Nutritional supplements and sleepRoss Finesmith MD

INTRODUCTION

It has been estimated that over 18% of the population use natural products as a sleep aid (Gyllenhaal, 2000). Modern research on herbal medicine is still in its infancy, but has increased in recent years. There has been with a 50% increase in the medical literature regarding nutritional supplements. Specifically, research on the effects of herbs and supplements on brain and behavior has markedly increased. There have been few attempts to organize and try to better understand the medical and health information available on the use of nutritional supplements to improve sleep patterns.

Traditional mainstream drug development typically uses isolated, single active agents that have been synthesized or separated from plants or biological organisms. The Complementary and Alternative Medicine approach uses the whole natural biological product or extracts derived directly from product. Herbs are essentially whole sections of specific plants.

Traditionally in science, the goal is to isolate a single active agent from a plant and test it as an independent “drug”. It is more commonly accepted now that plant and their extracts contain numerous potentially active components and the presence of several active compounds in one plant may have a synergistic effect.

Herbal supplement’s actions in the brain influence sleep primarily through the regulation of neuronal receptor function. Plant metabolites affect the neuron receptors and alter of their activity and function (Paredes, 2008). Herbal supplements are known to have a range of therapeutic actions that improve sleep as well through neurotransmitter and neurohormonal influences. The resultant central nervous system benefits include antidepressant, anti-anxiety, sedative, hypnotic and analgesic effects (Spinella, 2001). Depression, anxiety and pain syndromes are frequently associated with insomnia, or at least sleep problems. Therefore, the beneficial effect of a herb or supplement on mood, anxiety or chronic pain would result in a concomitant improvement of the associated sleep disturbance.

The first section of this chapter is devoted to understanding the basic biological nature of sleep, because it will provide a better understanding of

how nutrients can affect this process. The foods and nutrients we consume have an effect on our behavior and physical health. Our sleep behavior is consequently likely affected by our intake of food and supplements.

Dietary intake has been shown to have a direct effect on our body’s internal clock. This internal clock, more formally referred to as circadian rhythm, sets the human brain on a day-night schedule of wakefulness, temperature control, appetite and endocrine control. Eating, and therefore nutritional, patterns have been shown to affect this biological clock. Additional research studies have reported that specific nutrients and food components, such as glucose, ethanol, caffeine, thiamine and retinoic acid, affect the expression of genes that are responsible for the function of the circadian rhythm in the body (Zadeh, 2011). Therefore, when and what we consume likely effect our sleep pattern.

Sleep

The concept that sleep is a time of rest and brain inactivity has long been replaced with the evidence that the brain is very active during sleep. Research has shown that sleep is a dynamic behavior during which specific activity of the brain is orchestrated by elaborate and precise mechanisms (Stickgold, 2005).

Sleep evolves during life and changes with maturation and aging. During infancy, 16 to 18 hours a day sleeping is needed. A more prolonged sleep pattern occurs during the night by 6 months of age. The sleep time requirement in childhood continues to diminish through preadolescence, to about 8 hours per night. However, during the active growth and learning phase of adolescence, sleep requirements again increase. Insufficient amount of sleep at this age is due school schedules demand for early awakening. The need for sleep remains relatively constant in adulthood, sleep tends to become more fragmented as we age and night sleep may decrease with some compensating with daytime napping (Bliwise, 1993).

Sleep occupies approximately one-third of the adult life. Sleep deprivation effects mood, cognitive and motor performance and increases our risk of health problems. Irritability, anxiety, poor motivation and symptoms of depression are frequently seen in those with insufficient sleep. Cognitive problems include poor concentration, slower reaction times, distractibility,

forgetfulness and poor coordination. Several studies have shown there is an increased risk of hypertension, heart attack and obesity as well (Levy, 2012).

