Sleep-Calm is used for mild [transient]
insomnia to enhance sleep quality.
Sleep-Calm may be
useful in some cases of mild to moderate chronic primary insomnia in
conjunction with Webber Naturals® B-Calm™ with
Sensoril® to enhance sleep quality.
* Please Note: This information is based partly on Traditional Medicine which uses natural materials to support health. This information has not been evaluated or approved by the FDA. These statements have not been evaluated by the Food and Drug Administration (FDA). These products are intended to support general well being and are not intended to treat, diagnose, mitigate, prevent, or cure any condition or disease. If conditions persist, please seek advice from your medical doctor.
Description
How Sleep-Calm Helps in Transient InsomniaSleep-Calm is offered to intervene in problematic mild or short-term insomnia, otherwise referred to as transient insomnia.(32) The term transient insomnia conveys the idea of a short-term interruptive sleeping pattern, but the sleep itself is normal from a neurological perspective. Almost every one experiences mild or transient insomnia, simply as an unavoidable fact of life. Transient insomnia is associated with a plethora of sleep disruptors like jet-lag, an unfamiliar bed, new noise or temperature patterns, accidents with painful recoveries, and prominently, the effects of acute or chronic stressfulness that are imposed upon the night. In many cases, mild or transient insomnia last only for 1 to 3 days, requiring no intervention because its origin is understood to be a passing circumstance. This is not to say that there are no next day adversities, such as sleepiness, fatigue, or perhaps mental fog, but recovery is forth coming, and the whole matter soon forgotten.
Yet, transient insomnia can also be a persistent phenomenon, lasting for many days to weeks at a time. Such protracted episodes of transient insomnia are typically driven by ongoing stressfulness, and perhaps unrecognized issues.
Accumulative sleep loss over days and weeks imposes subjective or personal suffering, and adverse daytime consequences that should not be ignored, affecting quality of life, work and personal productivity, general health, and safety, especially in driving.(32-35)
Sleep-Calm is offered as a natural OTC intervention for those who what pharmacy help in addressing their imposing transient insomnia, and prefer to intervene with natural substances. Intervening in protracted transient insomnia is warranted. It has as its two principal goals, the preservation of daytime quality of life, general health, human performance, and safety to self and others, and the reduction of risk for developing the much more serious condition of chronic primary insomnia, that might be possible in ongoing life episodes of protracted sleep loss.(32)
Overview of Normal Sleep Neurobiology & Sleep Architecture
Two processes have become recognized as the regulatory mechanisms for controlling the sleep-wake cycle, acting cooperatively but independently as a restorative process: sleep homeostasis and circadian rhythmicity.(36,37,38) Sleep homeostasis tracts the duration of wakefulness, imposing a drive to sleep once wakefulness extends beyond approximately 16 hours.(39,40) Wakefulness extended into the remaining approximate 8 hours of the 24-hour sleep-wake cycle is the period of sleep loss. Even mild sleep loss is accounted for and reclaimed by increased sleep drive. Lamond et al. found that if the total sleep time that occurs over a 24-hour cycle is reduced below 5 to 6 hours or lower, then significant sleepiness and neurobehavioral impairment occurs.(35,39) Sleep loss is accumulative over successive nights of sleep deprivation and homeostatic recovery requires incremental "catch-up" occurring over a number nights.(39,40)
Circadian rhythmicity is mediated by a clock physiology residing in the suprachiasmatic nuclei (SCN) of the hypothalamus. It influences the timing of sleep and wakefulness. This is accomplished in part by facilitating melatonin sedation in preparation for sleep. The circadian clock also seems to continuously influence sleep propensity by supporting or inhibiting sleep at the appropriate time of day.(37,41)
The architecture of sleep refers to its structure or pattern. Sleep is divided into 5 stages, stages 1 through 4 are called non-REM sleep (NREM), and stage 5 is called REM or rapid eye movement sleep. These stages progress in a cycle that lasts for 90 to 110 minutes moving through stage 1 to REM sleep, then the cycle starts over again with stage 1. Almost 50 percent of total sleep time is in stage 2 sleep, about 20 percent in REM sleep, and the remaining 30 percent in the other stages. Infants, by contrast, spend about half of their sleep time in REM sleep.(42)
Definition of Insomnia
The International Classification of Sleep Disorders: Diagnostic and Coding Manuel,(43) and the Diagnostic and Statistical Manuel of Mental Disorders, Forth Edition-Text revised,(44) define insomnia as a symptom complex consisting of:(32)
difficulty in falling asleep, and/or
difficulty in maintaining sleep (including waking-up too early), and/or
difficulty in achieving restorative sleep (sleep quality), and
with daytime adverse consequences
Insomnia is unique in medicine because it can be both a symptom of extrinsic factors producing sleep disruption, and an intrinsic sleep disorder in its own right.(32)
The following paragraphs provide an overview on the nature and characteristics of transient insomnia, the primary target of Sleep-Calm. In broad terms, insomnia can be described from the point of view of duration, as either transient or chronic, and chronic insomnia can be broadly described from the point of view of its nature, as either a primary insomniaor a secondary insomnia.
