Principal Proposed Uses
• Insomnia; Jet Lag and Other Sleep Disorders
Other Proposed Uses
• ORAL USES Alzheimer’s Disease and Non-Alzheimer’s Dementia; Attention Deficit Disorder; Autism Spectrum Disorder; Cancer (as an Addition to Conventional Therapy) ; Cluster Headaches; Epilepsy in Children ; Fibromyalgia; Functional Dyspepsia (Chronic Indigestion of No Known Cause) ; Fighting Aging in General ; Immune Support; Irritable Bowel Syndrome; Migraine; Preventing Heart Disease; Quitting Smoking; Reducing Anxiety Before Surgery; Seasonal Affective Disorder; Tardive Dyskinesia
• TOPICAL USES Thinning Hair in Women
Melatonin is a natural hormone that regulates sleep. During daylight, the pineal gland in the brain produces an important neurotransmitter called serotonin. (A neurotransmitter is a chemical that relays messages between nerve cells.) But at night, the pineal gland stops producing serotonin and instead makes melatonin. This melatonin release helps trigger sleep.
The production of melatonin varies according to the amount of light you're exposed to; for example, your body produces more melatonin in a completely dark room than in a dimly lit one.
Melatonin supplements appear to be helpful for people whose natural sleep cycle has been disturbed, such as travelers suffering from jet lag. The hormone may also be helpful in various other sleep disorders.
Based on early reports that melatonin levels decline with age, the hormone was briefly marketed as a kind of fountain of youth. However, newer evidence suggests that melatonin levels do not decline with age after all. 65
Melatonin is not a nutrient. However, travelers and workers on rotating or late shifts can experience sleep disturbances that seem to be caused by changing melatonin levels.
You can boost your melatonin production naturally by getting thicker blinds for the bedroom windows or wearing a night mask. You can also take melatonin tablets.
Melatonin is typically taken half an hour before bedtime for the first 4 days after traveling.
For ordinary insomnia, melatonin is usually taken about 30 minutes to 1 hour before bedtime. To fall asleep on Sunday night after staying up late Friday and Saturday, one study suggests using melatonin 5.5 hours before the desired bedtime.
The optimum dose of melatonin is not clear, but it is probably in the 1 to 5 mg range.
Melatonin is available in two forms: immediate-release (just plain melatonin, also called "quick-release") and slow-release (a special preparation, also called "controlled-release," designed to spread melatonin absorption over many hours). It seems reasonable to suppose that quick-release melatonin helps in falling asleep, while slow-release melatonin helps in staying asleep, but study results are inconsistent on this issue. 1
Reasonably good evidence tells us that melatonin can help people with jet lag adjust to a new schedule. 46 Although it probably works in part by resetting the biological clock, it also appears to decrease or block wakefulness-promoting circuits in the nervous system 86 and may have other direct sedative effects. Based on this, melatonin has been tried for insomnia of various types, but results have been inconsistent 87 .
Three small double-blind studies suggest that use of melatonin might reduce symptoms of irritable bowel syndrome . 89-90,111 It has been suggested that melatonin might work through effects on the nervous system in the digestive tract.
Four double-blind studies performed by Saudi researchers reported that melatonin was useful for reducing anxiety prior to surgery, presumably due to its sedative effects. 2,3,95,102 However, other researchers have been unable to confirm these results. 99-100
A preliminary double-blind study suggests that melatonin may improve quality of life in children with epilepsy, perhaps by improving sleep and reducing medication side effects. 69
One surprising double-blind study suggests that topical application of melatonin may increase hair growth in women with thinning hair, for reasons that are entirely unclear. 70
Highly preliminary studies, including unblinded controlled trials, suggest that melatonin may enhance the effectiveness of standard therapy for breast cancer, prostate cancer, brain glioblastomas, non-small-cell lung cancer, and other forms of cancer. 4-6,51-53 (For information on why such studies are unreliable, see Why Does This Database Rely on Double-blind Studies? ) Melatonin has also shown some promise in animal studies for reducing side effects (specifically, cardiac toxicity) of the chemotherapy drug doxorubicin ; however, the only human trials supporting this use fall considerably beneath modern scientific standards. 103-110
Weak evidence supports a role for melatonin in reducing nicotine withdrawal symptoms. 91
What Is the Scientific Evidence for Melatonin?