Sleep-dependent memory consolidation, memory encoding and consolidation occur every night during sleep. Although determining how sleep contributes to our memory has been complex, there is clear evidence that memory processing during sleep is an important component of how our memories are formed and ultimately shaped. Memory formation and storage reflect molecular and cellular activity that converts fragmented memory representations into more permanent ones and enables us to recall information over extended periods (Stickgold, 2005). These processes, which are dependent on sleep, allow us to continually collect information, integrate with information in our memory and continue to learn.

Sleep is considered a biological function affects other biological systems in the body. Several compensatory regulatory mechanisms occur in most mammals after sleep deprivation. These include changes in heart rate, sleep continuity, reduced arousal threshold and alertness, and reduced motor activity (Levy, 2012). .

The incidence of insomnia in the general population is approximately 13%.The most common causes of insomnia are late-day napping, caffeine and nicotine intake, exercising in the hours immediately before bed andlate-night meals. Also using the bedroom to work, read, eat, or watchtelevision in the evening before bedtime may interfere with the ability to fall asleep. However, thousands experience insomnia that are not related to any of these behavioral factors. When the lack of sleep begins to effect daytime function, treatments are sought.

Nutritional Supplements and Sleep

Herbal and natural products represent one of the most common forms of complementary and alternative medicine. Almost 30% of those taking nutritional supplements do so for insomnia or sleep problems (Matt, 2005). This high number of people taking nutritional supplements for sleep is likely due the problems and side effects associated with prescription medications. The available medications available from the doctor come along with troublesome side effects. The most common side effects are excessive daytime sleepiness, nausea and poor concentration and dizziness during the

day. The use of many prescription medications for the treatment of insomnia is accompanied with the concern of becoming physically addicted to them.

In a study looking at nutrient intake in people with insomnia as compared to normal sleepers found that blood levels of many nutrients were significantly lower in those with insomnia.. The authors concluded that lack of nutrition could be the explanation for the poor sleep status (Zadeh et al, 2011)

This section will outline and provide medical information regarding dietary supplements for the treatment of insufficient sleep and insomnia. Since many of the health effects are not fully understood with dietary and herbal supplements it is suggested that women who are pregnant or nursing should not take these supplements without medical advice. In addition, children younger than 6 years old should not take herbal supplements because the possible risks to children of this age have not been evaluated.

MelatoninThe pineal gland is an endocrine gland in the brain that synthesizes and secretes melatonin (N-acetyl-5-methoxytryptamine). The input to the pineal gland is transmitted from the retinal preceptors in the eye. The day/night cycle of melatonin secretion is controlled by a vision-processing center in the brain and is strongly influenced by light. The main effect of light is to regulate melatonin secretion in synchrony with the days light-dark cycles. Light is first detected by melanopsin-containing retinal cells and transmitted to the suprachiasmatic nucleus (SCN) of the hypothalamus via the retinohypo-thalamic tract. The superior cervical ganglion delivers the SCN input to the pineal gland (Brzezinski et al. 2005). Melatonin secretion increases abruptly in the evening as sunset begins. As bedtime approaches the melatonin release continues to increase and reaches a peak level between 2 and 4 am. The release of the melatonin gradually falls during the latter part of the night and is present at very low levels during the day (Espana, 2004).

Melatonin is a natural hypnotic and has been determined to be a safe and effective sleep aid for long-term use in the elderly (Wade, 2007). Melatonin has minimal signs of toxicity and a limited side effect profile. Melatonin replacement therapy has been found beneficial in treating many with sleep disturbances.

The melatonin precursor tryptophan is absorbed from the gastrointestinal, tract from food intake, into the blood stream and converted into serotonin. Serotonin is acetylated and undergoes enzymatic modification to form melatonin. The pineal gland has the highest concentration of melatonin in the body and secretes low levels of the hormone during the day and increases secretion as daylight diminishes (Arendt, 2005).

The effect of light on the SCN, and subsequently the pineal gland, regulates the sleep/wake cycle. Changes in the SCN firing rate is influenced by the melatonin receptors, MT1 and MT2. These receptors are metabotropic G-protein coupled receptors (GPCRs). The MT1 and MT2 receptors are abundant in the SCN. This system complex acts by the G protein-linked receptor family and is involved in 3 intracellular processes that ultimately play a role in the regulation of circadian rhythm. The MT1 and MT2 receptors inhibit the acetylate cyclase (AC), cyclic guanosine (GC) activate phosholipase (PLC) and activates the phospholipase C pathway.

