Melatonin Easy Dissolve

5132-2 webber naturals 6-25273-05132-2 NPN: 80000847 Class: Hormone Melatonin Easy Dissolve Ingredients (alphabetical) Medicinal: Melatonin Non-medicinal: Croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, peppermint flavour, vegetable grade magnesium stearate Allergens Corn, dairy Source Synthesized Uses Sublingual melatonin is used to improve the quality of sleep in those with an age-relateddecline in melatonin [Jellin et al, 2004]. Sublingual melatonin is used to reestablish a normal circadian sleep rhythm in those suffering from disturbed sleep patterns relating to jet lag, shift-work, and in delayed sleep phase syndrome (DSPS) [Jellin et al, 2004]. Sublingual melatonin is used in circadian rhythm disorders in the blind, in sleep disturbances relating to depression, Alzheimer s Disease, and relating to benzodiazepine and nicotine withdrawal [Jellin et al, 2004]. Recommended Amount Use 1 tablet sublingually at bedtime, or as directed by a physician. Use up to 3 tablets daily. The sublingual route compared to the oral route is expected to provide a more consistent bioavailability of melatonin. Early pharmacokinetic studies indicated that 30 to 60 percent of an oral dose is metabolized during the first pass in the liver [Lane & Moss, 1985]. Furthermore, absorption of melatonin via the gut is thought to be highly variable [Kovacs et al, 2000]. One investigation using 80 mg in gelatin capsule form administered to 5 young males demonstrated a 25-fold variation in the concentration-time curve [350 to 10,000 times higher than the usual nocturnal peak] [Waldhauser et al, 1984]. Melatonin in Children Since melatonin is an endogenous human neuro-hormone, its use in children is expected to be safe, and effective on an empirical basis in children suffering from sleep problems associated with a variety of reasons [Coppola, 2004] [Forrester, 2004] [Gupta, 2004] [Gupta et al, 2004] [Phillips & Appleton, 2004]. In most cases of childhood chronic insomnia, a physician should be consulted for guidance in melatonin dosing and administration timing. Dosing and timing information can be suggested from two studies. In the Smits et. al. study [Smits et al, 2001], 40 children between 6 and 12 years old who suffered more than one year from chronic sleep onset insomnia were treated with 5 mg at 6:00 pm daily. Mild headache occurred in two children only during the first two days of melatonin treatment. Eighteen months after the start of the trial, in 13 of 38 children who could be followed-up, the melatonin treatment was stopped because their sleep problem was resolved, and in 1 child because sleep was not improved. One child developed mild generalized epilepsy 4 months after the trial started. The researchers concluded that melatonin at 5 mg taken at 6 PM was relatively safe to take in short term and significantly more effective than placebo in advancing sleep onset, dim light melatonin onset, and increasing sleep duration in elementary school children with chronic sleep onset insomnia. In the Dodge and Wilson study [2001], the investigators explored the safety and efficacy of 5 mg of melatonin administered at 8:00 PM in the treatment of sleep problems in 20 children with developmental disabilities, including cerebral palsy, autism, and mental retardation. The investigation was a randomized, double-blind, placebo-controlled, 6-week trial of melatonin versus UPDATED 6/5/2009 Melatonin, Easy Dissolve, 3 mg NF0390T PAGE 1 OF 5

placebo. All but 2 children fell asleep more quickly when receiving melatonin than placebo. Overall, the greater the sleep latency (time to fall asleep) was at baseline or when receiving placebo, the more pronounced was the decrease in sleep latency with melatonin. The effect of melatonin on sleep latency was significant (P<.05). The duration of sleep while receiving melatonin was significantly greater than baseline (P<.007), but was not significantly different from placebo, and no difference in the number of awakenings was noted. No side effects were reported. Eleven of 18 parents (61%) correctly identified the weeks their child received melatonin. This study suggests that melatonin can be used to reduce sleep latency in children with developmental disabilities. Adverse Side Effects The administration of melatonin 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 all doses compared to placebo significantly decreased oral temperature, the number of correct responses in auditory vigilance, response latency in reaction time, and self reported vigor [Dollins et al, 1993]. Other reports include headache, transient depressive symptoms, fatigue, confusion, drowsiness, mild tremor, mild anxiety, dizziness, and abdominal cramps [Citera et al, 2000] [Dagan et al, 1998] [Dollins et al, 1993] [Jellin et al, 2004] [Nishiyama et al, 2001] [Suhner et al, 1998a] [Wagner et al, 1998]. Dagan et. al. found in a six-week treatment course with 61 DSPS patients, 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 [Dagan et al, 1998]. Melatonin, its analogs, and its metabolites are not mutagenic, and melatonin possesses remarkably low acute toxicity in animals and humans [Weaver, 1997]. Interactions 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 [Suhner et al, 1998a]. Melatonin may potentiate the anticoagulant and antiplatelet actions of medications or herbs used to modulate blood clotting [Jellin et al, 2004]. Melatonin may have the ability in diabetic patients to impair glucose utilization and increase insulin resistance [Jellin et al, 2004]. Because contraceptive drugs can elevate endogenous melatonin, concomitant use of melatonin could be associated with melatonin adverse effects [Jellin et al, 2004]. Flumazenil may inhibit the effect of melatonin [Jellin et al, 2004]. Fluvoxamine significantly inhibits the elimination of melatonin [Hartter et al, 2000]. In one study, a 17-fold higher (P<.05) area under the concentration-time curve and a 12-fold higher (P<.01) serum peak concentration of melatonin was found [Hartter et al, 2000]. Melatonin can decrease the effectiveness of Nifedipine GITS monotherapy in the modulation of blood pressure [Lusardi et al, 2000]. 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 DBP and HR were particularly evident during the morning and the afternoon hours. Precautions / Cautions DRIVING PERFORMANCE: The impact of melatonin use on driving performance remains a central concern. One published investigation was conducted by the University of Zurich Travel Clinic, in the Institute of Social and Preventative Medicine [Suhner et al, 1998b]. 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 PM. 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. UPDATED 6/5/2009 Melatonin, Easy Dissolve, 3 mg NF0390T PAGE 2 OF 5

