Curr Sleep Medicine Rep DOI 10.1007/s40675-017-0091-2

INSOMNIA AND PHARMACOTHERAPY (H ATTARIAN AND M KAY-STACEY, SECTION EDITORS)

Dietary Supplements for Insomnia Melinda Ring 1 & Anthony Marchlewski 2 & Joshua Kaplan 2

# Springer International Publishing AG 2017

Abstract Purpose of Review This article provides an overview of the evidence of commonly used dietary supplements for insomnia. Recent Findings Many bioactive phytochemicals and other components have been identified in dietary supplements that could provide therapeutic effects in patients with insomnia. There is a paucity of high-quality clinical research on most supplements, though some have promising findings. Summary While additional research is warranted to establish safety and efficacy, in the interim, health professionals are encouraged to explore existing resources and partner with patients to understand their goals and advise on safe and effective use of dietary supplements. Keywords Dietary supplements . Botanicals . Herbal medicine . Integrative medicine . Insomnia . Sleep disorders

Introduction Insomnia is not just the most common sleep disorder; affecting one in four people, it is also one of the most common This article is part of the Topical Collection on Insomnia and Pharmacotherapy * Melinda Ring [email protected]

1

Osher Center for Integrative Medicine, Northwestern University Feinberg School of Medicine, 150 East Huron Avenue, Suite 1100, Chicago, IL 60611, USA

2

Osher Center for Integrative Medicine at Northwestern University, 150 East Huron Avenue, Suite 1100, Chicago, IL 60611, USA

reasons people turn to an integrative medicine approach. An analysis of the National Health Interview Survey reported that 1.6 million adults use some type of complementary and alternative medicine to treat insomnia [1]. Pharmaceutical options have been linked with adverse outcomes, such as the association of zolpidem, eszopiclone, and temazepam with a threefold increased risk of death [2] and disruptive side effects such as a Bhangover^ effect the next day from some sedatives. Given these risks, many patients explore dietary supplements to help with both acute and chronic insomnia. A study that explored patterns of natural products used for sleep in a Canadian community-based sample suggested that with 18.5% reported use over the past year, natural products were used more frequently than prescription or over-the-counter pharmaceuticals in this population [3]. According to the congressional Dietary Supplement Health and Education Act of 1994, a dietary supplement is a product (other than tobacco) that is intended to supplement the diet and contains one or more dietary ingredients (including vitamins; minerals, herbs, or other botanicals; amino acids) or their constituents [4••]. While there is an abundance of preclinical studies validating biopsychological effects of natural compounds intended for sleep restoration, clinical data is not as robust [5]. Rigorous research and definitive conclusions have been limited by a paucity of federal grants, lack of financial benefit to dietary supplement companies to invest in research due to an inability to patent known substances, varying doses and standardizations used in research protocols, and the inherent complexity of botanicals which often have multiple active and complementary constituents. Here, we focus on a core set of commonly recognized nutraceuticals with hypothesized impact on insomnia. Commonly used doses are provided; however, reference to dietary supplement resources as provided at the end of the chapter is encouraged in practice to ensure safe use based on

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the most current research and to minimize the risk of supplement-drug interactions or adverse effects.

