Age Related Insomnia
Nutraceutical and botanical management strategies
Insomnia represents one of the most frequent types of complaints seen in the elderly (Buysse 2008). One large epidemiological survey involving over 9000 adults aged 60 years and older found that 23 to 34% had symptoms of insomnia while a further 7 to 15% stated they did not awake feeling refreshed (Foley 1995). Most elderly report sleeping on average seven hours a night suggesting that although the total amount of sleep time does not change as we age, alterations in sleep architecture are common (Neikrug 2010). is includes a decrease in both deep sleep (stages 3 and 4 slow wave sleep) and rapid eye movement (REM sleep) as well as an increase in stage 1 (light) sleep (Fetveit 2009). Older individuals also have a reduction in endogenous melatonin production (likely due to a deterioration in the neuronal functioning of the suprachiasmatic nucleus-SCN) that in turn disrupts the normal wake sleep cycle (Pandi- Perumal 2005).
Other secondary factors leading to alterations in sleep also deserve consideration. is list includes but is not limited to medication use (i.e. beta blockers, corticosteroids, SSRI’s), painful conditions including arthritis and cancer, delirium, depression, dementia, Type 2 diabetes, obstructive sleep apnea, COPD, and restless leg syndrome (Cole 2007, McCrae 2009, Saddichha 2010). While benzodiazepines have been a prescriptive mainstay for use in older patients with insomnia, they are often fraught with potential side eff ects including drug dependence, cognitive impairment, daytime sedation, and an increased risk of falls due to a decrease in motor coordination (Wolkove 2007).
While newer generation hypnotic medications such as zopiclone may exhibit fewer side effects, it nonetheless can have a negative effect on body balance (Mets 2010), and according to the results of a recent study, chronic use of zopiclone over a 1 year time period may also increase sleep wake time, and reduce the duration of slow wave sleep (Sivertsen 2009). Integrative therapies, including melatonin, 5-HTP, L-theanine, GABA, magnesium, and several types of herbal medicines may represent a viable alternative for those with age related insomnia.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone that is synthesized in reply to neuronal signals arriving from the SCN of the anterior hypothalamus (Rios 2010, Wade 2008). This compound is secreted primarily by the pineal gland in response to darkness, described as the “opening of the sleep gate” (Srinivasan 2009). Research to date in older adults has supported the use of two types of melatonin: prolonged and rapid release.
Rapid release Melatonin and Age-related Insomnia
In a controlled clinical trial, 30 men and women over 50 years of age with both chronic insomnia and normal sleep patterns were randomized to receive capsules with either 0.1 mg, 0.3 mg, or 3 mg melatonin, or placebo 30 minutes before bedtime for 7 days. Treatments were separated by a 1 week washout period. Using polysomnography (PSG) on the last three nights of each treatment period, the researchers concluded that while melatonin did not improve sleep efficiency (i.e. the ratio of time spent in bed to the time spend asleep) in normal subjects, those with chronic insomnia had significant improvements in sleep efficiency at all three melatonin doses used, with the 0.3 mg dose triggering the strongest effect (p < 0.0001). The physiological dose acted primarily during the middle portion of the nights sleep and raised plasma melatonin levels to normal ranges (Zhdanova 2001).
Prolonged release (PR) melatonin: Quality of Sleep and Next Day Alertness in the Elderly
After a two week single blind run-in period, 354 elderly men and women (55 to 80 years of age) with primary insomnia were randomized to receive 2 mg of a prolonged release (PR) melatonin two hours before bedtime or placebo for three weeks. At the conclusion of the trial, those who took the melatonin had an improved percentage (26%) in the quality of sleep and morning alertness as recorded by the Leeds Sleep Evaluation Questionnaire (LSEQ) in contrast to placebo (15%) (p = 0.014). Sleep latency, as noted by the Pittsburg Sleep Quality Index (PSQI) results, improved in subjects employing the PR melatonin by 24.3 minutes compared to 12.9 minutes for the placebo group (p = 0.028). Quality of life as recorded by the WHO-5 Well Being Index was also improved in the active group (p = 0.034) (Wade 2007).
