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Sleep & Relaxation contains the natural hormone melatonin.  Melatonin supplements have been shown to induce sleepiness, improve sleep quality and alertness, and lower the risk of serious illness due to its antioxidant properties in the brain. 

Melatonin also helps regulate the immune system and protects the body from stress-related suppression of the immune system.

The University of Maryland Medical Center supports the use of melatonin supplements for a wide range of sleep-related conditions, including jet lag, delayed sleep phase syndrome (DSPS), insomnia in the elderly, sleep disturbances in children with neuro-psychiatric disorders, and for sleep enhancement in healthy people.  Melatonin supplements may also help treat sleep disorders associated with Alzheimer’s disease, bipolar disorder, depression, schizophrenia, seasonal affective disorder, and ADHD. 

(Click to read what the National Institutes of Health has to say about Melatonin.)

(Click for Ingredient.)


BACKGROUND:

Melatonin plays a role in the brain’s sleep cycle.  The body’s production of melatonin decreases in response to daylight, and increases in darkness, inducing sleepiness.  Many factors may disturb the body’s cyclic production of melatonin, including jet lag, night work, and poor vision.  Overexposure to light at night can decrease melatonin production, and it is believed that low-frequency electromagnetic fields such as those created by typical household appliances may also disturb melatonin production.  Melatonin supplements may benefit those who are regularly exposed to these factors.

Children have the highest levels of melatonin in their blood, but melatonin production declines with age.  Melatonin levels are very low or absent in the elderly, and this may be responsible for changes in the sleep cycle in older adults.  People with low melatonin levels may have trouble sleeping and following a regular sleep cycle.

OTHER ROLES FOR MELATONIN:

In addition to regulating the sleep cycle, melatonin is one of the most important anti-oxidants in the body because it protects the brain from free radical damage.  Free radicals are reactive byproducts of oxygen metabolism, and while they are essential for many chemical reactions, excessive amounts of free radicals become toxic as they damage cell membranes.  Free radical damage may be responsible for a number of degenerative diseases, including heart disease, cancer, Alzheimer’s, and Parkinson’s disease.

MELATONIN AND CANCER:

Melatonin has been studied as part of treatments for breast cancer and prostate cancer.  In one set of patients with breast cancer, melatonin supplements were found to protect against thrombocytopenia, a dangerous side effect of chemotherapy involving blood thinning.  In another group of patients, melatonin was even shown to help stop tumor growth.

Melatonin levels are lower in people with cancer than in normal, healthy adults.  Melatonin was shown in one study to improve the survival rate of men with prostate cancer.  Some studies cite meditation as an alternative treatment for cancer, and this claim may stem from the fact that meditation increases melatonin production.

MELATONIN AND OSTEOPOROSIS:

Melatonin may also regulate the production of osteoblasts, making it part of a possible treatment for osteoporosis.  Its anti-inflammatory properties are promising for treating heart disease and rheumatoid arthritis.  As a natural hormone, melatonin controls many processes in the body, and supplementation may help maintain healthy levels of melatonin.

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RESEARCH:

“Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal.”

Blask,-D-E; Dauchy,-R-T; Sauer,-L-A Endocrine. 2005 Jul; 27(2): 179-88

Physiological and pharmacological blood concentrations of melatonin inhibit tumorigenesis in a variety of in vivo and in vitro experimental models of neoplasia. Evidence indicates that melatonin's anticancer effects are exerted via inhibition of cell proliferation and a stimulation of differentiation and apoptosis. A new mechanism by which physiological and pharmacological blood levels of melatonin inhibit cancer growth in vivois via a melatonin-induced suppression of tumor linoleic acid (LA) uptake and its metabolism to the important mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Melatonin suppresses cAMP formation and inhibits tumor uptake of LA and its metabolism to 13-HODE via a melatonin receptor-mediated mechanism in both tissue-isolated rat hepatoma 7288 CTC and human breast cancer xenografts. It has been postulated that in industrialized societies, light at night, by suppressing melatonin production, poses a new risk for the development of breast cancer and, perhaps, other cancers as well. In support of this hypothesis, light during darkness suppresses nocturnal melatonin production and stimulates the LA metabolism and growth of rat hepatoma and human breast cancer xenografts.

Nocturnal dietary supplementation with melatonin, at levels contained in a melatonin-rich diet, inhibits rat hepatoma growth via the mechanisms described above. The nocturnal melatonin signal organizes tumor metabolism and growth within circadian time structure that can be further reinforced by appropriately timed melatonin supplementation. Dietary melatonin supplementation working in concert with the endogenous melatonin signal has the potential to be a new preventive/therapeutic strategy to optimize the host/cancer balance in favor of host survival and quality of life.


“Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease.”

