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Melatonin


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Melatonin

Background

Melatonin is a neurohormone 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 (1-9), 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 (10-12).

Synonyms

5-Methoxy-N-acetyltryptamine, acetamide, BMS-214778, luzindole, mel, MEL, melatonine, MLT, N-acetyl-5-methoxytryptamine, N-2- (5-methoxyindol-3-ethyl) -acetamide.

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 evidenceGrade*Jet lag
Several randomized, placebo controlled human trials suggest that melatonin taken by mouth, started on the day of travel (close to the target bedtime at the destination) and continued for several days, reduces the number of days required to establish a normal sleep pattern, diminishes the time it takes to fall asleep ("sleep latency"), improves alertness, and reduces daytime fatigue (13-21). Effects may be greatest when traveling eastward, and when crossing more than four time zones (results may be less impressive for westward travel or crossing of fewer time zones) (15;16). Combination with prescription sleep aids such as zolpidem (Ambien«) may add to these effects, although side effects such as morning sleepiness may occur (21). Although these results are compelling, the majority of studies have had methodological problems with their designs and reporting, and some trials have not found benefits (22;23). Overall, the scientific evidence does suggest benefits of melatonin in up to half of people who take it for jet-lag (number needed to treat = 2) (13;17;18). Further well-designed trials are necessary to confirm these findings, to determine optimal dosing, and to evaluate use in combination with prescription sleep aids. Preliminary research reports that starting melatonin on the day of travel, rather than prior to travel, may yield superior results. Higher doses (such as 5 milligrams nightly) may be slightly more effective than lower doses (for example, 0.1 to 0.5 milligrams nightly) for improvement of sleep quality and latency (18), although this area remains controversial with some studies suggesting no differences (17;23). Slow-release melatonin may not be as effective as standard (quick release) formulations (20). If the dose is taken too early in the day, it may actually result in excessive daytime sleepiness and greater difficulty adapting to the destination time zone.

A

Delayed sleep phase syndrome (DSPS)
Delayed sleep phase syndrome is a condition that results in delayed sleep onset, despite normal sleep architecture and sleep duration. Several small controlled studies and case series in healthy volunteers and in patients with delayed sleep phase syndrome have used 5 to 6 milligrams of melatonin, with reported improvements in sleep latency (24-28). Although these results are promising, additional research with large, well-designed controlled studies is needed before a stronger recommendation can be made.

B

Sleep disturbances in children with neuro-psychiatric disorders
There are multiple controlled trials and several case reports of melatonin use in children with various neuro-psychiatric disorders, including mental retardation, autism, psychiatric disorders, visual impairment, or epilepsy (29-47). Studies have demonstrated reduced time to fall asleep (sleep latency) and increased sleep duration. Oral doses of melatonin have ranged between 2.5 and 10 milligrams administered at the desired bedtime. Well-designed controlled trials in select patient populations are needed before a stronger or more specific recommendation can be made.

B

Insomnia in the elderly
Several human studies report that melatonin taken by mouth 30 to 120 minutes prior to bedtime decreases the amount of time it takes to fall asleep ("sleep latency") in elderly individuals with insomnia (48-56). It is not clear if melatonin increases the length of time that people are able to stay asleep. Low doses (0.1 to 0.3 milligrams taken nightly) appear to be equally effective as higher doses (3 to 5 milligrams nightly). However, most studies have not been high quality in their designs and some research has found limited or no benefits (57;58). The majority of trials have been brief in duration (several days long), and long-term effects are not known. Although the evidence overall does suggest short-term benefits, additional study is needed before a strong recommendation can be made. It is not known how melatonin compares to standard therapies used for insomnia, such as benzodiazepines like diazepam (Valium«) and lorazepam (Ativan«), or other sleep aids such as zolpidem (Ambien«).

B

Sleep enhancement in healthy people
Multiple human studies have measured the effects of melatonin supplements on sleep in healthy individuals (59;60;60;61;61;62;62;63;63;64;64-74). A wide range of doses has been used, including "low-dose" melatonin (0.1 to 1.0 milligrams), or doses between 5 and 10 milligrams, often taken by mouth 30 to 60 minutes prior to sleep time. Most trials have been small, brief in duration (often single-dose studies), and have not been rigorously designed or reported (inadequate blinding and randomization). However, the weight of scientific evidence does suggest that melatonin decreases the time it takes to fall asleep ("sleep latency"), increases the feeling of "sleepiness," and may increase the duration of sleep. Better quality research is needed in this area. It is not known how melatonin compares to standard therapies used for insomnia, such as benzodiazepines like diazepam (Valium«) and lorazepam (Ativan«), or other sleep aids such as zolpidem (Ambien«).

