Melatonin for Sleep and Cognition
Melatonin is a natural hormone produced in the pineal gland of the human brain and is involved with the natural sleep-wake cycle. In humans, serum levels are very low during the day, but increase during sleep, peaking in the middle of the night. They fall sharply shortly after awaking in the morning. In various animals, melatonin plays a role in regular their daily rhythm and even the seasonal one. It is involved in helping change the seasonal fur coat in some species, in storing fat for the winter, and in slowing down the body processes after winter arrives. It lowers blood pressure during the night, slows down cortisol excretion which had helped the body deal with the stresses of the day. It is a powerful anti-oxidant, helping clean up the excess oxygen radicals accumulated during the awake hours. It may help trigger reproduction cycles in some animals.
Melatonin's administration to humans results in a wide array of effects including a reduction of core body temperature. Melatonin production begins to fall sometime between 40 and 60 years of age. This fall appears to play a role in the sleep difficulties of the elderly. It is my favorite front-line treatment for insomnia due to its low cost, very low side-effect profile, and extensive animal research showing protective effects on the brain and increases in longevity.
Added melatonin for sleep has been heavily researched for many different patient populations, but studies have been small and of short duration. It has been found of value in at least 21 double-blind sleep studies covered below including roughly 500 people. Most of the research is from outside the U.S. In many studies, melatonin has been found of equal or greater value and with fewer side-effects when compared to the popular prescription sleeping pills. Several studies have found no benefit. Four double-blind cognition studies have also found melatonin of benefit for alertness in a variety of patient populations: after head injuries, in the elderly, in epileptic children, and in children with insomnia.
Melatonin affects many other parts of the body. It is a powerful antioxidant. Six double-blind studies, several quite large, have shown benefit for metastatic cancer of various types. Two studies each have found benefit for high blood pressure, and irritable bowel syndrome. Single double-blind studies in humans report benefit for nocturia from benign prostatic hypertrophy, hair loss, infant respiratory distress syndrome, seasonal affective disorder, and tardive dyskinesia. Of course, one or two small studies is not enough to draw any conclusion for any disease, but favorable studies with such a diversity of diseases is impressive. Melatonin may also help prevent migraines. See Other Benefits.
Animal Research suggests an amazing number of potential benefits, many appearing due to the potent anti-oxidant nature of melatonin. These include strong evidence of benefit for strokes, closed head injury, heart attacks, stomach ulcers, longevity, and many other conditions. However, whether any of these favorable effects apply to humans awaits future research. Despite the lack of research, when I had a subarachnoid hemorrhage (perimesencephalic), I took melatonin 15-18 mg/day and did very well. The neurosurgeons did not seem very well versed on the research on either perimesencephalic hemorrhages or melatonin in my opinion. Fortunately, I knew about melatonin beforehand and even took a dose before going to the hospital and discreetly took it in the hospital.
Melatonin is available without a prescription at U.S. pharmacies as a very inexpensive sleep remedy. While some studies use the very low dose 0.3 mg/night, most use 3-9 mg/night or one to three standard full-strength pills. Some people will need 9-12 mg/night. One study says the benefit is somewhat cumulative, so don't give up after one night. Other than not working for a significant minority of people and causing a broken sleep pattern in a small number of people, melatonin causes few side-effects.
Melatonin has become my favorite first line sleep medication. Of course, patients suffering from serious psychiatric problems like depression or psychosis will need something to deal directly with those problems as well. At least 10% to 20% won't experience any benefit. Sleep apnea and other sleep disorders must also be considered. Melatonin costs 3-5 cents for a 3 mg. tablet. Melatonin research is much more extensive and much more favorable than that of the more popular diphenhydramine (Benadryl, Nyquil, etc.). While melatonin tends to cause daytime alertness, diphenhydramine tends to cause grogginess and clouded thinking the next day. Some preliminary studies even suggest that diphenhydramine might increase the risk of Alzheimer's disease, while melatonin appears to decrease it.
