The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. In this installment, Ting Bao, MD, DABMA, MS, and Jyothirmai Gubili, MS, present information on melatonin, a pineal gland hormone that regulates circadian rhythms and sleep, among other functions.
Scientific Name: N-acetyl-methoxytryptamine
Produced endogenously by the pineal gland, melatonin is a pleiotropic hormone that plays an important physiologic role. It regulates circadian rhythms, sleep, mood, and aging; it may also be involved in the development of neurodegenerative diseases including Alzheimer’s and Parkinson’s. Melatonin is synthesized and released after the onset of darkness while being inhibited by light.
Current data show its utility in promoting sleep. Preliminary findings also suggest that melatonin may help improve quality of life in patients with cancer. More investigations are underway.
Supplemental melatonin is used as a sleep aid, marketed in the form of liquid, capsules, tablets, and as transdermal patches and for sublingual use. The prolonged-release forms of melatonin are also available.
Preliminary findings suggest the effectiveness of melatonin in reducing sleep latency and in improving sleep duration,1-3 although data from randomized trials are inconclusive.4-6 And a meta-analysis did not find any significant effects of melatonin on secondary sleep problems.7 But melatonin has been reported to alleviate anxiety8 and pain resulting from surgery9 and to reduce the frequency of migraine attacks.10 Melatonin may also help improve cognitive function and sleep maintenance in patients with Alzheimer’s disease.11 Studies in a pediatric population found melatonin useful in improving sleep-onset latency and disease severity in those with atopic dermatitis12; and comparable in effectiveness to midazolam in alleviating anxiety in children undergoing surgery.13
Melatonin has been investigated for potential anticancer effects as well. It demonstrated antioxidant14,15 and antiproliferative effects,16 in addition to exhibiting synergy with anticancer agents.17-19 Findings from small studies suggest the effectiveness of melatonin as monotherapy or in combination with other agents in improving the quality of life of patients with metastatic solid tumors,20-23 although similar effects were not observed in cachectic cancer patients.24
Interestingly, despite reports of association between melatonin and estrogen,25 short-term (4 months), low-dose (3 mg) supplementation in postmenopausal breast cancer survivors did not affect estradiol levels.26 However, a case report suggests that oral melatonin may delay menopause in premenopausal women by modulating levels of follicle-stimulating hormone and estrogen.27 Further studies are needed to resolve this ambiguity.
Mechanistic studies indicate that the G-protein–coupled receptors MT1 and MT2 are involved in mediating the circadian-resetting effects of melatonin.28 Melatonin also acts a potent free-radical scavenger14,29 and enhances antioxidative enzyme activities,15 interacting with cytosolic calmodulin and stimulating the production of interleukin (IL-4) in bone marrow T lymphocytes.30 The effects of melatonin on tumor cell growth may be mediated in part by melatonin receptor signaling.31,32 In endometrial cancer cells, it interferes with estrogen receptor expression.33 Other studies suggest that melatonin behaves both as a selective estrogen receptor modulator and an aromatase inhibitor.34,35 In addition, reduction in breast cancer metastasis is thought to be due to melatonin modulation of Rho-associated kinase protein 1 expression.36
Melatonin use has been associated with drowsiness, alterations in sleep patterns, altered mental status, disorientation, tachycardia, flushing, pruritus, abdominal cramps, headaches, trouble sleeping, bad dreams, and hypothermia.1,26,30,37,38
Nifedipine: Concurrent administration with melatonin resulted in elevated blood pressure and heart rate.39
Cytochrome P4501A2 substrates: Melatonin was shown to inhibit CYP1A2 and may increase the bioavailability of substrate drugs, such as fluvoxamine.40-42
Anticoagulants: Melatonin, taken orally, has been associated with reduced plasma levels of factor VIII and fibrinogen.43 Therefore, it may increase the risk of bleeding when used along with anticoagulants.
Melatonin may help improve sleep quality and other patient-reported outcomes in patients with cancer. It is being investigated for potential anticancer effects, but solid evidence has yet to be generated. Reported to be a selective estrogen receptor modulator and an aromatase inhibitor, melatonin may affect estrogen levels in premenopausal women. Further studies need to be conducted to evaluate the long-term safety and efficacy of using melatonin in cancer survivors, especially those with hormone-sensitive tumors. ■
DISCLOSURE: Dr. Bao and Ms. Gubili reported no conflicts of interest.
Ting Bao, MD, DABMA, MS
Jyothirmai Gubili, MS
Dr. Bao is Director, Integrative Breast Oncology, Memorial Sloan Kettering Cancer Center, New York. Ms. Gubili is Editor, Integrative Medicine, Memorial Sloan Kettering Cancer Center, New York.
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3. 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 23:2597-2605, 2007.
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21. Lissoni P, Chilelli M, Villa S, et al: 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 35:12-15, 2003.
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32. 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 35:177-182, 2003.
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38. Shamir E, Barak Y, Shalman I, et al: Melatonin treatment for tardive dyskinesia: A double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry 58:1049-1052, 2001.
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41. von Bahr C, Ursing C, Yasui N, 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 56:123-127, 2000.
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