Melatonin
Scientific Name(s): Melatonin , circadin , melatol
Common Name(s): MEL
Clinical Overview
Uses of Melatonin
Melatonin is used for numerous conditions but is showing the most promise in short-term regulation of sleep patterns, including jet lag.
Melatonin Dosing
Jet lag: (eastbound travel) - Take a preflight early evening treatment of melatonin followed by treatment at bedtime for 4 days after arrival. Westbound travel- Take melatonin for 4 days at bedtime when in the new time zone. Difficulty falling asleep: Take 5 mg of melatonin 3 to 4 hours before an imposed sleep period over a 4-week period. Difficulty maintaining sleep: Take a high dose, repeated low doses, or a controlled-release formulation. Children (6 months to 14 years of age with sleep disorders): 2 to 5 mg melatonin has been used.
Contraindications
Melatonin should not be used by patients who have autoimmune diseases.
Pregnancy/Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking.
Melatonin Interactions
Caffeine and fluvoxamine may increase the effects of melatonin, while melatonin may decrease the antihypertensive effect of nifedipine.
Melatonin Adverse Reactions
Possible adverse effects include headache and depression. Melatonin should not be used by patients who have autoimmune diseases. Drowsiness may be experienced within 30 minutes after taking melatonin and may persist for ≈ 1 hour and thus may affect driving skills.
Toxicology
There is little or no evidence of any major toxicities with melatonin, even at high doses.
History
Melatonin (MEL) is one of the hormones of the pineal gland that also is produced by extrapineal tissues. Early animal studies in the mid-1960s revealed its ability to affect sexual function, skin color, and other mammalian functions. It is a mediator of photo-induced antigonadotrophic activity in photoperiodic mammals while it affects thermoregulation and locomotor activity rhythms in birds. It also has been implicated in time-keeping mechanisms in the pineal gland. Early studies showed that diurnal variations in estrogen secretion in rats could be regulated by changes in melatonin synthesis and release, both induced by the daily cycle of light and dark via the efferent limb of the reflex in the sympathetic innervation of the pineal gland. Continual darkness depresses the estrous cycle. 1 , 2
Melatonin secretion is inhibited by environmental light and stimulated by darkness, with secretion starting at 9 p.m. and peaking between 2 and 4 a.m. Nocturnal secretion of melatonin is highest in children and decreases with age. 3 , 4 Studies in the 1990s have widely expanded the use of melatonin for easing insomnia, combating jet lag, preventing pregnancy (in large doses), protecting cells from free-radical damage, boosting the immune system, preventing cancer, and extending life. 5
Although melatonin is not approved for marketing as a drug product, it has been classified as an orphan drug since November 1993 4 for the treatment of circadian rhythm sleep disorders in blind people with no light perception. It is commercially available as a nutritional supplement either as a synthetic product or derived from animal pineal tissue. Use of the tissue-derived product should be discouraged because of a risk of contamination or viral transmission. Most commercial brands are available as 300 mcg or 1.5 or 3 mg tablets under various names. Patients should seek medical advice before undertaking therapy.
