Melatonin (N-acetyl-5-methoxytryptamine)
Melatonin (N-acetyl-5-methoxytryptamine)
Natural Standard Bottom Line Monograph, Copyright © 2013 (www.naturalstandard.com). Commercial distribution prohibited. This monograph is intended for informational purposes only, and should not be interpreted as specific medical advice. You should consult with a qualified healthcare provider before making decisions about therapies and/or health conditions.
While some complementary and alternative techniques have been studied scientifically, high-quality data regarding safety, effectiveness, and mechanism of action are limited or controversial for most therapies. Whenever possible, it is recommended that practitioners be licensed by a recognized professional organization that adheres to clearly published standards. In addition, before starting a new technique or engaging a practitioner, it is recommended that patients speak with their primary healthcare provider(s). Potential benefits, risks (including financial costs), and alternatives should be carefully considered. The below monograph is designed to provide historical background and an overview of clinically-oriented research, and neither advocates for or against the use of a particular therapy.
Related Terms
5-Methoxy-N-acetyltryptamine, 6-sulfatoxymelatonin, acetamide, agomelatine, aMT6s, beta-methyl-6-chloromelatonin, BMS-214778, CAS 73-31-4, hypnotic, indole, luzindole, mel, MEL, melatonine, MLT, MT, N-2-(5-methoxyindol-3-ethyl)-acetamide, N-acetyl-5-methoxytryptamine, neurohormone, ramelteon (CAS 196597-26-9, TAK-375), tryptophan.
Brand names: Accurate Release®; Appleheart Melatonin®; Circadin®; Inspired by Nature®; Mel®; Melatonin-BioDynamax®; Melatonin Controlled Release®; Melatonin-Metabolic Response Modifier®; Melatonin-New Hope Health Products®; Melatonin Olympian Labs®; Melatonin-Optimum Nutrition®; Melatonin Tablets®; Melatonin Time Release®; Melaxen®; Nature's Bounty®; Puritan's Pride®; Rozerem®; Twinlab® Melatonin; Valdoxan®.
Combination product examples: Melatonex® (vitamin B6); Melatonin Forte® (Piper methysticum, kavalactones, valeriana); Melatonin PM Complex® (vitamin B6, vitamin B2, vitamin B3); Melatonin spray® (gamma-aminobutyric acid, pyridoxal-5-phosphate); Super Snooze with Melatonin® (valerian root, hop, skullcap, chamomile, passion flower).
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 they may have uses in various disorders.
Scientific Evidence
Uses 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. |
Grade* |
Jet lag Several human trials have suggested 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 sleep latency (the time it takes to fall asleep), 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 have reported that melatonin taken by mouth before bedtime decreases sleep latency (the time it takes to fall asleep) in elderly individuals with insomnia. Improved sleep quality and morning alertness has also been reported. However, most studies have not been of 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 disorders (children with behavioral, developmental, and intellectual disorders) There have been multiple trials investigating melatonin use in children with various neuropsychiatric disorders, including mental retardation, autism, psychiatric disorders, visual impairment, or epilepsy. Studies have demonstrated reduced sleep latency (the time it takes to fall asleep) 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 30-60 minutes prior to sleep time. Most trials have been small and brief in duration, and have not been rigorously designed or reported. However, the weight of scientific evidence does suggest that melatonin decreases sleep latency (the time it takes to fall asleep), increases the feeling of sleepiness, and may increase the duration of sleep. Better research is needed in this area. |
B |
Age-related macular degeneration Melatonin may exert antioxidant effects, which may contribute to its beneficial effects on the eyes. According to clinical research, melatonin may play a role in protecting the retina to delay macular degeneration. Well-designed clinical trials are needed before a conclusion can be made. |
C |
Aging (thermoregulation) Melatonin may be helpful in regulating age-dependent changes in body temperature rhythm. More well-designed trials are needed before a conclusion can be made. |
C |
Anti-inflammatory Based on limited human research, melatonin may be an effective anti-inflammatory; however, results are conflicting. Well-designed clinical trials are needed before a conclusion can be made. |
C |
Anxiety (preoperative) Results are mixed. Melatonin may be as effective as benzodiazepines such as midazolam (Versed®). Additional research is needed to confirm these findings. |
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 |
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 cancers, 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 |
Chronic fatigue syndrome There is limited research into 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 research 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 disorders There is not enough evidence to support the use of melatonin in managing the cognitive and noncognitive conditions of dementia. |