Herbals/Botanicals Valerian Root: Valeriana officinalis The perennial herb valerian was recommended by the Greek physician Galen for insomnia and its reputation as a potent hypnotic/sedative continues to this day. Valerian ranks in the top 20 dietary supplements used in the USA, with 5.9% of respondents in the National Health Interview Survey reporting use within the past year [6]. Valerian and its constituent valerenic acid have demonstrated adenosine (A1 receptor) interactions, GABAA receptor (β3 subunit) agonism, and 5HT5a partial agonism [7, 8]. Clinical studies comparing valerian to placebo or active control have provided conflicting conclusions regarding efficacy. Several systematic reviews and meta-analyses have been completed, most recently in 2015 [9, 10, 11••]. In the Bent et al. review, six studies revealed significantly improved sleep quality over placebo using a dichotomous outcome (i.e., yes/no if subjectively improved; RR of improved sleep = 1.8, 95% CI 1.2, 2.9). However, the other nine studies showed no benefits. Two subsequent reviews suggest that despite some positive individual studies, there is minimal, if any, impact on measures of sleep quality, duration, latency, or efficiency. In terms of safety, valerian is generally well-tolerated and, in contrast to many pharmaceutical sedative-hypnotics, does not impair psychomotor or cognitive performance [12]. Given the plausible mechanism of action, and recognizing the limitations of prior studies in terms of questions about whether sufficient doses or duration were employed, further study of this botanical is warranted. For patient care, it is reasonable for patients to consider a trial of a high-quality supplement of valerian alone or in combination with other botanicals. If no significant improvement is noted after 6 weeks, the preparation should be stopped and other options explored. Dosage For adults, 300–900 mg standardized extract of 0.8% valerenic acid or as a tea (1.5–3 g of root steeped for 5– 10 min in 150 mL of boiling water) taken 30–120 min before bedtime. Hops: Humulus lupulus Humulus lupulus, commonly referred to as hops, is a component of beer with sedating properties. The bitter resins in the hops plant, specifically 2-methyl-3-buten-2-ol, xanthohumol, and myrcenol, increase activity of γ-aminobutyric acid

(GABA) and modulate its receptor, inducing a state of central nervous system inhibition [13]. Hop is also a partial agonist to the central adenosine receptor [14, 15]. An extract of 2methyl-3-buten-2-ol causes temporary narcosis at 0.80 g/kg in mice [17]. In humans, 17 work-stressed female nurses who ingested 333 mL of non-alcoholic beer containing hops experienced significant decrease in sleep latency and nocturnal mobility when compared to the non-beer control [13]. A study by the same investigator asked 30 university students with stress to ingest a non-alcoholic beer while having dinner [16]. The results revealed that subjective sleep quality improved, sleep latency decreased, and overall global score of sleep quality improved significantly in those students who drank one nonalcoholic beer compared to control sleep latency. In contrast to these naturally occurring liquid formulations, a 2010 trial of 101 adults (25–65 years old) with chronic primary insomnia reported no improvement of quality or duration of sleep, or elevation of urine melatonin levels, between groups given two 50-mg hop extract pills every night for a month vs. olive oil placebo [18]. The evidence of sleep promoting properties of a valerian root-hops combination is more compelling (see BValerian Root^ section); as taken together, they may act synergistically on sedative function [19]. In a multicenter trial of patients suffering from insomnia, taking two capsules, each containing 187 mg of valerian extract/41.9 mg of hops, nightly for 28 days reduced total Insomnia Severity Index (a seven-item questionnaire designed to assess the nature, severity, and impact of insomnia and monitor treatment response in adults) from placebo at a level comparable to diphenhydramine [20]. In another double-blind, randomized, controlled trial (DBRCT) in patients suffering from non-organic sleep disorders, the combination of 500 mg of valerian/120 mg of hops dried extract nightly for 4 weeks reduced sleep latency compared with both valerian 500 mg alone and placebo [21]. A third DBRCT found that a single dose of a valerian-hop combination was associated with improvement in total sleep time, sleep quality, and deep sleep, according to both objective and subjective measurements [22]. The combined results of these studies suggest the efficacy of hops may be related to both the preparation as well as the etiology (stress vs. primary) of the sleep disorder. Hops and hops oil have the generally recognized as safe (GRAS) status by the FDA, but moderate consumption of hops and hopscontaining products is still recommended. While hop shows promise as a sleep aid, over-administration may cause unwanted effects. In mice, 800 mg/kg of hop extract in association with ketamine resulted in a deep narcosis when compared to ketamine alone, and administration of hop extracts to mice at 5, 10, and 20 mg/kg showed a dose-dependent increase in phenobarbital-induced sleeping time [23, 24]. Both experiments suggest high doses of hops can cause potential oversedation.