Feng,-Z; Qin,-C; Chang,-Y; Zhang,-J-T.  Free-Radic-Biol-Med. 2006 Jan 1; 40(1): 101-9

Multiple lines of evidence demonstrated that increased brain oxidative stress is a key feature of Alzheimer's disease (AD). Melatonin is a potent endogenous antioxidant and free radical scavenger. A transgenic mouse model for AD mimics the accumulation of senile plaques, neuronal loss, and memory impairment. Four-month-old transgenic mice were administrated melatonin at 10 mg/kg for 4 months. We investigated the long-term influence of melatonin on these mice before amyloid plaques were deposited. We found an increase in the levels of brain thiobarbituric acid-reactive substances (TBARS) and a decrease in glutathione (GSH) content, as well as accelerated upregulation of the apoptotic-related factors, such as Bax, caspase-3, and prostate apoptosis response-4 (Par-4) in transgenic mice, but not in wild-type (WT) littermates. Significantly, the increase in TBARS levels, reduction in superoxide dismutase activity, and GSH content were reinstated by melatonin. In addition, transgenic mice administered melatonin (10 mg/kg) showed a significant reduction in upregulated expression of Bax, caspase-3 and Par-4, indicating inhibited triggering of neuronal apoptosis.

These results supported the hypothesis that oxidative stress was an early event in AD pathogenesis and that antioxidant therapy may be beneficial only if given at this stage of the disease process. In sharp contrast to conventional antioxidants, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential therapeutic candidate in AD treatment.


“Management of chronic insomnia in elderly persons.”

Bain,-K-T.  Am-J-Geriatr-Pharmacother. 2006 Jun; 4(2): 168-92

BACKGROUND: Chronic insomnia is common among the elderly These elderly patients are often viewed as difficult to treat, yet they are among the groups with the greatest need of treatment. OBJECTIVE: This article reviews the literature on the management of chronic insomnia in elderly persons. METHODS: A search of MEDLINE was conducted for articles published in English between January 1966 and March 2006 using the terms insomnia, behavioral therapy, estsazolsam, fluvsazepsam, qusazepsam, teMsazepsam, tvisazolsam, eszopiclone, zaleplon, zolpidem, mirtazapine, nefazodone, trazodone, and ramelteon. Articles were selected if they were meta-analyses or evidence-based reviews of therapeutic modalities; randomized controlled trials of nonpharmacologic or pharmacologic treatment; or review articles covering the characteristics and management of insomnia. Preference was given to meta-analyses, evidence-based reviews, and articles that included relevant new information. RESULTS: Available options for the treatment of insomnia include nonpharmacologic approaches, foremost among them cognitive behavioral therapy, and pharmacotherapies, including chloral hydrate, barbiturates, over-the-counter (OTC) and prescription antihistamines, OTC dietary supplements (including melatonin), sedating antidepressants, benzodiazepine and nonbenzodiazepine sedative-hypnotics, and melatonin agonists.

There is considerable evidence to support the effectiveness and durability of nonpharma-cologic interventions for insomnia in adults of all ages, yet these interventions are underutilized. With some recent exceptions, the majority of identified studies of pharmacotherapy were of short duration (< or =6 weeks) and did not exclusively enroll older adults. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. CONCLUSIONS: Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.


“Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole.”

Pereira,-Rde-S.  J-Pineal-Res. 2006 Oct; 41(3): 195-200

The prevalence of gastroesophageal reflux disease (GERD) is increasing. GERD is a chronic disease and its treatment is problematic. It may present with various symptoms including heartburn, regurgitation, dysphagia, coughing, hoarseness or chest pain. The aim of this study was to investigate if a dietary supplementation containing: melatonin, l-tryptophan, vitamin B6, folic acid, vitamin B12, methionine and betaine would help patients with GERD, and to compare the preparation with 20 mg omeprazole. Melatonin has known inhibitory activities on gastric acid secretion and nitric oxide biosynthesis. Nitric oxide has an important role in the transient lower esophageal sphincter relaxation (TLESR), which is a major mechanism of reflux in patients with GERD. Others biocompounds of the formula display anti-inflammatory and analgesic effects. A single blind randomized study was performed in which 176 patients underwent treatment using the supplement cited above (group A) and 175 received treatment of 20 mg omeprazole (group B). Symptoms were recorded in a diary and changes in severity of symptoms noted. All patients of the group A (100%) reported a complete regression of symptoms after 40 days of treatment. On the other hand, 115 subjects (65.7%) of the omeprazole reported regression of symptoms in the same period. There was statiscally significant difference between the groups (P < 0.05). This formulation promotes regression of GERD symptoms with no significant side effects.


“Epidemiology, etiology, and natural treatment of seasonal affective disorder.”

Miller,-A-L.  Altern-Med-Rev. 2005 Mar; 10(1): 5-13

There is much more seasonal difference in higher latitudes than in lower latitudes. In a significant portion of the population of the northern United States, the shorter days of fall and winter precipitate a syndrome that can consist of depression, fatigue, hypersomnolence, hyperphagia, carbohydrate craving, weight gain, and loss of libido. If these symptoms persist in the winter, abate as the days grow longer, and disappear in the summer, the diagnosis of seasonal affective disorder (SAD) can be made. Many hypotheses exist regarding the biochemical mechanisms behind the predisposition toward this disease, including circadian phase shifting, abnormal pineal melatonin secretion, and abnormal serotonin synthesis. Although the mechanism(s) behind this disease is not fully known, one treatment appears to address each of the theories. Light therapy is a natural, non-invasive, effective, well-researched method of treatment for SAD. Various light temperatures and times of administration of light therapy have been studied, and a combination of morning and evening exposure appears to offer the best efficacy. Other natural methods of treatment have been studied, including L-tryptophan, Hypericum perforatum (St. John's wort), and melatonin.

