Ross Finesmith MD

1. Nutritional supplements and sleep
Ross 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

2. 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,

3. 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 and
late-night meals. Also using the bedroom to work, read, eat, or watch
television 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

4. 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.
Melatonin
The 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 retinohypothalamic 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.

5. 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 Gprotein 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)

6. Metabotropic Melatonin receptors regulate intracellular signal transduction
pathways
MT1
MT2
K+
Ca
GC
AC
ATP
cAMP
GTP
PLC
cGMP
PIP2
DAG/IP3
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)

7. 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 PRmelatonin 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

8. 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’s
There 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

9. 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)
Chamomile
The 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

10. 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.

11. 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.
Kiwifruit
There 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).

12. 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 D
Any 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

13. 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 A
Nuclear 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.

14. 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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