The result of melatonin binding to MT1 and MT2 receptors in the SCN is to inhibit the AC and GC pathways, which reduces intracellular calcium and an increase in potassium. The reduction of AC/GC activity results in a reduction in cellular excitability via inhibiting Ca2+ channels and enhancing K+ channels. The combined effect is the inhibition of the SCN firing. The MT1 receptor has been implicated in the hypnotic effect of melatonin while the MT2 receptor has been implicated in the phase shifting effects of melatonin (Dubocovich et al, 2003)

Metabotropic Melatonin receptors regulate intracellular signal transduction pathways

MT1 MT2

K+

Ca

Figure 1 ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; PIP2, phosphatidylinositol-4, 5-biphosphate; DAG, diacylglycerol; IP3, inositol triphosphate.

Recently, an additional melatonin-binding site termed MT3 has been identified as a quinone reductase but its role in sleep and circadian rhythm has not been (Leclerc, 2011).

Exogenous melatonin is used commonly for both hypnotic and circadian entrainment reasons; however, the clinical use of melatonin is complicated by unstandardized commercial preparations, variability of effect and blood levels between users. Despite the variability in preparation and dose-response dynamics, meta-analysis suggested that melatonin improved objective sleep measures such as latency, efficiency, and total sleep time, although effects were small and possibly influenced by subjects with delayed circadian phase (Buscemi et al , 2005)

AC

ATP cAMP

GC PLC

GTP cGMP PIP2 DAG/IP3

Orally administered melatonin is rapidly absorbed, with peak plasma concentrations occurring between 20 and 120 minutes. Improved sleep onset and quality is seen with 1-3 mg doses. This is effective for those who have trouble falling asleep. However, this is inadequate for those with frequent nighttime or early morning awakening. Therefore, in order to maintain continued elevated concentrations of melatonin throughout the night, repeated administration of low doses are required or a sustained released formulation with a higher dose is required. A formulation of a prolonged-release melatonin (PR-melatonin), is available to provide a sustained elevation of melatonin throughout the night and more closely mimics to the normal physiological release pattern of endogenous melatonin. (Wade et al. 2007)

The sleep-promoting effects of melatonin become most prominent about 2 hours after intake, similar to the physiological sequence at night. It has been demonstrated that melatonin participates in the regulation of the sleep–wake cycle by inhibiting the wakefulness-generating system in the SCN. (Shochat et al. 1998). Melatonin was found to be effective in adjusting the sleep–wake cycle in the blind individuals, where the light–dark cycles do not exist. In addition, exogenous melatonin administration synchronized neuroendocrine rhythms (cortisol, body temperature) to the day–night cycles in blind subjects as well (Sack et al. 2000). Melatonin enables phase shift of circadian rhythms, to induce transient sleepiness and to suppress core body temperature.

Melatonin has a short half-life and therefore is less effective with those who have problems with frequent nighttime awakenings or early morning awakenings. A prolonged release formulation (PR-melatonin) of melatonin was subsequently introduced in the marked. Patients with insomnia that were treated with PR-melatonin 2 mg at bedtime for 3 weeks, benefits were compared to a control group treated with placebo. In the PR-melatonin group there were improvements in sleep latency and in subjective quality of sleep as well as improved daytime functioning. The subjects taking the melatonin formulation were found to have no impairment of vigilance the following day and even some improvements in performance in the morning were recorded. The reported quality of sleep, number of nighttime awakenings, morning alertness and quality of life were significantly improved with PR-melatonin compared to placebo (Wade et al, 2007). The sleep-promoting effects of PR-melatonin are similar in magnitude to those of other hypnotics (i.e. zaleplon,67 zopiclone68,69). At the same time, PR-melatonin does not impair psychomotor performance such as driving performance, and memory

Brzezinsli et al (2005) conducted a meta-analysis of 284 subjects in 17 studies to evaluate the effectiveness on exogenous melatonin. The authors concluded that melatonin was effective reducing time to sleep onset and reducing nighttime awakenings.