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 [Steward, 2001]. Melatonin is an effective treatment for biological rhythm related insomnia, but it is not necessarily an effective treatment for psychophysiologically related insomnia [Dagan et al, 1998]. Contraindications Do not use in people with seizure disorder. Do not use during pregnancy, or the breast-feeding period. Do not use with sedatives, or immuno-suppressive drugs. Do not operate a motor vehicle or machinery for 5 hours after taking this product. Pharmaceutical Commentary Melatonin is a neurohormone produced in the pineal gland located in the center of the brain and is associated with inducing a sedative effect. During conditions of dim light, special retinal photoreceptors spontaneously release norepinephrine, activating neural pathways that run to the pineal gland, through the suprachiasmatic nuclei (SCN) in the hypothalamus, resulting in pineal synthesis of melatonin, and its passive diffusive secretion into the bloodstream [Brzezinski, 1997]. However, light of sufficient intensity reaching the retinal tissues hyperpolarizes these special photoreceptors, preventing pineal melatonin synthesis [Brzezinski, 1997]. The photoreceptors mediating this process are different from the rod and cone photoreceptors that produce colour and light perception [Kavita et al, 2001]. Some blind people who evidence no pupillary light reflexes or visual perception still have light-induced suppression of melatonin synthesis [Brzezinski, 1997] [Czeisler et al, 1995]. Most aspects of physiology and behavior are time-integrated by sensitive biological clock mechanisms centered in the suprachiasmatic nuclei (SCN) of the hypothalamus, which acts on neural and endocrine pathways to regulate a variety of different circadian rhythms so that internal states vary predictably over a 24-hour cycle [Hastings, 1998]. (The word circadian is made up of two Latin roots; circa = about, and diem = day). The suprachiasmatic nuclei are comprised of approximately 10,000 neurons and if these nuclei are destroyed, the ability to express overt circadian rhythms is destroyed [Hastings, 1997] [Kline et al, 1991]. The circadian mechanisms associated with the SCN are autonomous, and individual neurons from the SCN demonstrate clock regulation that is so powerful that the rhythms of a single neuron can be recorded continuously for several weeks with only the slightest deviation from a 24 hour cycle [Hastings, 1998] [Welsh et al, 1995]. In terms of hypothalamic SCN sleep regulation, most people achieve a satisfactory sleep-wake circadian rhythm over each 24- hour day. However, due to age-related decline in endogenous melatonin synthesis, jet travel over time zones, or shift work, a discrepancy can arise between the established biological sense of time, and the actual local time. Such desynchronization causes the biological clock to impose a sleep-wake rhythm that is out of synch with local time, resulting in sleep deficits and numerous minor physiological and psychological complaints [Forger et al, 2003]. A condition of chronic desynchronization that typically requires clinical management is delayed sleep-phase syndrome (DSPS). In this condition, the person is unable to attain sleep in the common nocturnal time-frame because the SCN clock delays the sleep-phase of the sleep-wake rhythm until 2 AM to 3 AM. Clinicians observe that the sleep duration [say 7-8 hours] and quality [required sleep stages are achieved] in DSPS are considered to be normal. Thus, the point of awakening is correspondingly delayed [shifted forward by approximately 4 hours] until around 11 AM. Patients with DSPS usually find it difficult to function well if they are required to rise in the early hours of the morning. Melatonin is thought to act in at least two ways in relation to maintaining a restful sleep pattern. Firstly, melatonin is known to produce a sedative effect in animals and humans. This sedative effect is thought to stem from enhanced gammaaminobenzoic acid (GABA) receptor binding, producing an inhibitory action on the reticular activating system, which mediates wakefulness [Golombek et al, 1996] [Mignot et al, 2002] [Wang et al, 2002]. Melatonin is necessary to turn-down imposed wakefulness, but UPDATED 6/5/2009 Melatonin, Easy Dissolve, 3 mg NF0390T PAGE 3 OF 5