Chemistry
Chemically, melatonin is defined as N-acetyl-5-methoxytryptamine. It can be isolated from the pineal glands of beef cattle or synthesized from 5-methoxyindole as a starting material via 2 different routes. It is a relatively low molecular weight hormone (M.W. 232.27) and is a pale yellow crystalline material. 1
Melatonin Uses and Pharmacology
Pharmacological disruption of melatonin production can occur via beta-1 and alpha-1 receptors because of sympathetic innervation in the pineal gland. Tryptophan is converted to serotonin, the immediate precursor of melatonin. 3 , 4 , 6 Its synthesis is inhibited by light and stimulated by periods of darkness independent of sleep. To date, three G-protein-coupled melatonin receptors have been cloned as well as one nuclear receptor. They are present in the periphery and CNS. 7 Once in circulation, melatonin is metabolized in the liver with more than 85% excreted as 6-sulphatoxyMEL, a reliable marker for melatonin production. Plasma half-life is short, 20 to 50 minutes, 3 , 4 , 8 and plasma levels return to baseline within 24 hours after discontinuation of chronic dosing (less than 10 mg/day). 4 , 9 Melatonin doses of 5 mg produce estimated peak blood levels 25 times above physiological levels but do not alter endogenous melatonin production. 4 , 9 In the 1990s, dozens of articles appeared in the medical literature on the various purported activities of melatonin. A selected overview of studies includes those regarding melatonin's role as an antioxidant and free radical scavenger, 10 , 11 , 12 use in general health and disease, 3 hypothermic properties, 13 control of seasonality and winter depression, 14 , 15 oncostatic actions on estrogen-responsive MCF-7 human breast cancer cells, 16 treatment of neoplastic cachexia, 17 effect on primary headaches 18 and prophylaxis of cluster headache, 19 direct effect on the immune system 20 , 21 including activation of human monocytes, 22 role in GI physiology, 23 function in thermoregulatory processes, 24 involvement in the cardiopulmonary system, 25 potentially beneficial cardiovascular effects 26 , 27 including reduction in hypercholesterolemia, 28 use in treatment of myoclonus in children, 29 effects on puberty, 30 improvement in tinnitus, 31 its place in human and animal reproduction, 32 studies on human sleep, 33 use as a premedication for gynecological procedures, 34 modulation of sympathetic neurotransmission, 35 possible role in infant colic, 36 as a proconvulsive hormone, 37 and purported chronobiotic and anti-aging properties. 38 , 39
A number of trials have attempted to resolve some unanswered questions and have shown a lack of effect on tardive dyskinesia, 40 rapid-cycling bipolar disorder, 41 and rate of improvement of major depressive disorder. 42
Among the most common medical claims for positive effects are entraining the blind, overcoming jet lag, having immunotherapeutic potential, hastening the onset of sleep, and dampening the release of estrogen. Melatonin may diminish breast cancer rates and be useful at higher doses (ie, 75 mg) for oral contraception.
The FDA has not yet controlled melatonin and warns users that they are taking it “without any assurance that it is safe or that it will have any beneficial effect.” In the meantime, many health food manufacturers and some pharmacies and clinics have begun to make this inexpensive hormone available for various medical and related purposes.
Blind entrainmentThe sleep-wake cycle in humans without light-dark cues approximates 25 hours, causing the sleep cycle to shift by 1 hour each day, so that after several weeks, such individuals are awake at night and asleep during the day. Blind people with little or no perception of light often develop free-running circadian rhythms of more than 24 hours and subsequently develop sleep disturbances characterized by chronic fatigue and involuntary napping during the day. In case reports and small controlled studies, oral melatonin (daily dosage range, 0.5 to 10 mg) has been used to entrain free-running activity rhythms in blind people by advancing and stabilizing the phase of endogenous melatonin secretion. 4 , 9 , 43 Although success has varied in these reports, the importance of melatonin administration time has been recognized. For example, the administration of melatonin (5 or 10 mg for 2 to 4 weeks at bedtime) to an 18-year-old blind man with chronic sleep disturbances produced slightly improved sleep onset but did not reduce daytime fatigue or hypersomnolence. 4 , 43
However, the administration of melatonin (5 mg for 3 weeks) at 2 to 3 hours prior to habitual bedtime decreased sleep onset (approximately 1.4 hours), slightly increased sleep duration (34 minutes), and improved sleep quality and daytime alertness. The authors suggest that there is a Phase Response Curve (PRC) for the exogenous administration of melatonin; the maximum phase advancing effects occur when melatonin is administered approximately 6 hours prior to onset of endogenous melatonin secretion. 4 , 44 The average cumulative phase advancement (CPA) of melatonin rhythms after 3 weeks of treatment with 5 and 0.5 mg daily was 8.4 and 7 hours, respectively. 4 , 9
Jet lagMelatonin's ability to modulate circadian rhythms has prompted several studies investigating the use of this agent in the prevention of jet lag. 4 , 45 , 46 , 47 Although the effects have been variable, most patients have reported general improvement in daytime fatigue, disturbed sleep cycles, mood, and recovery times. These studies are limited by the small number of participants and a focus on subjective ratings of effects with little or no evidence of actual changes in circadian shift (ie, changes in oral temperature or cortisol levels).