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MEDLINE----FROM THE NATIONAL
INSTITUTES OF HEALTH:

Background
Melatonin is a hormone produced in the brain by the pineal gland, from the amino acid tryptophan. The synthesis and release of melatonin are stimulated by darkness and suppressed by light, suggesting the involvement of melatonin in circadian rhythm and regulation of diverse body functions. Levels of melatonin in the blood are highest prior to bedtime.

Synthetic melatonin supplements have been used for a variety of medical conditions, most notably for disorders related to sleep.

Melatonin possesses antioxidant activity, and many of its proposed therapeutic or preventive uses are based on this property.

New drugs that block the effects of melatonin are in development, such as BMS-214778 or luzindole, and may have uses in various disorders.

Synonyms
5-Methoxy-N-acetyltryptamine, acetamide, beta-methyl-6-chloromelatonin, BMS-214778, luzindole, mel, MEL, melatonine, MLT, N-acetyl-5-methoxytryptamine, N-2-(5-methoxyindol-3-ethyl)-acetamide, Ramelteon ((TAK-375) a selective MT1/MT2-receptor agonist).

Evidence
These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Uses based on scientific evidence:          Grade*

Alzheimer's disease (sleep disorders)
There is limited study of melatonin for improving sleep disorders associated with Alzheimer's disease (including nighttime agitation or poor sleep quality in patients with dementia). It has been reported that natural melatonin levels are altered in people with Alzheimer's disease, although it remains unclear if supplementation with melatonin is beneficial. Further research is needed in this area before a firm conclusion can be reached.        C

Antioxidant (free radical scavenging)
There are well over 100 laboratory and animal studies of the antioxidant (free radical scavenging) properties of melatonin. As a result, melatonin has been proposed as a supplement to prevent or treat many conditions that are associated with oxidative damage. However, well-designed trials in humans are lacking.   C

Attention deficit hyperactivity disorder (ADHD)
There is limited research of the use of melatonin in children with ADHD both on the treatment of ADHD and insomnia in ADHD children. A clear conclusion cannot be made at this time.         C

Benzodiazepine tapering
A small amount of research has examined the use of melatonin to assist with tapering or cessation of benzodiazepines such as diazepam (Valium®) or lorazepam (Ativan®). Although preliminary results are promising, further study is necessary before a firm conclusion can be reached. C

Bipolar disorder (sleep disturbances)
There is limited study of melatonin given to patients with sleep disturbances associated with bipolar disorder (such as insomnia or irregular sleep patterns). No clear benefits have been reported. Further research is needed in this area before a clear conclusion can be reached.        C

Cancer treatment
There are several early-phase and controlled human trials of melatonin in patients with various advanced stage malignancies, including brain, breast, colorectal, gastric, liver, lung, pancreatic, and testicular cancer, as well as lymphoma, melanoma, renal cell carcinoma, and soft-tissue sarcoma.Currently, no clear conclusion can be drawn in this area. There is not enough definitive scientific evidence to discern if melatonin is beneficial against any type of cancer, whether it increases (or decreases) the effectiveness of other cancer therapies, or if it safely reduces chemotherapy side effects.          C

Chemotherapy side effects
Several human trials have examined the effects of melatonin on side effects associated with various cancer chemotherapies. Although these early reported benefits are promising, high-quality controlled trials are necessary before a clear conclusion can be reached in this area. It remains unclear if melatonin safely reduces side effects of various chemotherapies without altering effectiveness.      C

Circadian rhythm entraining (in blind persons)
Limited human study is available in this area. Present studies and individual cases suggest that melatonin, administered in the evening, may correct circadian rhythm. Large, well-designed controlled trials are needed before a stronger recommendation can be made.        C

Depression (sleep disturbances)
Depression can be associated with neuroendocrine and sleep abnormalities, such as reduced time before dream sleep (REM latency). Melatonin has been suggested for the improvement of sleep patterns in patients with depression, although research is limited in this area. Further studies are needed before a clear conclusion can be reached.     C

Glaucoma
It has been theorized that high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy and myopia, or retinal damage. However, there is preliminary evidence that melatonin may actually decrease intraocular pressure in the eye, and it has been suggested as a possible therapy for glaucoma. Additional study is necessary in this area. Patients with glaucoma taking melatonin should be monitored by a healthcare professional. C

Headache prevention
Several small studies have examined the possible role of melatonin in preventing various forms of headache, including migraine, cluster and tension-type headache (in people who suffer from regular headaches). Limited initial research suggests possible benefits in all three types of headache, although well-designed controlled studies are needed before a firm conclusion can be drawn.             C

High blood pressure (hypertension)
Several controlled studies in patients with high blood pressure report small reductions blood pressure when taking melatonin by mouth (orally) or inhaled through the nose (intranasally). Better-designed research is necessary before a firm conclusion can be reached.    C

HIV/AIDS
There is a lack of well-designed scientific evidence to recommend for or against the use of melatonin as a treatment for AIDS. Melatonin should not be used in place of more proven therapies, and patients with HIV/AIDS should be treated under the supervision of a medical doctor.       C

Inflammatory bowel disease (IBS)
Based on preliminary study, melatonin is a promising therapeutic agent for IBS. Further research is needed before a recommendation can be made.     C