Nature and Characteristics of Transient Insomnia
Transient insomnia is a symptom of disruptive sleeping environments or conditions, and/or disruptive stressfulness. Transient insomnia is defined as a relatively short sleeping problem, lasting from days to weeks.(32,44) Conceptually, transient insomnia is about sleep disruption and sleep loss in the context of normal sleep neurobiology, which mediates the sleep-wake cycle. Transient insomnia may be protracted because of unresolved relational or other deeply emotional stressfulness or anxiety, but normal sleep neurobiology remains fundamentally intact. However, it is hypothesized that transient insomnia might be able to evolve into chronic primary insomnia, which is understood to be an intrinsic or primary sleeping disorder emerging from an aberration(s) in sleep neurobiology rather than from imposing circumstances, and characteristically chronic in nature rather than episodic.(32,45)
Individual differences exist in vulnerability to transient insomnia, what is sleep disruptive to one person may not be disruptive to another person.(32,46) People who are vulnerable to transient insomnia appear to be susceptible to hyperarousal.(47,48) In contrast, people who rarely or never experience transient insomnia when exposed to typical extrinsic triggers do not exhibit hyperarousal patterns.(47)
Transient insomnia is characterized by sleep loss, a condition that creates next day sleepiness and fatigue,(32) and neurobehavioral ldeficits [having to do with the way the brain affects emotion, behavior, and learning] which accumulate across days of partial sleep loss.(35,49-51) Banks and Dinges state that neurobehavioral deficits can accumulate to levels equivalent to those found after 1 to 3 nights of total sleep loss.(51) Notable deficits that characterize transient insomnia include psychomotor deficits in reaction time, vigilance, and divided attention, with psychomotor vigilance being the most affected (measures the ability to sustain attention).(32)
Lamond, et al. published in 2007 that their research indicated that increasing severity of sleep loss resulted in a dosedependent like decrease in psychomotor vigilance performance.(39) They also found recovery from sleep loss deficits in psychomotor vigilance performance following one night of sleep loss required two recovery sleep opportunities (nights) of at least 9 hours, for both vigilance performance and sleepiness. When the recovery sleep opportunity was restricted to 6 hours, even five consecutive recovery sleep opportunities were insufficient to reverse the effects of moderate sleep loss and restore base-line waking function.(39) When the severity of sleep loss was increased, vigilance performance failed to recover to base-line, even after five 9-hour recovery sleep opportunities. Yet, sleepiness was restored to baseline latency in one or two 9-hour recovery sleep opportunities.(39) These neurobehavioral deficits mixed with sleepiness and fatigue can easily explain why sleep deprivation is associated with reduced quality of life, production, and safety. Very importantly, from the results of the Lamond et al. research, an early recovery from next day sleepiness is not proof that all aspects of neurobehavioral deficits are restored to normal.
The effects on general health caused by transient insomnia are not usually perceived, the obvious exception being that most people associate immune deficits with problematic sleep loss, and this is supported with objective evidence.(52,53)
However, stressfulness might be the common factor, by leading to transient insomnia and at the same time inducing hyper-secretion of cortisol through activation of the HPA axis that reduces immune function.(54) Persistent experience in transient insomnia is associated with risk for obesity, coronary artery disease, and diabetes.(55,56,57)
Sleep exerts marked modulatory effects on glucose metabolism, and molecular mechanisms for the interaction between sleeping and feeding have been documented. The potential impact of recurrent sleep loss on the risk for diabetes and obesity is now being recognized.(58)
Spiegel et al. in 2005, investigated in a laboratory setting healthy young adults who submitted to recurrent partial sleep restriction. Marked alterations in glucose metabolism including decreased glucose tolerance and insulin sensitivity were demonstrated. The neuroendocrine regulation of appetite was also affected as the levels of the appetite suppressing (anorexigenic) hormone leptin were decreased, whereas the levels of the appetite promoting (orexigenic) hormone ghrelin were increased.
This is an important area of pharmacy counseling to those who are known to be at risk of obesity, metabolic syndrome, prediabetes, and type 2 diabetes, and who also complain of frequent episodes of transient insomnia, or who voluntarily experience sleep loss because of life-style.
Emphasis is given to chronic Primary Insomnia. It also addresses how Sleep-Calm in conjunction with B-Calm might be helpful in managing sleep loss in those with chronic primary insomnia.