Melatonin appears to produce sedation comparable to that of conventional pharmaceuticals used for inducing sleep 75 without impairing mental function. 76 Melatonin has shown promise as a treatment for a variety of sleep disorders, of which the best studied is jet lag.
For example, one double-blind, placebo-controlled study enrolled 320 people and followed them for 4 days after a long plane trip. 12 The participants were divided into four groups and given a daily dose of 5 mg of standard melatonin, 5 mg of slow-release melatonin, 0.5 mg of standard melatonin, or placebo. 12 The group that received 5 mg of standard melatonin slept better, took less time to fall asleep, and felt more energetic and awake during the day than the other three groups.
Another small double-blind trial found that airplane crews experienced improved rest when using melatonin (10 mg) as compared to placebo, and equivalent benefits as compared to the drug zopiclone. 44 Neither group experienced any impairment in mental function the following morning.
According to one review of the literature, melatonin treatment for jet lag is most effective for those who have crossed a significant number of time zones, perhaps eight. 13
Studies of melatonin for the treatment of insomnia related to shift work have yielded mixed results. 15,19,20,42-44,92,117 Researchers have been surprised by these findings, but suggest that perhaps working at night upsets the biological rhythm even more profoundly than traveling over many time zones, too profoundly for melatonin to help.
Sleep in the Elderly
Mixed results have been seen with the use of melatonin for treating insomnia in the elderly. 14-18,21,57,78,115 Not only have many studies failed to find melatonin helpful, those studies with positive results found widely varying benefits; for example, some studies found a decreased time to falling asleep, but no change in sleep throughout the night, while others found the reverse. These differences have not followed dose or type of melatonin in any obvious way, making them somewhat suspect.
One small study failed to find benefit for general insomnia in healthy people. 79
Sleep Problems in Children
A 4-week, double-blind trial evaluated the benefits of melatonin for children with difficulty falling asleep. 22 A total of 40 children who had experienced this type of sleep problem for at least 1 year were given either placebo or melatonin at a dose of 5 mg. The results showed that use of melatonin significantly helped participants fall asleep more easily. Similar results were seen in a double-blind, placebo-controlled study of 62 children 80 and in a study of 20 developmentally disabled children with sleep problems. 23
Researchers have also focused on sleep problems in children and teens with autism spectrum disorders. In a systematic review of 5 randomized trials and 13 observational studies, melatonin was associated with faster sleep onset and longer sleep duration. 120
Delayed Weekend Sleep Pattern (Monday Morning Fatigue)
Many individuals stay up late on Friday and Saturday nights, and then find it difficult to get to sleep at a reasonable hour on Sunday. A small double-blind, placebo-controlled study found evidence that taking melatonin 5.5 hours before the desired Sunday bedtime improved the ability of participants to fall asleep. 24
Sleep in Hospitalized Patients
Benefits were seen in a small, double-blind trial of patients in a pulmonary intensive care unit. 25 It is famously difficult to sleep in an ICU, and the resulting sleep deprivation is not helpful for those recovering from disease or surgery . In this study of 8 hospitalized individuals, 3 mg of controlled-release melatonin "dramatically improved" sleep quality and duration.