Magnesium, Melatonin, and Zinc on Insomnia in the Elderly
Magnesium along with zinc is crucial for the endogenous synthesis of melatonin according to the results of one study. Elderly men and women (n = 43; average age 78.3 years) living in a long term care facility were invited to participate in a double-blind, placebo controlled study of 60 days duration on melatonin, zinc and magnesium on primary insomnia. Each volunteer was randomized to receive a 100 g pear pulp food supplement with 5 mg melatonin, 225 mg of magnesium and 11.25 mg of zinc, or placebo 1 hour before bedtime for 2 months. At the conclusion of the trial, those employing the active supplement experienced an improvement in their overall PSQI scores compared to placebo (p < 0.001). Moreover, the LSEQ results confirmed that those employing the food-supplement mixture had better quality of sleep and greater ease getting to sleep (p < 0.001). Adverse effects were minimal with only two participants in the treatment group complaining of headache while one volunteer in the placebo group reported epigastric pain (Rondanelli 2011).
PR Melatonin, Zolpidem, and Side Effects in the Elderly
Drug-natural product interactions are always a concern to clinicians. In one study, the use of zolpidem and zolpidem with PR-melatonin significantly impaired memory and psychomotor performance 1 to 4 hours after administration in elderly volunteers (average age 59.4 years). In a simulated driving task, the number of collisions significantly increased at the 1 to 4 hour mark by 1.4 in the zolpidem (p < 0.05) group and worsened to 2.8 in the zolpidem-PR melatonin (p < 0.001) group compared to placebo respectively (Otmani 2008). Melatonin should be administered with caution among individuals already utilizing prescription medications for insomnia, regardless of whether the medication is of the benzodiazepine class or not. The results of the study also demonstrated that compared to placebo, PR melatonin on its own did not impair any of the variables tested.
5-hydroxy-L-tryptophan (5-HTP) is an intermediate compound in the synthesis of serotonin from the amino acid L-tryptophan. While research has shown that it is of benefit in treating depression (Byerley 1987), there have been limited studies supporting its efficacy in primary insomnia. Intravenous 5-HTP, when administered in a progressive fashion from 50 to 150 mg to one subject during the night, increased the time spent in REM sleep from 22.4 to 30.6% (Mandell 1965). In another study, eight healthy volunteers (7 women, 1 man; 17 to 21 years of age) were given 200 mg of 5-HTP at 9:15 pm and 400 mg of 5-HTP or placebo at 11:15 pm over a five day period. Those individuals using the 5-HTP had a significant improvement in their REM sleep (118 minutes) versus placebo (98 minutes) (p < 0.005) (Wyatt 1971).
GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter in the CNS (Chebib 1999). Recent reports have also suggested a role for the use of GABA derived from a naturally fermented strain of lactic acid bacteria in the treatment of general anxiety (Abdou 2006). In another study, insomnia in women with either menopause, senile dementia/depression, or autonomic ataxia were treated with GABA for two months. Using a modest amount of GABA (26.4 mg) in a defatted rice germ food 15 menopausal women (average age 49.4 years) achieved an overall significant improvement in the Kupperman symptom scale (46.2%) compared to 7.7% in placebo (p < 0.05). Moreover, 62.5% of the menopausal patients experienced an improvement in their sleeplessness (p < 0.01) (Okada 2000).
L Theanine and Insomnia
L-theanine is a naturally occurring amino acid found in Green tea (Camellia sinensis). Per 200 ml serving of green tea, the amount of L-theanine present varies from 25 to 60 mg (Cartwright 1954). Research scientists have determined that in healthy volunteers, 50 mg of L-theanine increases alpha band EEG activity relative to placebo over the 105 minute test period (Nobre 2008). In addition to promoting a relaxed mental state, L-theanine is important for sleep. One controlled study examined 22 men (12 workers and 12 students; average age 27.5 to 28 years) who were asked to consume four 50 mg tablets of L-theanine or placebo one hour prior to bedtime for six consecutive evenings. Total sleep time, as measured by actigraph, was not different between the overall active and placebo groups. However, the student sub-group demonstrated a significant improvement in both sleep efficiency and a reduction in wake after sleep onset (WASO) (p < 0.05) on actigraphic evaluation (Juneja 2004). If L-theanine affects age-related insomnia is not yet known.
Magnesium and Sleep:
A Critical Nutrient Deficiency in magnesium, whether through malabsorption, inadequate dietary intake, or multiple drug use, is common in the elderly (Barbagallo 2010). As such, poor quality sleep may be associated with magnesium status in the elderly. In a double-blind placebo-controlled crossover trial, 12 healthy volunteers (average age 68.1 years), were given an effervescent tablet containing 403 mg of magnesium oxide (10 mmol) in an increasing dose regimen from one tablet per day in the morning on the first day, one tablet in the morning and at noon on the second day, and one tablet three times a day (morning, noon, and evening) on the third day. The full dose or placebo tablets were taken for two weeks. At the conclusion of the trial, those taking the magnesium had a significant increase in the amount of slow wave sleep (16.5 minutes) compared to placebo (10.1 minutes) (p < 0.05). Delta (p < 0.05) and sigma (p < 0.01) frequency ranges, an indicator of non-REM sleep, were also improved with supplemental magnesium. Moreover, there was a significant reduction in cortisol levels by radioimmunoassay (8.3 ug/ml x min) in the first part of the night compared to placebo (11.8 ug/ml x min) (p < 0.01) (Held 2002).