How Sleep-Calm Can Help in Transient Insomnia
Sleep-Calm is comprised of L-theanine, Griffonia simplicifolia seed powder as a source of 5-hydroxytryptophan (5-HTP), and melatonin. Since insomnia is about difficulty in falling asleep and in maintaining sleep, these ingredients act together to facilitate sleep onset and maintenance.
L-Theanine Relaxation to Favor Falling Asleep
A central part of the difficulty in achieving sleep onset in problematic transient insomnia is the intrusion of daytime arousal into the nighttime space, especially when stressfulness and anxiety drive insomnia. In transient insomnia, normal sleep neurobiology is intact and sleep homeostasis and circadian rhythmicity exert an intrinsic pressure to sleep, but this pressure is being inhibited by lingering excitation. Overall, a state of functional imbalance exists between bedtime quiescence and residual daytime excitation.
L-Theanine is one of the predominant amino acids found in green tea, and historically has been used as a relaxing agent consumed at 50 to 200 mg per day for years across the Japanese population for this benefit.(62) L-theanine is gamma-ethylamino-L-glutamic acid, a derivative of glutamic acid that is able to competitively bind to glutamate receptors, inhibiting glutamate mediated excitation.(60,61) It crosses the blood-brain barrier and exerts an effect within 30 to 40 minutes following ingestion.(61) The subjective perception of this inhibitory effect historically has been reported as a sense of calmness or relaxation. The objective evidence of L-theanine inhibition of excitation is demonstrable enhancement of alpha-brain waves on an encephalogram.(62,63)
It is well known that alpha-brain waves are generated during a state of alertness under relaxation. In contrast, beta-brain waves indicate a state of alert mental activity, or mental engagement. The enhancement of alpha-wave generation by L-theanine on a dose-related basis is understood to demonstrate its practical value in inhibiting glutamic acid excitation and favor sleep onset if sleep pressure is present.(62,63) L-theanine is also thought to possibly enhance the release of gammaamino-butyric acid (GABA), which is the most important endogenous inhibitory neurotransmitter for inhibiting glutamic acid excitatory action.(64,65)
Because L-theanine offers improved calmness or relaxation at bedtime, it is expected to facilitate an enhancement of sleep onset.
HTP-5 Raises Serotonin Levels to Favor Sleep Maintenance
Transient insomnia is also about disruptive awakenings. Having problems with sleep continuity can relate to CNS serotonergic tone, which is integral to regulating both non-REM (NREM) and REM sleep.(66) Serotonergic tone promotes NREM sleep and functionally counterbalances cholinergic tone which promotes and maintains REM sleep, but with the potential for cholinergic mediated arousal affecting sleep continuity and inducing premature REM sleep onset (called shortened REM latency).(66-69) When there is a reduction of serotonergic tone, it appears that requisite sleep architecture is disturbed in various critical ways, putting sleep continuity through the night at risk.
A number of investigators have researched in healthy subjects, and in patients with primary insomnia, the functional consequences on sleep that is produced by deliberately lowered CNS tryptophan levels in order to manipulate serotonergic tone.(66,70,71) This is done by lowering available CNS tryptophan by having the subjects consume a drink of amino acids excluding tryptophan several hours prior to the test period. This procedure is called the tryptophan depletion challenge and it reduces plasma tryptophan levels by 80 to 85 percent. Experimental nighttime reductions in CNS serotonin levels as a consequence of tryptophan plasma depletion have been consistently associated with awakenings, particularly in stage 2 sleep, which represents the major part of sleep in humans, and such awakenings are thought to relate to cholinergic tone that is inadequately opposed by serotonergic tone.(66)
It has been shown consistently that cholinergic stimulation induces arousal in some aspects of brain function when it mediates REM sleep onset and duration.(66) This is why REM sleep is also referred to as paradoxical sleep, because sleep and arousal would seem to be unlikely bed fellows. An indirect enhancement of the cholinergic tone by a naturally occurring relative CNS tryptophan short-fall, as a function of personal protein diet, could be important in the susceptible sufferer.
An inadequate counterbalancing serotonergic tone might explain increased awaking periods and wake percentage in association with transient insomnia. Interestingly, other research has pointed to reduced serotonergic tone as a gateway for increased corticotropin-releasing factor (CRF), increased plasma cortisol, and an exacerbation of depression symptoms.(72,73) Thus in the susceptible, frequent episodes over time of transient insomnia relating to reduced serotonergic tone might be an evolutionary pathway into primary insomnia, and its frequently associated co-morbidity of depression.
