Melatonin - Chempedia

Melatonin

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, suggesg the involvement of melatonin in circadian rhythm and regulation of diverse bo 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, melatonine, MLT, N-acetyl-5-methoxytryptamine, N-2-(5-methoxyindol-3-ethyl)-acetamide, ((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*
Jet lag Several 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. Although these results are compelling, the majority of studies have had problems with their designs and reporting, and some trials have not found benefits. Overall, the scientific evidence does suggest benefits of melatonin in up to half of people who take it for jet-lag. More trials are needed to confirm these findings, to determine optimal dosing, and to evaluate use in combination with prescription sleep aids.	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. Although these results are promising, additional research with larger studies is needed before a stronger recommendation can be made.	B
Insomnia in the elderly Several human studies report that melatonin taken by mouth before bedtime decreases the amount of time it takes to fall asleep ("sleep latency") in elderly individuals with insomnia. Improved sleep quality and morning alertness has also been reported. However, most studies have not been high quality in their designs and some research has found limited or no benefits. The majority of trials have been brief in duration (several days long), and long-term effects are not known.	B
Sleep disturbances in children with neuro-psychiatric disorders There are multiple trials investigating melatonin use in children with various neuro-psychiatric disorders, including mental retardation, autism, psychiatric disorders, visual impairment, or epilepsy. Studies have demonstrated reduced time to fall asleep (sleep latency) and increased sleep duration. Well-designed controlled trials in select patient populations are needed before a stronger or more specific recommendation can be made.	B
Sleep enhancement in healthy people Multiple human studies have measured the effects of melatonin supplements on sleep in healthy individuals. A wide range of doses has been used often taken by mouth 30 to 60 minutes prior to sleep time. Most trials have been small, brief in duration, and have not been rigorously designed or reported. 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 research is needed in this area.	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). 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
Anesthesia (adjunct therapy) Melatonin premedication may decrease the amount of standard anesthesia regimens needed. Additional research is needed before a strong recommendation can be made.	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 on the use of melatonin in children with ADHD both for the treatment of ADHD and insomnia in ADHD children. Beneficial effects in sleep quality have been reported; however, no effect on behavior problems has been noted. 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
Cardiac ischemia Melatonin may decrease cardiac damage during ischemia-reperfusion. Further research is needed in this area before a clear conclusion can be reached.	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
Chronic fatigue syndrome There is limited study of melatonin given to patients with chronic fatigue syndrome. Benefits have been reported. Further research is needed in this area before a clear conclusion can be reached.	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
Cognitive enhancement There is not enough evidence to support the use of melatonin in managing the cognitive and non-cognitive conditions of dementia.	C
Critical illness/ICU sleep disturbance Melatonin may improve sleep disturbances in patients in the ICU. Further studies are needed before a clear conclusion can be reached.	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
Diabetes (adjunct therapy) Melatonin when used with zinc may improve glycemic control in patients with poor response to metformin. More evidence is needed before a conclusion can be made.	C
Dyspepsia Several studies show that treatment with melatonin may be useful in patients with functional dyspepsia. Well-designed clinical trials are required before a strong recommendation can be made.	C
Exercise performance Currently, there is not enough evidence to recommend melatonin for exercise performance.	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 delay macular degeneration, 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, and other headache syndromes (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). Specifically, nocturnal high blood pressure may improve with melatonin use. Better-designed research is necessary before a firm conclusion can be reached.	C
High cholesterol (diabetes-related complication, adjunct therapy) One clinical trial found that melatonin when used with zinc and the diabetes drug, metformin, may improve diabetes-related complications such as impaired lipid profile. However, there is also evidence that melatonin will increase cholesterol levels. More research is needed to clarify mixed results.	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 (IBD) Based on preliminary study, melatonin is a promising therapeutic agent for IBD. Further research is needed before a firm 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
Irritable bowel syndrome (IBS) Melatonin has shown some beneficial effects in patients with IBS. Further study using a larger number of patients is needed before a recommendation can be made.	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 mixed. Melatonin may be as effective as benzodiazepines such as midazolam (Versed®). Additional study is needed to confirm these findings.	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 firm recommendation can be made in this area.	C
Sarcoidosis Beneficial effects have been reported in people with chronic sarcoidosis who took melatonin. Additional research is needed before a recommendation can be made.	C
Schizophrenia (sleep disorders) There is limited study of melatonin for improving sleep latency (time to fall asleep) in patients with schizophrenia. Improvements in quality and depth of sleep, reduced number of nighttime awakenings, and increased duration of sleep without producing morning hangover has also been reported in schizophrenic patients with insomnia. 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
Sedation (children) According to one clinical trial, melatonin provided sedative effects in children undergoing hearing tests. Further research is needed before a strong recommendation can be made.	C
Seizure disorder (children) The role of melatonin in seizure disorders is controversial. Better evidence is needed in this area before a clear conclusion can be drawn regarding the safety or effectiveness of melatonin.	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
Tinnitus Melatonin use has been associated with improvement of tinnitus and sleep. However, additional research is needed before a conclusion can be made.	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. Results have been mixed. Further study is necessary before a clear conclusion can be drawn about clinical effectiveness in humans.	C
Urinary disorders (frequent urination, nocturia) Melatonin may have beneficial effects for nocturia in the elderly. Further research is needed to before a recommendation can be made.	C
Work shift sleep disorder There are several studies of melatonin use in people who work irregular shifts, such as emergency room personnel. Modest improvements have been reported when melatonin was used with bright light. 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.

Grading rationale

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, analgesic, anti-inflammatory, anxiety, asthma, beta-blocker sleep disturbance, cancer prevention, cardiac syndrome X, colitis, contraception, depression, edema (swelling), duodenal ulcer, erectile dysfunction, fibromyalgia, gastroesophageal reflux disease (GERD), gentamicin-induced kidney damage, 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, non-Hodgkin''s lymphoma, pancreatitis, polycystic ovarian syndrome (PCOS), postmenopausal osteoporosis, post-operative adjunct, post-operative delirium, prevention of post-lung transplant ischemia-reperfusion injury, psychiatric disorders, rheumatoid arthritis, sedation, sexual activity enhancement, schistosomiasis, sudden infant death syndrome (SIDS) prevention, tachycardia, 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 (over 18 years old)

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 (under 18 years old)

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 (three months or less). 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. Melatonin may also cause infection. 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). Psychotic symptoms have been reported, including hallucinations and paranoia, possibly due to overdose. Patients with underlying major depression or psychotic disorders taking melatonin 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 have been 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; it has also been linked to the 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 the 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, 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 birth control pills, hormone replacement therapy, loop diuretics, hydralazine, or 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. Additionally, carbamazepine and valproate may alter melatonin levels and should be used with caution. Patients with seizure disorders 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 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 (tranquilizer) 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.

Melatonin premedication may decrease the doses of propofol and thiopental required to induce anesthesia.

Interactions with Herbs and Dietary Supplements

Melatonin may increase daytime sleepiness or sedation when taken with herbs or supplements that may cause drowsiness.

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); her Boon, BScPhm, PhD (University of Toronto); Michelle Corrado, PharmD (Harvard Vanguard Medical Association); Dawn Costa, BA, BS (Natural Standard Research Collaboration); Cynthia Dacey, PharmD (Natural Standard Research Collaboration); Paul Hammerness, MD (Harvard Medical School); Nikos Linardakis, MD (Natural Standard Research Collaboration); Shaina Tanguay-Colucci, BS (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).

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