Phytotherapy and Insomnia
Valerian root (Valeriana officinalis) has a long history of successful use in humans as both a single agent and in combination with hops (Humulus lupulus) for the treatment of primary insomnia (Salter 2010). Several studies have considered its use in elderly populations greater than 60 years of age. One study involving 14 elderly women (average age 61.6 years) with poor sleep were given three tablets of 405 mg of aqueous valerian root extract (5-6:1) or placebo on the first night one hour before PSG analysis and then 1 tablet three times per day at mealtimes for seven consecutive days. PSG results concluded that those who took the valerian root had an increase in slow wave sleep from 7.7% to 12.5% (p = 0.0273) and a decrease in stage 1 sleep from 16.4% to 11.9% (p = 0.0273). As such, valerian is effective in improving non-REM sleep in older adults but there was no change in REM sleep, sleep onset time, or WASO. (Schulz 1994). However, two controlled clinical trials concluded that valerian was ineffective for acute sleep problems. One paper in five men and 11 women (55.9 years) concluded that 300 or 600 mg of valerian extract (3-6:1) given at 22:00 hours one night in six for a period of three weeks, was ineffective in improving sleep as measured by EEG and other psychometric measures (i.e. LSEQ) (Diaper 2004). In another controlled study, 16 elderly women (69.4 years) were given 300 mg of standardized valerian root extract (0.8% valerenic acid per 100 mg tablet) 30 minutes before bedtime for two weeks. Although compared to baseline, valerian did improve WASO (+ 17.7 minutes; p = 0.02) overall no change was noted in WASO, sleep efficiency, sleep latency, or self rated sleep quality compared to placebo. (Taibi 2009).
Valerian and Hops:
Better Combination for Seniors? In a pilot study, 30 patients (average age 57.6 years) with mild to moderate sleep disorders were given two tablets of valerian (250 mg per tablet) and two tablets of hops extract (60 mg per tablet) two hours before bedtime for two weeks. Using PSG as a tool to measure outcomes, researchers concluded that taking the herbal combination resulted in a significant reduction in sleep latency (36.1 to 24 minutes), total waking time (30.7 to 13.8 min) as well an increase in sleep efficiency (80.4 to 86.9%) (p < 0.05) (Fussel 2000).
According to Government of Canada statistics, approximately 4.8 million Canadians were 65 years of age or older in 2010. This figure is expected to reach 10.4 million by the year 2036 (Human Resources and Skills Canada 2011). With the latter increase in seniors as a population group, medical issues such as insomnia will inevitably increase. For clinicians working with elderly patients, several types of natural therapeutic options are available which can have a positive impact on the sleep architecture of seniors.
Abdou AM, Higashiguchi S, Horie K, Kim M, Hatta H, Yokogoshi H. Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans. Biofactors. 2006;26(3):201-8.
Barbagallo M, Dominguez LJ. Magnesium and aging. Curr Pharm Design 2010;16:832-839.
Buysse DJ. Chronic insomnia. Am J Psychiatry. 2008 Jun;165(6):678-86.
Byerley WF, Judd LL, Reimherr FW, Grosser BI. 5 Hydroxytryptophan: a review of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol. 1987 Jun;7(3):127-37.
Cartwright RA, Roberts EAH, Wood DJ. Theanine an amino acid of N-ethyl amide present in tea. J Sci Food Agric 1954;5:597-599.
Chebib M, Johnston GA. The ‘ABC’ of GABA receptors: a brief review. Clin Exp Pharmacol Physiol. 1999 Nov;26(11):937-40.
Cole C, Richards K. Sleep disruption in older adults. Am J Nursing 2007;107: 40-49.
Diaper A, Hindmarch I. A double-blind, placebo controlled investigation of the effects of two doses of valerian preparation on the sleep, cognitive, and psychomotor function of sleep-disturbed older adults. Phytother Res 2004; 18:831-836.
Fetveit A. Late-life insomnia: a review. Geriatr Gerontol Int 2009;9:220-234.