Sleep-Calm incorporates 5-hydroxytryptophan (5-HTP) from Griffonia simplicifolia seed powder to enhance serotonergic tone through the night and favor sleep continuity. Intestinal absorption of 5-HTP is approximately 70 percent because it does not require the presence of gut transport molecules and is not affected competitively by the presence of other amino acids.(74,75) Because 5-HTP is hydroxylated tryptophan, it is precluded from being diverted into the synthesis of niacin or proteins, as expected for dietary tryptophan. Furthermore, 5-HTP easily crosses the blood-brain barrier and effectively increases the CNS synthesis of serotonin.(74) Because 5-HTP is the immediate precursor for serotonin synthesis, it is expected by mass law to enhance CNS serotonin levels if they are functionally reduced.
Attention: The label recommended amount of Sleep-Calm is 1 tablet, delivering 15 mg of 5-HTP. Pharmacist counseling can recommend using 2 tablets prior to bed because in doing so no active constituent will exceed the known safe amount. If sleep maintenance through the night is still not fully enough realized by the sufferer, the Webber Naturals "stand-alone" 5-HTP product can be used in 50 mg caplets, titrated up to 300 mg per day, as stated on its label.
Using 5-HTP compensates for any dietary tryptophan short-fall. People who suffer from sleep continuity complaints may be involved with inadequate dietary tryptophan intake to meet their whole-body negotiation of life, unknowingly failing to enhance serotonergic tone by judicious protein choices. Since tryptophan is an essential amino acid, it must be supplied in the diet. Ultimately, a competent serotonergic tone goes back to dietary tryptophan. Yet, even if one consumes the average daily intake of tryptophan, is this idiosyncratically enough? Furthermore, several factors may be collectively at work to effectively lower CNS tryptophan levels in association with episodes of transient insomnia:(74)
Throughout the body, dietary tryptophan is diverted into numerous synthetic pathways, effectively lowering tryptophan availability for CNS serotonin synthesis.
Elevated cortisol levels in chronic stressfulness, and vitamin B6 deficiency, promote the liver conversion of dietary tryptophan to kynurenine, effectively lowering tryptophan availability for CNS serotonin synthesis.
Furthermore, elevated serum levels of kynurenine inhibit the transport of serum tryptophan into the CNS, lowering tryptophan availability for serotonin synthesis.
Transport of serum tryptophan across the blood-brain barrier requires competition with tyrosine, phenylalanine, valine, leucine, and isoleucine for transport molecules, effectively lowering tryptophan availability for CNS serotonin synthesis.
Thus with Sleep-Calm supplying 5-HTP, it directly addresses serotonergic tone, and thereby favors sleep continuity through the night.
Melatonin favors sedation
Melatonin produces a sedative effect in animals and humans. This sedative effect is thought to stem from enhanced gamma-aminobenzoic acid (GABA) receptor binding, producing an inhibitory action on the reticular activating system, which mediates wakefulness.(76,77,78) Melatonin is necessary to increase sedation, but melatonin-related sedation is not sufficient for the establishment of sleep. Sleep like wakefulness is imposed, but by another set of neurological properties mediated by the SCN circadian clock governing the sleep-wake rhythm. A rising melatonin plasma level commensurate with room darkness facilitates the onset of sedation, and this presumably matches a mounting SCN clock commitment to impose sleep.
In transient insomnia, there is often if not predominately an undercurrent of stressfulness disturbing normal sleep. With stressfulness there is also increased cortisol secretion mediated by corticotropin-releasing hormone (CRH).
Reduced melatonin secretion, referred to as low-melatonin syndrome, has been demonstrated in patients suffering from major depression and CRH, which is an important etiological factor for depression, has been postulated as an inhibitory factor on melatonin secretion.(79) While transient insomnia occurs within the context of a normal neurobiology of sleep, it is commonly involved with stressfulness and an inordinate nighttime CRH presence can be postulated. Kellner et al. in 1997 demonstrated that CRH has an inhibitory effect on pineal secretion of melatonin in healthy volunteers.(79)
Accordingly, Sleep-Calm incorporates melatonin to address any critical short-fall in melatonin secretion in association with stressfulness induced transient insomnia. Thus, Sleep-Calm provides these three natural constituents acting together to favor normal sleep onset and sleep maintenance through the night.
How Sleep-Calm & B-Calm Together May Help in Chronic Primary Insomnia
Because Sleep-Calm is an OTC product generally associated with insomnia alleviation, it may be self-selected by a person suffering from diagnosed or undiagnosed chronic primary insomnia. (An overview of chronic insomnia, as opposed to transient insomnia, and chronic primary insomnia is given below.) Chronic primary insomnia is an intrinsic sleeping disorder thought to be principally caused by an over active HPA axis, with cortisol hyper-secretion producing a condition of hyperarousal when the brain should be otherwise able to enter into a sedated state for sleep support. Sleep-Calm by itself is not expected to be helpful in chronic primary insomnia because it cannot address cortisol hyper-secretion and hyperarousal.