Several melatonin regimens have been examined (5 to 10 mg daily) for various durations. In one study, 52 aircraft personnel were randomized to placebo, early, or late melatonin groups. The early group started melatonin (5 mg daily) 3 days before departure until 5 days after arrival. 4 , 46 The late group received melatonin upon arrival and for 4 additional days. When compared with placebo, the late melatonin group self-reported less jet lag, fewer overall sleep disturbances, and a faster recovery of energy and alertness. However, the early group (receiving melatonin for 8 days) reported jet lag symptoms similar to the placebo group and a worsened overall recovery.
Additional data suggest that benefits were also experienced by international travelers. However, there is little information on the optimal dose or formulation. As a guide, the most appropriate timing for melatonin administration appears to be preflight early evening treatment followed by treatment at bedtime for 4 days after arrival when traveling eastbound, whereas on a westbound flight it is better to take melatonin for 4 days at bedtime when in the new time zone. 48 Note that drowsiness may be experienced within 30 minutes after taking melatonin and may persist for about 1 hour, and thus may affect driving skills.
InsomniaAlthough the administration of melatonin has been shown to shift melatonin secretion and circadian rhythm patterns, its direct hypnotic effect, if any, has not been clearly established. Decreased circulating melatonin serum levels have been demonstrated in people of all ages with insomnia and in the healthy elderly. 3 , 4
In small studies of healthy volunteers or people with chronic insomnia, very large doses of melatonin (75 to 100 mg) administered at night (9 to 10 p.m.) have produced serum melatonin levels exceeding normal nocturnal ranges and hypnotic effects. These include decreases in sleep onset, fewer nighttime awakenings, and increases in stage 2 sleep and sleep efficiency (percentage of time asleep/time in bed). 4 , 49 , 50 Midday administration of large doses also has increased serum melatonin levels beyond normal nocturnal ranges, increased subjective fatigue, and decreased cognitive function and vigor. 4 , 51
The administration of smaller doses (0.3 to 6 mg) has produced inconsistent hypnotic results, but this may be because of the inclusion of patients with a variety of sleep disorders, different drug formulations, and different administration times (midday to 15 minutes before bedtime). 4 , 52 , 53 , 54 , 55 , 56 , 57 The time to reach peak hypnotic effect was longer when melatonin (5 mg) was administered at 12 p.m. vs 9 p.m. (3.66 hours vs 1 hour). 4 , 53 Delayed latency with daytime administration may be related to the already low circulating melatonin levels during the day. Low doses (0.3 or 1 mg) administered to healthy volunteers at 6 p.m., 8 p.m., or 9 p.m. decreased onset latency and latency to stage 2 sleep, but did not suppress REM sleep nor induce hangover effects.
In patients with difficulty falling asleep, low doses of melatonin should be sufficient in promoting sleep onset. Administration of 5 mg of melatonin 3 to 4 hours before an imposed sleep period over a 4-week period decreased the time to sleep onset without affecting other sleep parameters, such as total duration or sleep architecture. 58 However, in patients with difficulty maintaining sleep, low doses of melatonin may not produce sufficient blood concentrations to maintain slumber. A 2 mg oral melatonin dose produced peak levels ≈ 10 times higher than physiological levels, but it remained elevated for only 3 to 4 hours. 4 , 8 To maintain effective serum concentrations of melatonin throughout the night, a high dose, repeated low doses, or a controlled-release formulation may be needed. When compared with placebo in a trial of 12 elderly people with chronic insomnia, melatonin increased sleep efficiency (75% vs 83%) and decreased wake time after sleep onset (73 vs 49 minutes). 4 , 56 However, there were no differences between the groups for total sleep time (365 vs 360 minutes) or sleep onset (33 vs 19 minutes).