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Dosage Based on the few positive studies, the use of a non-alcoholic beer with dinner or a 120–400 mg of hop extract combined with 374–500 mg of valerian root extract may potentially help sleep quality. Traditional doses have included 0.5–1 mL of liquid extract (1:1 in 45% alcohol) taken three times daily. Caution should be used when ingesting hops along with other CNS depressants. Kava Kava: Piper methysticum Kava kava (kava) is an extract prepared from the root of Piper methysticum, a pepper plant native to the Pacific Polynesian Islands [25]. Since the eighteenth century, it has been used in the South Pacific in both social and medical settings as an intoxicant akin to alcohol [26] and a treatment for insomnia and anxiety. The psychopharmacological activity of kava kava is a function of kavalactone molecules, with yangonin, desmethoxyyangonin, methysticin, 7,8-dihyrokawain, and kawain inducing most effects [25]. Recent research suggests the γ-aminobutyric acid (GABAA) receptor as the target for kavalactones. During human trials, GABAA transport polymorphisms appeared to modify anxiolytic response to kava, leading to a significant reduction of anxiety in the kava kava group [27]. Given this mechanism of action, it has been postulated that kava may be beneficial for insomnia. Studies on mice have implicated anti-insomnia effects for kava, where a dose of 300 mg/kg of kava kava extract led to a significant decrease in sleep latency [25]. Furthermore, this same dose increased delta wave activity, believed to reflect increased sleep quality during non-REM sleep [25]. However, one study looking at insomnia treatment with kava and valerian root in humans found no significant change from baseline with self-administered kava over 2 weeks when compared to placebo, suggesting that the benefits may have been a result of patient expectation [28]. While there are limited and conflicting results on kava’s efficacy as a sleep aid, caution should be exercised before trying this herb due to several cases of kava kava-induced fulminant hepatic failure after as little as 1 to 3 months of use [29]. The underlying mechanism of toxicity is uncharacterized, but theorized as cytochrome P450 inhibition or reduction in liver glutathione rather than kava’s constituents directly. However, when used orally in short term, kava has been used safely in clinical trials under medical supervision for up to 6 months [30]. Rate of incidence of hepatotoxicity for kava is 0.3 cases per million daily doses, meaning that while it is safer than some GABAergics (e.g., diazepam: 2.12 cases per million daily doses), hepatotoxicity is still a risk factor [31]. For this reason, use of kava should be monitored by a physician, with any signs of hepatic impairment resulting in immediate cessation. Kava should be avoided in

patients with known liver disease, those with excessive alcohol use, or those using drugs that are metabolized by cytochrome P450 CYP2E1 due to the risk of an herb-drug interaction. Dosage For insomnia, kava may be taken as 200 mg of an extract standardized to 70% kavalactones nightly for 4 weeks. The specific kava extract used in human studies is WS 1490 (Dr. Willmar Schwabe Pharmaceuticals) [32]. Caution should be exercised regarding potential interactions with CNS depressants and liver toxicity. German Chamomile: Matricaria recutita Matricaria recutita, or German chamomile, is derived from several plants in the Asteraceae family. It has traditionally been used as an infusion (a water extract of herbs), though it can also be used in a number of other forms, such as tablets and powders. Chamomile contains several compounds with sedative effects, most notably the flavonoid apigenin, which acts as an antagonist at α1β1γ2S GABAA receptors and at ρ1 GABAC receptors [33]. It is estimated that a million cups of chamomile tea are consumed daily. However, despite being the primary component of many popular sleep-aiding tea blends, chamomile lacks the scientific support of some other popular soporifics [34]. Much of the evidence for the restorative properties of chamomile comes from historical usage or case studies, with relatively few clinical studies regarding the effectiveness of German chamomile for the treatment of insomnia. The highest quality clinical study to date showed no significant difference in improvement of sleep quality when using chamomile 270 mg vs. placebo twice daily for 28 days in any of the following markers: sleep onset latency, wake after sleep onset time, sleep duration, nocturnal awakenings, daytime functioning, sleep quality, and sleep efficiency [35]. This randomized, double-blind, placebo-controlled study was conducted in 34 patients ages 18 to 65 with DSM-IV primary insomnia. Another recent clinical study examined the benefit of chamomile tea for 2 weeks vs. a control group who received usual care in a randomized trial of 80 Taiwanese postnatal women with poor sleep quality [36]. Compared with the control group, the experimental group demonstrated significantly lower physical symptom-related sleep inefficiency measurements and Edinburgh Postnatal Depression Scale scores. At 4 weeks, the scores were similar for both groups, suggesting that the positive effects were limited to the immediate term. In contrast to the paucity of studies on chamomile for insomnia, many studies support chamomile as an effective anxiolytic [37]. Thus, though a recommendation for chamomile is not yet provably beneficial for patients with primary insomnia, it