C |
Depression Melatonin has been suggested as serving as a possible treatment for depression. There is some support in animal research. However, human research remains inconclusive. More evidence is needed before a conclusion can be made. |
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 |
Exercise performance Based on human research, daytime administration of melatonin had no effects on maximal jumping ability or on maximal strength. More well-designed trials are needed before a conclusion can be made. |
C |
Gastrointestinal disorders Several studies show that treatment with melatonin may be useful in patients with functional dyspepsia. Other research has shown that melatonin has some beneficial effects in patients with irritable bowel syndrome (IBS) and possibly inflammatory bowel disease (IBD), although findings have been mixed. Well-designed clinical trials are required before a strong recommendation can be made. |
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 headaches, 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 orally (by mouth) or intranasally (inhaled through the nose). 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 increases cholesterol levels. More research is needed to clarify these 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 |
Insomnia (children) Based on human research, melatonin may be beneficial in children with insomnia. More well-designed studies are needed before a conclusion can be made. |
C |
Memory Preliminary research has suggested that melatonin may improve memory in certain stressful situations. Further research is required before a conclusion can be made. |
C |
Menopause Melatonin has shown some beneficial effects for symptoms associated with menopause. Further research using a larger number of patients is needed before a conclusion can be made. |
C |
Parkinson's disease There is very limited research to date for the use of melatonin as a treatment for Parkinson's disease. Melatonin was indicated as being well tolerated, but side effects may have included skin flushing, diarrhea, abdominal cramps, somnolence during the day, scotoma lucidum, and headaches. Melatonin had no effect on signs of parkinsonism or levodopa effects. Further research of higher methodological strength is needed before a recommendation can be made in this area. |
C |
Periodic limb movement disorder There is very limited study to date for the use of melatonin as a treatment for periodic limb movement disorder. Better-designed research is needed before a recommendation can be made in this area. |
C |
REM sleep behavior disorder Limited case reports describe benefits in patients with REM sleep behavior disorder who received melatonin. However, better research is needed before a clear conclusion can be drawn. |
C |
Restless leg syndrome Preliminary research has suggested that melatonin may have a detrimental effect on motor symptoms associated with restless leg syndrome; however, evidence remains inconclusive. Further study is required in this field. |
C |
Rett's syndrome Rett syndrome is a presumed genetic disorder that affects female children, characterized by decelerated head growth and global developmental regression. There is limited research 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 |
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 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 disturbance Melatonin may improve sleep disturbances in a wide range of patients, including those in the intensive care unit (ICU) and patients with Alzheimer's disease. 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. Based on preliminary research, melatonin may improve sleep in patients with asthma or depression. Further research is needed in these areas before a firm conclusion can be reached. |
C |
Sleep quality A small amount of research has examined the use of melatonin to improve sleep quality. Further research is necessary before firm conclusions can be reached. |
C |
Smoking cessation Although preliminary results are promising, due to weaknesses in the design and reporting of this research, further research 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 (thrombopoiesis) has been suggested but not clearly demonstrated. Additional research is necessary in this area 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 |
Urination (nocturia) Melatonin may have beneficial effects for nocturia in the elderly. Further research is needed to before a recommendation can be made. |
C |
UV-induced erythema prevention/sunburn It has been proposed that the antioxidant properties of melatonin may be protective. Results have been mixed. Further study is necessary before a clear conclusion can be drawn about its 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. 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. |
D |
*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). |
|
Tradition/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 health care professional.
