History & Overview Annual Report President's Pages Center News Community Affairs
Make a Gift Cycle for Survival Fred's Team Rock & Run on the River Yankees Universe Fund Thomas Blake Sr. Memorial Research Fund Donating Blood & Platelets Volunteering Thrift Shop Park Avenue Potluck CELEBRATIONS
Press Releases In the News Information for Journalists News@MSKCC
Manhattan New Jersey Long Island Westchester
Working at Memorial Sloan-Kettering Work Sites College Recruitment About Nursing Job Fairs & Career Days IS Careers Job Search & Apply Online
Making an Appointment
Search About Herbs:

Melatonin

How It Works

Bottom Line: Melatonin has not been shown to treat cancer in humans.
Melatonin is a hormone naturally produced by the brain in humans. Scientists believe it controls the circadian rhythm of sleep and wakefulness: nighttime darkness causes increased production of melatonin at night, 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 a potent antioxidant and stimulates limited aspects of the immune system, but it is not known if this effect occurs in humans. It also inhibits the growth of certain cancer cells (including breast cancer and melanoma) when directly applied to them in laboratory studies and in animals. Studies in humans, however, do not show an anti-cancer effect. When used at the same time as certain chemotherapy drugs, however, melatonin may increase survival time. 

Purported Uses

  • To prevent or slow the progression of Alzheimer's disease
    Clinical trials have had conflicting results.
  • To prevent aging
    Clinical trials show that melatonin can help treat age-related sleeping problems, but NO evidence supports its use as an "anti-aging" supplement.
  • To treat cancer
    Clinical trials do not support this use.
  • To reduce the severity of chemotherapy side effects
    One study suggests that melatonin may reduce side effects commonly associated with chemotherapy.
  • To treat depression
    Clinical trials have found melatonin effective in treating depression associated with other syndromes (fibromyalgia, menopause), but have NOT found it effective in treating major depression.
  • To treat HIV and AIDS
    No scientific evidence supports this use.
  • To treat insomnia
    Several clinical trials support this use.
  • To prevent and manage jet lag
    Clinical trials yielded mix results.
  • To treat seasonal affective disorder (SAD)
    Clinical trials have had conflicting results.
  • To ease the withdrawal from benzodiazepines
    Two clinical trials have studied this use, with conflicting results.
  • For migraine prevention
    One small study suggests melatonin can reduce the frequency of migraine attack.

  • Research Evidence

    Side effects of chemotherapy
    A randomized controlled trial looked at the effect of melatonin on blood counts while patients were undergoing chemotherapy (carboplatin and etoposide) for non-small cell and small cell lung cancer. Twenty patients who had not received chemotherapy before took part in the study. 40 mg of melatonin or a placebo pill was given once daily, started two days before chemotherapy and continued for 21 days. Half of the patients randomly received melatonin during the first chemotherapy cycle; the other half received it during the second cycle. Final analysis showed no difference in blood counts between when patients were taking melatonin and when they took the placebo pill. This indicates that melatonin supplements do not improve the blood counts of patients undergoing chemotherapy.

    Cancer treatment
    The combination of 20 mg of melatonin and 20 mg of tamoxifen as a cancer treatment was tested in 25 patients with metastatic solid tumors other than breast and prostate. All of the patients had been unresponsive to previous treatments or had no alternate treatment option. All 25 patients were given this combination, melatonin at bedtime and tamoxifen at noon, until their disease progressed or until death. Three patients had a partial response (tumor shrinkage) for five to eight months, while 13 patients had stable disease for an average of six months. No patients had a complete response (tumor disappearance). The positive effects in this clinical trial were probably due to tamoxifen, which is an approved drug. These results do not support the use of melatonin for treating cancer.

    Fifty patients with brain metastases from solid tumors participated in a clinical trial of melatonin therapy. These patients had not responded to previous treatment with radiation and nitrosourea-based chemotherapy. Twenty-six were randomly assigned to receive supportive care only, while 24 were assigned to receive supportive care plus 20 mg of melatonin once daily. The melatonin group had a longer time until progression of their brain tumor(s) and lived slightly longer than the supportive care only group. The researchers concluded that melatonin improved the performance status of their patients, but these results do not support its use as a cancer treatment.

    100 patients with non-small cell lung cancer (NSCLC) took part in a study to see if melatonin would be effective when taken at the same time as chemotherapy. Patients received either four regular cycles of chemotherapy or four cycles of chemotherapy with melatonin. Patients receiving melatonin in addition to chemotherapy had longer survival rates. In addition, some side effects due to chemotherapy were significantly lower in the melatonin group. Researchers conclude that melatonin may help make chemotherapy work better and be better tolerated by patients


    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 the effects of melatonin.

    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).