However, B-Calm is used to botanically modulate HPA axis function to inhibit cortisol hyper-secretion in managing chronic stress. The principle of specifically modulating cortisol hyper-secretion as a treatment modality in managing chronic primary insomnia has been the rationale in proposing the low-dose therapeutic use of the tricyclic antidepressant doxepin (Sinequan), which has produced significant sleep improvements by lowering cortisol.(105-107) As well, using B-Calm to lower cortisol is expected to offer improvements in managing primary insomnia in those who prefer natural medicine as a first-step under pharmacist consultation.
B-Calm and Cortisol
B-Calm provides the patented proprietary ashwagandha extract, Sensoril®. Ashwagandha, also called Indian ginseng, has been an important adaptogenic herb in Ayurvedic medicine for over 3000 years.(80) Studies indicate ashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory, hemopoietic, rejuvenating properties, and appears to exert a positive influence on the endocrine, cardiopulmonary, and central nervous systems.(81) Sensoril® is incorporated in B-Calm because it has achieved U. S. patented status, has received human clinical research evaluation, and provides a standardized extract with optimal concentrations and ratios of relevant bioactive constituents that together provide the most effective stress adaptogenic support.
Sensoril® has been shown in a 2005-2006 multi-phase, randomized, double-blind, placebo-controlled clinical trial to demonstrate efficacy in modulating the negative effects associated with chronic stress.82 Sensoril® treatment was evaluated in terms of the subjective feelings and effects associated with the stressed-out state, and in terms of objective serum cortisol levels and cortisol-related lipid and glycemic effects, as well as the DHEA level. The treatment group demonstrated statistically significant improvements in both objective and subjective criteria compared to the placebo group.(82)
Subjective features associated with Sensorilr treatment included:
Increased energy
Reduction in fatigue
Better sleep
Less irritability
Enhanced cognition
Enhanced overall feeling of well being
Objective features associated with Sensorilr treatment included:
Serum cortisol levels reduced by up to 30.5% (P<0.001 vs placebo)
Reduction in fasting blood sugar
Reductions in total cholesterol, LDL, VLDL, and triglycerides
Increase in HDL cholesterol
Increase in serum DHEA up to 32.5% (P<0.001 vs placebo)
The ashwagandha-related reduction in cortisol of up to 26 percent may also be helpful in chronic primary insomnia.
Furthermore, DHEA is the natural hormone for metabolically counterbalancing cortisol action and the ashwagandha induced increase in serum DHEA serves to further modulate cortisol action.
Contraindication for ashwagandha extracts: In myeloproliferative disorders, the use of ashwagandha extract should be provisionally contraindicated. Mice studies demonstrate the ability of ashwagandha extract to significantly increase hemoglobin concentration, red blood cell count, white blood cell count, and platelet count.(103,104)
Chronic Insomnia
Chronic insomnia is much more complex than transient insomnia. The term encompasses insomnias that by their etiological nature are inherently chronic. Medical practitioners often find insomnias in this collection to be difficult to resolve. The American Psychiatric Association defines chronic insomnia as insomnia that lasts for at least three nights a week for longer than a month.(32,44) Chronic insomnia is divided into primary and secondary insomnia.
Chronic Primary insomnia Primary insomnia is generally considered to be related to a state of HPA axis hyperarousal throughout the 24-hour sleep-wake cycle.(83,84) It is specifically differentiated from the chronic secondary insomnia associated with existing medical or psychiatric conditions, or environmental causes.(44)
Several etiological concepts and research approaches have tried to account for primary insomnia. Pigeon and Perlis point out that hyperarousal, circadian dysrhythmia, and sleep homeostatic dysregulation are each thought to contribute to the emergence of primary insomnia, but that most of the empirical research has focused on hyperarousal, either as an elevated basal level of arousal, or stemming from a failure to sufficiently down-regulate daytime arousal at night.(85)
Since the early 1970s many studies have demonstrated a strong association between insomnia and psychological factors driving insomnia, and especially in relation to perceived stress.(83) In 2001, Vgontzas et al. published the first controlled study that clearly demonstrated through objective sleep testing and frequent non-disturbing blood sampling that chronic primary insomnia is associated with an activation of the hypothalamic-pituitary-adrenal (HPA) axis and an overall hypersecretion of adrenocorticotrophic hormone (ACTH), and cortisol, which are known to cause arousal and sleeplessness in animals,(86,87) and humans.(88)
The subjects in the Vgontzas et al. study with insomnia slept poorly compared to the controls, demonstrating significantly higher sleep latency (time required to fall asleep). The 24-hour ACTH and cortisol secretions were significantly higher in those with insomnia compared with the control subjects. Within the 24-hour period, the greatest ACTH and cortisol elevations were observed in the evening and first half of the night, making it more difficult to fall asleep and maintain sleep. Furthermore, those with insomnia with a high degree of objective sleep disturbance (percent of sleep time being < 70), secreted a higher amount of cortisol compared with those with a low degree of sleep disturbance.