Side-effects possibly due to melatonin are very rare, although it should not be taken when trying to get pregnant, during pregnancy, and while nursing. A small percentage experience daytime drowsiness and should decrease the dose. Melatonin can cause broken sleep in a small percentage. A few people have reported headaches, nightmares, low sex drive, and mild depression, although these may not have been due to the melatonin. People with transplants should exercise caution since melatonin can affect corticosteroid production.
The Japanese drug company Takeda has come out with an expensive ($80/month) melatonin receptor agonist named Rozerem (ramelteon)(see below). There is no evidence in humans that it is as good as or better than melatonin, and its benefits on the amount of sleep are minor, probably no greater than with melatonin. It has few side-effect, but those reported include sleepiness, dizziness, nausea, fatigue, headache, and insomnia. One study found an elevated prolactin level in 32% of patients, which could theoretically lead to infertility, decreased libido, and osteoporosis. There is no research as to Rozerem's anti-oxidant effect, one of the strong benefits of melatonin. Rozerem may be as good for sleep, but the markedly higher cost and lack of evidence of other benefits makes me strongly favorite melatonin itself.
Melatonin Side-Effects Rare: In a review searching for side-effect reports covering a 35-year (1966-2000) bibliographic search using the Medline database and covering 307 articles, the adverse reactions occrruing to patients while on melatonin were: one patient with autoimmune hepatitis, one case of confusion due to MLT overdose, one case of optic neuropathy, four subjects with fragmented sleep, one psychotic episode, one case of nystagmus, four cases of seizures, one case of headache and two cases of skin eruptions. Safety in melatonin use. Morera AL, et al. Universidad de La Laguna, Tenerife, Spain. . Actas Esp Psychiatr 2001 Sep-Oct;29(5):334-7. Ed: These findings do not mean that the adverse reactions were caused by melatonin, only that they may have been. In such a huge number of studies, this is an extremely low side-effect profile.
Adults with Insomnia
Melatonin as Good or Better than Zolpidem Sleeping Pill and Without Memory or Performance Impairment: In a DB PC study of 80 adults after a good night's sleep, zolpidem 0, 5, 10, or 20 mg was given at 10:00 am and then oral melatonin 0 or 5 mg at 10:30 am (thus, n = 10 per drug combination). Subjects napped from 10:00 am to 11:30 am, at which time they were awakened for cognitive tests. A second nap ensued from 12:45 pm to 4:00 pm, followed by further testing. Melatonin 5 mg plus zolpidem 0 mg enhanced daytime sleep (P < .05) with no memory or performance impairment (P > .05). Zolpidem 20 mg plus melatonin 0 mg also enhanced daytime sleep nonsignificantly, but memory and vigilance were impaired (P < .05). Melatonin's sleep-promoting effects were not evident until the second nap. Daytime sleep and performance following a zolpidem and melatonin cocktail. Wesensten NJ, Balkin TJ, et al. Walter Reed. Sleep. 2005 Jan 1;28(1):93-103.
Melatonin Helped Mentally Ill in DB: In a DB PC study of 33 adult psychiatric inpatients, melatonin patients fell asleep in an average of 20 min. vs. 1 hr for placebo. Patients experienced five hours of sleep with placebo vs. almost six hours with melatonin. In the study, 3 mg tabs, up to 4 at bedtime, were allowed but patients averaged 5.4 mg at betimes. Good quality sleep without hangover or withdrawal. Andrade, Bangalore, J Clin Psychiatry 01;62:41.
Melatonin Helped Sleep in DB of Psychiatric Patients: Dolberg in Am J Psychiatry 8/98 155:1119-21 found helpful in DB study for 4 wk with fluoxetine with melatonin better sleep quality than placebo in a 19 patient study. A slow-release melatonin was used. Author refers to studies where melatonin is said to help sleep in primary sleep disorder (Lancet ’91;337:1121), elderly insomniacs (Lancet ’95;346:541-4), aircrews with jet lag (Ergonomics ’87;30:1379), normal volunteers (Psychopharm (Berlin) ’90;100:222). Says slow release is reported to be better. 2.5-10mg/night. Studies for sleep call melatonin promising. Exp Gerontol 11/98. Cajocen of Basel in J Sleep Res 9/98 7:145-57 found 5 mg HS shortened sleep latency and patients reported better sleep than with bright light therapy which lengthened sleep latency. But Wright in Ann Emerg Med 9/98 32:334-40 found 5 mg no value for 15 ER MDs for 3 nights vs. placebo.