Insomnia (of unknown origin in the non-elderly)
Study results have been inconsistent, with some studies reporting benefits on sleep latency and subjective sleep quality, and other research finding no benefits. Most studies have been small and not rigorously designed or reported. Better research is needed before a firm conclusion can be drawn.Notably, several studies in elderly individuals with insomnia provide preliminary evidence of benefits on sleep latency (discussed above).   C

Parkinson's disease
Due to very limited study to date, a recommendation cannot be made for or against the use of melatonin in Parkinsonism or Parkinson's disease. Better-designed research is needed before a firm conclusion can be reached in this area.            C

Periodic limb movement disorder
There is very limited study to date for the use of melatonin as a treatment in periodic limb movement disorder. Better-designed research is needed before a recommendation can be made in this area.             C

Preoperative sedation / anxiolysis
Results are promising, with similar results reported for melatonin as for benzodiazepines such as midazolam (Versed®), and superiority to placebo. There are also promising reports using melatonin for sedation/anxiolysis prior to magnetic resonance imaging (MRI). However, due to weaknesses in the design and reporting of the available research, better studies are needed before a clear conclusion can be drawn.Melatonin has also been suggested as a treatment for delirium following surgery, although there is little evidence in this area.     C

REM sleep behavior disorder
Limited case reports describe benefits in patients with REM sleep behavior disorder who receive melatonin. However, better research is needed before a clear conclusion can be drawn.     C

Rett syndrome
Rett syndrome is a presumed genetic disorder that affects female children, characterized by decelerated head growth and global developmental regression. There is limited study of the possible role of melatonin in improving sleep disturbance associated with Rett syndrome. Further research is needed before a recommendation can be made in this area.        C

Schizophrenia (sleep disorders)
There is limited study of melatonin for improving sleep latency (time to fall asleep) In patients with schizophrenia. Further research is needed in this area before a clear conclusion can be reached.   C

Seasonal affective disorder (SAD)
There are several small, brief studies of melatonin in patients with SAD. This research is not well designed or reported, and further study is necessary before a clear conclusion can be reached.           C

Seizure disorder (children)
The role of melatonin in seizure disorder is controversial. Better evidence is needed in this area before a clear conclusion can be drawn regarding the safety or effectiveness of melatonin in seizure disorder.        C

Sleep disturbances due to pineal region brain damage
Several published cases report improvements in sleep patterns in young people with damage to the pineal gland area of the brain due to tumors or surgery. Due to the rarity of such disorders, controlled trials may not be possible. Consideration of melatonin in such patients should be under the direction of a qualified healthcare provider. C

Sleep in asthma
Based on preliminary study, melatonin may improve sleep in patients with asthma. Further studies looking into long-term effects of melatonin on airway inflammation and bronchial hyper-responsiveness are needed before melatonin can be recommended.     C

Smoking cessation
Although preliminary results are promising, due to weaknesses in the design and reporting of this research, further study is necessary before a firm conclusion can be reached.   C

Stroke
At this time, the effects of melatonin supplements immediately after stroke are not clear.         C

Tardive dyskinesia
Tardive dyskinesia (TD) is a serious potential side effect of antipsychotic medications, characterized by involuntary muscle movements. Limited small studies of melatonin use in patients with TD report mixed findings. Additional research is necessary before a clear conclusion can be drawn.     C

Thrombocytopenia (low platelets)
Increased platelet counts after melatonin use have been observed in patients with decreased platelets due to cancer therapies (several studies reported by the same author). Stimulation of platelet production (thrombopoeisis) has been suggested but not clearly demonstrated. Additional research is necessary in this area before a clear conclusion can be drawn.     C

Ultraviolet light skin damage protection
It has been proposed that antioxidant properties of melatonin may be protective. Further study is necessary before a clear conclusion can be drawn about clinical effectiveness in humans.   C

Work shift sleep disorder
There are several studies of melatonin use in people who work irregular shifts, such as emergency room personnel. Results are mixed. Additional research is necessary before a clear conclusion can be drawn.           C

*Key to grades
A: Strong scientific evidence for this use;
B: Good scientific evidence for this use;
C: Unclear scientific evidence for this use;
D: Fair scientific evidence against this use;
F: Strong scientific evidence against this use.

Uses based on tradition or theory
The below uses are based on tradition or scientific theories. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Acetaminophen toxicity, acute respiratory distress syndrome (ARDS), aging, aluminum toxicity, asthma, beta-blocker sleep disturbance, cancer prevention, cardiac syndrome X, cognitive enhancement, colitis, contraception, critical illness/ICU sleep disturbance, depression, edema (swelling), duodenal ulcer, erectile dysfunction, fibromyalgia, gastroesophageal reflux disease (GERD), gentamicin-induced kidney damage, glaucoma, heart attack prevention, heart disease, hyperpigmentation, immunostimulant, interstitial cystitis, intestinal motility disorders, itching, kidney damage (amikacin-induced, cyclosporin-induced), lead toxicity, liver damage, melatonin deficiency, memory enhancement, multiple sclerosis, neurodegenerative disorders, noise-induced hearing loss, pancreatitis, polycystic ovarian syndrome (PCOS), postmenopausal osteoporosis, post-operative adjunct, post-operative delirium, prevention of post-lung transplant ischemia-reperfusion injury, rheumatoid arthritis, sarcoidosis, sedation, sexual activity enhancement, schistosomiasis, sudden infant death syndrome (SIDS) prevention, tachycardia, tinnitus (ringing in the ears), tuberculosis, tuberous sclerosis, ulcerative colitis, wasting, withdrawal from narcotics, wound healing.