Vgontzas et al. observed that the pattern of ACTH and cortisol secretion in those with primary insomnia suggested that the hyperactivation of the HPA axis in their subjects was different from that described in chronically stressed individuals.
Similar hyperactive HPA axis neuroendocrine effects have been noted by other researchers.(89,90,91) Vgontzas et al. concluded that primary insomnia was associated with an overall increase of ACTH and cortisol secretion, yet within a normal circadian pattern and that their findings concerning subjects with primary insomnia were consistent with a disorder of central nervous system hyperarousal. Furthermore, those with chronic activation of the HPA axis in insomnia are probably at risk not only for mental disorders like depression and anxiety, but also for whole-body medical complications associated with ongoing elevated cortisol levels.
Another line of research in the cause of primary insomnia is in brain imaging through computed tomography. Neuroimaging results suggest that primary insomnia may be associated with reduced brain blood flow in critical areas, with abnormal central nervous system activity during NREM sleep that is particularly linked to basal ganglia dysfunction.(92,93,94)
Characteristics of Primary Insomnia
The over-riding characteristic is neuroendocrine arousal interference on the sleep-wake cycle, so that at bed-time the time to sleep onset (sleep latency) is increased due to residual daytime alertness, and there is increased arousal-propensity for awakenings during the night. There is obvious sleep loss in primary insomnia that in transient insomnia would be adjusted by sleep homeostasis causing daytime sleepiness. However, those who suffer from primary insomnia, characteristically do not experience daytime sleepiness and cannot fall asleep if they try, remaining alert through the day following sleep loss.(32,95-97)
In primary insomnia, daytime fatigue and an inability to function normally is the most reported complaint.(32,45,95) Fatigue is not subjective sleepiness per se, but is a subjective state of persistent tiredness as physical and/or mental exhaustion.(32)
The pro-inflammatory cytokines interleukin 6 and tumor necrosis factor alpha (TNFa) are fatigue-inducing cytokines associated with reduced quantity and quality of sleep.(45) Another common characteristic of primary insomnia is the high risk that it will lead to depression if not corrected.(32,45,98)
Basic research and clinical studies have demonstrated that chronically elevated secretion of hypothalamic corticotropin releasing hormone (CRH), as associated with primary insomnia, can cause depression and anxiety disorders.(99-101)
Chronic Secondary insomnia
Secondary insomnia is caused by an existing medical or psychiatric condition, or an environmental cause.(44) Examples of preexisting medical conditions that cause chronic insomnia include arthritis, end-stage renal disease, COPD, sleep apnea, periodic limb movement disorder (PLMD), restless leg syndrome, Parkinson's disease, Alzheimer's disease, depression, and anxiety.(32,102) In the case of affective disorders like depression and anxiety, it is often not possible to determine whether insomnia is the cause or the effect of affective disorders.(32,102)
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Directions
Chew 1 or 2 tablets 30 to 45 minutes before bedtime, or as directed by a physician.
Using 2 tables will not exceed the known safe amounts of each active constituent. Added 5-HTP can be used as a stand-alone item if sleep maintenance through the night remains problematic with 2 Sleep-Calm tablets.
Cautions
ADVERSE SIDE EFFECTS
Regarding L-theanine:
None reported.(1)
Regarding 5-Hydroxytryptophan (5-HTP):
The most common adverse effects associated with supplementing 5-HTP include heartburn, stomach discomfort, belching, anorexia, nausea, vomiting, flatulence, and diarrhea.(1,2) These GI effects may be due to peripheral conversion of 5-HTP to serotonin which increases gut motility.(2) Less common adverse effects include headache, insomnia, and palpitations.(2)
Gastrointestinal adverse effects associated with supplementing 5-HTP are usually moderate and often lessen or disappear once a steady dose is achieved.(2,3)
Intravenous administration of 200 to 300 mg of 5-HTP can induce confusion, memory impairment, and symptoms of behavioral activation, primarily anxiety.(2) These effects are rare with oral administration.(2,4)
Regarding Melatonin:
Use of melatonin for sleep enhancement is usually well tolerated, but it can be associated with mild adverse effects.