Foley DJ, Monjan AA, Brown SL, Simonsick EM, Wallace RB, Blazer DG. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995;18:425-32.
Fussel A. Wolf A, Brattstrom A. Effect of a fixed valerian-hop extract combination (Ze 91019) on sleep polygraphy in patients with non-organic insomnia: a pilot study. Eur J Med Res 2000; 5:385-90.
Held K, Antonijevic IA, K√ºnzel H, Uhr M, Wetter TC, Golly IC, Steiger A, Murck H. Oral Mg(2+) supplementation reverses age-related neuroendocrine and sleep EEG changes in humans. Pharmacopsychiatry. 2002 Jul;35(4):135-43.
Human Resources and Skills Canada (http://www4.hrsdc.gc.ca/.3ndic.1t.4r@- eng.jsp?iid=33) accessed on April 30th, 2011.
Juneja LR, Ozeki M, Shirakawa S. The effect of using L-theanine on sleep using actigraph. Japanese Journal of Physiological Anthropology 2004; 9:13-20.
Mandell MP, Mandell AJ, Jacobson A. Biochemical and neurophysiological studies of paradoxical sleep. Recent Adv Biol Psychiatr 1965;7:115-122.
McCrae CS. Late-life comorbid insomnia: diagnosis and treatment. Am J Mang Care 2009;15:S14-S23.
Mets MA, Volkerts ER, Olivier B, Verster JC. Effect of hypnotic drugs on body balance and standing steadiness. Sleep Med Rev. 2010;14:259-67.
Neikrug AB. Ancoli-Israel S. Sleep disorders in the older adult-a mini-review. Gerontology 2010;56:181-189.
Okada T, Sugishita T, Murakami T. Effect of defatted rice germ enriched with GABA for sleeplessness, depression, autonomic disorder by oral administration. Nippon Shokuhin Kagaku Kaishi.2000;47: 596-603.
Nobre AC, Rao A, Owne GN. L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr 2008; 17(S1):167-68.
Otmani S, Demazieres A, Staner C, Jacob N, Nir T, Zisapel N, Staner L. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol. 2008 Dec;23(8):693-705.
Pandi-Perumal SR, Zisapel N, Srinivasan V, Cardinali DP. Melatonin and sleep in aging population. Exp Gerontol 2005;40:911-25.
Rios ER, Venancio ET, Rocha NF, Woods DJ, Vasconcelos S, Macedo D, Sousa FC, Fonteles MM. Melatonin: pharmacological aspects and clinical trends. Int J Neurosci. 2010 Sep;120(9):583-90.
Rondanelli M, Opizzi A, Monteferrario F, Antoniello N, Manni R, Klersy C. The effect of melatonin, magnesium, and zinc on primary insomnia in long-term care facility residents in Italy: a double-blind, placebo-controlled clinical trial. J Am Geriatr Soc. 2011 Jan;59(1):82-90.
Saddichha S. Diagnosis and treatment of chronic insomnia. Ann Indian Acad Neurol 2010;13:94-102.
Salter S, Brownie S. Treating primary insomnia: the efficacy of valerian and hops. Austral Fam Phys 2010;39:433-437.
Schulz H, Stolz C, Muller J. The effect of valerian extract on sleep polygraphy in poor sleepers: a pilot study. Pharmacopsychiatr 1994;27:147-151.
Srinivasan V, Pandi-Perumal SR, Trahkt I, Spence DW, Poeggeler B, Hardeland R, Cardinali DP. Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci. 2009;119(6):821-46.
Taibi DM, Vitiello MV, Barsness S, Elmer GW, Anderson GD, Landis CA. A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia. Sleep Med. 2009 Mar;10(3):319-28.
Wade A, Downie S. Prolonged-release melatonin for the treatment of insomnia in patients over 55 years. Expert Opin Investig Drugs 2008;17:1567-1572.
Wade AG, Ford I, Crawford G, McMahon AD, Nir T, Laudon M, Zisapel N. Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin. 2007 Oct;23(10):2597-605.
Wolkove N, Elkholy O, Baltzan M, Palayew M. Sleep and aging: 2. Management of sleep disorders in older people. CMAJ. 2007 May 8;176(10):1449-54.
Wyatt RJ, Zarcone V, Engelman K, Dement WC, Snyder F, Sjoerdsma A. Effects of 5-hydroxytryptophan on the sleep of normal human subjects. Electroencephalogr Clin Neurophysiol. 1971 Jun;30(6):505-9.
Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonintreatment for age-related insomnia. J Clin Endocrinol Metab. 2001 Oct;86(10):4727-30.