Melatonin is available at most health food stores and has received strong public attention. Melatonin is also found in small amounts in the plants that used in Feverfew (Tanacetum parthenium), and St John's wort (Hypericum perforatum) (Paredes et al, 2008).

Ramelton is the first FDA approved medication designed to mimic the effects of melatonin. Ramelton similarly acts by activating MT1 and MT2 receptors in the SCN. The advantage of Ramelton is the fact that it is regulated as a drug and therefore the purity and strength are standardized with specific dose recommendations. The recommended dose of Ramelton is an oral dose of 8 mg., the peak absorption occurs between 30-90 minutes and the drugs half-life is 1-2.6 hours.

Vitamin B’sThere are 5 forms of vitamin B. These are Thiamine, Riboflavin, Niacin, vitamin B-6 and vitamin B-12. The B vitamins play an integrate role in the function of neurons both in the brain and throughout the body. This group of vitamins are also involved many metabolic functions including protein and glucose synthesis. Deficiencies in the vitamin B’s can occur as a result of poor intestinal absorption, those taking corticosteroids or some anti-seizure medications and those with kidney and liver problems.

A large study evaluated the dietary intake differences between individuals with insomnia and normal sleepers revealed significant differences in several of the vitamin B amount consumed by the two groups. It was found that both B12 and thiamine were consumed in higher levels in normal sleepers than in those with insomnia.

Vitamin B12 is reported to affect the body’s biological rhythm including the circadian rhythm. Clinically B12 supplementation improves the symptoms of sleep-wake rhythm disorders. Experimental studies on humans and clinical evidence suggest that vitamin B12 plays a role in the entraining mechanism of the biological clock and allows for a more regular sleep pattern

Thiamine and B12 are both play key essential roles in brain cell function. In addition to maintaining healthy cells in the brain, B12 is plays a significant role in the formation of GABA in the brain. Animal studies have shown increased levels of B12 result is a corresponding increase in GABA during sleep (Ikeda, 1997).

Nocturnal leg cramps significantly affect sleep in some elderly patients and women during pregnancy. In a randomized, double blind, placebo-controlled study in elderly patients suffering from frequent nocturnal leg muscular cramping showed significant improvement when they were administered vitamin B complex capsules (Chan et al, 1998)

Iron Iron has not been shown to directly improve sleep parameters however was found to be consumed more in individuals with normal sleep patterns than those with insomnia. In addition, it is a well-established medical finding that iron-deficiency anemia can cause restless leg syndrome (RLS) and resolves with iron therapy (Allen, 2011). In addition, iron has been found to be an etiological cause of periodic limb movements and responds to administration of supplemental iron therapy (Simakajornboon, 2003)

ChamomileThe scientific name for chamomile is Chamomilla recutita or Matricaria. Recutita. There are two forms; Roman chamomile and German chamomile. Chamomile has been used for many years for a variety of health conditions. It is most commonly used for insomnia, anxiety and gastrointestinal problems. The flower of the chamomile plant is dried and used for teas, capsules and tablets. Extract in a liquid form is made as well. Chamomile binds to GABA receptors and increases its level in the brain.

There is one study using randomized, placebo-controlled, double blind protocol to evaluate to effectiveness in chamomile to treat insomnia. Placebo or 270 mg of chamomile or was given to 34 adults with a diagnosis of insomnia. The subject’s reports revealed no difference in sleep time, time required to fall asleep or number of night time awakenings. There was a “modest” benefit rating for chamomile on the daytime function score, meaning those subjects assigned to chamomile reported feeling more awake and alert the following day. There were also small chamomile benefits

reflected in the findings of reduced time required to fall asleep and fewer nighttime awakenings. There were no differences in side effects reported.