Melatonin Helped Schizophrenia with Insomnia: Low melatonin levels have also been observed in patients with schizophrenia. In a DB PC study of 40 stable DSM-IV schizophrenic outpatients with initial insomnia of at least 2 weeks' duration, melatonin (3-12 mg/night did better than placebo and significantly improved the quality and depth of nighttime sleep, reduced the number of nighttime awakenings, and increased the duration of sleep without producing a morning hangover (p < .05). Subjectively, melatonin also significantly reduced sleep-onset latency, heightened freshness on awakening, improved mood, and improved daytime functioning (p < .05). The authors conclude, “Melatonin could be considered for patients in whom conventional hypnotic drug therapy or higher sedative antipsychotic drug doses may be problematic.” Melatonin in schizophrenic outpatients with insomnia: a double-blind, placebo-controlled study. Suresh Kumar PN, et al. Kozhikode . J Clin Psychiatry 2007 Feb;68(2):237-41.
Melatonin Did Well Compared to Addictive Sleep Meds in DB: Nine men and 14 women, ages 21-53, were assessed for psychomotor performance before and for 7 hours after taking a single dose of placebo, zaleplon (Sonata) 10 mg, zopiclone (Ambien) 7.5 mg, temazepam (Restoril) 15 mg, or time-released melatonin 6 mg in a double-blind crossover study with counterbalanced treatment order. More sleep, shorter sleep latency, and more drowsiness occurred immediately after psychomotor testing compared to before testing for all medications. Melatonin did not cause any sleep prior to psychomotor testing sessions, but caused sleep and reduced sleep latency after psychomotor test sessions from 1 3/4 h to 4 3/4 h post-ingestion. The sleep-inducing power of the medications before psychomotor testing was zopiclone > zaleplon > melatonin > temazepam. The corresponding effect after psychomotor testing was zopiclone > melatonin > zaleplon > temazepam. Sleep-inducing pharmaceuticals: a comparison of melatonin, zaleplon, zopiclone, and temazepam. Paul MA, Gray G, MacLellan M, Pigeau RA. North York, Ontario. Aviat Space Environ Med. 2004 Jun;75(6):512-9
Melatonin Does Just as Well in Single Dose as Powerful and Addictive Sleeping Pill in DB: In a DB crossover study of 30 aircrew flying 3 transatlantic missions over which they took each of the 3 medications (placebo, sustained-release melatonin 2 mg, or zopiclone 5 mg), the results of the actigraphic data show that relative to placebo, aircrew on melatonin and zopiclone fell asleep more quickly (melatonin: p < 0.01, zopiclone: p < 0.003), slept more (melatonin: p < 0.02, zopiclone: p < 0.005), had fewer awakenings after sleep onset (melatonin: p < 0.004, zopiclone: p < 0.01), and spent less time awake after sleep onset (melatonin: p < 0.01, zopiclone: p < 0.05). The results of the questionnaire data show that relative to placebo, aircrew on melatonin and zopiclone experienced less difficulty getting to sleep (melatonin: p < 0.0001, zopiclone: p < 0.001), had fewer awakenings (melatonin: p < 0.005, zopiclone: p < 0.001), less difficulty returning to sleep after awakening (melatonin: p < 0.0001, zopiclone: p < 0.0001), and reported a better sleep quality (melatonin: p < 0.0003, zopiclone: p < 0.0004). There were no statistically significant differences between melatonin and zopiclone in any of the actigraphic or questionnaire sleep parameters. Melatonin and zopiclone as facilitators of early circadian sleep in operational air transport crews. Paul MA, Gray G, Sardana TM, Pigeau RA. North York, Ontario, Canada. Aviat Space Environ Med. 2004 May;75(5):439-43. Ed: Zopiclone (Imovane) is an addictive hypnotic medication popular in Europe as a sleeping remedy. A Norwegian study found 60% of 100 drivers stopped under suspicion of being drugged drivers tested positive for elevated levels of zopiclone.