Acetaminophen toxicity, acute respiratory distress syndrome (ARDS), adaptogen, addiction, ADHD, adrenal insufficiency, aflatoxin toxicity, aging, alcoholic liver disease, alopecia (baldness), aluminum toxicity, Alzeimer's disease, amenorrhea, amyotrophic lateral sclerosis (ALS), analgesic, antioxidant, antiparasitic, anxiety (travel anxiety in animals), ataxia (Machado-Joseph disease), atopic dermatitis, autoimmune diseases (demyelination), beta-blocker sleep disturbance, bipolar disorder, bladder disorders, bone diseases (fibrous dysplasia), bone healing, brain injuries, cachexia, cardiac syndrome X, cardiovascular conditions, cataracts, central nervous system diseases (Venezuelan equine encephalomyelitis virus), chemotherapy toxicity, cholestatic liver injury, colic, colitis, contraception, coronary artery disease, delirium, dental conditions, Duchenne muscular dystrophy, duodenal ulcer, eating disorders (low-level, enhanced circadian rhythm), eczema, edema (swelling), endometriosis, erectile dysfunction, esophagitis (inflammation of the esophagus), exercise recovery, fetal development, fibromyalgia, food preservation, fragile X syndrome, gastric ulcers, gastritis (inflammation of the stomach lining), gastroesophageal reflux disease (GERD), gentamicin toxicity, growth (growing pains), heart attack prevention, heart disease, helminthic infections, hepatic encephalopathy, hormonal/endocrine disorders (McCune-Albright syndrome), hyperpigmentation, immune system diseases (Langerhans cell histiocytosis), immunostimulant, infant development / neonatal care, interstitial cystitis, intestinal motility disorders, ischemia-reperfusion injury protection, ischemic stroke (impaired nocturnal excretion), itching, jaundice, jellyfish stings, kidney protection (amikacin-induced, cyclosporin-induced), lead toxicity, liver damage, lung inflammation, major depressive disorder (low nocturnal melatonin), malaria, mania, melatonin deficiency, metabolic disorders, migraine (impaired pineal function), movement disorders, multiple sclerosis, myocardial injury, nerve regeneration, neurodegenerative disorders, neurofibromatous scoliosis, neurological disorders, neuropathy (neuronal damage from bacterial meningitis), neuroprotective, nitrate tolerance, noise-induced hearing loss, non-Hodgkin's lymphoma, obesity, obstructive sleep apnea, organophosphate poisoning, osteoarthritis, ovarian disorders, pain, pancreatitis, phenylketonuria (PKU), photoprotection, polycystic ovarian syndrome (PCOS), postmenopausal osteoporosis, post-operative adjunct, post-operative delirium, pregnancy nutritional supplement, premenstrual dysphoric disorder (PMDD), protection against alcohol toxicity, psychiatric disorders, pulmonary fibrosis, radiation protection, retinal protection, rheumatic diseases, scalds, schizophrenia, sepsis, sexual activity enhancement, shock, spinal cord injury, spine problems (idiopathic scoliosis), stomach ulcers, stomatitis, stroke, sudden infant death syndrome (SIDS) prevention, surgical recovery, tachycardia, testicular damage, toluene neurotoxicity, toxic liver damage, toxicity, transplants (ovary), tuberculosis, ulcer, ulcerative colitis, uterine disorders, Wilson's disease, 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 0.1-80 milligrams of melatonin taken nightly by mouth for up to three years for a variety of conditions. 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. For the prevention of sunburn, melatonin preparations, alone and in combination with ascorbic acid and vitamin E, in doses ranging from 20-100 milligrams in 70% ethanol, have been studied.
Intranasal melatonin (1% solution in ethanol) at a dose of two milligrams daily for one week has also been studied for high blood pressure.
A dose of 0.5 milligrams of transbuccal melatonin for two sessions on four consecutive nights,at least three days apart, has been studied for insomnia in the elderly.
There are other uses with limited supportive research 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 it should not be substituted for more proven therapies.
Children (under 18 years old)
There is limited study of melatonin supplements in children, and its safety is not established. Doses of up to up to nine or 10 milligrams per kilogram of body weight, as a single dose or over several months, have been studied. 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
Avoid in those with known allergies to melatonin or related products. 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 (five milligrams daily) for up to two years. Available trials report that overall adverse effects are not significantly more common with melatonin than placebo.
Commonly reported adverse effects include fatigue, dizziness, headache, irritability, drowsiness, and sleepiness, although these effects may occur due to jet lag and not due to melatonin itself. Fatigue may occur particularly with morning use or high doses, and irregular sleep-wake cycles may occur. Disorientation, ataxia (difficulties with walking and balance), confusion, sleepwalking, vivid dreams, and nightmares have also been noted, with effects often resolving after the cessation of melatonin. Due to the risk of drowsiness or sedation, use caution if driving or operating heavy machinery.
Mild gastrointestinal distress commonly occurs, including nausea, vomiting, cramping, stomach pain, altered taste, abnormal feces, increased appetite, or diarrhea. Melatonin has been linked to the triggering of Crohn's disease symptoms.