Valerian The scientific name for valerian is Valeriana officinalis and is a plant originally found only in Europe and Asia but is now cultivated in North America. The dietary supplement is derived from the roots and the stems of the plant. These components are dried and prepared for teas and tinctures. The extracts of the valerian plant are incorporated into capsules and tablets.includes many different components, just as any other plant, so it is not completely clear which substance is responsible for the sedative effects. There are two types of oils in the plant as well as a substance comprised of iridoids. It is believed that the combination of two oils in the valerian plants, sesquiterpenes and the valepotriates, are responsible for the beneficial sleep effects. Both of these oils have been shown to have sedating effects in animals. Valerian increases both GABA and serotonin levels (Holz, 1989).

There is evidence that valerian acts to increase the amount of GABA in the cortex of the brain. GABA is an inhibitory neurotransmitter that is used by the cortex to reduce overall brain activity. Valerian increases the release of GABA and also prevents its destruction, thereby significantly increasing the amount of valerian in the brain (Holz, 1989).

There have been nine clinical trials of the effects of valerian as a treatment for insomnia. Three were designed with the highest clinical protocols to determine the effectiveness without bias. The studies all were based on randomized, placebo-controlled, double blind protocols. This means that there was a documented record of which preparation the subjects were taking (valarien or placebo), but neither the researchers nor subject knew which one it was. This prevents any bias on both the researcher and subject.

The first study looked at 128 individuals without a diagnosis of insomnia and was designed to evaluate: time to fall asleep, quality of sleep and number of nighttime awakenings. Although these are all subjective ratings, the participant was randomized to either placebo or the valerian preparation and therefore did not have a bias when reporting their scores. There were statistically significant findings that supported the administration 400 mg of valerian aqueous extract benefits the sleep patterns and resulted less time required to fall asleep, less nighttime awakenings and a subjective better quality of sleep.

The second study included only 8 subjects with difficulty falling asleep and again randomly assigned them to placebo, 450 mg or 900 mg of aqueous valerian. The subjects wore nighttime motion recorders worn on the wrist and onset of sleep was determined as the first 5-minute period with no movement. The time to sleep onset was 7 minutes sooner in the valerian 450 mg group, however with only 8 subjects in this study this was not considered a clinically significant difference from placebo. Incidentally, the valerian 900mg resulted in more subjects reporting sleepiness in the morning.

The third study randomized 121 subjects with a diagnosis of insomnia, to either placebo or 600 mg of dried valerian root for 28 days. The group receiving the valerian extract showed a decrease in insomnia symptoms on several therapeutic effect and assessment tools compared with the placebo group.

In summary there have ben several well-designed studies that support valerian as an effective supplement to improve sleep patterns. Both 400 mg of the aqueous solution and 600 mg of the dried root preparation were effective.

KiwifruitThere have been several studies that have assessed the effect of kiwifruit on sleep. Kiwifruits (Actinidiaceae) are native to eastern Asia and their use for treating several medical conditions has been reported. It is high in serotonin, antioxidants, flavonoids, anthocyanins, vitamin C and E. Serotonin has been shown to be involved in REM sleep.

In one study, 22 subjects were to eat 2 kiwis, 1 hour before going to bed for 4 weeks. The subjects maintained a sleep diary and completed a questionnaire. In addition, an ambulatory monitoring motion detector was worn on the subject’s wrists each night to assess sleep onset and duration. There were significant increases in total sleep time and sleep efficiency measured by the sleep/activity monitor logger watch during the nights kiwi was consumed before bedtime. The limitation of this study is that it was an open label study and not a blinded study. This means the subjects knew when they were taking the intervention that was suppose to work. Nonetheless, the findings are important and do suggest kiwi fruit may help promote a good sleep pattern (Hsiao-Han, 2011).

St. John’s Wort (Hypericum perforatum) enhances serotonin activity and inhibits glutamate activity in the brain. Glutamate is an excitatory neurotransmitter in the brain. St. Johns wort has been shown in many studies to have beneficial effects on anxiety and depression.