B

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) (75-77). It has been reported that natural melatonin levels are altered in people with Alzheimer's disease (78-81), 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 (1-9). As a result, melatonin has been proposed as a supplement to prevent or treat many conditions that are associated with oxidative damage. However, there are no well-designed trials in humans that have demonstrated benefits of melatonin as an antioxidant for any health problem.

C

Attention deficit hyperactivity disorder (ADHD)
There is limited research of the use of melatonin in children with ADHD (82). 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«) (83-86). 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

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) (87;88). 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 (89-117). Many of these studies have been conducted by the same research group. In this research, melatonin has been combined with other types of treatment, including radiation therapy (107), chemotherapies (such as cisplatin, etoposide, or irinotecan) (92;110;113;118;118-122), hormonal treatments (such as tamoxifen) (106;123;124), or immune therapies such as interferon (125), Interleukin-2 (102;126-144), or tumor necrosis factor (135;145;146). Most of these trials have been published by the same research group, and have involved giving melatonin orally, intravenously, or injected into muscle. Results have been mixed, with some patients stabilizing and others progressing. There are some promising reported results, including small significant improvements in the survival of patients with non-small cell lung cancer given oral melatonin with chemotherapy (cisplatin and etoposide). However, the design and results of this research are not sufficient to provide definitive evidence in favor of safe/effective use of melatonin in cancer patients. High-quality follow-up trials are necessary to confirm these preliminary results. It has been proposed that melatonin may benefit cancer patients through antioxidant, immune-enhancing, hormonal, anti-inflammatory, anti-angiogenic, apoptotic, or direct cytotoxic (cancer cell-killing) effects, and there are many ongoing laboratory and animal studies in these areas. Some experts believe that antioxidants can improve the effectiveness of chemotherapy drugs and reduce side effects, while others suggest that antioxidants may actually interfere with the effectiveness of chemotherapies. 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 (such as carboplatin, cisplatin, daunorubicin, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, and mitoxantrone) (92;104;108;110;113;118-122). Most of these studies are published by the same research group, and involve giving melatonin through the veins or injected into muscle. Studies have included patients with advanced lung, breast, gastrointestinal, prostate, and head/neck cancers, as well as lymphoma. Promising early results include reductions in nerve injury (neuropathy), mouth sores (stomatitis), wasting (cachexia), and platelet count drops (thrombocytopenia) with various chemotherapy agents. Animal studies note reduced severity of heart damage from anthrocycline drugs (147-151) or lung damage from bleomycin (152;153). Some researchers attribute these reported benefits to antioxidant properties of melatonin. Overall, it remains controversial whether antioxidants increase effectiveness and reduce side effects of chemotherapies, or whether antioxidants actually reduce effectiveness of chemotherapies. 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) (113;115;120-122;130;131), and stimulation of platelet production (thrombopoeisis) has been suggested but not clearly demonstrated. 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)
In blind individuals, light and dark stimuli are not received by the eye to trigger melatonin release and the onset of sleep. In these patients, natural melatonin levels peak at a different hour every night to the point where individuals may sleep during the day and awake at night. This is commonly referred to as "free running" circadian rhythm. There are multiple published small case series and case reports in the literature, yet limited controlled trials to date in this population (154-167). 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 (168-171). Further studies are needed before a clear conclusion can be reached.

C

Glaucoma
It has been theorized that due to effects on photoreceptor renewal in the eye, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy and myopia (172), or retinal damage (173). 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 (174;175). 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) (176-179). 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 in diastolic and systolic blood pressure when taking melatonin by mouth (orally) or inhaled through the nose (intranasally) (180-184). Most trials have been small and not well designed or reported. 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 (185). Melatonin should not be used in place of more proven therapies, and patients with HIV/AIDS are advised to be treated under the supervision of a medical doctor.

C

Insomnia (of unknown origin in the non-elderly)
There are several small controlled human trials and pilot research of melatonin taken by mouth in people with insomnia (186-193). 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) (48-56;58).

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 (194) or Parkinson's disease (195-197). 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 (198). Better-designed research is needed before a recommendation can be made in this area.

C

Preoperative sedation / anxiolysis
A small number of controlled studies has compared melatonin with placebo and standard drugs (benzodiazepines) for sedation and anxiety reduction (anxiolysis) prior to general anesthesia for surgery (199-202). 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 (203).