Asthmatic Women with Insomnia Helped: In a DB PC study of 22 asthmatic women, melatonin 3 mg/night for 4 weeks significantly improved subjective sleep quality, as compared with placebo (p = 0.04). There were no significant difference in asthma symptoms, use of relief medication and daily peak expiratory flow rate. Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Campos FL, da Silva-Junior FP, et al. Universidade Federal do Ceara, Fortaleza, Brazil. Am J Respir Crit Care Med. 2004 Nov 1;170(9):947-51. Ed: There are some theoretic concerns about melatonin for asthmatics. This study suggests that any harm is probably minimal.
Melatonin Helps REM Sleep Disorder: Mayo Clinic study shows that melatonin successfully alleviates many patients' symptoms of REM-sleep behavior disorder (RBD), a violent sleep condition that manifests during rapid eye movement (REM) sleep, a stage of deep sleep in which most dreaming occurs. "Melatonin can be considered as one possible option for RBD. Brad Boeve. RBD appear to act out their dreams, in which screaming, yelling, hitting, kicking and jumping out of bed.. July 2003 issue of Sleep Medicine. Retrospective study of 15 elderly males who also had Lewy Body Dementia, Parkinson’s or another disorder. Eight were helped for a full year. Can occur in 20s, usually after 40 and rare.
Melatonin Low Doses Didn't Help: 10 subjects in crossover study of 0.3 mg HS, 1.0 mg HS or placebo for 1 week each found no difference. Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J, Heinze Martin G. J Psychiatry Neurosci. 2003 May;28(3):191-6. Ed: While the lower doses are sold at Walmart, etc., most people need 6 mg/night or six times as much as the larger dose in this study.
Children: Melatonin Helped Sleep Onset and Health Status of Children with Insomnia in DB: In a 62-child (ages 6-12) DB PC study of chronic sleep-onset insomnia, 4 weeks of melatonin 5 mg/night resulted in much higher improvement than placebo. The RAND General Health Rating Index (RAND-GHRI) and Functional Status II (FS-II) questionnaires found the RAND-GHRI average of 0.69 for melatonin versus 0.07 for placebo and for the FS-II of 1.61 versus 0.64. Melatonin treatment also significantly advanced sleep onset by 57 minutes, sleep offset by 9 minutes, and decreased sleep latency by 17 minutes. Lights-off time and total sleep time did not change. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. Smits MG, van Stel HF, et al. the Netherlands. J Am Acad Child Adolesc Psychiatry. 2003 Nov;42(11):1286-93
ADHD: Insomnia Helped But Not ADHD: Twenty-seven stimulant-treated children with ADHD and initial insomnia (>60 minutes) received sleep hygiene intervention. Nonresponders were randomized to a 30-day double-blind, placebo-controlled, crossover trial of 5-mg pharmaceutical-grade melatonin. Sleep hygiene reduced initial insomnia to <60 minutes in 5 cases, with an overall effect size in the group as a whole of 0.67. Analysis of the trial data able to be evaluated showed a significant reduction in initial insomnia of 16 minutes with melatonin relative to placebo, with an effect size of 0.6. Adverse events were generally mild and not different from those recorded with placebo treatment. Sleep Hygiene and Melatonin Treatment for Children and Adolescents With ADHD and Initial Insomnia. Weiss M et al. University of British Columbia, Vancouver, British Columbia, Canada.
Children with Seizures and Insomnia Helped in DB: In a DB PC study of 31 children ages 3-12 with seizures treated with valproate, the decrease in the median total sleep score was 24% with valproate + melatonin vs. 14% with valproate + placebo group(P < .05). The decrease in the parasomnias score was 60% with melatonin vs. 36% with placebo (P < .05). There was no significant difference in daytime drowsiness or sleep fragmentation. Add-on melatonin improves sleep behavior in children with epilepsy: randomized, double-blind, placebo-controlled trial. Gupta M, Aneja S, Kohli K. Lady Hardinge Medical College, New Delhi, India. J Child Neurol. 2005 Feb;20(2):112-5.
