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An array of clinical research shows the safety and efficacy of melatonin in healthy and compromised populations
Many a time in life when the stress hormones are flying, we also have the unfortunate experience of struggling to sleep. The experience of insomnia is not uncommon, with about one-third to two-thirds of adults experiencing insomnia symptoms of any severity, with 10 to 15% of individuals dealing with chronic insomnia.[1],[2] Sleep difficulties are more common in women and individuals who are single (widowed, divorced, or separated), and often coexist with psychiatric disorders such as depression, or more commonly, anxiety.[3] Insomnia can also be caused by medication side effects, including those used to treat anxiety and depression.[4] Many individuals who experience insomnia never receive a formal diagnosis, and self-medication with substances such as alcohol or over-the-counter medications is not uncommon.[5],[6] However, alcohol can be a contributing factor to poor sleep quality, and negatively affects the body’s circadian rhythm when consumed chronically, obliterating the perceived benefits one may attribute to its use.[7]
Melatonin – the body’s natural sleep regulator
Melatonin, primarily produced in the body by the pineal gland, is the body’s natural sleep promoting hormone. Melatonin levels have a circadian rhythm, rising at night and returning to low levels during the day, nearly opposite in profile to the cortisol pattern.[8] Light is one factor which mediates melatonin secretion, and bright light in particular can be used to shift its circadian pattern.[9] Decreased melatonin production and altered rhythms have been seen with increasing age, in individuals who experience conditions including depression, visual impairment, and neurodevelopmental disorders.[10],[11],[12],[13] The receptors activated by melatonin play not only a beneficial role in sleep, but also in mood disorders, learning and memory, drug abuse, and cancer.[14]
The receptors activated by melatonin play not only a beneficial role in sleep, but also in mood disorders, learning and memory, drug abuse, and cancer.
Melatonin also has importance in the body as an antioxidant that protects the brain and nervous system. It not only has antioxidant action on its own, but also stimulates the body’s production of other antioxidants that are important for detoxification, and recycling of our most common intracellular antioxidant glutathione.[15],[16],[17]
Clinical studies and meta-analyses support the use of melatonin
Melatonin has been studied clinically as a sleep-supportive agent in populations ranging from 2 to 84 years of age.[18],[19] In these studies, no serious side effects caused by melatonin supplementation were observed. Some mild side effects included morning drowsiness, headache, or nighttime awakening. Occasionally, a loss of therapeutic effect was seen with time and continued nightly melatonin use. In some studies, melatonin was even combined with multiple other psychotropic medications in the very young and elderly without any adverse events.[20],[21],[22] In clinical studies, the duration of treatment ranged from days to as long as four years.[23] Dosages in studies for the purpose of supporting sleep range from 0.75 to 15 mg,[19],[24] and often if higher the dosages were used, the dose was titrated gradually over time.[25]
Melatonin has been studied clinically as a sleep-supportive agent in populations ranging from 2 to 84 years of age. In these studies, no serious side effects caused by melatonin supplementation were observed.
In children with neurodevelopment disorders, melatonin was found to significantly improve total sleep time as well as shorten the time it took to fall asleep, although no difference was seen in nighttime awakenings.[26] Although many people argue that melatonin supplementation may reduce the body’s endogenous production of this important hormone, in adults and children with trouble falling asleep, melatonin supplementation was found not only to advance the sleep-wake rhythm but also to stimulate the brain’s own production of melatonin.[27] In patients with sleep disorders associated with dementia, a meta-analysis of seven clinical studies found that melatonin significantly prolonged total sleep time and marginally improved sleep efficacy, although no significant changes were seen in cognitive function.[28] In neurodegenerative disease including Parkinson’s disease and Alzheimer’s, melatonin was found to positively impact certain markers of sleep as evaluated by the Pittsburgh Sleep Quality Index (PSQI), as well as clinical and neurophysiological aspects of rapid eye movement sleep behavior disorder.[29]
The largest meta-analysis considered 19 studies involving 1,683 individuals with primary sleep disorders found that melatonin improved several measurements of healthy sleep and that the effects did not dissipate with continued use.[30] The authors conclude with the statement, “Although the absolute benefit of melatonin compared to placebo is smaller than other pharmacological treatments for insomnia, melatonin may have a role in the treatment of insomnia given its relatively benign side-effect profile compared to these agents,” which fairly well summarizes the majority of research surrounding melatonin.
Extended-release formats of melatonin may more closely mimic the brain’s natural release of melatonin, thus enabling lower dosing and reduced residual daytime sleepiness.
Outside of these selected meta-analyses which broadly assess the impact of melatonin on common conditions associated with altered sleep, melatonin has also been studied in the setting of traumatic brain injury (TBI). Many individuals who experience a TBI subsequently have fragmented or disrupted sleep, which can further negatively impact neuropsychiatric, physical and cognitive outcomes.[31] Altered sleep is in part due to a dramatic decline in the nocturnal melatonin production, but also may be due to oxidative stress and a disrupted blood-brain barrier.[32] In a study of patients with TBI-associated sleep disturbances, prolonged-release melatonin was found to significantly improve sleep efficiency, vitality, and mental health.[33] Again, no serious adverse events were reported, and additionally, patients did not experience increased daytime sleepiness. It has been suggested that melatonin also be considered for other events of trauma leading to intensive care hospitalization, as these conditions also are associated with declines in melatonin secretion.[34]
Consideration for an extended-release format
Although hereunto not discussed specifically, at times, an extended-release format of melatonin was used within some of these studies which were referenced explicitly or existed within the meta-analysis reviews.[33],[35] Prolonged-release formats may more closely mimic the brain’s natural release of melatonin, thus enabling lower dosing and reduced residual daytime sleepiness.[36] For the melatonin-naïve, children, elderly, and individuals who are sensitive to medications and supplemental therapies, this may be beneficial.