C

REM sleep behavior disorder
Limited case reports describe benefits in patients with REM sleep behavior disorder who receive melatonin (204;205). However, better research is needed before a clear conclusion can be drawn.

C

Rett's syndrome
Rett's 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's syndrome (206;207). 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 (208;209). 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 (59;210-213). 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. There are several reported cases of children with intractable seizures or neurologic damage who improved with regular nighttime melatonin administration (214-219). Limited animal research also suggests possible anti-seizure effects (220;221). However, there has also been a report that melatonin may actually lower seizure threshold and increase the risk of seizures (222). 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 (223-225). 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

Smoking cessation
A small amount of research has examined the use of melatonin to reduce symptoms associated with smoking cessation, such as anxiousness, restlessness, irritability, and cigarette craving. 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
It has been proposed that melatonin may reduce the amount of neurologic damage patients experience after stroke, based on antioxidant properties (226-233). In addition, melatonin levels may be altered in people immediately after stroke (234;235), and it has thus been suggested that melatonin supplementation may be beneficial, although this has not been shown in humans. 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 (236-242). Additional research is necessary before a clear conclusion can be drawn (236).

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) (113;115;120-122;130;131). 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. Cases of idiopathic thrombocytopenic purpura (ITP) treated with melatonin have been reported (243;244).

C

Ultraviolet light skin damage protection
Several small, randomized trials have examined the use of melatonin in protecting human skin against UV-light damage (245-248). It has been proposed that antioxidant properties of melatonin may be protective. Although this preliminary research reports reductions in erythema (skin redness) with the use of melatonin, 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 (249-255). Results are mixed, with some studies finding no significant benefits, and others reporting benefits in sleep quality compared to placebo. Because most published trials are small, with incomplete reporting of design or results, 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 (it may not work);
F:
Strong scientific evidence against this use (it likely does not work).

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 (256), acute respiratory distress syndrome (ARDS) (257), aging, aluminum toxicity, Alzheimer's disease, amikacin-induced kidney damage (258), asthma, beta-blocker sleep disturbance (259;260), cachexia, cancer prevention (261), cardiac syndrome X, cognitive enhancement, colitis, contraception, coronary artery disease, critical illness/ICU sleep disturbance, cyclosporin-induced kidney toxicity (262), depression, edema, erectile dysfunction, fibromyalgia, itching, intestinal motility disorders, lead toxicity, gastroesophageal reflux disease (GERD), gentamicin-induced kidney damage, glaucoma, heart attack prevention (263;264), hyperpigmentation, immunostimulant, interstitial cystitis, lead toxicity (265), melatonin deficiency, memory enhancement, multiple sclerosis, neurodegenerative disorders, noise-induced hearing loss, pancreatitis, polycystic ovarian syndrome (PCOS) (266), postmenopausal osteoporosis, post-operative adjunct, post-operative delirium (203), prevention of post-lung transplant ischemia-reperfusion injury, rheumatoid arthritis, sarcoidosis, sedation, sexual activity enhancement, schistosomiasis (267), sudden infant death syndrome (SIDS) prevention, tachycardia, tinnitus, toxic kidney damage, toxic liver damage, tuberculosis (268), tuberous sclerosis, ulcerative colitis (269;270), withdrawal from narcotics, wound healing (271).

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.

Standardization

Standardization involves measuring the amount of certain chemicals in products to try to make different preparations similar to each other. It is not always known if the chemicals being measured are the "active" ingredients. There is no widely accepted standardization for melatonin. Experts have noted that most brands contain impurities that cannot be characterized, as well as dissimilar amounts of actual hormone.

In 2002, ConsumerLab.com evaluated 18 melatonin-containing supplements (15 quick-release and 3 time-release products), of which 12 were melatonin-only products. It was reported that 16 of the 18 products contained between 100-135% of the claimed amount of melatonin, one rapid-release product contained only 83% of the claimed amount of melatonin, and another rapid-release product contained a small amount of lead (slightly more than 0.5 micrograms per daily recommended serving size). Among the 12 melatonin-only products that "passed" these standards are: Nature's Bounty« Melatonin 1mg and 3mg tablets, Puritan's Pride« Inspired by Nature« Melatonin 3mg tablets, Twinlab« Melatonin Caps, Highest Quality, Quick Acting 3mg tablets. Further information is available at www.ConsumerLab.com.

Adults (18 years and older)

Alzheimer's Disease (sleep disturbances) : Studies have evaluated 0.5 milligrams of melatonin taken nightly by mouth one hour prior to sleep.