Sleep onset and sleep maintenance were improved in elderly people with insomnia after 1 week of immediate (1 mg) and sustained release (2 mg) melatonin preparations. Sleep onset improved further when the sustained-release form was continued for 2 months. 4 , 57 Physically ill patients with insomnia in a hospital setting who were given a low dose (averaging 6 mg) also fell asleep faster and slept longer than their placebo-matched counterparts. 59 Melatonin may be particularly useful when traditional hypnotics are contraindicated.
Children with sleep disordersSeveral case reports have described the use of melatonin (2 to 5 mg) in children (6 months to 14 years of age). 4 , 60 Outcomes of studies in children have been similar to those in adults. Melatonin given to either healthy or developmentally impaired children was most effective in treating delayed sleep onset. 61 A controlled-release formulation was required for sleep maintenance. It has been proposed that children with multiple complex neurodevelopmental problems may require higher doses (2 to 12 mg) than initially proposed. 62
Immunotherapeutic potentialActivation of melatonin receptors has been shown to enhance the release of a number of cytokines, including gamma-interferon, IL-1, IL-2, IL-6, and IL-12 in human monocytes. It has been suggested that melatonin may be used to stimulate the immune system during viral and bacterial infections. A potential role has been postulated in the treatment of viral encephalitis, septic shock, and secondary immunodeficiencies (eg, acute stress). However, through this proinflammatory action, melatonin may play an adverse role in autoimmune diseases. 21
Cancer protectionSeveral studies suggest that partial responses and stabilization of disease occur, to varying degrees, with the use of melatonin as adjunctive therapy in patients with malignant solid tumors. However, the majority of these studies are open-labeled trials in patients in poor clinical condition with advanced disease who had not responded to conventional therapy. Melatonin has demonstrated some inhibitory effects on tumor growth in animal models 63 and in vitro cancerous breast cell lines. 3 Proposed oncoprotective mechanisms of melatonin include stimulatory effects on circulating natural killer cells and potent antioxidant activity. Preliminary studies have examined the use of melatonin in patients with solid tumors, for example, melanoma and pineal tumors, 64 and as adjunctive amplifier therapy with interleukin in various metastatic tumors (eg, endocrine, colorectal). 4 , 65 , 66 , 67 , 68 , 69 European studies on B-Oval (containing melatonin) appear to show that it can slow the growth rate of human tumor cells. A nightly supplement (10 mg of melatonin) has been shown to improve 1-year survival rates in patients with metastatic lung cancer. 3
Well-controlled trials are needed before the role of melatonin as an oncostatic agent can be confirmed.
Oral contraceptiveBecause melatonin plays a role in the endocrine-reproductive system and reduces circulating LH, the use of melatonin as a contraceptive agent has been studied. 4 , 70 Melatonin administered in various dosage combinations with a synthetic progestin in 32 women for 4 months produced anovulatory effects.
Anovulatory properties might not translate to contraceptive efficacy but might reduce fertility. One should not count on efficacy similar to accepted methods.
Skin protection from ultraviolet lightTopical melatonin was tested in combination with vitamins C and E in a randomized, double-blind study. The agents were applied topically either alone or in combination 30 minutes before ultraviolet irradiation of the skin. The best protection was obtained using all 3 agents in combination. The role of reactive oxygen species and oxygen-derived free radicals, as well as potential sunscreening properties, may explain the photoprotective effect. 71
Dosage
Jet lagEastbound travel: Take a preflight early evening treatment of melatonin followed by treatment at bedtime for 4 days after arrival. Westbound travel: Take melatonin for 4 days at bedtime when in the new time zone.