  • Side Effects

  • Headache
  • Drowsiness
  • Alterations in sleep patterns
  • Altered mental status, disorientation
  • Tachycardia (fast heart rate) 
  • Flushing
  • Itching
  • Abdominal cramps
  • Hypothermia (abnormally low body temperature)

  • Scientific Name

    N-acetyl-methoxytryptamine

    Common Name

    MLT, pineal hormone

    Clinical Summary

    Hormonal supplement primarily of synthetic origin, but occasionally derived from animal sources. Patients use melatonin to treat insomnia, jet lag, and cancer. Melatonin is produced endogenously in humans by the pineal gland. Exogenous melatonin is absorbed poorly following oral administration and is metabolized rapidly by the liver. The exact mechanism of action is unknown, but melatonin is thought to control the circadian pacemaker and promote sleep (3). Clinical studies suggest that doses of 0.3-5 mg 30 minutes to four hours before bedtime may decrease sleep latency and improve overall sleep (2). But according to findings from a meta-analysis, melatonin does not have a significant effect on secondary sleep disorders assoicated with medical, neurological, or substance abuse disorders (23). More recent clinical studies on sleep improvement yield mixed results (24) (25) (26). Melatonin demonstrates antiproliferative effects on cancer cell lines both in vitro and in animal models (4) (5). Clinical trials evaluating melatonin as monotherapy and in combination with other agents in patients with solid tumors suggest improvements in quality of life and survival (19) (20), and a few cases of complete response (21) are documented. Melatonin can decrease frequency of migraine attacks (22) . Reported adverse effects are rare, but include drowsiness, headache, hypothermia, pruritus, abdominal cramps, and tachycardia (1) (2) (3) (15). Melatonin may interact with nifedipine (Procardia XL®), resulting in elevated blood pressure and heart rate (9). Optimal dose, length of therapy, and effect on endogenous melatonin are unknown, thus additional research is necessary.


    Purported uses

    • Alzheimer's disease
    • Antiaging
    • Cancer treatment
    • Chemotherapy side effects
    • Depression
    • Drug withdrawal symptoms
    • HIV and AIDS
    • Insomnia
    • Jet lag
    • Migraine prophylaxis
    • Seasonal affective disorder (SAD)

    Mechanism of Action

    Melatonin is an endogenously produced indolamine hormone secreted by the pineal glands in humans. Nocturnal secretion is regulated by circadian rhythms and nighttime darkness (8). Its exact mechanism of action is unknown, but melatonin is thought to control the circadian pacemaker and promote sleep. Ironically, melatonin is associated with wakefulness and activity in nocturnal animals (1). 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 appears to be a potent free-radical scavenger (7), interact with cytosolic calmodulin, and stimulate the production of IL-4 in bone marrow T-lymphocytes (3). In vitro and animal studies suggest anti-tumor effects exerted through antimitotic or immunomodulatory activity. In vitro studies demonstrate that melatonin has antiproliferative effects on human breast cancer (HS578T) (6) and mouse melanoma (B16BL6, PG19) (5). Melatonin reduces the proliferation of PC-3 and LNCaP in mice, but has no effect on apoptosis (4).

    Pharmacokinetics

    Doses of 1-2,000 mg melatonin given to healthy volunteers cause no significant toxicity. Intravenous administration of melatonin displays one compartment pharmacokinetics (1). Tablets are absorbed following oral administration, but appear to undergo extensive first pass metabolism (10). Melatonin is metabolized rapidly in the liver to hydroxy metabolites, possibly by cytochrome P450 isoenzymes 1A2 and 2C19. Oral bioavailability is estimated to be 15% for the parent compound. Elimination half-life is approximately 45 minutes with a total body clearance of 10 hours for a 3 mg dose (12).

    Warnings

    Melatonin may cause drowsiness; patients should not drive or operate heavy machinery until familiar with the effects of melatonin.

    Adverse Reactions

    Reported: Drowsiness, alterations in sleep patterns, altered mental status, disorientation, tachycardia, flushing, pruritus, abdominal cramps, headache, hypothermia.
    (1) (2) (3) (15)

    Herb-Drug Interactions

    Nifedipine: Concomitant administration of melatonin and nifedipine has resulted in elevations in blood pressure and heart rate (9).
    Fluvoxamine: Fluvoxamine may increase circulating plasma levels of melatonin resulting in sedation (10) (11).

    Literature Summary and Critique

    Ghielmini M, et al. Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer. Br J Cancer 1999;80:1058-61.
    A prospective, randomized, double-blind, cross-over design study evaluating the effect of 40 mg oral melatonin supplementation on hematologic indices. Twenty previously untreated patients with inoperable lung cancer (16 non-small-cell and 4 small-cell) received two cycles of carboplatin (AUC = 5, Calvert formula) on day 1 and 150mg/m2 IV etoposide on days 1-3 every 4 weeks. Melatonin or placebo was given once daily, initiated 2 days before chemotherapy and continued for 21 days. Patients were randomized to receive melatonin with either the first or the second cycle. Median age of the cohort was 60 years. Multivariate analysis including age, sex, diagnosis, stage, performance status, doses of carboplatin and etoposide, and concomitant treatment of melatonin or placebo, indicate no difference in hematological indices between treatment arms. No significant adverse effects related to melatonin were reported. Ghielmini et al. conclude that 40 mg oral melatonin does not improve hematologic status in lung cancer patients receiving carboplatin and etoposide.

