Nutritional supplements and sleep
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 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 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.
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)
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’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
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 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.
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).
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 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.
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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