stay updated with our newsletter

Melatonin: Coping with the Difficulties of Insomnia and Disrupted Sleep

Insomnia and Disrupted Sleep

Many a time in life when stress hormones are flying, our patients experience the unfortunate experience of insomnia and disrputed sleep. The experience of insomnia is not uncommon, with about one-third to two-Insomnia and Disrupted Sleepthirds of adults in cross-sectional surveys describing insomnia symptoms of any severity, with 10 to 15% of individuals describing chronic insomnia which bleeds into daytime difficulties as well.1,2 Sleep difficulties are more common in women, individuals who are single (widowed, divorced, or separated), and often coexist with psychiatric disorders such as depression, or more commonly, an anxiety disorder.3 Insomnia and disrupted sleep can also be due to a medication including those used to treat anxiety and depression, so this should not be neglected in assessing for the possible cause.4 Many individuals who experience insomnia never have a 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, and rise at night, and are low during the day, nearly opposite in profile to the diurnal cortisol pattern.8 Light is one factor which mediates melatonin secretion, and bright light 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 MT1 and MT2 which are activated by melatonin play not only a role in sleep, but also in mood disorders, learning and memory, drug abuse, and cancer.14

Melatonin also has importance in the body as a neuroprotective antioxidant, and not only has antioxidant action on its own, but also stimulates the body’s production of other antioxidants including superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.15,16,17

Clinical Studies and Meta-Analysis 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, serious medication-related adverse events have not been observed. Typical adverse events included morning drowsiness, headache, or night-time 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 4 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

Several meta-analysis have been performed looking at the effectivity of melatonin for various types of sleep disorders. In children with neurodevelopment disorders, melatonin was found to significantly improve total sleep time as well as sleep onset latency, although no difference was seen in nocturnal awakenings.26 In adults and children with delayed phase sleep disorders, melatonin was found to advance the sleep-wake rhythm as well as the endogenous melatonin onset.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 1683 individuals with primary sleep disorders, and found that melatonin improved several measurements of healthy sleep (sleep onset latency, total sleep time and overall sleep quality) 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.

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 randomized, double-blind, placebo-controlled cross-over study of patients with sleep disturbances subsequent to a mild to severe TBI, prolonged-release melatonin was found to significantly improve the primary outcome of PSQI scores as well as secondary outcomes of 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 endogenous 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 sub-optimal endogenous melatonin levels, but also for the antioxidant action it also 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.

Dr. Decker is a Naturopathic Doctor, graduating with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Dr. Decker sees patients at her office in Portland, OR, as well as remotely, with a focus on gastrointestinal disease, mood imbalances, eating disorders, autoimmune disease, and chronic fatigue. Prior to becoming a naturopathic physician, Dr. Decker was an engineer, and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectfully.  Dr. Decker continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr. Decker supports Allergy Research Group® as a member of their education and product development team.
These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.

 

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.

JOIN OUR MAILING LIST

Weekly round-up, access to thought leaders, and articles to help you improve health outcomes and the success of your practice.