Other side effects include skin rash, infection, decreased mental performance, increased risk of inflammation, and increased urination.
It has been suggested that melatonin may lower the 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 may increase the risk of bleeding. Caution is advised in patients with bleeding disorders or those taking drugs that may increase the risk of bleeding. Dosing adjustments may be necessary.
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 or atherosclerosis, or in those at risk for cardiovascular disease. Abnormal heart rhythms have been associated with melatonin.
Hyperglycemia (elevated blood sugar levels) has 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 the cessation of melatonin). Decreased sperm motility and decreased libido have been reported in rats and humans.
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.
Use cautiously in patients using anesthetics, cytochrome P450 1A2 inhibitors like fluvoxamine, methamphetamine, nifedipine (a calcium channel blocker), or in children with a history of enuresis.
Avoid in patients using CNS depressants, including benzodiazepines and alcohol, as concomitant use may cause increased sedation.
Avoid use in women who are pregnant or are attempting to become pregnant, based on possible hormonal effects and a possible increased risk of developmental disorders.
Avoid with known allergies to melatonin or related products.
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 was 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
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.
Melatonin is metabolized (broken down) 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 was reported when melatonin was used at the same time as the prescription sleep aid zolpidem (Ambien®), although it is not clear that effects were 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, alcohol, and central nervous system depressants. Caution is advised while driving or operating machinery.
Melatonin may increase the risk of bleeding when taken with drugs that increase the risk of bleeding. Some examples include aspirin, anticoagulants (blood thinners) such as warfarin (Coumadin®) or heparin, antiplatelet drugs such as clopidogrel (Plavix®), and nonsteroidal anti-inflammatory drugs such as ibuprofen (Motrin®, Advil®) or naproxen (Naprosyn®, Aleve®).
Hyperglycemia (elevated blood sugar levels) has 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 medications that may also lower blood sugar. Patients taking insulin or drugs for diabetes by mouth should be monitored closely by a qualified healthcare professional, including a pharmacist. Medication adjustments may be necessary.
Based on preliminary evidence, melatonin should be avoided in patients taking antiseizure medications. It has been suggested that melatonin may lower the 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. Caution is advised.
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 its effects on liver enzymes. However, caffeine may also alter circadian rhythms in the body, with effects on melatonin secretion.
Melatonin may also interact with Alzheimer's agents, analgesics, anesthetics, antianxiety drugs, antiasthma agents, anticancer agents, antiglaucoma agents, anti-inflammatories, antiparasitic agents, antipsychotic agents, antivirals, beta-blockers, calcium channel blockers, central nervous system stimulants, cholesterol lowering agents, dextromethorphan, diuretics, drugs used for osteoporosis, drugs that affect GABA, flumazenil, gastrointestinal agents, haloperidol, hormonal agents, drugs that affect the immune system, isoniazid, lithium, methamphetamine, methoxamine, muscle relaxants, radioprotective agents, remifentanil, skin agents, somatostatin, stimulants, tacrine, temazepam, valproic acid, vasodilators, verapamil, and weight loss agents.
Interactions with Herbs and Dietary Supplements
Melatonin is metabolized (broken down) in the body by liver enzymes. As a result, herbs and supplements that alter the activity of these enzymes may increase or decrease the effects of melatonin supplements.
Melatonin may increase or decrease blood pressure; study results conflict. Caution is advised in patients taking herbs or supplements that lower blood pressure.
Melatonin may increase daytime sleepiness or sedation when taken with herbs or supplements that may cause drowsiness, such as sedatives, central nervous system depressants, or some anti-depressants.
Melatonin may increase the risk of bleeding when taken with herbs and supplements that are believed to increase the risk of bleeding. Multiple cases of bleeding have been reported with the use of Ginkgo biloba, and fewer cases with garlic and saw palmetto. Numerous other agents may theoretically increase the risk of bleeding, although this has not been proven in most cases.
Hyperglycemia (elevated blood sugar levels) has 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 lower blood sugar. Blood glucose levels may require monitoring, and doses may need adjustment.
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 its effects on liver enzymes. However, caffeine may also alter circadian rhythms in the body, with effects on melatonin secretion.
