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 that it controls the circadian rhythm 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 a potent antioxidant that stimulates 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 it is 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 specific chemotherapy drugs, melatonin may increase survival time.
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 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 have found that a combination of melatonin with standard chemotherapy may increase survival time in cancer patients.
To reduce the severity of chemotherapy side effects Two clinical trials suggest that melatonin does not increase blood cell counts that were reduced during chemotherapy or radiation therapy. One clinical trial showed patients treated with melatonin had reduced chemotherapy-associated side effects, such as weight loss and thrombocytopenia (low blood platelets).
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.
To prevent or slow the progression of Alzheimer's disease Clinical trials have had conflicting results.
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 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
Sleep disturbances and behavior In this study, 189 elderly participants, many with dementia, were split into 4 treatment groups: 1) placebo and dim light; 2) melatonin and dim light; 3) placebo and bright light; or 4) melatonin and bright light. After approximately 15 months, slower decline in cognitive performance and functional limitations was seen with bright light therapy. In addition, the patients exposed to bright light had reduced depression. Melatonin improved sleep in these patients, but it also negatively affected mood and behavior. When melatonin was combined with bright light, mood and behavior improved. The researchers concluded that the combination of bright light and melatonin may improve both physical and psychological symptoms in the elderly.
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.
Melatonin is a hormonal supplement of synthetic origin, but occasionally derived from animal sources. It is used to treat insomnia, jet lag, and cancer. Melatonin is produced endogenously in humans by the pineal gland. Although the exact mechanism of action is unknown, melatonin is thought to control the circadian pacemaker and promote sleep (1). Clinical studies suggest that melatonin may decrease sleep latency and improve sleep duration (2)(3)(4), but randomized trials yielded mixed data (27)(28)(29). No significant effects of melatonin on secondary sleep disorders associated with medical, neurological, or substance abuse disorders were found in a meta-analysis (5). Melatonin may decrease surgery-associated anxiety and pain (6) as well as the frequency of migraine attacks (7).
The anti-proliferative effects of melatonin on cancer cell lines have been reported in both in vitro and in vivo studies (8)(9). Clinical trials evaluating melatonin as a monotherapy, as well as in combination with other agents, in patients with solid tumors, suggest improvements in quality of life and survival time (10)(11)(12)(13).
Reported adverse effects are rare, but include drowsiness, headache, hypothermia, pruritus, abdominal cramps, and tachycardia (1)(2)(14)(15). Melatonin may interact with nifedipine (Procardia XL®), resulting in elevated blood pressure and heart rate (16). Optimal dose, length of therapy, and effect on endogenous melatonin are as yet unknown.
Melatonin is an endogenously produced indolamine hormone secreted by the pineal glands in humans. Nocturnal secretion is regulated by circadian rhythms and nighttime darkness (17). 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 (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 appears to be a potent free radical scavenger (18), interacting with cytosolic calmodulin and stimulating the production of IL-4 in bone marrow T-lymphocytes (1). In vitro and animal studies suggest that anti-tumor effects may occur through anti-mitotic or immunomodulatory activity. In vitro studies demonstrate that melatonin has anti-proliferative effects on human breast cancer (HS578T) (19) and mouse melanoma (B16BL6, PG19) (8). Melatonin reduces the proliferation of PC-3 and LNCaP cells in mice, but has no effect on apoptosis (9). The effect of melatonin 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).
Doses of 1-2,000 mg melatonin given to healthy volunteers cause no significant toxicity. Intravenous administration of melatonin displays one compartment pharmacokinetics (14). Tablets are absorbed following oral administration, but appear to undergo extensive first pass metabolism (23). 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 (24).
Nifedipine: Concomitant administration of melatonin and nifedipine has resulted in elevations in blood pressure and heart rate (16). Fluvoxamine: Fluvoxamine may increase circulating plasma levels of melatonin, resulting in sedation (23)(26).
Riemersma-van der Lek RF, 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. Because disturbances in circadian rhythm have been associated with reduced cognitive function in addition to behavioral and sleep alterations, the effects of bright light versus dim light with or without melatonin (2.5 mg daily) were analyzed in 189 elderly participants (mean age of 85.8 y) many of whom had dementia (87%) for an average of 15 months. Reduced depression (as measured using the Cornell Scale for Depression and Dementia) as well as decline in cognitive performance (as assessed by the Mini-Mental State Examination) and functional limitations were seen in the bright light only group whereas melatonin improved sleep latency and duration. However, melatonin negatively affected mood and behavior, which was reversed when combined with light. The authors conclude that for the elderly, melatonin should only be used in combination with bright light therapy.
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.
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.