Dollins et al. using higher than normal doses of 10, 20, 40 or 80 mg in 20 healthy males found that when compared to placebo all doses significantly decreased oral temperature, the number of correct responses in auditory vigilance, response latency in reaction time, and self-reported vigor.(5) Other reports include headache, transient depressive symptoms, fatigue, confusion, drowsiness, mild tremor, mild anxiety, dizziness, and abdominal cramps.(1,5-10)
Dagan et al. found in a six-week treatment course with 61 patients with delayed sleep phase syndrome (DSPS), using 5 mg at 10 pm, that 57.4 percent reported no adverse effects, 34.4 percent reported slight daytime fatigue, and 8.2 percent reported headaches and nausea.(10)
Melatonin, its analogs, and its metabolites are not mutagenic, and melatonin appears to possess remarkably low acute toxicity in animals and humans.(11)
Adverse reaction to melatonin therapy and development of tolerance were not evident in a long-term study of up to 3.8 years in children with circadian rhythm sleep disorders (CRSD).(12)
INTERACTIONS
Regarding Theanine:
L-Theanine may increase the action of antihypertensive medication.(1) L-Theanine decreased hypertension significantly in spontaneously hypertensive rats.(13) Concomitant use of L-theanine with caffeine being used as a stimulant might decrease the effects of caffeine.(1)
L-Theanine may be able to confound the clinical use of selective serotonin reuptake inhibitors in humans. L-Theanine in animal studies has had no affect,(14) or decreased,(15,16) or raised,(17) brain serotonin levels. Patients on SSRI medications should be guided by their physician before initiating L-theanine.
L-Theanine is thought to be able to increase GABA levels. Since benzodiazepine medications increase GABA receptors, initiation of L-theanine may result in benzodiazepine over treatment effects.
Regarding 5-HTP:
Parkinson's disease patients on carbidopa-levodopa using 5-HTP will experience a significant reduction in the peripheral conversion rate of 5-HTP to serotonin and will experience a significant increase in plasma 5-HTP as a reult. This is analogous to the peripheral blocking of L-dopa to dopamine via carbidopa. In a 2002 study with healthy subjects, the addition of carbidopa resulted in a 14-fold increase in 5-HTP plasma levels.(2,18)
Selective serotonin reuptake inhibitors (SSRIs) and any medication that effectively raises serotonin levels or potentiates its actions may negatively interact with 5-HTP to produce serotonin syndrome.
Regarding Melatonin:
Melatonin may interact adversely when used in combination with medications for improving sleep. One study found a combination of melatonin and zolpidem had reports of nausea, vomiting, amnesia, and somnambulia (sleep-walking) to the point of incapacitation.(8) Melatonin may potentiate anticoagulant and antiplatelet medications, or herbs used to modulate blood clotting.(1)
Melatonin may have the ability in diabetic patients to impair glucose utilization and increase insulin resistance.(1) One study in postmenopausal women found evidence that melatonin might impair insulin action and glucose tolerance, suggesting that people with diabetes should not use it.(19) However, another study found melatonin safe and effective for people with diabetes.(20)
Because contraceptive drugs can elevate endogenous melatonin, concomitant use of melatonin contraception medications could be associated with melatonin adverse effects.(1) Flumazenil may inhibit the effect of melatonin.(1) Fluvoxamine significantly inhibits the elimination of melatonin. In one study, Fluvoxamine produced a 17-fold higher area under the concentration-time curve (P<.05), and a 12-fold higher serum peak concentration of melatonin (P<.01).(21)
Melatonin can decrease the effectiveness of Nifedipine GITS monotherapy in the modulation of blood pressure.(22) Lusardi et al. found in a placebo-controlled, double-blind, and cross-over study with 47 well controlled mild to moderate hypertensive patients on 30-60 mg daily of Nifedipine GITS, that when 5 mg of melatonin was added nightly over 4 weeks, there was a daily average increase in systolic blood pressure of 6.5 mmHg, and in diastolic blood pressure of 4.9 mmHg, with an average increase in heart rate of 3.9 beats per minute. The increase in DBP and HR were particularly evident during the morning and the afternoon hours.
PRECAUTION / CAUTION
Regarding L-Theanine:
Caution should be used when L-theanine is used with caffeine in conjunction with late machine operation or late driving, especially long distance driving. Concomitant use of theanine with caffeine might decrease caffeine's effect.(1) Theanine is known to block the stimulation of caffeine.
L-theanine initiation on an established benzodiazepine dosage regiment might result in benzodiazepine over treatment. Benzodiazepine medications increase GABA receptors and L-theanine is thought to be able to increase GABA levels.