Difficulty falling asleepTake 5 mg of melatonin 3 to 4 hours before an imposed sleep period (over a 4-week period).
Difficulty maintaining sleepTake a high dose, repeated low doses, or a controlled-release formulation.
Children (6 months to 14 years of age with sleep disorders)2 to 5 mg melatonin has been used.
Pregnancy/Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking.
Interactions
CaffeineMelatonin plasma concentrations may be elevated by caffeine, increasing the effects (eg, drowsiness). Twelve healthy subjects were given melatonin (6 mg) alone and with 200 mg caffeine tablets 1 hours before and 1 and 3 hours after melatonin ingestion. Caffeine increased the area under the curve and peak plasma concentration of melatonin 120% and 142%, respectively. The effect was more pronounced in nonsmokers than smokers. Caffeine may inhibit the metabolism (cytochrome P450 1A2) of melatonin. 72
FluvoxamineFluvoxamine may inhibit melatonin metabolism (CYP1A2), 73 , 74 elevating melatonin plasma concentrations and increasing the effects (eg, drowsiness). In a study in 5 healthy men, each subject ingested a single 5 mg dose of melatonin alone and 3 hours after a 50 mg dose of fluvoxamine. 75 Fluvoxamine administration resulted in a 23-fold increase in the area under the curve and a 12-fold increase (from 2.2 to 25.1 ng/mL) in the peak plasma concentration of melatonin. All subjects reported remarkable drowsiness after melatonin ingestion, which was more pronounced after coadministration of fluvoxamine.
NifedipineMelatonin may decrease the therapeutic effect of nifedipine, resulting in increased blood pressure. The effect of evening ingestion of melatonin on the antihypertensive action of nifedipine GI therapeutic system (GITS) was evaluated in 47 patients with mild to moderate hypertension. 76 Compared with placebo, melatonin ingestion in the evening increased the systolic and diastolic blood pressure throughout the day (ie, 24-hour period) by 6.5 and 4.9 mm Hg, respectively. The increase in systolic blood pressure was highest during the afternoon and first part of the evening, while the increase in diastolic blood pressure was highest in the evening. In addition, there was a 3.9 bpm increase in heart rate throughout the day, being greatest in the morning.
Adverse Reactions
Most clinical studies note the absence of adverse events associated with melatonin administration. A randomized, double-blind trial (n = 40), in which melatonin or placebo was administered for 28 days, found no statistical difference between the adverse effects reported by patients nor in their lab results (including CBC, urinalysis, electrolytes, cholesterol, LFTs). 77 Minor side effects with doses < 8 mg have included “heavy head,” headache, and transient depression. 4 , 46 , 47 In psychiatric patients, melatonin has aggravated depressive symptoms. 3 , 4 , 6 Single case reports in the literature have related use to a fixed drug eruption, 78 a psychotic episode, 79 painful gynecomastia, 80 and autoimmune hepatitis. 81 However, melatonin was not the drug definitively identified as the causal agent in any of these reports.
Morning ingestion of melatonin could be more problematic. A small study of 9 patients has shown impaired psychomotor vigilance. 82 Prolonged studies are needed to verify its safety.
Drowsiness may be experienced within 30 minutes after taking melatonin and may persist for ≈ 1 hour and thus may affect driving skills.
Toxicology
There are very few short-term and no long-term safety data. Toxicological studies have shown that an LD 50 could not be obtained even at extremely high doses. Researchers gave human volunteers 6 g of melatonin each night for 1 month and found no major problems, except for stomach discomfort or residual sleepiness. 5
Bibliography
1. Windholz M, et al. Merck Index . 11th ed. Rahway, NJ: Merck and Co., 1989.2. Bowman WC, Rand MJ. Textbook of Pharmacology . 2nd ed. St. Louis: Blackwell Scientific Publications; 1980.