Children: Retarded Children with Insomnia Helped by Melatonin in DB: In a 12-week DB PC crossover study of melatonin 3-9 mg at bedtime, 25 mentally-retarded patients from 4-26 years of age suffering from insomnia, melatonin had a significant benefit on sleep latency with no side-effects and no net impact on seizure disorders. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial. Coppola G, Iervolino G, Mastrosimone M, La Torre G, Ruiu F, Pascotto A. Second University of Naples, Italy. Brain Dev. 2004 Sep;26(6):373-6.
Children: Asperger Children Tried on Melatonin; Might Have Helped Behavior and Sleep Latency: In a very poorly designed "open trial" of melatonin 3 mg/night given to 15 children with Asperger disorder for just 14 days and then stopped, the authors report that the sleep patterns of all the children improved, and half of them did very well while of the melatonin. The authors erroneously report that the children "responded to melatonin," a conclusion impossible to draw from an open trial. Actigraphically measured sleep latency decreased from 40 minutes to 22 minutes (p = 0.002), whereas sleep duration remained steady at 477 vs. 480 minutes. Behavioral measures also displayed a significant improvement. Most of the effect disappeared after the discontinuation of the melatonin (p = 0.001). Effectiveness of melatonin in the treatment of sleep disturbances in children with Asperger disorder. Paavonen EJ, Nieminen-von Wendt T, Vanhala R, Aronen ET, von Wendt L. University of Helsinki. J Child Adolesc Psychopharmacol. 2003 Spring;13(1):83-95
Children: Melatonin Use Reported in Children: In a very poorly designed open-label study of 32 children with chronic sleep initiation and sleep maintenance problems, an average of 2 months of 1-3 mg/night of melatonin claimed that 29 (90.6%) children exhibited partial improvement to complete resolution of their sleep problems as measured by sleep latency time and number of awakenings reported by parents. Melatonin in children and adolescents with insomnia: a retrospective study. Ivanenko A, Crabtree VM, Tauman R, Gozal D. University of Louisville. Clin Pediatr (Phila). 2003 Jan-Feb;42(1):51-8
Elderly: Melatonin Helped Elderly Japanese in Small DB Study: In a very small 20 patient 4-week DB PC study of elderly adults, melatonin 3 mg/night resulted in no mean sleep time change with placebo and a 33% increase with melatonin. The mean activity counts with placebo were increased 29.8%; in melatonin it was decreased 45%. Melatonin significantly prolonged the sleep time (p=0.017) and decreased activity (p=0.014), although no significant difference in sleep time or activity in the daytime. ADAS cognition scores increased 0.3 with placebo and decreased 4.3 with melatonin. ADAS non-cognition scores decreased 0.8 with placebo and 4.1 with melatonin. (p=0.017) and (p=0.002). Otherwise there was no significant difference in improvement of MMSE between both groups. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. Nippon Medical School, Tokyo. J Nippon Med Sch. 2003 Aug;70(4):334-41
Elderly: Melatonin Helped in Elderly in DB: In a 10 patient DB PC crossover study, all had some cognitive impairment and insomnia. They were given 6 mg/day of melatonin 2 hours before bedtime. Improved sleep quality, reduced awakenings, reduced time to fall asleep occurred but total duration not affected. Some reduced depressed mood and improved delayed memory recall was reported. J Pineal Research 98;25:177.