such 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. The second way melatonin acts to ensure a restful sleep pattern pertains to SCN clock synchronization. As the seasonal dark-light pattern varies throughout the year, the SCN clock must adapt to the way sleep requirements change in real time. Endogenous melatonin is thought to act as an entrainment agent to accomplish this adaptation [Kovacs et al, 2000] [Shantha et al, 2003] [Sharkey & Eastman, 2002]. Entrainment is the complex process of resynchronizing the biological clock with real time. Critical incremental changes in dim light timing, serve as entrainment information for re-setting the clock. The SCN neurons are able to decipher the trending darkness pattern, mirrored in the corresponding dark-mediated melatonin plasma levels. SCN neurons continuously perceive shifts in melatonin as a function of the dark-light cycle, adapting the clock imposed sleep-wake rhythm throughout the year accordingly. Desynchronization is a condition of failed adaptation and is represented in the concept of a phase-shift. In other words, the sleep-phase of the sleep-wake circadian rhythm has been shifted to another time that is out of synch with real time. Usually the sleep-phase is pushed or shifted forward, meaning sleep is postponed or delayed. The overt use of exogenous melatonin can induce entrainment to correct for desynchronization [Dagan et al, 1998] [Lewy et al, 1992] [Shantha et al, 2003] [Sharkey & Eastman, 2002]. Such entrainment may provide completely satisfactory management of jet-lag, shift work, or more challenging sleep aberrations as seen in DSPS, depression, or Alzheimer s disease. In more challenging categories, physician or pharmacist guidance may be more appropriate than self medication alone. Melatonin can entrain the free-running circadian rhythms of blind people and it has been used to treat the symptoms of circadian maladaptation associated with delayed sleep-phase syndrome [Dagan et al, 1998] [Lewy et al, 1992] [Sharkey & Eastman, 2002]. Dagan et. al. described the results of a 6-week clinical trial using 5 mg of melatonin for treating 61 DSPS patients [Dagan et al, 1998]. The mean duration of sleep before treatment was 8 hours and 21 minutes, demonstrating that delayed sleep-phase syndrome is not about the lack of sleep but rather about the timing of sleep onset. The mean pretreatment sleep onset and waking times were respectively 3:09 AM and 11:31 AM. Melatonin was administered at 10:00 PM, five hours before the average pretreatment sleep onset time. A survey of the patients was conducted between 12 and 18 months after the 6-week melatonin treatment ended. The response rate was 59 of the 61 original patients. Of this 59 patients, 54 (91.5%) reported relapse to their pretreatment sleeping patterns within one year after stopping the melatonin treatment. However, 17 (28.8%) respondents reported that their relapse occurred within one week of discontinuing melatonin. Dagan and his fellow investigators stated that their findings confirm earlier evidence that melatonin was effective in changing the sleep-wake patterns of DSPS patients. However, the finding that the new sleep patterns were not permanently retained suggests that exogenous melatonin does not cause a fundamental and permanent change in sleep regulation, thus DSPS patients may need to take melatonin regularly [Dagan et al, 1998]. Lewy and fellow investigators generated a phase-response curve (PRC) to melatonin that demonstrated circadian phase advances with melatonin administration in the late afternoon and evening, and circadian phase delays with administration in the later hours of sleep and the morning [Lewy et al, 1992]. Their observations offer some basis on how to empirically time a melatonin dose in DSPS, but also in better managing sleep problems associated with shift work and on going episodes of jet lag. UPDATED 6/5/2009 Melatonin, Easy Dissolve, 3 mg NF0390T PAGE 4 OF 5

References Brzezinski, A., Melatonin in humans, N Eng J Med, Jan; 16, 336(3):186-195, 1997 Citera G., et al, The effect of melatonin in patients with fibromyalgia: a pilot study, Clin Rheumatol, 19:9-13, 2000 Coppola, G., Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a doubleblind, cross-over, placebo-controlled trial, Brain Dev, Sep; 26(6):373-376, 2004 Czeisler, C. A., et al, Suppression of melatonin secretion in some blind patients by exposure to bright light, N Eng J Med, 332:6-11, 1995 Dagan, Y., et al, Evaluating the role of melatonin in the long-term treatment of delayed sleep phase syndrome(dsps), Chronobiol Int, 15(2):181-190, 1998 Dodge, N.N., G.A. 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COMMENTS? CALL 1.800.430.7898 For more monographs go to: www.webbernaturals.com/downloads.html UPDATED 6/5/2009 Melatonin, Easy Dissolve, 3 mg NF0390T PAGE 5 OF 5