Dosing
The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.

Adults (18 years and older)
Studies have evaluated 0.5-50 milligrams of melatonin taken nightly by mouth. Research suggests that quick-release melatonin may be more effective than sustained-release formulations for sleep related conditions. Intramuscular injections of 20 milligrams of melatonin have also been studied.

In studies of patients with melanoma, melatonin preparations have been applied to the skin. Patients are advised to discuss cancer treatment plans with an oncologist and pharmacist before considering use of melatonin either alone or with other therapies.

Intranasal melatonin (1% solution in ethanol) at a dose of 2 milligrams daily for one week has also been studied for high blood pressure.

There are other uses with limited study and unclear effectiveness or safety. Use of melatonin for any condition should be discussed with a primary healthcare provider, appropriate specialist and pharmacist prior to starting and should not be substituted for more proven
therapies.

Children (younger than 18 years)
There is limited study of melatonin supplements in children, and safety is not established. Use of melatonin should be discussed with the child's physician and pharmacist prior to starting.

Safety
The U.S. Food and Drug Administration does not strictly regulate herbs and supplements.

There is no guarantee of strength, purity or safety of products, and effects may vary. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy. Consult a healthcare provider immediately if you experience side effects.

Allergies
There are rare reports of allergic skin reactions after taking melatonin by mouth. Melatonin has been linked to a case of autoimmune hepatitis.

Side Effects and Warnings
Based on available studies and clinical use, melatonin is generally regarded as safe in recommended doses for short-term use. Available trials report that overall adverse effects are not significantly more common with melatonin than placebo. However, case reports raise concerns about risks of blood clotting abnormalities (particularly in patients taking warfarin), increased risk of seizure, and disorientation with overdose.
 
Commonly reported adverse effects include fatigue, dizziness, headache, irritability, and sleepiness, although these effects may occur due to jet-lag and not to melatonin itself. Fatigue may particularly occur with morning use or high doses, and irregular sleep-wake cycles may occur. Disorientation, confusion, sleepwalking, vivid dreams and nightmares have also been noted, with effects often resolving after cessation of melatonin. Due to risk of daytime sleepiness, those driving or operating heavy machinery should take caution. Headache has been reported. Ataxia (difficulties with walking and balance) may occur following overdose.

It has been suggested that melatonin may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders. However, multiple other studies actually report reduced incidence of seizure with regular melatonin use. This remains an area of controversy. Patients with seizure disorder taking melatonin should be monitored closely by a healthcare professional.

Mood changes have been reported, including giddiness and dysphoria (sadness). Psycho-tic symptoms have been reported, including hallucinations and paranoia, possibly due to overdose. Patients with underlying major depression or psychotic disorders taking mela-tonin should be monitored closely by a healthcare professional.
 
Melatonin should be avoided in patients using warfarin, and possibly in patients taking other blood-thinning medications or with clotting disorders.

Melatonin may cause drops in blood pressure. Caution is advised in patients taking medications that may also lower blood pressure. Based on preliminary evidence, increases in cholesterol levels may occur. Caution is therefore advised in patients with high cholesterol levels, atherosclerosis, or at risk for cardiovascular disease. Abnormal heart rhythms have been associated with melatonin.

Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity. Caution is advised in patients with diabetes or hypoglycemia, and in those taking drugs, herbs, or supplements that affect blood sugar. Serum glucose levels may need to be monitored by a healthcare provider, and medication adjustments may be necessary.

Hormonal effects are reported, including decreases or increases in levels of luteinizing hormone, progesterone, estradiol, thyroid hormone (T4 and T3), growth hormone, prolactin, cortisol, oxytocin and vasopressin. Gynecomastia (increased breast size) has been reported in men, as well as decreased sperm count (both which resolved with cessation of melatonin). Decreased sperm motility has been reported in rats and humans.

Mild gastrointestinal distress commonly occurs, including nausea, vomiting, or cramping. Melatonin has been linked to a case of autoimmune hepatitis and with triggering of Crohn's disease symptoms.

It has been theorized that high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy and myopia, or retinal damage. However, there is preliminary evidence that melatonin may actually decrease intraocular pressure in the eye, and it has been suggested as a possible therapy for glaucoma. Patients with glaucoma taking melatonin should be monitored by a healthcare professional.

Pregnancy and Breastfeeding
Melatonin supplementation should be avoided in women who are pregnant or attempting to become pregnant, based on possible hormonal effects. High levels of melatonin during pregnancy may increase the risk of developmental disorders. In animal studies, melatonin is detected in breast milk and therefore should be avoided during breastfeeding. In men, decreased sperm motility and decreased sperm count are reported with use of melatonin.
Interactions

Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy.

Interactions with Drugs
Melatonin is broken down (metabolized) in the body by liver enzymes. As a result, drugs that alter the activity of these enzymes may increase or decrease the effects of melatonin supplements.