Elderly: Melatonin Helped Sleep: In a DB PC crossover study of 21 elderly insomniacs on benzodiazepines already, three weeks of CR-melatonin 2 mg/night significantly increased sleep efficiency and total sleep time and decreased wake after sleep onset, sleep latency, number of awakenings and fragmental index, as compared to placebo. Improvement of sleep quality by controlled-release melatonin in benzodiazepine-treated elderly insomniacs. Garfinkel D, Laudon M, Zisapel N. Bat-Yam, Israel. Arch Gerontol Geriatr. 1997 Mar-Apr;24(2):223-31
Elderly: Melatonin Didn't Help Healthy Elderly with Insomnia: In a 20-patient DB PC crossover study with 4 weeks in each phase, melatonin 5 mg/night did not significantly improve any sleep parameter measured in either group. Does melatonin improve sleep in older people? A randomised crossover trial. Baskett JJ, Broad JB, Wood PC, Duncan JR, Pledger MJ, English J, Arendt J. Auckland, New Zealand. Age Ageing. 2003 Mar;32(2):164-70
Elderly: Melatonin Didn't Help Elderly Demented: In a DB PC crossover study of 44 demented elderly given melatonin 6 mg or placebo for 7 weeks, 25 completed the trial. Melatonin had no effect on median total time asleep (p=0.18), number of awakenings (p=0.75) or sleep efficiency (p=0.24). Nor were there any carry over effects from melatonin. Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Serfaty M, Kennell-Webb S, Warner J, Blizard R, Raven P. Royal Free and University College Medical School, London, UK. Int J Geriatr Psychiatry. 2002 Dec;17(12):1120-7
Elderly: Alzheimer's Patients Not Helped with Sleep in Large Study: In a careful 2 month DB PC study of 157 Alzheimer's patients, nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. Trends for a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group were also seen. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5-mg sustained-release melatonin group relative to placebo. There were no significant differences in the number or seriousness of adverse events between the placebo and melatonin groups. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M, Thomas R, Thal LJ; Alzheimer's Disease Cooperative Study. Oregon Health & Science University. Sleep. 2003 Nov 1;26(7):893-901
Elderly: Melatonin Helps Parkinson Patients Sleep: In a 2-week per treatment DB PC crossover study of 40 Parkinson's patients with 1-week washouts, a significant improvement in total nighttime sleep time occurred only with the 50 mg melatonin compared to placebo, not with the 5 mg. However, there was significant improvement in subjective sleep disturbance, sleep quantity, and daytime sleepiness during the 5 mg melatonin treatment compared to placebo. Melatonin for sleep disturbances in Parkinson's disease. Dowling GA, et al. University of California, San Francisco. Sleep Med. 2005 Aug 3. Ed: Subjective reports may be more important than objective ones. If you feel better rested, maybe you slept better, even though you didn't sleep longer!
Elderly: Helped Sleep and Cognition: In a small, 26-patient, 4-week DB PC study of healthy elderly, melatonin 1 mg improved reported morning "restedness" and sleep latency after nocturnal awakening, and also improved scores on the California Verbal Learning Test-interference subtest. The authors conclude that it may prove to be a useful therapeutic agent in the treatment of age-related cognitive decline. Cognitive effects of exogenous melatonin administration in elderly persons: a pilot study. Peck JS, LeGoff DB, et al. University of Hawaii, Am J Geriatr Psychiatry. 2004 Jul-Aug;12(4):432-6
Elderly: Melatonin Did Not Reduce Benzodiazepine Withdrawal Insomnia: In a 6-week DB PC study of 45 elderly on nightly low dose benzodiazepines for minor sleep difficulties, 3 mg of melatonin did no better than placebo. The benzo dose was cut in hlf at day 14 and stopped at day 28. Sleep quality of patients taking melatonin during the first two weeks of treatment was significantly lower than that of placebo. Melatonin advanced sleep onset by 27.9 min and decreased significantly the variability of sleep onset time (p= 0.03). A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly. Cardinali DP, et al. University of Buenos Aires, Argentina. Neuro Endocrinol Lett. 2002 Feb;23(1):55-60. A previous study had shown benefit in patients on still higher doses of benzos.