3. Webb SM, Puig-Domingo M. Role of melatonin in health and disease. Clin Endocrinol . 1995;42:221-234.
4. Generali JA. Keeping Up: Melatonin. Drug Newsletter . 1996;15:3.
5. Cowley G. Melatonin. Newsweek . 1995;Aug 7:46.
6. Arendt J. Melatonin. Clin Endocrinol . 1988;29:205-229.
7. Borbely AA. Commentary on the articles by Arendt, Weaver, Mahle, et al, and Guardiola-Lemaitre. J Biol Rhythms . 1997;12:707-708.
8. Aldhous M, Franey C, Wright J, Arendt J. Plasma concentrations of melatonin in man following oral absorption of different preparations. Br J Clin Pharmacol . 1985;19:517-521.
9. Sack RL, Lewy AJ, Blood ML, Stevenson J, Keith LD. Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms . 1991;6:249-261.
10. Reiter RJ, Melchiorri D, Seweryneck E, et al. A review of the evidence supporting melatonin's role as an antioxidant. J Pineal Res . 1995;18:1-11.
11. Poeggeler B, Saarela S, Reiter R, et al. Melatonin—a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Ann N Y Acad Sci . 1994;738:419-420.
12. Loffler M. Melatonin as antioxidant—use or misuse? Exp Clin Endocrinol Diabetes . 1996;104:308-310.
13. Cagnacci A, Soldani R, Yen SS. Hypothermic effect of melatonin and nocturnal core body temperature decline are reduced in aged women. J Appl Physiol . 1995;78:314-317.
14. Morgan PJ, Mercer JG. Control of seasonality by melatonin. Proc Nutr Soc . 1994;53:483-493.
15. Partonen T. Involvement of melatonin and serotonin in winter depression. Med Hypotheses . 1994;43:165-166.
16. Cos S, Blask DE. Melatonin modulates growth factor activity in MCF-7 human breast cancer cells. J Pineal Res . 1994;17:25-32.
17. Lissoni P, Paolorossi F, Tancini G, et al. Is there a role for melatonin in the treatment of neoplastic cachexia? Eur J Cancer . 1996;32A:1340-1344.
18. Leone M. Melatonin and primary headache. Cephalgia . 1994;14:183.
19. Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalgia . 1996;16:494-496.
20. Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF. Evidence for a direct action of melatonin on the immune system. Biol Signals . 1994;3:107-117.
21. Maestroni GJ. The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs . 2001;10:467-476.
22. Morrey KM, McLachlan JA, Serkin CD, Bakouche O. Activation of human monocytes by the pineal hormone melatonin. J Immunol . 1994;153:2671-2680.
23. Bubenik GA, Pang SF. The role of serotonin and melatonin in gastrointestinal physiology: ontogeny, regulation of food intake and mutual serotonin-melatonin feedback. J Pineal Res . 1994;16:91-99.
24. Saarela S, Reiter RJ. Function of melatonin in thermoregulatory processes. Life Sci . 1994;54:295-311.
25. Pang CS, Brown GM, Tang PL, Cheng KM, Pang SF. 2-[125 I ]iodomelatonin binding sites in the lung and heart: a link between the photoperiodic signal, melatonin and the cardiopulmonary system. Biol Signals . 1993;2:228-236.
26. Cagnacci A, Arangino S, Angolucci M, Maschio E, Longu G, Melis GB. Potentially beneficial cardiovascular effects of melatonin administration in women. J Pineal Res . 1997;22:16-19.
27. Cagnacci A, Arangino S, Angiolucci M, et al. Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy. Clin Endocrinol . 2001;54:261-266.
28. Pittalis S, Lissoni P, Giani L, et al. Effect of a chronic therapy with the pineal hormone melatonin on cholesterol levels in idiopathic hypercholesterolemic patients. Resenti Prog Med . 1997;88:401-402.
29. Jan JE, Connolly MB, Hamilton D, Freeman RD, Laudon M. Melatonin treatment of non-epileptic myoclonus in children. Dev Med Child Neurol . 1999;41:255-259.