Increased daytime drowsiness is reported when melatonin is used at the same time as the prescription sleep-aid zolpidem (Ambien®), although it is not clear that effects are greater than with the use of zolpidem alone. In theory, based on possible risk of daytime sleepiness, melatonin may increase the amount of drowsiness caused by some other drugs, for example benzodiazepines such as lorazepam (Ativan®) or diazepam (Valium®), barbiturates such as phenobarbital, narcotics such as codeine, some antidepressants, and alcohol. Caution is advised while driving or operating machinery.

Based on preliminary evidence, melatonin should be avoided in patients taking the blood-thinning medication warfarin (Coumadin®), and possibly in patients using other blood-thinners (anticoagulants) such as aspirin or heparin.

Multiple drugs are reported to lower natural levels of melatonin in the body. It is not clear that there are any health hazards of lowered melatonin levels, or if replacing melatonin with supplements is beneficial. Examples of drugs that may reduce production or secretion of melatonin include non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin®, Advil®) or naproxen (Naprosyn®, Aleve®); beta-blocker blood pressure medications such as atenolol (Tenormin®) or metoprolol (Lopressor®, Toprol®); and medications that reduce levels of vitamin B6 in the body (such as oral contraceptives, hormone replacement therapy, loop diuretics, hydralazine, theophylline). Other agents that may alter synthesis or release of melatonin include diazepam, vitamin B12, verapamil, temazepam, and somatostatin.

Based on preliminary evidence, melatonin should be avoided in patients taking anti-seizure medications. It has been suggested that melatonin may lower seizure threshold and increase the risk of seizure. However, multiple other studies actually report reduced incidence of seizure with regular melatonin use. This remains an area of controversy. Patients with seizure disorder taking melatonin should be monitored closely by a healthcare professional.
 
Melatonin may increase or decrease blood pressure; study results conflict. Therefore it may interact with heart or blood pressure medications making close monitoring necessary.

It is not clear if caffeine alters the effects of melatonin supplements in humans. Caffeine is reported to raise natural melatonin levels in the body, possibly due to effects on liver enzymes. However, caffeine may also alter circadian rhythms in the body, with effects on melatonin secretion.

Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity. Caution is advised in patients taking drugs for diabetes by mouth or insulin. Serum glucose levels may need to be monitored by a healthcare provider, and medication adjustments may be necessary.

Alcohol consumption seems to affect melatonin secretion at night.
 
Preliminary reports suggest that melatonin may aid in reversing symptoms of tardive dyskinesia associated with haloperidol use.

Based on preliminary evidence, melatonin may increase the effects of isoniazid against  Mycobacterium tuberculosis.

Based on animal research, melatonin may increase the adverse effects of methamphetamine on the nervous system.

Based on laboratory study, melatonin may increase the neuromuscular blocking effect of the muscle relaxant succinylcholine, but not vecuronium.

Interactions with Herbs & Dietary Supplements
Melatonin may increase daytime sleepiness or sedation when taken with herbs or supplements that may cause sedation.

Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity. Caution is advised when using herbs or supplements that may also raise blood sugar levels, such as arginine, cocoa, DHEA, and ephedra (when combined with caffeine).

Based on preliminary evidence of an interaction with the blood thinning drug warfarin, and isolated reports of minor bleeding, melatonin may increase the risk of bleeding when taken with herbs and supplements that are believed to increase the risk of bleeding.
 
It is not clear if caffeine alters the effects of melatonin supplements in humans. Caffeine is reported to raise natural melatonin levels in the body, possibly due to effects on liver enzymes. However, caffeine may also alter circadian rhythms in the body, with effects on melatonin secretion.

Chasteberry ( Vitex agnus-castus ) may increase natural secretion of melatonin in the body, based on preliminary research.
 
In animal study, DHEA and melatonin have been noted to stimulate immune function, with slight additive effects when used together. Effects of this combination in humans are not clear.

Based on animal study, a combination of echinacea and melatonin may reduce immune function. Effects of this combination in humans are not clear.

Severe folate deficiency may reduce the body's natural levels of melatonin, based on preliminary study.

Methodology
This information is based on a systematic review of the scientific literature, edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com): Serguei Axentsev, MD, PhD, DSci (Natural Standard Research Collaboration); Ethan Basch, MD (Memorial Sloan-Kettering Cancer Center); Heather Boon, BScPhm, PhD (University of Toronto); Michelle Corrado, PharmD (Harvard Vanguard Medical Association); Cynthia Dacey, PharmD (Natural Standard Research Collaboration); Paul Hammerness, MD (Harvard Medical School); Nikos Linardakis, MD (Natural Standard Research Collaboration); Candy Tsourounis, PharmD (University of California, San Francisco); Catherine Ulbricht, PharmD (Massachusetts General Hospital); Mamta Vora, PharmD (Northeastern University); Wendy Weissner, BA (Natural Standard Research Collaboration).


Selected references

1.         Arendt J, Aldhous M, Wright J. Synchronisation of a disturbed sleep-wake cycle in a blind man by melatonin treatment. Lancet 4-2-1988;1(8588):772-773.

2.         Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J, et al. Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci. 2003;28(3):191-196.

3.         Andrade C, Srihari BS, Reddy KP, et al. Melatonin in medically ill patients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2001;62(1):41-45.