The Mentally Retarded
Retarded Adults Helped by Melatonin in Short DB Study: In a 20-patient DB PC crossover study of melatonin 0.3 mg, 0.1 mg, and placebo with 1 week on each with one week washout between phases, mentally retarded adults with insomnia found the physiologic melatonin dose (0.3 mg) restored sleep efficiency (p < 0.0001), acting principally in the midthird of the night; it also elevated plasma melatonin levels (p < 0.0008) to normal. The lowest dose (0.1 mg) also improved sleep. Brief report: melatonin facilitates sleep in individuals with mental retardation and insomnia. Niederhofer H, Staffen W, Mair A, Pittschieler K. Salzburg, Austria. J Autism Dev Disord. 2003 Aug;33(4):469-72
Retarded Young Epileptics' Sleep Helped: In a 3-week DB PC crossover study of 25 mentally retarded ages 4-26, most with seizures and all with sleep-wake difficulties, 3-9 mg/night of melatonin decreased sleep latency (P = 0.019) without side effects. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial. Coppola G, Iervolino G, et al. Second University of Naples, Italy. Brain Dev. 2004 Sep;26(6):373-6
Pre-operative Sedation: Melatonin as Good as Addictive Benzodiazepine: In a 66-patient DB PC study of patients undergoing laparoscopic cholecystectomy, those given melatonin 5 mg or midazolam 15 mg 90 min before anesthesia, sublingually, had a significant increase in sedation and decrease in anxiety before operation compared with placebo. After operation, there was no difference in sedation scores of all groups. There were no significant differences among the groups in terms of neuropsychological performance after the operation. Amnesia was notable only in the midazolam group for one preoperative event. Perioperative effects of melatonin and midazolam premedication on sedation, orientation, anxiety scores and psychomotor performance. Acil M, Basgul E, et al. Hacettepe University, Ankara, Turkey. Eur J Anaesthesiol. 2004 Jul;21(7):553-7
Non-Addictive Melatonin as Good as Addictive Midazolam for Pre-Laparoscopy Anxiety and Sedation in DB: In a DB PC study of 66 patients undergoing laparoscopic cholecystectomy, patients were given melatonin 5 mg, midazolam 15 mg or placebo, 90 min before anaesthesia, sublingually. Patients who received premedication with either melatonin or midazolam had a significant increase in sedation and decrease in anxiety before operation compared with controls. Perioperative effects of melatonin and midazolam premedication on sedation, orientation, anxiety scores and psychomotor performance. Acil M, Basgul E, Celiker V, Karagoz AH, Demir B, Aypar U.Hacettepe University, Ankara, Turkey. Eur J Anaesthesiol. 2004 Jul;21(7):553-7
Melatonin Not Help Depressed Sleep After ECT: In a DB PC study of 35 patients with major depression, all responding to ECT were put on fluoxetine or fluoxetine + melatonin for 3 months. 28% relapsed into depression which was the same in both groups. Melatonin didn’t help with sleep, which is often precursor of relapse. Grunhaus, Israel, J ECT 2001 Jun;17(2):124-8
Elderly Insomniacs More Likely Low Melatonin Levels: In a DB PC study of 517 insomnia patients, compared to 29 age-matched and 30 younger healthy volunteers, the average 6-sulfatoxymelatonin excretion was lower in the insomnia patients (9.0 microg per night) than in volunteers of the same age (18.1 microg per night, P <0.05) and in younger volunteers (24.2 microg per night, P <0.05). About 30% were "low excretors." They had a significantly higher response to melatonin replacement therapy (58% vs. 47%, P <0.05). Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Leger D, Laudon M, Zisapel N. Hotel-Dieu de Paris, France. Am J Med. 2004 Jan 15;116(2):91-5
Blind Adults: Sleep and Cortisol Patterns Normalized: In blind individuals, the absence of light cues results in disturbances of sleep and sleep-related neuroendocrine patterns. In a DB PC crossover study of 12 totally blind adults, 5 mg melatonin increased blood melatonin concentrations to supraphysiological levels. Melatonin increased total sleep time and sleep efficiency (P < 0.05) and reduced time awake (P < 0.05). The increment in total sleep time was primarily due to an increase in stage 2 sleep (P < 0.01) and a slight increase in rapid eye movement sleep (P < 0.06). Melatonin normalized in parallel the temporal pattern of ACTH and cortisol plasma concentration. While after placebo, ACTH and cortisol levels did not differ between early and late sleep, melatonin induced the typical suppression of pituitary-adrenal activity during early sleep and a distinct rise during late sleep (P < 0.01). Cortisol nadir values were decreased after melatonin (P < 0.05). Melatonin acutely improves the neuroendocrine architecture of sleep in blind individuals. Fischer S, Smolnik R, et al. University of Lubeck, Germany. J Clin Endocrinol Metab. 2003 Nov;88(11):5315-20; A 7-year-old blind child with a chronic sleep disorder was given a trial of placebo, 0.14 mg (physiologic dose), and 2.2 mg of melatonin a night. Only the higher dose helped. Sleep Med. 2002 Mar;3(2):159-61
Melatonin Can Cause Fragmented Sleep: 2 small crossover studies of melatonin found 4 of 15 men had extremely irregular sleep after starting it. Middleton B et al: Melatonin and fragmented sleep patterns (letter). Lancet 96;348:551-2, U Surrey.