Regarding 5-HTP:
In late 1989 and through 1990, an epidemic of eosinophilia-myalgia syndrome (EMS) was identified in the U.S., affecting over 1500 people, with at least 38 deaths.(2,23) Eosinophiliamyalgia syndrome has been linked with the ingestion of industrially produced L-tryptophan containing one or more trace toxic contaminants originating in the manufacturing process. The term eosinophilia myalgia syndrome was coined in 1989 to describe the symptoms of incapacitating myalgias in association with eosinophilia.(24)
Concern may exist for some pharmacists and physicians that consumption of 5-HTP might lead to the development of eosinophilia-myalgia syndrome (EMS). However, the consumption of 5-HTP derived from Griffonia simplicifolia seeds is considered safe. Das et al. have noted that 5-HTP has become a popular dietary supplement and has been vigilantly observed by consumers, industry, academia, and government for its safety.(25) They state in 2004 that no definitive cases of toxicity have emerged despite the worldwide usage of 5-HTP for the last 20 years, with the possible exception of one unresolved case of a Canadian woman. Extensive analyses of several sources of 5-HTP have shown no toxic contaminants similar to those associated with industrially manufactured L-tryptophan, nor the presence of any other significant impurities.(25)
As to the unexpected crises of 1989 and 1990, evidence from an array of scientific studies have strongly supported the conclusion that a subset of contaminated L-tryptophan batches produced by the Japanese company Showa Denko KK caused the epidemic of eosinophilia-myalgia syndrome.(26,27) Birdsall writes that contamination in affected L-tryptophan batches has been related to production methods using bacterial fermentation and subsequent inadequate filtration.(28)
Regarding 5-HTP and EMS, Turner et al. note that in August 1998, the American FDA reported that 10 cases of EMS possibly associated with 5-HTP had been documented worldwide, with none resulting in death.(2) Furthermore, at the time of their writing in 2006 no new cases of EMS associated with 5-HTP ingestion had been reported.(2) However, Das et al. in 2004 state that none of the 10 FDA reported cases of EMS have been definitely linked with 5-HTP.(25)
Writing in 1999, Klarskov et al. performed HPLC-UV analysis on eight EMS-implicated commercial 5-HTP samples and reported finding the presence of an unknown absorption peak, called peak X and described as EMS case-implicated.(29) They found that peak X is a family of contaminants with the same molecular weight (234 Da) and similar HPLC retention times. They also demonstrated that all eight samples of the commercially available 5-HTP analyzed by HPLC/MS contained three or more contaminants of the peak X family.
Das et al. consider the peak X family to present a minor chromatographic peak and to lack credibility due to chromatographic artifacts and infinitesimal concentrations, and to have raised undue speculations concerning 5-HTP chemistry and toxicity.(25)
The 5-HTP in this product is extracted from Griffonia simplicifolia seeds. This intrinsic botanical source is not expected to be associated with fermentation/filtration toxic contaminants that might otherwise be associated with industrially made L-tryptophan or 5-hydroxy-L-tryptophan.
Regarding Melatonin:
Driving Performance: The use of melatonin in this product assumes it will be consumed just prior to bedtime. However, driving could become necessary after consuming melatonin. The impact of melatonin on driving performance (or machinery performance) has been a central concern in its OTC status. One published investigation was conducted by the University of Zurich Travel Clinic, in the Institute of Social and Preventative Medicine.(30)
Researchers investigated the effects of melatonin on driving performance parameters in 20 men and women aged 21-57 years. On each testing day, subjects received 5 mg or placebo, taken at 4:30 in the afternoon. One hour later, a test series was performed consisting of a medical examination, body sway measurement, and a standardized driving computer test battery to assess attention, reaction time, power of concentration, and sensomotor coordination. Subjective sleepiness was measured on three occasions during each test session using the Stanford Sleepiness Scale questionnaire.
Results: In assessing the results, the investigators reported that only one of the 16 main variables of the driving computer test battery [selective attention tested by signal-detection] was significantly affected by melatonin. However, even those values were still within normal range. Subjective sleepiness was increased by melatonin, although this affect became significant only after the prolonged concentration task. Neither the medical examination nor the body sway test demonstrated signs of drug influence.
Conclusion: The researchers concluded that overall the results of the computer test battery demonstrated no objective adverse impact of melatonin on driving performance. However, due to the increased subjective sleepiness after administration of melatonin, caution should be exercised when driving under the influence of melatonin.
Melatonin may cause epileptic seizure in the susceptible. Dopamine is considered an endogenous down-regulator of seizure activity and melatonin is capable of causing a decrease in dopamine output within areas of the brain thought to participate in the control of epileptic seizure.(31)
Melatonin is an effective treatment for biological rhythm related insomnia, but it is not necessarily an effective treatment for chronic primary insomnia.(10)
CONTRAINDICATIONS
Because Sleep-Calm supplies 5-HTP, and to avoid the risk for serotonin syndrome, Sleep-Calm is contraindicated for use in combination with selective serotonin reuptake inhibitors (SSRIs) and any other medication class that effectively raises serotonin levels or potentiates serotonin actions.
Sleep-Calm should not be used to treat chronic secondary insomnia except as directed by a physician.
Additional Information
References
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