Bipolar disorder (sleep disturbances) : Studies have evaluated 10 milligrams of melatonin taken nightly by mouth.

Cancer : Various doses of melatonin have been studied in patients with cancer, usually given in addition to other standard treatments such as chemotherapy, radiation therapy, or immune therapy. Oral doses have ranged between 10 and 50 milligrams taken nightly, with the most common dose being 20 milligrams nightly. 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 before considering use of melatonin either alone or with other therapies. Safety and effectiveness are not proven, and melatonin should not be used instead of more proven therapies.

Circadian rhythm entraining (in blind persons) : 5 to10 milligrams of melatonin taken by mouth, administered in the evening, has been studied in blind patients to set the circadian rhythm to a 24-hour schedule.

Critical illness/ICU sleep disturbance : Studies have evaluated 3 milligrams of melatonin taken nightly by mouth.

Delayed sleep phase syndrome : 5 milligrams of melatonin given by mouth five hours prior to bedtime have been studied.

Depression (sleep disturbances) : Studies have evaluated 5 milligrams of melatonin taken nightly by mouth.

Headache prevention : Studies have evaluated regular use of 5 to 10 milligrams of melatonin taken nightly by mouth.

Hypertension : Studies have evaluated 1 to 3 milligrams of melatonin taken daily by mouth for short periods of time. Intranasal melatonin (1% solution in ethanol) at a dose of 2 milligrams daily for one week has also been studied.

Insomnia in the elderly : Studies have evaluated melatonin taken by mouth 30 to 120 minutes prior to bedtime for insomnia in the elderly. Low doses (0.1 to 0.3 milligrams taken nightly) appear to be equally effective as higher doses (3 to 5 milligrams nightly).

Insomnia of unknown origin (in the non-elderly) : Doses ranging from 1 to 5 milligrams taken by mouth shortly before bedtime have been studied.

Jet lag : Melatonin is usually started on the day of travel (close to the target bedtime at the destination), then taken every 24 hours for several days. Various doses have been used and studied, including low doses between 0.1-0.5 milligrams (20), a more common dose of 5 milligrams (13-15;19;20), and a higher dose of 8 milligrams (17). Overall, 0.5 milligrams appears to be slightly less effective than 5 milligrams for improvement of sleep quality and latency (18), although this area remains controversial and other research suggests no differences (17;23). Slow-release melatonin may not be as effective as standard (quick release) formulations (20). If the dose is taken too early in the day, it may actually result in excessive daytime sleepiness and greater difficulty adapting to the destination time zone.

Schizophrenia (sleep disturbances) : Studies have evaluated 2 milligrams of controlled-release melatonin taken by mouth for three weeks.

Seasonal affective disorder : Studies have evaluated 0.25 to 5 milligrams of melatonin daily by mouth.

Sleep enhancement in healthy people : Various doses of melatonin taken by mouth 30 to 60 minutes before bedtime have been studied and reported to have beneficial effects, including 0.1, 0.3, 1, 3, 5, and 6 milligram doses. Studies report that 0.1 to 0.3 milligrams may produce melatonin levels in the body within the normal physiologic range of nighttime melatonin, and may be sufficient. Research suggests that quick-release melatonin may be more effective than sustained-release formulations.

Other : There are other uses with limited study and unclear effectiveness or safety. Use of melatonin for these conditions should be discussed with a primary healthcare provider and should not be substituted for more proven therapies.

Children (younger than 18 years)

General : 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 prior to starting.

Circadian rhythm entraining in blind children : Studies have evaluated 2.5 to 10 milligrams of melatonin taken nightly at the desired bedtime.

Seizure disorder in children : Studies have evaluated 5 to 10 milligrams of melatonin taken nightly. Research is limited in this area, and there are other reports that melatonin may actually increase risk of seizure or lower seizure threshold. Therefore, caution is advised, and use of melatonin should be discussed with the child's physician.

Sleep disturbances in children with neuro-psychiatric disorders (mental retardation, autism, psychiatric disorders) : Studies have evaluated 0.5 to 10 milligrams of melatonin taken nightly for reduced sleep latency and increased sleep duration. Fast release melatonin may be most useful for sleep induction and the slow release formulation for sleep maintenance.

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 (172;272). Melatonin has been linked to a case of autoimmune hepatitis (273).

Side Effects and Warnings

General : 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 (18;20;21). However, case reports raise concerns about risks of blood clotting abnormalities (particularly in patients taking warfarin), increased risk of seizure, and disorientation with overdose.