Other Sleep Problems and Sleep Problems Among People With Specific Medical Problems
Small double-blind trials have found benefits for improving sleep in people with diabetes , 26asthma (however, see Safety Issues), 81 head injury, 82schizophrenia , 27Alzheimer’s disease , 83 and Parkinson's disease . 94 Melatonin has also shown benefit for improving sleep in people with attention deficit disorder ; 93,112 it has failed, however, to show benefit for the symptoms of ADHD per se. 112
Blind people often have trouble sleeping on any particular schedule, because there are no "light cues" available to help them get tired at night. A small double-blind, placebo-controlled, crossover trial found that the use of melatonin at a dose of 10 mg per day was able to resynchronize participants' sleep schedules. 28
Some individuals find it impossible to fall asleep until early morning, a condition called delayed sleep phase syndrome (DSPS). Melatonin may be beneficial for this syndrome. 29
Individuals trying to quit using sleeping pills in the benzodiazepine family may find melatonin helpful. A double-blind, placebo-controlled study of 34 individuals who regularly used such medications found that melatonin at a dose of 2 mg nightly (controlled-release formulation) could help them discontinue the use of the drugs. 30 Interestingly, another study failed to find melatonin helpful for reducing benzodiazepine use among people taking drugs in that family for anxiety . 58
Note : There can be risks in discontinuing benzodiazepine drugs. Consult your physician for advice.
Melatonin has been used with conventional anticancer therapy in more than a dozen clinical studies. Results have been surprisingly good, although this research must be considered preliminary. For example, a double-blind study on 30 people with advanced brain tumors suggested that melatonin might prolong life and also improve the quality of life. 33 Participants received standard radiation treatment with or without 20 mg daily of melatonin. After 1 year, 6 of 14 individuals in the melatonin group were still alive, compared with just 1 of 16 from the control group. The melatonin group also had fewer side effects due to the radiation treatment—a notable improvement in their quality of life.
Improvements in symptoms and a possible reduction of mortality were also seen in other studies. 34,35 Melatonin appears to work by increasing levels of the body's own tumor-fighting proteins, known as cytokines. 36
Some evidence suggests that individuals with cluster headaches have lower than average levels of the hormone melatonin. 47-50 In a double-blind, placebo-controlled study of 20 individuals with cluster headaches, use of melatonin (10 mg daily) for 14 days appeared to reduce headache severity and/or frequency in about half the participants. 59 Overall, use of melatonin produced better effects than placebo.
Seasonal Affective Disorder
One study found that people with seasonal affective disorder (SAD) have higher levels of melatonin than those without the condition. 60 On this basis, it would seem that supplemental melatonin should worsen SAD symptoms. However, the evidence for such an effect is inconsistent. 61 Some researchers have proposed that interaction between SAD and melatonin might be more complex than merely high or low levels, and that, when taken at certain times of day, melatonin might help the condition. A very small study found that when melatonin was given in the afternoon, it produced some benefit for people with SAD. 62 However, a study of melatonin used in the early morning or the late evening failed to find any benefit. 63
Melatonin has shown equivocal effects for two conditions related to SAD: subsyndromal seasonal affective disorder (S-SAD) and weather associated syndrome (WAS). According to the one reported study, use of melatonin improved some symptoms but worsened others. 84
In a sizable Danish trial, researchers investigated the effects of melatonin on mood, sleep, and cognitive decline in elderly patients, most of whom suffered from dementia . 115 They found that melatonin (2.5 mg) given nightly for an average of 15 months, slightly improved sleep, but it worsened mood. The latter effect was reversed by adding light therapy during the day. Melatonin apparently had no significant effect on cognition. In a systematic review of 5 randomized trials including 323 people with dementia, researchers failed to find evidence that melatonin is helpful in enhancing memory and other cognitive abilities. 119 In 2 of the trials, however, melatonin was associated with short-term improvement in mood and behavior.