Coffee Decreases Melatonin at Night: A study found that caffeinated, but not decaf coffee reduced the 6-SMT metabolite of melatonin. Sleep Med. 2002 May;3(3):271-3
Human Studies on Melatonin for Alertness
Melatonin Helped Cognition in Elderly in DB: In a small 4-week DB PC study of 26 elderly, those taking melatonin 1 mg/night had improved morning restedness and decreased sleep latency after noctural awakening as well as improved verbal learning scores suggesting improved cognitive functioning. Cognitive effects of exogenous melatonin administration in elderly persons: a pilot study. Peck JS, LeGoff DB, Ahmed I, Goebert D. University of Hawaii. Am J Geriatr Psychiatry. 2004 Jul-Aug;12(4):432-6. Ed: Melatonin 3-12 mg/night has become my favorite first line treatment for insomnia.
Melatonin Might Help Post-Head Injury in DB: In a DB cross-over trial of head injury patients comparing melatonin 5 mg/night vs. amitriptyline 25 mg/night, there were no differences in sleep latency, duration, quality or daytime alertness for either drug compared to baseline using significance testing. However, effect sizes revealed some encouraging changes. Patients on melatonin reported improved daytime alertness. On amitriptyline, patients reported increased sleep duration. There were no adverse drug effects. The value of melatonin for sleep disorders occurring post-head injury: a pilot RCT. Kemp S, Biswas R, Neumann V, Coughlan A. Leeds UK. Brain Inj. 2004 Sep;18(9):911-9
Melatonin Might Help Epileptic Children in DB: In a DB PC study of 31 epileptic children ages 3-12, those on melatonin had some evidence of improved quality of life. Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial. Gupta M, Aneja S, Kohli K. New Delhi. Epilepsy Behav. 2004 Jun;5(3):316-21. The same study found that melatonin might have had some neuroprotective effect. Br J Clin Pharmacol. 2004 Nov;58(5):542-7
Ramelteon, like melatonin, is highly selective for melatonin type 1 and type 2 receptors, i.e., it's a melatonin receptor agonist. These inhibit adenylate cyclase and lead to a decrease in cyclic AMP. Type 1 regulates sleepiness, while type two may phase-shift the 24-hr biological clock. It has little impact on the type 3 receptors (MT3 is the enzyme dihydronicotinamide riboside:quinone reductase 2; this may reduce intraocular pressure. J Glaucoma 2004 Oct;13(5):385-8 and Br J Pharmacol 2003 Mar;138(5):831-6.). The quickness of falling asleep was reduced by 7-16 minutes and total sleep time increased by 12-19 minutes. The number of awakenings was no better than with placebo. There is no rebound effect or addictiveness.
While the 8 mg dose of ramelteon costs $81/month, several studies have used 16 mg. per night and one used 64 mg/night, which would markedly increase the cost. It appears that all research to date has been funded by the manufacturer. While melatonin has over 10,000 mentions in research articles, ramelteon has only 19 on PubMed as of 12/6/05.
19 Minutes More Sleep: In a 35-day DB PC study of 405 adults with chronic insomnia, ramelteon at 8 mg led to more sleep than placebo. Zammit G, et al. Sleep 2005;28 abstract suppl:A228.
8 Minutes More Sleep: In a 35-day DB PC study of 848 adults over age 63 with chronic insomnia, ramelteon at 8 mg leg to more sleep than placebo. Roth T, et al. New Clinical Drug Evaluation Unit, June 6-9, 2005 poster session.
Thomas E. Radecki, M.D., J.D.