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might be a reasonable treatment option for patients with anxiety as a significant part of their sleep disorder.

twice daily, as the quantity of whole cherries needed to obtain adequate levels of active constituents would be considerable.

Dose

Other Botanicals

Chamomile may be taken as a tea (infusion), tablets, tinctures, and inhalations or essential oils. German chamomile supplements are typically in doses of 90–400 mg (standardized to apigenin). A cup of chamomile tea can be prepared by steeping two teaspoons of dried flower per 8 oz of hot water.

There are also numerous other traditional herbal sleep aids, including Passiflora incarnata (passionflower), Eschscholzia californica (California poppy), Scutellaria lateriflora (skullcap), Melissa officinalis (lemon balm), Hypericum perforatum (St. John’s wort), Lavandula (lavender), and Magnolia officinalis (magnolia bark). While the majority of these forms of intervention have not been adequately investigated in the scientific literature, many can be found in sleep-aid supplements.

Cherry: Prunus cerasus Initially investigated because of anecdotal evidence claiming their influence on sleep, cherries have been proven through multiple studies to reduce symptoms of insomnia. Cherries, especially tart cherries (Prunus cerasus), contain high levels of anti-inflammatory substances and melatonin, both related to sleep modulation [38]. Additionally, tart cherries contain tryptophan (see BTryptophan^ section), a compound with sleep-enhancing properties [39]. A pilot study on the effect of tart cherries on older adults (age ≥ 65 years) with insomnia used a randomized, double-blind, crossover design in which each participant (n = 15) received both treatment and placebo in an 8-oz serving twice daily for 2 weeks, with an intervening 2-week washout period [40]. This study found a statistically significant reduction in insomnia severity with cherry ingestion, as measured in minutes awake after sleep onset per 2week mean patient diary values [40]. In a separate study on twenty healthy men and women (aged 18 to 40), melatonin levels in urine samples were found to be significantly elevated after the consumption of 30 mL of sour cherry juice concentrate containing 1.42 mcg/mL of melatonin, with associated significant increases in time in bed, total sleep time, and sleep efficiency [41]. An additional study conducted on 6 middleaged (35–55 years old) and 6 older (65–85 years old) people found that the consumption of cherry cultivars yielded improvements in actual sleep time, total nocturnal activity, assumed sleep, and immobility [38]. The most recent published research examined the impact of the tart cherry juice by age (ten subjects per age range, 20–30 years old; 35–55; and 65– 85) and found that positive improvements in nocturnal rest as measured by sleep efficiency, number of awakenings, total nocturnal activity, and sleep latency were noted, particularly in those in the older age group [42]. Given the small sample size, additional correlation with more participants would be advantageous. Dosage Tart cherry is available in supplement form; however, a dose has not yet been established. At present, it is reasonable to recommend tart cherry juice (no added sugars) 8 oz once or

