Danielsen AK, Hageman I, et al. The therapeutic or prophylactic effect of exogenous melatonin against depression and depressive symptoms: a systematic review and meta-analysis. Eur Neuropsychopharmacol. Nov 2014;24(11):1719-1728.

  48. Kaminski-Hartenthaler A, Nussbaumer B, Forneris CA, et al. Melatonin and agomelatine for preventing seasonal affective disorder. Cochrane Database Syst Rev. Nov 11 2015(11):Cd011271.

  49. Baandrup L, Fagerlund B, Glenthoj B. Neurocognitive performance, subjective well-being, and psychosocial functioning after benzodiazepine withdrawal in patients with schizophrenia or bipolar disorder: a randomized clinical trial of add-on melatonin versus placebo. Eur Arch Psychiatry Clin Neurosci. Mar 2017;267(2):163-171.

  50. Baandrup L, Fasmer OB, Glenthoj BY, et al. Circadian rest-activity rhythms during benzodiazepine tapering covered by mlatonin versus placebo add-on: data derived from a randomized clinical trial. BMC Psychiatry. Oct 13 2016;16(1):348.

  51. Paul MA, Miller JC, Gray GW, et al. Melatonin treatment for eastward and westward travel preparation. Psychopharmacology (Berl). Feb 2010;208(3):377-386.

  52. Revell VL, Burgess HJ, Gazda CJ, et al. Advancing human circadian rhythms with afternoon melatonin and morning intermittent bright light. J Clin Endocrinol Metab. Jan 2006;91(1):54-59.

  53. Drake MJ, Canham L, Cotterill N, et al. Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of nocturia in adults with multiple sclerosis (MeNiMS). BMC Neurol. Aug 6 2018;18(1):107.

  54. Wang Y, Wang P, Zheng X, et al. Therapeutic strategies of melatonin in cancer patients: a systematic review and meta-analysis. Onco Targets Ther. 2018;11:7895-7908.

  55. Jiang W, Tian X, Wang Y, et al. The natural anthraquinones from Rheum palmatum induced the metabolic disorder of melatonin by inhibiting human CYP and SULT enzymes. Toxicol Lett. 2016 Nov 16;262:27-38.

  56. Norouzi A, Fateh S, Modir H, Kamali A, Akrami L. Premedication effect of melatonin on propofol induction dose for anesthesia, anxiety, orientation and sedation after abdominal surgery: a double-blinded randomized trial.  Med Gas Res. 2019 Apr-Jun;9(2):62-67.

  57. Ng KT, Teoh WY, Khor AJ. The effect of melatonin on delirium in hospitalised patients: A systematic review and meta-analyses with trial sequential analysis. J Clin Anesth. 2020 Feb;59:74-81.

  58. Kouhi Habibi N, Shabestani Monfared A, Ebrahimnejad Gorji K, et al. The protective effects of melatonin on blood cell counts of rectal cancer patients following radio-chemotherapy: a randomized controlled trial. Clin Transl Oncol. 2019 Jun;21(6):745-752.