A safety study found that melatonin at a dose of 10 mg daily produced no toxic effects when given to 40 healthy males for a period of 28 days. 37 However, this does not prove that melatonin is safe when taken on a regular basis over the long term. Keep in mind that melatonin is not truly a food supplement but a hormone. As we know from other hormones used in medicine, such as estrogen and cortisone, harmful effects can take years to appear. Hormones are powerful substances that have many subtle effects in the body, and we're far from understanding them fully. While in one small study, use of melatonin over an 8-day period by healthy men did not affect natural release of melatonin or levels of pituitary or sex hormones, 85 another study found effects on testosterone and estrogen metabolism in men and possible impairment of sperm function. 66 Also, a small study in women found possible effects on the important female hormone called LH (luteinizing hormone). 96
Melatonin appears to cause drowsiness and decreased mental attention for about 2 to 6 hours after using it and may also impair balance. 38,39,64 For this reason, you should not drive or operate machinery for several hours after taking melatonin. In a study of healthy middle-aged and older adults, however, an extended release version of melatonin, which is said to more closely mimic natural fluctuations of the hormone in the body, did not impair mental ability or driving skills 1 to 4 hours later compared to placebo. 116 In either case, melatonin does not appear to have any "hangover" effects the following day. 44
Based on theoretical ideas of how melatonin works, some authorities specifically recommend against using it in people with depression, schizophrenia, autoimmune diseases, and other serious illnesses. One study in postmenopausal women found evidence that melatonin might impair insulin action and glucose tolerance, suggesting that people with diabetes should not use it. 40 However, another study found melatonin safe and effective for people with diabetes. 41 Because of these contradictions, we suggest that individuals with diabetes seek physician supervision before using melatonin.
Two exceedingly preliminary studies reported by one research group has led to publicized concerns that use of the supplement melatonin might increase night-time asthma. 97 However, one double-blind study of melatonin in people with asthma found evidence of improved sleep without worsening of symptoms. 98 Again, at the current state of knowledge, caution must be advised for people with night-time asthma who wish to try melatonin.
There is some evidence that melatonin may interfere with the ability of blood to clot normally, at least in healthy volunteers, 114 though the clinical significance of this finding is at yet unknown.
Maximum safe dosages for young children, pregnant or nursing women, or those with serious liver or kidney disease have not been established.
1. Jan JE, Hamilton D, Seward N, et al. Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res . 2000;29:34-39.
2. Naguib M, Samarkandi AH. Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam. Br J Anaesth . 1999;82:875-880.
3. Naguib M, Samarkandi AH. The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg . 2000;91:473-479.
4. Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology . 1996;53:43-46.
5. Lissoni P, Paolorossi F, Ardizzoia A, et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res . 1997;23:15-19.
6. Neri B, de Leonardis V, Gemelli MT, et al. Melatonin as biological response modifier in cancer patients. Anticancer Res . 1998;18:1329-1332.
7. Fauteck JD, Schmidt H, Lerchl A, et al. Melatonin in epilepsy: first results of replacement therapy and first clinical results. Biol Signals Recept . 1999;8:105-110.
8. Rasmussen DD, Boldt BM, Wilkinson CW, et al. Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology . 1999;140:1009-1012.
9. Cagnacci A. Melatonin in relation to physiology in adult humans. J Pineal Res . 1996;21:200-213.
10. Nelson RJ, Demas GE. Role of melatonin in mediating seasonal energetic and immunologic adaptations. Brain Res Bull . 1997;44:423-430.
11. Oaknin-Bendahan S, Anis Y, Nir I, et al. Effects of long-term administration of melatonin and a putative antagonist on the aging rat. Neuroreport . 1995;6:785-788.
12. Suhner A, Schlagenhauf P, Johnson R, et al. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int . 1998;15:655-666.
13. Arendt J, Skene DJ, Middleton B, et al. Efficacy of melatonin in jet lag, shift work and blindness. J Biol Rhythms . 1997;12:604-617.
14. Garfinkel D, Laudon M, Nof D, et al. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet . 1995;346:541-544.
15. Chase JE, Gidal BE. Melatonin: therapeutic use in sleep disorders. Ann Pharmacother . 1997;31:1218-1226.
16. Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep . 1995;18:598-603.
17. Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep . 1998;21:52-68.
18. Garfinkel D, Laudon M, Zisapel N. Improvement of sleep quality by controlled-release melatonin in benzodiazepine-treated elderly insomniacs. Arch Gerontol Geriatr . 1997;24:223-231.
19. Folkard S, Arendt J, Clark M. Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Chronobiol Int . 1993;10:315-320.
20. Dawson D, Encel N, Lushington K. Improving adaptation to simulated night shift: timed exposure to bright light versus daytime melatonin administration. Sleep . 1995;18:11-21.