Dietary Supplements: Amino Acids, Enzymes, Probiotics, Hormones, Vitamins, and Minerals Amino Acid: Tryptophan Common lore attributes the soporific effects of warm milk and Thanksgiving turkey to the essential amino acid tryptophan. It can also be found in varied foods such as eggs, oats, spirulina, and sesame and sunflower seeds. Indeed, tryptophan and its downstream metabolite in the brain, 5-hydroxytryptophan, are precursors to the neurotransmitter serotonin and hormone melatonin. There are at least 15 serotonin receptors, many of which influence sleep-wake behavior, and melatonin is a key modulator of circadian rhythm (see BMelatonin^ section) [43–45]. The availability of ingested tryptophan in the brain is impacted significantly by dietary factors, including the presence of other amino acids, macronutrient balance, and adequacy of cofactors for enzymatic conversion such as vitamin B6 and omega-3 fatty acids [46••]. Therefore, tryptophan as a nutraceutical has been a target for sleep restoration, with the aim of achieving high levels of this key building block. A 2010 rigorous systematic review identified three randomized controlled trials of tryptophan that met inclusion criteria, with an average quality rating of 6.7 out of 10; one study was excluded due to small sample size [5]. Two of these were positive on several outcomes including sleep duration and quality [47–49]. In the study rated highest quality (8/10), tryptophan 250 mg in either diet or supplement form performed better than placebo over 3 weeks in sleep efficiency, quality, and awakening time as measured by sleep diary [49]. Research into tryptophan and its popularity as a sleep aid were curtailed by an epidemic of eosinophilia-myalgia syndrome (EMS) in 1989 associated with supplements containing imported tryptophan; over 1500 cases, including 38 deaths, were eventually reported to the U.S. Centers for Disease Control and Prevention [50]. The FDA issued a public

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advisory, recalled dietary supplements containing 100 mg or more of L-tryptophan in a daily dose, and blocked imports of foreign manufactured L-tryptophan. In 1994, domestically manufactured L-tryptophan became available in the USA, and the import alert was canceled in 2005. While the initial outbreak was initially attributed to a contaminant in a single manufacturer’s product, others theorize that in susceptible patients, large doses of isolated L-tryptophan result in metabolites which can inhibit the breakdown of histamines, causing EMS [51]. Three cases of EMS with a possible link to highdose tryptophan have been reported since its return to market; therefore, while the risk is low, patients taking tryptophan should be monitored for any early symptoms of EMS [52]. Prescribers should also be aware of the theoretical risk of serotonin syndrome if tryptophan is used in conjunction with certain antidepressants. Dose The most common dose is 1 g of L-tryptophan taken 20 minutes before bedtime. Smaller doses ¼–½ g may also provide some benefit [49]. Amino Acid: Theanine L-theanine, an amino acid commonly found in the tea plant Camellia sinensis, has become a popular option for anxiety and sleeplessness, showing up as an ingredient in Brelaxation beverages,^ such as Just Chill™ and NeuroSleep™. Although human research is limited, animal studies and anecdotal experience suggest that L-theanine may be useful in managing anxiety, hypertension, the stimulant effects of caffeine, and sleeplessness. Several studies have shown that intake of L-theanine significantly increases α-wave activity in different areas of the cerebral cortex, leading to a relaxed state without drowsiness [53]. L-theanine also increases dopamine and serotonin production, neurotransmitters associated with relaxed, positive emotional states, and decreases stress-related norepinephrine and cortisol levels, salivary IgA, and heart rate in response to an acute stressor [54]. L-theanine has been shown in animal studies to partially reverse caffeine-induced reductions in slow wave sleep [55]. There are only a few clinical studies of L-theanine specifically for insomnia. A study of 98 boys (age 8–12 years) formally diagnosed with attention deficit hyperactivity disorder (ADHD) randomized subjects to placebo vs. a chewable proprietary supplement containing 200 mg of L-theanine twice a day for 6 weeks that improved both sleep time and quality [56]. Compared to baseline measurements, actigraph watch data after 6 weeks indicated that the L-theanine cohort obtained significantly higher sleep percentage and sleep efficiency scores along with a non-significant trend for less wake time