4.         Campos FL, Silva-Junior FP, de Bruin VM, et al. Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Am.J.Respir.Crit Care Med. 11-1-2004;170(9):947-951.

5.         Coppola G, Iervolino G, Mastrosimone M, et al. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial. Brain Dev. 2004 Sep;26(6):373-6.

6.         Dowling GA, Mastick J, Colling E, et al. Melatonin for sleep disturbances in Parkinson's disease. Sleep Med. 2005 Sep;6(5):459-66.

7.         Gupta M, Gupta YK, Agarwal S, et al. A randomized, double-blind, placebo controlled trial of melatonin add-on therapy in epileptic children on valproate monotherapy: effect on glutathione peroxidase and glutathione reductase enzymes. Br J Clin Pharmacol. 2004 Nov;58(5):542-7.

8.         Lewy AJ, Lefler BJ, Emens JS, et al. The circadian basis of winter depression. Proc Natl Acad Sci U S A. 2006 May 9;103(19):7414-9.

9.         Lu WZ, Gwee KA, Moochhalla S, et al. Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2005 Nov 15;22(10):927-34.

10.       Peres MF, Zukerman E, da Cunha Tanuri F, et al. Melatonin, 3 mg, is effective for migraine prevention. Neurology. 2004 Aug 24;63(4):757.

11.       Samarkandi A, Naguib M, Riad W, et al. Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study. Eur J Anaesthesiol. 2005 Mar;22(3):189-96.

12.       Shamir E, Barak Y, Shalman I, et al. Melatonin treatment for tardive dyskinesia: a double-blind, placebo- controlled, crossover study. Arch Gen.Psychiatry 2001;58(11):1049-1052.

13.       Shamir EZ, Barak Y, Shalman I, et al. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, cross-over study. Annual Meeting of the American Psychiatric Association, May 5-10 2001.

14.       Weiss MD, Wasdell MB, Bomben MM, et al. Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry. 2006 May;45(5):512-9.

15.       Zemlan FP, Mulchahey JJ, Scharf MB, et al. The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial. J Clin Psychiatry. 2005 Mar;66(3):384-90.
August 01, 2006.

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UNIVERSITY OF MARYLAND MEDICAL CENTER:

Overview
Melatonin is secreted by the pineal gland in the brain and is important in the regulation of many hormones in the body. Among its key roles, melatonin controls the body's circadian rhythm, an internal 24-hour time-keeping system that plays an important role in when we fall asleep and when we wake up. Darkness stimulates the release of melatonin and light suppresses its activity. Normal melatonin cycles are disrupted when we are exposed to excessive light in the evening or too little light during the daytime. For example, jet lag, shift work, and poor vision can disrupt melatonin cycles. In addition, some experts claim that exposure to low-frequency electromagnetic fields (as is common in household appliances) may disrupt normal cycles and production of melatonin.

Melatonin is also one of the hormones that controls the timing and release of female reproductive hormones. As a result, melatonin helps determine when menstruation begins, the frequency and duration of menstrual cycles, and when menstruation ends (menopause). Many researchers also believe that levels of melatonin in the body are related to the aging process. For example, young children have the highest levels of nighttime melatonin and these levels are thought to diminish progressively with age. This decline likely contributes to why many older adults suffer from disrupted sleep patterns and tend to go to bed earlier and wake up earlier in the morning than when they were younger. However, emerging research is bringing the idea of diminished melatonin levels in the elderly into some question. Therefore, those considering use of this supplement should first talk to their healthcare provider about having blood levels of melatonin checked.

In addition to its hormone actions, melatonin also has strong antioxidant properties and preliminary evidence suggests that it may help strengthen the immune system. Because melatonin is a potent hormone, it's advisable to check with a healthcare provider before using it as an antioxidant supplement.

Uses of Melatonin:

How to Take It
There is currently no recommended dose range for melatonin supplements. Different people will be more sensitive or less sensitive to its effects. For those especially sensitive, lower doses may work effectively while a higher dose could cause anxiety and irritability. The best approach for any condition is to begin with very low doses of melatonin that match the amounts our bodies normally make on a daily basis (< 0.3 mg) and keep the dose to a minimum. Your healthcare provider can help guide what is best and most appropriate, including how to increase the amount as needed.

Pediatric
•          Less than 0.3 mg/day
Although studies including small numbers of children suggest that doses of 1-10 mg melatonin have little to no side effects, there is not enough information at this point to clearly say that doses greater than 0.3 mg per day are safe in children under age 15. In fact, doses between 1 to 5 mg may cause seizures in this age group. Until more information is available, it is safest to keep the dose close to the amount that our bodies normally produce (< 0.3 mg per day).

Adult
•          Insomnia: 3 mg one hour before bedtime is usually effective, although doses as low as 0.1 to 0.3 mg may improve sleep for some people. If 3 mg per night is not effective after three days, try 5-6 mg one hour before bedtime. An effective dose should produce restful sleep with no daytime irritability or fatigue.

•          Jet lag: 0.5 to 5 mg of melatonin one hour prior to bedtime at final destination has been successful in several studies. Another approach that has been used clinically is 1 to 5 mg one hour before bedtime for two days prior to departure and for 2 to 3 days upon arrival at final destination.