21. Zhdanova IV, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab . 2001;86:4727-4730.
22. Smits MG, Nagtegaal EE, van der Heijden J, et al. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. J Child Neurol . 2001;16:86-92.
23. Dodge NN, Wilson GA. Melatonin for treatment of sleep disorders in children with developmental disabilities. J Child Neurol . 2001;16:581-584.
24. Yang CM, Spielman AJ, D'Ambrosio P, et al. A single dose of melatonin prevents the phase delay associated with a delayed weekend sleep pattern. Sleep . 2001;24:272-281.
25. Shilo L, Dagan Y, Smorjik Y, et al. Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int . 2000;17:71-76.
26. Garfinkel D, Wainstein J, Halabe A, et al. Beneficial effect of controlled release melatonin on sleep quality and hemoglobin A1C in type 2 diabetic patients. Presented at: World Congress of Gerontology; July 1-6, 2001; Vancouver, Canada.
27. Shamir E, Laudon M, Barak Y, et al. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry . 2000;61:373-377.
28. Sack RL, Brandes RW, Kendall AR, et al. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med . 2000;343:1070-1077.
29. Kayumov L, Brown G, Jindal R, et al. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med . 2001;63:40-48.
30. Garfinkel D, Zisapel N, Wainstein J, et al. Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. Arch Intern Med . 1999;159:2456-2460.
31. Naguib M, Samarkandi AH. Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam. Br J Anaesth . 1999;82:875-880.
32. Naguib M, Samarkandi AH. The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg . 2000;91:473-479.
33. Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology . 1996;53:43-46.
34. Lissoni P, Paolorossi F, Ardizzoia A, et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res . 1997;23:15-19.
35. Lissoni P, Tancini G, Barni S, et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer . 1997;5:126-129.
36. Neri B, de Leonardis V, Gemelli MT, et al. Melatonin as biological response modifier in cancer patients. Anticancer Res . 1998;18:1329-1332.
37. de Lourdes M, Seabra V, Bignotto M, et al. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res . 2000;29:193-200.
38. Graw P, Werth E, Krauchi K, et al. Early morning melatonin administration impairs psychomotor vigilance. Behav Brain Res . 2001;121:167-172.
39. Fraschini F, Cesarani A, Alpini D, et al. Melatonin influences human balance. Biol Signals Recept . 1999;8:111-119.
40. Cagnacci A, Arangino S, Renzi A, et al. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol (Oxford). 2001;54:339-346.
41. Garfinkel D, Wainstein J, Halabe A, et al. Beneficial effect of controlled release melatonin on sleep quality and hemoglobin A1C in type 2 diabetic patients. Presented at: World Congress of Gerontology; July 1-6, 2001; Vancouver, Canada.
42. Sharkey KM, Fogg LF, Eastman CI. Effects of melatonin administration on daytime sleep after simulated night shift work. J Sleep Res . 2001;10:181-192.
43. James M, Tremea MO, Jones JS, et al. Can melatonin improve adaptation to night shift? Am J Emerg Med . 1998;16:367-370.
44. Paul MA, Brown G, Buguet A, et al. Melatonin and zopiclone as pharmacologic aids to facilitate crew rest. Aviat Space Environ Med . 2001;72:974-984.
45. Shamir E, Barak Y, Shalman I, et al. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry . 2001;58:1049-1052.
46. Herxheimer A, Petrie KJ. Melatonin for preventing and treating jet lag. Cochrane Database Syst Rev . 2001;CD001520.
47. Chazot G, Claustrat B, Brun J, et al. A chronobiological study of melatonin, cortisol, growth hormone, and prolactin secretion in cluster headache. Cephalalgia . 1984;4:213-220.
48. Leone M, Lucini V, D’Amico D, et al. Abnormal 24-hour urinary excretory pattern of 6-sulphatoxymelatonin in both phases of cluster headache. Cephalalgia . 1998;18:664-667.