after sleep onset. L-theanine was well tolerated with no significant adverse events. In a Japanese study, 22 healthy adult men were randomized to 200 mg a day for six days or placebo [57]. Measurements by wrist actigraphy showed no significant difference in total sleeping time, but the treatment group reported feeling more relaxed before bedtime, having fewer nightmares, and feeling less tired and more refreshed during the day. Dosage Typical recommendations range from 50 to 400 mg of Ltheanine taken 30–60 min before bedtime. A typical cup of green tea may have less than 50 mg of L-theanine. If taking a typical dose of 200 mg in the evening for 2 weeks is insufficient, doses can be safely increased to three times a day without risk of daytime drowsiness. Theanine can have an antihypertensive effect, so it should be used with caution when combined with antihypertensive medications. Hormone: Melatonin Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland that endogenously modulates sleep. The suprachiasmatic nucleus adjusts melatonin levels in response to light cues, inhibiting production during the day and enhancing production at night [58]. Melatonin acts on melatonin 1 (M1) and melatonin 2 (M2) G protein-coupled receptors, which have been localized to the suprachiasmatic nucleus in humans [59]. M1 and M2 agonism is hypothesized to increase rapid eye movement (REM) sleep and non-REM sleep, respectively [58]. Melatonin also acts on some of the same GABA receptors as benzodiazepines, enhancing binding of GABA both in vivo and in vitro [60]. Because of these neurochemical GABA-mediated mechanisms [61] and its daydependent anxiolytic activity, melatonin has been considered as a safer alternative to sedative hypnotic benzodiazepines (BZD) and type Z drugs [62]. Exogenous melatonin supplements have shown sleeppromoting effects, decreasing sleep onset latency and increasing total sleep time. A recent systematic review of melatonin sleep studies covering 1510 patients ages 18 to 80 with primary insomnia, delayed sleep phase disorder (DSPS), blindness, and REM behavior disorder compared the effects of oral melatonin and placebo on different sleep parameters [63]. Doses of melatonin ranged from 0.1 to 10 mg with two- to five-week treatment. Analysis concluded that melatonin has significant effects in treating primary insomnia, DSPS, and non-24 h sleep-wake syndrome in blind individuals. Melatonin has also shown promise in treating children with chronic sleep onset insomnia, where administration of 3 mg melatonin to 84 children with the condition resulted in

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decreased sleep latency when compared to the placebo group or bright light therapy [64]. Unlike BZD-Z drugs, melatonin does not cause significant memory and cognition impairment, psychomotor retardation, or next-day hangover effects [65]. Most importantly, physical dependence to melatonin has not been observed [66]. Melatonin supplements are generally well tolerated, with occasional reports of dizziness, headache, and nausea. Although melatonin has a low risk profile, it is still a powerful hormonal regulator which warrants careful and conservative application. While no adverse effects were recorded in studies lasting over 6 months of daily use, negative effects could potentially manifest with prolonged use. For example, there is evidence that melatonin can suppress reproductive hormones over long time periods; for this reason, use in children and teenagers should be monitored and limited to shortterm, sporadic episodes [67]. It is also important to ensure use of high-quality supplements because, like tryptophan, melatonin preparations with contaminants have been implicated in a few cases of eosinophilia-myalgia syndrome [68]. Dosage Melatonin occurs naturally in some foods, but for supplementation, it is typically synthesized in a laboratory and can be delivered in both immediate and controlled release formulations. While controlled release more closely emulates natural melatonin cycles, there is some concern that extended durations of elevated melatonin levels may be physiologically unsafe [69]. In fact, even 3–5 mg of fast-release melatonin may result in levels above physiological range for the duration of the night [62]. Melatonin physiology differs between individuals, so a dosage plan should be optimized to the patient. In most research for primary insomnia, controlled, fast, and slow release 2–3 mg before bedtime has been used for 29 weeks [70]. However, fast-release melatonin at lower doses of 0.3–2 mg an hour before bed may minimize prolonged unnatural levels and conform to normal circadian rhythms [69]. The authors recommend starting at these lower doses, with patients increasing as needed to 6 mg. For children with chronic sleep onset insomnia, 3 mg has been successful in decreasing sleep latency, but not the total sleep time. As such, a starting dose of 1 mg has been recommended for children, as lowering the dose may decrease waking [71]. Higher doses of 15–20 mg are being studied for antioxidant and anticancer effects, but should not be used for the management of chronic sleep disorders. Minerals: Magnesium and Zinc Magnesium and zinc have been identified as key minerals affecting sleep. Dietary surveys of people in the USA