Neurologic (general) : Commonly reported adverse effects include fatigue, dizziness, headache, irritability, and sleepiness (20;194;274), although these effects may occur due to jet-lag and not to melatonin itself. Fatigue may particularly occur with morning use or high doses (greater than 50mg) (275), and irregular sleep-wake cycles may occur (276). Disorientation, confusion, sleepwalking, vivid dreams and nightmares have also been noted, with effects often resolving after cessation of melatonin (18;167;277-279). Due to risk of daytime sleepiness, caution should be taken by those driving or operating heavy machinery (274;275;277;278;280). Headache has been reported (189;279). Ataxia (difficulties with walking and balance) may occur following overdose (279).

Neurologic (seizure risk) : It has been suggested that melatonin may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders, as reported in 4 out of 6 children in one study (222), and in an adult in whom symptoms recurred when melatonin was given a second time (279). However, multiple other studies actually report reduced incidence of seizure with regular melatonin use (214-219). This remains an area of controversy (281). Patients with seizure disorder taking melatonin should be monitored closely by a healthcare professional.

Psychiatric : Mood changes have been reported, including giddiness and dysphoria (sadness) (282). Psychotic symptoms have been reported in at least two cases, including hallucinations and paranoia, possibly due to overdose (18;283). Patients with underlying major depression or psychotic disorders taking melatonin should be monitored closely by a healthcare professional.

Hematologic (blood clotting abnormalities) : There are at least six reported cases of alterations in prothrombin time (a measurement of blood clotting ability) in patients taking both melatonin and the blood-thinning medication warfarin (Coumadin«) (279). These cases have noted decreases in prothrombin time (PT), which would tend to decrease the effects of warfarin and increase the risk of blood clots. However, blood clots have not been noted in these patients. Rather, minor bleeding was noted in two of these cases (nosebleed and internal eye bleed), which may have been due to the blood-thinning effects of warfarin alone without a relationship to use of melatonin, or possibly to an interaction between melatonin and warfarin. It is not known if melatonin has effects on blood clotting in people who are not taking warfarin. Based on these reports, melatonin should be avoided in patients using warfarin, and possibly in patients taking other blood-thinning medications or with clotting disorders (173).

Cardiovascular : Melatonin may cause drops in blood pressure, as observed in animals (284) and in preliminary human research (285-289). Whether these reductions in blood pressure are clinically relevant is not clear. Caution is advised in patients taking medications that may also lower blood pressure. Based on preliminary evidence, increases in cholesterol levels may occur. Preliminary research suggests that regular use of melatonin may increase atherosclerotic plaque buildup in humans (290) and animals (291-293). Caution is therefore advised in patients with high cholesterol levels, atherosclerosis, or at risk for cardiovascular disease. There are several poorly described reports of abnormal heart rhythms, fast heart rate, or chest pain, although in most cases patients were taking other drugs that could account for these symptoms (18;279).

Endocrine (blood sugar elevations) : Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) (172;294), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity (295). 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.

Endocrine (hormonal effects) : Hormonal effects are reported, including decreases or increases in levels of luteinizing hormone (223;296-299), progesterone (300), estradiol, thyroid hormone (T4 and T3) (301), growth hormone, prolactin (280), cortisol, oxytocin and vasopressin, although there are other reports of no significant hormonal effects (55;302-305). Variations may occur based on underlying patient characteristics. Gynecomastia (increased breast size) has been reported in men, as well as decreased sperm count (both which resolved with cessation of melatonin) (173). Decreased sperm motility has been reported in rats (306) and humans (307).

Gastrointestinal : Mild gastrointestinal distress commonly occurs, including nausea, vomiting, or cramping (172). Melatonin has been linked to a case of autoimmune hepatitis (273) and with triggering of Crohn's disease symptoms (308).

Ocular (glaucoma) : It has been theorized that due to effects on photoreceptor renewal in the eye, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy and myopia (172), or retinal damage (173). 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 (174;175). 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, including alterations of pituitary-ovarian function and potential inhibition of ovulation (309) or uterine contractions (310). High levels of melatonin during pregnancy may increase the risk of developmental disorders (311). In animal studies, melatonin is detected in breast milk and therefore should be avoided during breastfeeding (312). In men, decreased sperm motility (307) and decreased sperm count are reported with use of melatonin (173;313).

References

1. (1) Reiter RJ, Tan DX, Manchester LC, et al. Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging. Ann N Y Acad Sci 2002;959:238-250.

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