49. Leone M, Lucini V, D’Amico D, et al. Twenty-four-hour melatonin and cortisol plasma levels in relation to timing of cluster headache. Cephalalgia . 1995;15:224-229.
50. Waldenlind E, Gustafsson SA, Ekbom KA, Wetterberg L. Circadian secretion of cortisol and melatonin during active cluster periods and remission. J Neurol Neurosurg Psychiatry . 1987;50:207-213.
51. Cos S, Fernández R, Güézmes A, Sánchez-Barceló EJ. Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res . 1998;58:4383-4390.
52. Lissoni P, Barmo S. Meregalli S, 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;71:854-856.
53. Lissoni P, Cazzanga M, Tancini G, et al. Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone. Eur Urol . 1997;31:178-181.
54. Lockwood K, Moesgaard S, Hanioka T, Folkers K. Apparent partial remission of breast cancer in ‘high risk’ patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Molec Aspects Med Suppl . 1994;5:S231-S240.
55. Lockwood K., Moesgaard S., Folkers K. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q 10 . Biochem Biophys Res Comm . 1994;199:1504-1508.
56. Lockwood K., Moesgaard S., Yamamoto T., Folkers K. Progress on therapy of breast cancer with vitamin Q 10 and the regression of metastases. Biochem Biophys Res Comm . 1995;212:172-177.
57. Baskett JJ, Broad JB, Wood PC, et al. Does melatonin improve sleep in older people? A randomised crossover trial. Age Ageing . 2003;32:164-170.
58. Cardinali DP, Gvozdenovich E, Kaplan MR, et al. A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly. Neuroendocrinol Lett . 2002;23:55-60.
59. Leone M, D’Amico D, Moschiano F, et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia . 1996;16:494-496.
60. Karadottir R, Axelsson J. Melatonin secretion in SAD patients and healthy subjects matched with respect to age and sex. Int J Circumpolar Health . 2001;60:548-551.
61. Rosenthal NE, Sack DA, Jacobsen FM, et al. Melatonin in seasonal affective disorder and phototherapy. J Neural Transm . 1986;21(Suppl):257-267.
62. Lewy AJ, Bauer VK, Cutler NL, Sack RL. Melatonin treatment of winter depression: a pilot study. Psychiatry Res . 1998;77:57-61.
63. Wirz-Justice A, Graw P, Krauchi K, et al. Morning or night-time melatonin is ineffective in seasonal affective disorder. J Psychiatr Res . 1990;24:129-137.
64. Nave R, Iani C, Herer P, et al. Residual effects of daytime administration of melatonin on performance relevant to flight. Behav Brain Res . 2002;131:87-95.
65. Zeitzer J, Daniels J, Duffy J, et al. Do plasma melatonin concentrations decline with age? Am J Med . 1999;107:432-436.
66. Luboshitzky R, Shen-Orr Z, Nave R, et al. Melatonin administration alters semen quality in healthy men. J Androl . 2002;23:572-578.
67. Scheer FA, Van Montfrans GA, Van Someren EJ, et al. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension . 2004 Jan 19. [Epub ahead of print]
68. Nelson LA, McGuire JM, Hausafus SN. Melatonin for the treatment of tardive dyskinesia. Ann Pharmacother . 2002;37:1128-31.
69. Gupta M, Aneja S, Kohli K. Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial. Epilepsy Behav . 2004;5:316-21.
70. Fischer TW, Burmeister G, Schmidt HW, Elsner P. Melatonin increases anagen hair rate in women with androgenetic alopecia or diffuse alopecia: results of a pilot randomized controlled trial. Br J Dermatol . 2004;150:341-345.
71. Pringsheim T, Magnoux E, Dobson CF, et al. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache . 2002;42:787-792.
72. Citera G, Arias MA, Maldonado-Cocco JA, et al. The effect of melatonin in patients with fibromyalgia: a pilot study. Clin Rheumatol . 2000;19:9-13.
73. Secreto G, Chiechi LM, Amadori A, et al. Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double-blind, randomized study. Maturitas . 2004;47:11-20.