consistently show insufficient intake of magnesium and zinc: Magnesium consumption via diet is below the estimated average requirement in 61% of adults and 90% of teenage girls, and 12% and 24%, respectively, for zinc [72, 73]. The most recent Dietary Guidelines for Americans, released by the U.S. Departments of Health and Human Services and of Agriculture, identified magnesium as a key nutrient Bconsumed by many individuals in amounts below the Estimated Average Requirement^ [74]. Magnesium Magnesium blocks the N-methyl-d-aspartate (NMDA) receptor and is a GABA-receptor agonist, both of which may favor improved sleep architecture [75]. Magnesium also has been shown to alter EEG and neuroendocrine characteristics. A double-blinded, randomized, placebo-controlled (DBPCT) crossover study in healthy older adults (average age 68.1) showed that treatment for 20 days with escalating doses of magnesium resulted in significantly more slow-wave sleep on polysomnogram (PSG) compared to placebo, but no significant change in total sleep time. The magnesium group also had significantly lower cortisol and higher renin for the first part of the night and significantly higher renin and aldosterone for the second part of the night [76]. Another DBPCT using magnesium oxide twice a day (total dose 500 mg of elemental magnesium) for 8 weeks showed both objective and subjective improvements in sleep measures [77]. The supplemented group had statistically significant increases in sleep time (P = 0.002), sleep efficiency (P = 0.03), concentration of serum melatonin (P = 0.007), and a significant decrease of Insomnia Severity Index (ISI) score (P = 0.006), sleep onset latency (P = 0.02), and serum cortisol concentration (P = 0.008). Zinc Zinc also plays a role in sleep potentiation. It is found in the synaptic vesicles of cortical glutamatergic neurons and hippocampal mossy fibers in the brain. Animal studies show zincenriched diets increase the total non-rapid eye movement sleep and decrease locomotor activity [78]. A randomized controlled trial in 120 healthy individuals over 12 weeks showed that zinc enrichment led to improved sleep onset latency as well as improved sleep efficiency [79]. Magnesium + Zinc Using magnesium and zinc together also may benefit sleep for people across the age spectrum. In children with attention deficit hyperactivity disorder, magnesium and zinc plus essential fatty acids helped relieve difficulties with falling asleep [80]. A DBPCT done at a long-term care facility offered

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magnesium (225 mg), melatonin (5 mg), and zinc (11.25 mg) every day for 2 months to residents who had insomnia. The sleep aid improved not only the quality of sleep, but also the quality of life according to the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Leeds Sleep Evaluation Questionnaire (LSEQ), the Short Insomnia Questionnaire (SDQ), and the Short Form-36 (SF-36) [81].

Other Non-Botanical Dietary Supplements Preliminary animal and clinical studies suggest possible benefit from other dietary supplements including prebiotics [87], the amino acids L-ornithine [88] and glycine [89], and the polyphenol resveratrol [90]. Additional research is warranted to confirm the findings.

Dietary Supplements: Regulation and Resources Dosage: Magnesium Since 99% of magnesium is in the bone and soft tissue, clinical assessment of magnesium status can be a challenge. Intracellular magnesium measurements (e.g., RBC magnesium) may be superior to serum magnesium as an assay of total body stores [82]. The average adult recommended dietary allowance (RDA) is 420 and 320 mg/day, respectively, for men and women. However, approximately half of Americans do not obtain this through their diet [83]. In dietary supplements, elemental magnesium is linked with other substances such as amino acid chelates (arginine, lysine, and taurine), citrate, threonate, oxide, and sulfate. These compounds have varying bioavailability, laxative effects, and penetration of the blood-brain barrier. Magnesium chloride also comes as a topical oil preparation. Typical doses of magnesium supplements range from 200 to 1000 mg; taking higher doses with food and in divided doses may help mitigate some gastrointestinal effects.