Hops (Humulus lupulus) also work in the melatonin system. Hops have been shown to have the ability to bind to melatonin receptors and simulate its effects (Butterweck et al., 2007).

A study designed to examine interaction of sedative herbs with selected central nervous system receptors revealed that a hop dried extract was found to bind to serotoninergic 5-HT6 receptors as well as melatoninergic ML1 receptors (Abourashed et al., 2004). The involvement of 5-HT receptors in depression and sleep disturbances has been demonstrated and the role of melatonin in the regulation of circadian rhythm is well established. However no studies have shown improvement in sleep patterns with Hops.

Kava (Piper methysticum) is used to treat anxiety and sleep disorders in Europe and the U.S. Kava exerts its effects as a central nervous system depressant. Animal studies confirmed that it has effects on GABA binding in neurons (Schultz, 1998). A well-designed study revealed the biological activity on GABA receptors was similar to benzodiazepines (Woelk, 1993)

There have been several studies indicating Kava is effective in treating anxiety, but few convincing studies on sleep in subjects without anxiety traits (Volz, 1997). Kava has specifically demonstrated improved sleep patterns in those with anxiety, but not in the general population (Klimke, et al 1992). There have been no cognitive side effects noted on formal testing with doses as high as 600 mg.

Vitamin DAny literature today about nutritional supplements would be remiss with out mention of vitamin D. Although this vitamin has recently been discovered in numerous bodily functions and preventive disease strategies, there have been no reports in the medical of health literature regarding the use of vitamin D to

treat sleep disturbances of any form. However, there was one compelling study from Saudi Arabia that evaluated the treatment of fibromyalgia, and the associated sleep symptoms.

The authors found that 42 of 61 women with fibromyalgia and vitamin D deficiency had marked reduction in their symptoms, including problems sleep. It is not clear whether vitamin D simply reduced the painful symptoms of fibro myalgia so the women slept better, or if vitamin D treats the core of the sleep problem in individuals with fibromyalgia. Regardless, there is still no evidence vitamin D effects sleep in healthy persons (Matthana, 2011)

Vitamin ANuclear retinoid receptor proteins are highly dependent on vitamin A to maintain function and structure. There is experimental data that illustrates vitamin A metabolites retinoid play a critical role in the signaling mechanism of the homeostatic component of sleep regulation (Hiroyoshi, 2008). Maret demonstrated that gene encoding of the retinoic acid receptor determines the contribution of delta oscillations to the sleep EEG. The authors concluded that retinoic acid signaling regulates cortical synchrony in the adult sleep patterns (Maret et al. 2005).

Summary

Several foods and nutrients have traditionally been associated with sleep status. Researchers have recently begun to investigate the effectiveness of such foods as substitutes for pharmacological interventions. The effects of food and food constituents on sleep disturbances are only beginning to be understood. It is noteworthy to mention that sleep-related problems are associated with specific food consumption behaviors including consumption of tea, coffee, or alcohol, as well as, eating proteins and fat rich foods just before bedtime.

There are many well-designed research studies that have demonstrated associations between food and nutrient deficiencies and sleep disturbances. However, similar research is still needed to firmly establish the effectiveness of nutritional supplements in management of insomnia. The studies presented in this book certainly support the fact that many nutritional supplements and herbs are beneficial in treating some sleep disturbances, but the field of herbal and nutritional science is still very young.

The available literature provides basic evidence that certain nutrients and herbs positively affect sleep by altering neural responses and re-establishing NREM and REM sleep patterns. The precise role of specific nutritional supplements, or combinations of them, will be the subject of future research.

Meanwhile it appears clear that several of the supplements, such as melatonin, valarien and chamomile have sufficient support that they are effective in promoting an improved sleep pattern. It is likely the addition of other supplements may have a synergistic effect together. Equally important regarding the current use of any of the supplements reviewed in these pages is that they all appear safe. Outside of an allergic reaction, or mild gastrointestinal effects there have been no significant side effects reported.

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