•          Sarcoidosis: 20 mg per day for 4 to 12 months. Use of melatonin to treat this specific health condition should only be done under medical supervision. Do not take melatonin supplements long-term without consulting your healthcare provider.

•          Depression: 0.125 mg twice in the late afternoon, each dose four hours apart (for example, 4 PM and 8 PM). People with depression tend to be particularly sensitive to the effects of melatonin -- meaning that a very low dose is generally enough to get the desired outcomes.

Precautions
Because of the potential for side effects and interactions with medications, dietary supplements should be taken only under the supervision of a knowledgeable healthcare provider.

Some people may experience vivid dreams or nightmares when they take melatonin. Overuse or incorrect use of melatonin could disrupt circadian rhythms. Melatonin can cause drowsiness if taken during the day. Individuals experiencing morning drowsiness after taking melatonin at night should take less of the supplement. Additional side effects that have been reported from melatonin include stomach cramps, dizziness, headache, irritability, decreased libido, breast enlargement in men (called gynecomastia), and decreased sperm count.

Melatonin could interfere with fertility and also should not be taken by pregnant or nursing women.

A 1973 study including only 4 people with depression found that melatonin supplements actually worsened symptoms of the condition. For this reason, individuals with depression should consult a healthcare practitioner before using melatonin supplements.
Although many researchers believe that levels of melatonin diminish with age, emerging evidence has brought this theory into question. Given these inconsistent findings, people older than 65 years of age should consult a healthcare practitioner before taking melatonin supplements so that blood levels of this hormone can be monitored appropriately.

Possible Interactions
If you are currently being treated with any of the following medications, you should not use melatonin without first talking to your healthcare provider.

Antidepressant Medications
In an animal study, melatonin supplements reduced the antidepressant effects of desipramine and fluoxetine. More research is needed to determine whether these effects would occur in people. In addition, fluoxetine (a member of a class of drugs called selective serotonin reuptake inhibitors or SSRIs) has led to measurable depletion of melatonin in people.

Antipsychotic Medications
A common side effect of antipsychotic medications used to treat schizophrenia is a condition called tardive dyskinesia, a movement disorder of the mouth characterized by a constant chewing motion and darting action of the tongue. In a study of 22 people with schizophrenia and tardive dyskinesia caused by antipsychotic medications, those who took melatonin supplements had significantly reduced mouth movements compared to those who did not take the supplements.

Benzodiazepines
The combination of melatonin and triazolam (a benzodiazepine medication used for the treatment of anxiety and sleep disorders) improved sleep quality in one study. In addition, there have been a few reports suggesting that melatonin supplements may help individuals stop using long-term benzodiazepine therapy. (Benzodiazepines are highly addictive.)

Blood Pressure Medications
Melatonin may reduce the effectiveness of blood pressure medications like methoxamine and clonidine. In addition, medications in a class called calcium channel blockers (such as nifedipine, verapamil, diltiazem, amlodipine, nimodipine, felodipine, nisoldipine, and bepridil) may decrease melatonin levels.

Use of beta-blockers (another class of high blood pressure medications including propranolol, acebutolol, atenolol, labetolol, metoprolol, pindolol, nadolol, sotalol, and timolol) may reduce melatonin production in the body.

Blood-thinning Medications, Anticoagulants
Melatonin may increase the risk of bleeding from anticoagulant medications such as warfarin.

Interleukin-2
In one study of 80 cancer patients, use of melatonin in conjunction with interleukin-2 led to more tumor regression and better survival rates than treatment with interleukin-2 alone.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs such as ibuprofen may reduce the levels of melatonin in the blood.
Steroids and Immunosuppressant Medications
Melatonin should not be taken with corticosteroids or other medications used to suppress the immune system because the supplement may cause them to be ineffective.

Tamoxifen
Preliminary research suggests that the combination of tamoxifen (a chemotherapy drug) and melatonin may benefit certain patients with breast and other cancers. More research is needed to confirm these results.

Other Substances
Caffeine, tobacco, and alcohol can all diminish levels of melatonin in the body while cocaine and amphetamines may increase melatonin production.


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Review Date: April 2002

Reviewed By: Participants in the review process include: Ruth DeBusk, RD, PhD, Editor, Nutrition in Complementary Care, Tallahassee, FL; Jacqueline A. Hart, MD, Department of Internal Medicine, Newton-Wellesley Hospital, Harvard University and Senior Medical Editor Integrative Medicine, Boston, MA; Gary Kracoff, RPh (Pediatric Dosing section February 2001), Johnson Drugs, Natick, Ma; Steven Ottariono, RPh (Pediatric Dosing section February 2001), Veteran's Administrative Hospital, Londonderry, NH. All interaction sections have also been reviewed by a team of experts including Joseph Lamb, MD (July 2000), The Integrative Medicine Works, Alexandria, VA;Enrico Liva, ND, RPh (August 2000), Vital Nutrients, Middletown, CT; Brian T Sanderoff, PD, BS in Pharmacy (March 2000), Clinical Assistant Professor, University of Maryland School of Pharmacy; President, Your Prescription for Health, Owings Mills, MD; Ira Zunin, MD, MPH, MBA (July 2000), President and Chairman, Hawaii State Consortium for Integrative Medicine, Honolulu, HI.

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