Dosage: Zinc Like magnesium, zinc’s nutritional status is difficult to measure adequately using laboratory tests due to its distribution throughout the body. Plasma or serum zinc levels are most commonly used, but these levels do not necessarily reflect cellular zinc status. Importantly, clinical effects of zinc deficiency can be present in the absence of abnormal serum indices [84]. For adults, RDA quantities of zinc range from 9 to 13 mg/day. An analysis of NHANES III data found that 35– 45% of adults over age 60 had zinc intakes below the estimated average requirement [85]. Supplements contain forms such as zinc gluconate, zinc sulfate, and zinc acetate, which have variable percentages of elemental zinc. For example, approximately 23% of zinc sulfate consists of elemental zinc; thus, 220 mg of zinc sulfate contains 50 mg of elemental zinc. The elemental zinc content appears in the Supplement Facts panel on the supplement container. Typical doses of elemental zinc supplements range from 15 to 50 mg, though higher doses are sometimes used. High dose of zinc should not be used for extended durations due to the potential interference with iron and copper status and reduced immune function [86].

Dietary supplements are regulated by the FDA differently from foods and pharmaceuticals. It is important for patients and providers to understand that, unlike drug products, the FDA does not have the authority to review dietary supplements for safety or effectiveness before they reach the consumer. Instead, the onus is on the FDA to prove that a product is not safe to restrict its use or remove it from the market. Health professionals should counsel patients on the importance of ensuring the safe and effective use of dietary supplements by getting reliable information, having open discussions about current or anticipated use, and choosing highquality brands at the dose shown to be effective in studies. There are a number of qualified health professionals available to assist with dietary supplements. Integrative medicine physicians are increasingly available, with the growth of academic fellowship training and the American Board of Integrative Medicine certification through the American Board of Physician Specialties (ABPS) [91]. Naturopathic doctors, traditional Chinese medicine providers, and herbalists are also valuable resources for a team-based approach to care. There are both free and subscription online resources for researching dietary supplements at the point of care to understand indications for use, effectiveness, and potential sideeffect profiles. Examples recommended by the authors include the following: 1. Natural Medicines https://naturalmedicines. therapeuticresearch.com 2. American Botanical Council (ABC) http://abc. herbalgram.org 3. Cochrane Complementary Medicine http://cam.cochrane. org/ 4. European Scientific Cooperative on Phytotherapy (ESCOP) http://escop.com 5. National Center for Complementary and Integrative Health (NCCIH) https://nccih.nih.gov/ In addition, providers can direct patients to purchase brands that have passed quality control testing by independent agencies that provide information on whether supplements contain the stated ingredients and are free of contaminants. These organizations often have a seal on products that pass

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independent certification. The four primary organizations currently are as follows: 1. Consumer Lab: http://www.consumerlab.com 2. Natural Products Association: http://www.npainfo.org/ 3. NSF International: http://www.nsf.org/services/byindustry/dietary-supplements 4. United States Pharmacopeia: http://www.usp.org/ verification-services/usp-verifieddietary-supplements

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Conclusion Botanicals have been used as soporifics and hypnotics since ancient times and remain popular for sleep disturbances today, although the data to support their use is mixed. Dietary supplements are being increasingly investigated for their bioactive phytochemicals and other components that could provide therapeutic effects. Establishing definitively whether or not dietary supplements are beneficial and safe for patients struggling with insomnia will require additional research to generate scientific evidence. In the interim, health professionals are encouraged to explore existing resources and partner with patients to understand their goals and advise on safe and effective use of dietary supplements.

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15. Compliance with Ethical Standards Conflict of Interest Melinda Ring, Anthony Marchlewski, and Joshua Kaplan declare no conflict of interest.

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Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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References

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Papers of particular interest, published recently, have been highlighted as: •• Of major importance Pearson NJ. Insomnia, trouble sleeping, and complementary and alternative medicine. Arch Intern Med. 2006;166:1775. 2. Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open 2012;2: e000850. 3. Sánchez-Ortuño MM, Bélanger L, Ivers H, Leblanc M, Morin CM. The use of natural products for sleep: a common practice? Sleep Med. 2009;10:982–7. 4.•• Office of Dietary Supplements (ODS) [Internet]. NIH Office of Dietary Supplements. U.S. Department of Health and Human Services; [cited 2017Jul23]. Available from: https://ods.od.nih. gov/. An important resource for understanding the current state of regulation of dietary supplements.

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