    Lissoni P, et al. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients. Br J Cancer 1996:74:1466-8.
    A prospective, open-label evaluation of 20 mg melatonin and 20 mg tamoxifen in patients with metastatic solid tumors other than breast or prostate. Subjects were refractory to previous treatment, had poor performance status, or had no alternate treatment option. Twenty-five patients (M:F 10:15, aged 38-81, 6 unknown primary, 4 melanoma, 4 uterine cervical, 5 pancreatic, 3 hepatocarcinoma, 2 ovarian, 1 non-small cell lung) were administered melatonin at bedtime and tamoxifen at noon, regardless of estrogen receptor status until progression of disease or death. Patients received CT or MRI scan every 3 months and routine labs every 14 days. No complete response was documented. Three partial responses (12%) ranging from 5-8 months were recorded (melanoma, uterine cervical, and unknown primary). Stable disease, average duration 6 months, was noted in 13 patients (52%) while remaining 9 patients (36%) had progressive disease. No toxicity related to melatonin was reported. Lissoni et al. suggest that neuroendocrine treatment with 20 mg of melatonin and tamoxifen may be feasible for refractory solid tumors other than breast or prostate, but additional research is necessary.

    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.
    A prospective, randomized, open-label evaluation of patients with brain metastases from solid tumors refractory to radiation and nitrosourea-based chemotherapy. Patients were randomized to supportive care (n=26) or supportive care plus 20 mg melatonin once daily (n=24). Primary outcome was time to progression of disease and survival. Baseline characteristics and demographics did not differ significantly between groups. One year survival, progression of brain disease, and mean survival were significantly better in patients receiving melatonin as compared to placebo, 37% versus 12%, 5.9 versus 2.7 months, and 9.2 versus 5.5 months, respectively (p < 0.05). No adverse events related to melatonin were noted. Lissoni et al. suggest that melatonin reduces the frequency of hyperglycemia and steroid-related infective complications, and improves performance status. Additional research in controlled patient populations must be conducted to determine optimal dose for melatonin.

    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.
    100 patients with non-small cell lung cancer (NSCLC) participated in a study of melatonin as an adjunct to chemotherapy treatment. Patients were randomly assigned to receive either chemotherapy alone (cisplatin and etoposide) or chemotherapy plus melatonin (20 mg/day in the evening seven days prior to chemotherapy). Patients receiving melatonin continued to take the herbal supplement after the completion of the four cycles of chemotherapy. No patients in the control group showed complete response after five years of followup, whereas, two patients in the chemotherapy plus melatonin group showed complete response. increased response rates (17% versus 35%) and decreased progressive disease rates were statistically significant. Furthermore, incidents of neurotoxicity, thrombocytopenia, weight loss greater than 10% and asthenia were significantly lower as well. Researchers suggest that the study demonstrates that melatonin is a safe and effective adjunct to chemotherapy for NSCLC.

    References

    1. Sack RL, Lewy AJ, Hughes RJ. Use of melatonin for sleep and circadian rhythm disorders. Ann Med 1998;30:115-21.
    2. Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med 1998:30:122-30.
    3. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186-95.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. Reppert SM, Weaver DR. Melatonin Madness. Cell 1995;83:1059-62.
    9. 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.
    10. Hartter S, et al. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther 2000;67:1-6.
    11. 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.
    12. DeMuro RL, et al. The absolute bioavailability of oral melatonin. J Clin Pharmacol 2000;40:781-4.
    13. Zhdanova IV, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab 2001;86:4727-30.
    14. Leone M, et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996;16:494-6.
    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. Garfinkel D, et al. Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. Arch Intern Med 1999;159:2456-60.
    17. Wolfler A, et al. Questionable benefit of melatonin for antioxidant pharmacologic therapy. J Clin Oncol 2002;20:4127-9.
    18. Ghielmini M, et al. Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer. Br J Cancer 1999;80:1058-61.
    19. Lissoni P, et al. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients. Br J Cancer 1996:74:1466-8.
    20. 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.
    21. 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.
    22. Peres MF, et al. Melatonin, 3 mg, is effective for migraine prevention. Neurology. 2004 Aug 24;63(4):757.
    23. 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.
    24. 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.
    25. 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.
    26. 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.

    Last Updated: Apr. 1, 2009
    E-mail your questions and comments to aboutherbs@mskcc.org.
    Bookmark and SharePrintEmail This Page