74. Williams G, Waterhouse J, Mugarza J, et al. Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy. Eur J Clin Invest . 2002;32:831-837.
75. Paul MA, Gray G, MacLellan M, Pigeau RA. Sleep-inducing pharmaceuticals: a comparison of melatonin, zaleplon, zopiclone, and temazepam. Aviat Space Environ Med . 2004;75:512-519.
76. Rogers NL, Kennaway DJ, Dawson D. Neurobehavioural performance effects of daytime melatonin and temazepam administration. J Sleep Res . 2003;12:207-212.
77. Beaumont M, Batejat D, Pierard C, et al. Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel. J Appl Physiol . 2003 Sept 5. [Epub ahead of print]
78. Baskett JJ, Broad JB, Wood PC, et al. Does melatonin improve sleep in older people? A randomised crossover trial. Age Ageing . 2003;32: 164-170.
79. Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J, et al. Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci . 2003;28:191-196.
80. Smits MG, Van Stel HF, Van Der Heijden K, et al. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry . 2003;42:1286-1293.
81. Campos FL, Da Silva-Junior FP, De Bruin VM, et al. Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med . 2004 Aug 11. [Epub ahead of print]
82. Kemp S, Biswas R, Neumann V, et al. The value of melatonin for sleep disorders occurring post-head injury: a pilot RCT. Brain Inj . 2004;18:911-919.
83. Asayama K, Yamadera H, Ito T, et al. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch . 2003;70:334-341.
84. Leppamaki S, Partonen T, Vakkuri O, et al. Effect of controlled-release melatonin on sleep quality, mood, and quality of life in subjects with seasonal or weather-associated changes in mood and behaviour. Eur Neuropsychopharmacol. 2003;13:137-145.
85. Rajaratnam SM, Dijk DJ, Middleton B, et al. Melatonin phase-shifts human circadian rhythms with no evidence of changes in the duration of endogenous melatonin secretion or the 24-hour production of reproductive hormones. J Clin Endocrinol Metab . 2003;88:430-39.
86. Wyatt JK, Dijk DJ, Ritz-De Cecco A, et al. Sleep-facilitating effect of exogenous melatonin in healthy young men and women is circadian-phase dependent. Sleep . 2006;29:609-618.
87. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med . 2006;20:1151-1158.
88. Cagnacci A, Cannoletta M, Renzi A, et al. Prolonged melatonin administration decreases nocturnal blood pressure in women. Am J Hypertens . 2005;18:1614-1618.
89. Song GH, Leng PH, Gwee KA, et al. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised double blind placebo controlled study. Gut . 2005 May 24. [Epub ahead of print]
90. Lu WZ, Gwee KA, Moochhalla S, et al. Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Aliment Pharmacol Ther . 2005;22:927-934.
91. Zhdanova IV, Piotrovskaya VR. Melatonin treatment attenuates symptoms of acute nicotine withdrawal in humans. Pharmacol Biochem Behav . 2001;67:131-135.
92. Smith MR, Lee C, Crowley SJ, et al. Morning melatonin has limited benefit as a soporific for daytime sleep after night work. Chronobiol Int . 2005;22:873-888.
93. Weiss M, Wasdell M, Bomben M, et al. Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry . 2006 Mar 10 [Epub ahead of print].
94. Dowling GA, Mastick J, Colling E, et al. Melatonin for sleep disturbances in Parkinson's disease. Sleep Med . 2005 Aug 3 [Epub ahead of print].
95. Samarkandi A, Naguib M, Riad W et al. Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study. Eur J Anaesthesiol . 2005;22:189-96.
96. Kripke DF M D, Kline LE D O, Shadan FF M D Ph D, et al. Melatonin effects on luteinizing hormone in postmenopausal women: A pilot clinical trial NCT00288262. BMC Womens Health . 2006 May 16 [Epub ahead of print].
97. Sutherland ER, Ellison MC, Kraft M, et al. Elevated serum melatonin is associated with the nocturnal worsening of asthma. J Allergy Clin Immunol . 2003;112:513-517.