Based on preliminary evidence, melatonin should be avoided in patients taking herbs or supplements that could alter the seizure threshold. It has been suggested that melatonin may lower the 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 disorders taking melatonin should be monitored closely by a healthcare professional.
Melatonin may also interact with analgesics, anesthetics, anti-Alzheimer's herbs or supplements, antianxiety herbs or supplements, antiasthma herbs or supplements, anticancer herbs or supplements, antiglaucoma herbs or supplements, anti-inflammatory herbs or supplements, antioxidants, antiparasitics, antipsychotics, antivirals, central nervous system stimulants, chasteberry (Vitex agnus-castus), cholesterol lowering herbs or supplements, DHEA, echinacea, folate, gastrointestinal herbs and supplements, herbs or supplements that affect the immune system, hormonal herbs or supplements, herbs or supplements used for osteoporosis, radioprotective herbs or supplements, herbs or supplements used on the skin, stimulants, vasodilator herbs or supplements, vitamin B12, and weight loss herbs or supplements.
Author Information
This information is based on a systematic review of scientific literature edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
References
Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.
Bendz LM, Scates AC. Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder. Ann Pharmacother 2010 Jan;44(1):185-91. View Abstract
Bjorvatn B, Stangenes K, Oyane N, et al. Randomized placebo-controlled field study of the effects of bright light and melatonin in adaptation to night work. Scand J Work Environ Health 2007 Jun;33(3):204-14. View Abstract
Caumo W, Levandovski R, Hidalgo MP. Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy: a double-blind, randomized, placebo-controlled study. J Pain 2009 Jan;10(1):100-8. View Abstract
Hallam KT, Begg DP, Olver JS, et al. An investigation of the effect of immediate and extended release venlafaxine on nocturnal melatonin and cortisol release in healthy adult volunteers. Hum Psychopharmacol 2008 Mar;23(2):129-37. View Abstract
Kandil TS, Mousa AA, El-Gendy AA, et al. The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease. BMC Gastroenterol 2010 Jan18;10:7. View Abstract
Lopez-Gonzalez MA, Santiago AM, Esteban-Ortega F. Sulpiride and melatonin decrease tinnitus perception modulating the auditolimbic dopaminergic pathway. J Otolaryngol 2007 Aug;36(4):213-9. View Abstract
Medeiros CA, Carvalhedo de Bruin PF, et al. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson's disease. A randomized, double blind, placebo-controlled study. J Neurol 2007 Apr;254(4):459-64. View Abstract
Rahman SA, Kayumov L, Shapiro CM. Antidepressant action of melatonin in the treatment of Delayed Sleep Phase Syndrome. Sleep Med 2010 Feb;11(2):131-6. View Abstract
Rimmele U, Spillmann M, Bärtschi C, et al. Melatonin improves memory acquisition under stress independent of stress hormone release. Psychopharmacology (Berl) 2009 Mar;202(4):663-72. View Abstract
Schemmer P, Nickkholgh A, Schneider H, et al. PORTAL: pilot study on the safety and tolerance of preoperative melatonin application in patients undergoing major liver resection: a double-blind randomized placebo-controlled trial. BMC Surg 2008 Jan 23;8:2. View Abstract
Schmidt CM, Knief A, Deuster D, et al. Melatonin is a useful alternative to sedation in children undergoing brainstem audiometry with an age dependent success rate--a field report of 250 investigations. Neuropediatrics 2007 Feb;38(1):2-4. View Abstract
Serfaty MA, Osborne D, Buszewicz MJ, et al. A randomized double-blind placebo-controlled trial of treatment as usual plus exogenous slow-release melatonin (6 mg) or placebo for sleep disturbance and depressed mood. Int Clin Psychopharmacol 2010 May;25(3):132-42. View Abstract
Suresh Kumar PN, Andrade C, Bhakta SG, Singh NM. Melatonin in schizophrenic outpatients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2007 Feb;68(2):237-41. View Abstract
Todisco M. Low-grade non-Hodgkin lymphoma at advanced stage: a case successfully treated with cyclophosphamide plus somatostatin, bromocriptine, retinoids, and melatonin. Am J Ther 2007 Jan-Feb;14(1):113-5. View Abstract
Wade AG, Ford I, Crawford G, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin 2007 Oct;23(10):2597-605. View Abstract
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Updated:
March 22, 2017