In many of these clinical settings, melatonin is not only indicated to support the body’s melatonin levels, but also for the antioxidant action it delivers. Adequacy of melatonin is one critically important thing to consider when supporting a normal, healthy sleep cycle, and volumes of clinical research support its use in a range of healthy and challenged individuals.
Click here to see References
[1] Shochat T, et al. Insomnia in primary care patients. Sleep. 1999 May 1;22 Suppl 2:S359-65.
[2] Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002 Apr;6(2):97-111.
[3] Ohayon MM, Lemoine P. [A connection between insomnia and psychiatric disorders in the French general population]. Encephale. 2002 Sep-Oct;28(5 Pt 1):420-8.
[4] Schweitzer PK. Drugs that disturb sleep and wakefulness. In: Principles and practice of sleep medicine, 4th ed, Kryger M, Roth T, Dement WC (Eds), Saunders, New York 2005. p.499.
[5] Roehrs T, et al. Substance use for insomnia in Metropolitan Detroit. J Psychosom Res. 2002 Jul;53(1):571-6.
[6] Abraham O, et al. Over-the-counter medications containing diphenhydramine and doxylamine used by older adults to improve sleep. Int J Clin Pharm. 2017 Aug;39(4):808-817.
[7] Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and abuse. Sleep Med Rev. 2001 Aug;5(4):287-297.
[8] Cajochen C, et al. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol. 2003 Apr;15(4):432-7.
[9] Skene DJ, Arendt J. Human circadian rhythms: physiological and therapeutic relevance of light and melatonin. Ann Clin Biochem. 2006 Sep;43(Pt 5):344-53.
[10] Sack RL, et al. Human melatonin production decreases with age. J Pineal Res. 1986;3(4):379-88.
[11] Zhou JN, et al. Alterations in the circadian rhythm of salivary melatonin begin during middle-age. J Pineal Res. 2003;34(1):11-6.
[12] Aubin S, et al. Melatonin and cortisol profiles in the absence of light perception. Behav Brain Res. 2017 Jan 15;317:515-521.
[13] Melke J, et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry. 2008 Jan;13(1):90-8.
[14] Liu J, et al. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol. 2016;56:361-83.
[15] Ali T, et al. Acute dose of melatonin via Nrf2 dependently prevents acute ethanol-induced neurotoxicity in the developing rodent brain. J Neuroinflammation. 2018 Apr 21;15(1):119.
[16] Rodriguez C, et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res. 2004;36(1):1-9.
[17]Reiter RJ. Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol. 1998;56(3):359-84.
[18] Rossignol DA, Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol. 2011 Sep;53(9):783-92.
[19] Garfinkel D, et al. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995 Aug 26;346(8974):541-4.
[20] Andersen IM, et al. Melatonin for insomnia in children with autism spectrum disorders. J Child Neurol. 2008 May;23(5):482-5.
[21] Galli-Carminati G, et al. Melatonin in treatment of chronic sleep disorders in adults with autism: a retrospective study. Swiss Med Wkly. 2009 May 16;139(19-20):293-6.
[22] Garfinkel D, et al. Improvement of sleep quality by controlled-release melatonin in benzodiazepine-treated elderly insomniacs. Arch Gerontol Geriatr. 1997 Mar-Apr;24(2):223-31.
[23] Jan JE, O’Donnell ME. Use of melatonin in the treatment of paediatric sleep disorders. J Pineal Res. 1996 Nov;21(4):193-9.
[24] Wasdell MB, et al. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res. 2008 Jan;44(1):57-64.
[25] Galli-Carminati G, et al. Melatonin in treatment of chronic sleep disorders in adults with autism: a retrospective study. Swiss Med Wkly. 2009 May 16;139(19-20):293-6.
[26] Abdelgadir IS, et al. Melatonin for the management of sleep problems in children with neurodevelopmental disorders: a systematic review and meta-analysis. Arch Dis Child. 2018 May 2.
[27] van Geijlswijk IM, et al. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep. 2010 Dec;33(12):1605-14.
[28] Xu J, et al. Melatonin for sleep disorders and cognition in dementia: a meta-analysis of randomized controlled trials. Am J Alzheimers Dis Other Demen. 2015 Aug;30(5):439-47.
[29] Zhang W, et al. Exogenous melatonin for sleep disorders in neurodegenerative diseases: a meta-analysis of randomized clinical trials. Neurol Sci. 2016 Jan;37(1):57-65.
[30] Ferracioli-Oda E, et al. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013 May 17;8(5):e63773.
[31] Lucke-Wold BP, et al. Sleep disruption and the sequelae associated with traumatic brain injury. Neurosci Biobehav Rev. 2015 Aug;55:68-77.
[32] Grima NA, et al. Circadian Melatonin Rhythm Following Traumatic Brain Injury. Neurorehabil Neural Repair. 2016 Nov;30(10):972-977.
[33] Grima NA, et al. Efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial. BMC Med. 2018 Jan 19;16(1):8.
[34] Seifman MA, et al. Measurement of serum melatonin in intensive care unit patients: changes in traumatic brain injury, trauma, and medical conditions. Front Neurol. 2014 Nov 17;5:237.
[35] Gringras P, et al. Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2017 Nov;56(11):948-957.e4.
[36] Lemoine P, Zisapel N. Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia. Expert Opin Pharmacother. 2012 Apr;13(6):895-905.
The information provided is for educational purposes only. Consult your physician or healthcare provider if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.
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Dr. Carrie Decker
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