98. Campos FL, Da Silva-Junior FP, De Bruin VM, et al. Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med . 2004 Aug 11. [Epub ahead of print]
99. Sury MR, Fairweather K. The effect of melatonin on sedation of children undergoing magnetic resonance imaging. Br J Anaesth. 2006 Jun 17 [Epub ahead of print].
100. Capuzzo M, Zanardi B, Schiffino E, et al. Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery. Anesth Analg. 2006;103:121-123.
101. Grossman E, Laudon M, Yalcin R, et al. Melatonin reduces night blood pressure in patients with nocturnal hypertension. Am J Med. 2006;119:898-902.
102. Turkistani A, Abdullah KM, Al-Shaer AA, et al. Melatonin premedication and the induction dose of propofol. Eur J Anaesthesiol . 2006 Nov 10. [Epub ahead of print]
103. Wahab MH, Akoul ES, Abdel-Aziz AA. Modulatory effects of melatonin and vitamin E on doxorubicin-induced cardiotoxicity in Ehrlich ascites carcinoma-bearing mice. Tumor . 2000;86:157-162.
104. Oz E, Ilhan MN. Effects of melatonin in reducing the toxic effects of doxorubicin. Mol Cell Biochem . 2006;286:11-15.
105. Oz E, Erbas D, Surucu HS, et al. Prevention of doxorubicin-induced cardiotoxicity by melatonin. Mol Cell Biochem . 2005;282:31-37.
106. Kim C, Kim N, Joo H, et al. Modulation by melatonin of the cardiotoxic and antitumor activities of adriamycin. J Cardiovasc Pharmacol . 2005;46:200-210.
107. Balli E, Mete UO, Tuli A, et al. Effect of melatonin on the cardiotoxicity of doxorubicin. Histol Histopathol . 2004;19:1101-1108.
108. Kocak G, Erbil KM, Ozdemir I, et al. The protective effect of melatonin on adriamycin-induced acute cardiac injury. Can J Cardiol . 2003;19:535-541.
109. Reiter RJ, Tan DX, Sainz RM, et al. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol . 2002;54:1299-1321.
110. Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer . 1999;35:1688-1692.
111. Saha L, Malhotra S, Rana S, et al. A preliminary study of melatonin in irritable bowel syndrome. J Clin Gastroenterol . 2007;41:29-32.
112. Van der Heijden KB, Smits MG, Van Someren EJ, et al. Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry . 2007;46:233-241.
113. Klupinska G, Poplawski T, Drzewoski J, et al. Therapeutic effect of melatonin in patients with functional dyspepsia. J Clin Gastroenterol . 2007;41:270-274.
114. 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. 2008;44:127-133.
115. 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. 2008;299:2642-2655.
116. Otmani S, Demazieres A, Staner C, et al. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol. 2008 Sep 2.
117. Sadeghniiat-Haghighi K, Aminian O, Pouryaghoub G, et al. Efficacy and hypnotic effects of melatonin in shift-work nurses: double-blind, placebo-controlled crossover trial. J Circadian Rhythms. 2008;6:10.
118. Alstadhaug KB, Odeh F, Salvesen R, Bekkelund SI. Prophylaxis of migraine with melatonin: a randomized controlled trial. Neurology. 2010;75(17):1527-1532.
119. Jansen S, Forbes D, Duncan V, Morgan D, Malouf R. Melatonin for the treatment of dementia. Cochrane Database Syst Rev. 2011;(1):CD003802.
120. Rossignol DA, Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol. 2011 Apr 19.
Last reviewed August 2013 by EBSCO CAM Review Board
Please be aware that this information is provided to supplement the care provided by your physician. It is neither intended nor implied to be a substitute for professional medical advice. CALL YOUR HEALTHCARE PROVIDER IMMEDIATELY IF YOU THINK YOU MAY HAVE A MEDICAL EMERGENCY. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with any questions you may have regarding a medical condition.
Copyright (C) 2011 EBSCO Publishing. All rights reserved.