30. Cavallo A. Melatonin and human puberty: current perspectives. J Pineal Res . 1993;15:115-121.
31. Rosenberg SI, Silverstein H, Rowan PT, Olds MJ. Effect of melatonin on tinnitus. Laryngoscope . 1998;108:305-310.
32. Pevet P. Present and future of melatonin in human and animal reproduction functions [in French]. Contracept Fert Sex . 1993;21:727-732.
33. Dawson D, Encel N. Melatonin and sleep in humans. J Pineal Res . 1993;15:1-12.
34. 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.
35. Carneiro RC, Pereira EP, Cipolla-Neto J, Markus RP. Age-related changes in melatonin modulation of sympathetic neurotransmission. J Pharmacol Exp Ther . 1993;266:1536-1540.
36. Weissbluth L, Weissbluth M. The photo-biochemical basis of infant colic: pineal intracellular calcium concentrations controlled by light, melatonin and serotonin. Med Hypotheses . 1993;40:158-164.
37. Sandyk R, Tsagas N, Anninos PA. Melatonin as a proconvulsive hormone in humans. Int J Neurosci . 1992;63:125-135.
38. Armstrong SM, Redman JR. Melatonin: a chronobiotic with anti-aging properties? Med Hypotheses . 1991;34:300-309.
39. Reiter RJ. Pineal function during aging: attenuation of the melatonin rhythm and its neurobiological consequences. Acta Neurobiol Exp . 1994;(54 suppl):31.
40. Shamir E, Barak Y, Plopsky I, Zisapel N, Elizur A, Weizman A. Is melatonin treatment effective for tardive dyskinesia? J Clin Psychiatry . 2000;61:556-558.
41. Leibenluft E, Feldman-Naim S, Turner EH, Wehr TA, Rosenthal NE. Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. J Clin Psychiatry . 1997;58:383-388.
42. Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry . 1998;155:1119-1121.
43. Tzichinsky O, Pal I, Epstein R, Dagan Y, Lavie P. The importance of timing in melatonin administration in a blind man. J Pineal Res . 1992;12:105-108.
44. Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human circadian rhythms according to a phase response curve. Chronobiol Int . 1992;9:380-392.
45. Lino A, Silvy S, Condorelli L, Rusconi AC. Melatonin and jet lag: treatment schedule. Biol Psychiatry . 1993;34:587.
46. Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatry . 1993;33:526-530.
47. Claustrat B, Brun J, David M, Sassolas G, Chazol G. Melatonin and jet lag: confirmatory result using a simplified protocol. Biol Psychiatry . 1992;32:705-711.
48. Arendt J. Jet-lag and shift work: (2). Therapeutic use of melatonin. J R Soc Med . 1999;92:402-405.
49. Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacology (Berl) . 1990;100:222-226.
50. MacFarlane JG, Cleghorn JM, Brown GM, Streiner DL. The effects of exogenous melatonin on the sleep time and daytime alertness of chronic insomniacs: a preliminary study. Biol Psychiatry . 1991;30:371-376.
51. Dollins AB, Lynch HJ, Wurtman RJ, et al. Effect of pharmacological daytime doses of melatonin on human mood and performances. Psychopharmacology (Berl) . 1993;112:490-496.
52. James SP, Sack DA, Rosenthal NE, Mendelsohn WB. Melatonin administration in insomnia. Neuropsychopharmacology . 1989;3:19.
53. Tzichinsky O, Lavie P. Melatonin possesses time-dependent hypnotic effects. Sleep . 1994;17:638-645.
54. Nave R, Peled R, Lavie P. Melatonin improves evening napping. Eur J Pharmacol . 1995;275:213-216.
55. Zhdanova IV, Wurtman RJ, Lynch HJ, et al. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther . 1995;57:552-558.
56. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled release melatonin. Lancet . 1995;346:541-544.
57. Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy in elderly insomniacs. Sleep . 1995;18:598-602.
58. Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro C. 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.
59. Andrade C, Srihari BS, Reddy KP, Chandramma L. Melatonin in medically ill patients with insomnia: a double blind, placebo-controlled study. J Clin Psychiatry . 2001;62:41-45.
60. Jan JE, Espezel H, Appleton RE. The treatment of sleep disorders with melatonin. Dev Med Child Neurol . 1994;36:97-107.
61. Smits MG, Nagtegaal E, van der Hiejden J, Coenen AML, Kerkhof GA. Melatonin for chronic sleep onset insomnia in children: a randomized placebo controlled trial. J Child Neurol . 2001;16:86-92.
62. Jan JE, Hamilton D, Seward N, Fast DK, Freeman RD, Laudon M. Clinical trials of controlled release melatonin in children with sleep-wake cycle disorders. J Pineal Res . 2000;29:34-39.
63. Sauer LA, Dauchy RT, Blask DE. Polyunsaturated fatty acids, melatonin, and cancer prevention. Biochem Pharmacol . 2001;61:1455-1462.
64. Jan JE, Tai J, Hahn G, Rothstein RR. Melatonin replacement therapy in a child with a pineal tumor. J Child Neurol 2001;16:139-140.
65. Lissoni P, Barni S, Cattaneo G, et al. Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard anti-tumor therapies. Oncology . 1991;48:448-450.
66. Zumoff B. Hormonal profiles in women with breast cancer. Obstet Gynecol Clin North Am . 1994;21:751-772.
67. Lissoni P, Barni S, Tancini G. Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumors. Oncology . 1995;52:163-166.
68. Lissoni P, Barni S, Brivio F, Rossini F, Fumagalli L, Tancini G. A biological study on the efficacy of low dose subcutaneous interleukin-2 plus melatonin in the treatment of cancer related thrombocytopenia. Oncology . 1995;52:360-365.
69. Barni S, Lissoni P, Cazzaniga M, et al. A randomized study of low dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colorectal cancer patients progressing under 5-fluorouracil and folates. Oncology . 1995;52:243-245.
70. Voordouw BC, Euser R, Verdonk RE, et al. Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinol Metab . 1992;74:108-117.
71. Dreher F, Gabard B, Schwindt DA, Maibach HI. Topical melatonin in combination with vitamins E and C protects skin from ultraviolet-induced erythema: a human study in vivo. Br J Dermatol . 1998;139:332-339.
72. Härtter S, et al. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. Br J Clin Pharmacol . 2003;56;679-682.
73. Härtter S, et al. Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. J Clin Psychopharmacol . 2001;21:167-174.
74. Facciolá G, et al. Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. Eur J Clin Pharmacol . 2001;56:881-888.
75. Härtter S, et al. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther . 2000;67:1-6.
76. Lusardi P, et al. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol . 2000;49:423-427.
77. Seabra ML, Bignotto M, Pinto LR Jr., Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res . 2000;29:193-200.
78. Bardazzi F, Placucci A, Neri I, D'Antuono A, Patrizi A. Fixed drug eruption due to melatonin. Acta Derm Venereol . 1998;78:69-70.
79. Force RW, Hansen L, Bedell M. Psychotic episode after melatonin. Ann Pharmacother . 1997;31:1408.
80. De Bleeker JL, Lamont BH, Verstraete AG, Schelfhout VJ. Melatonin and painful gynecomastia. Neurology . 1999;53:435-436
81. Hong YG, Riegler JL. Is melatonin associated with the development of autoimmune hepatitis? J Clin Gastroenterol . 1997;25:376-378.
82. Graw P, Werth E, Krauchi K, Guzwiller F, Cajochen C, Wirz-Justice A. Early morning melatonin administration impairs psychomotor vigilance. Behav Brain Res . 2001;121:167-172.
| Link to this page |  |
Printable Version |  |
Email Page |  |
Add to my drug list |
