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Melatonin

Nutrient Name: Melatonin.

Summary Table
nutrient description

Chemistry and Form

Melatonin is an amino acid–based (indole) hormone, produced in the brain by the pineal gland. It is synthesized from the amino acid tryptophan, which is converted to the neurotransmitter serotonin, which is then converted to melatonin.

Physiology and Function

Melatonin is the central hormone involved in the regulation of numerous environmental and body cycles. As the biological timekeeper of hormone secretion, melatonin functions as a hormonal interface between the body and the environment. The greatest regulatory influence involves the daily cycle of light and darkness; melatonin production by the pineal gland begins to rise slowly with nightfall, reaching its maximum between midnight and 3AM. After its synthesis is triggered by various external environmental cues, melatonin integrates the environmental feedback of daily and seasonal cycles, sets the biological clock, and activates bodily functions associated with these cues. The most notable example is the circadian (24-hour) cycle of sleep and waking, in which darkness triggers melatonin production, which helps to engender a feeling of sleepiness, and light suppresses secretion. Thus, melatonin possesses both phase-shifting and sleep-promoting properties. Many other cycles influence melatonin production as well, such as the annual cycle of longer and shorter days and the monthly female reproductive cycle, and many events tied to these cycles are linked to melatonin. Melatonin is metabolized by the liver after a half-life of 30 to 50 minutes.

Melatonin acts on multiple systems, appears to be high on the hierarchy of regulatory hormones (i.e., it regulates hormones that regulate hormones), and demonstrates antioxidant, antiestrogenic, and oncostatic activity. For example, melatonin appears to be such as powerful regulator of the secretion of growth hormone (GH) and gonadotropic hormones (the hormones that regulate production of sex hormones such as estrogen and progesterone) that it is a crucial element in the timing of the female reproductive cycle; rising melatonin levels may bring on menstruation, and their decline may induce a surge of luteinizing hormone (LH) and ovulation. Thus, melatonin influences menarche; the frequency, timing, and duration of menstrual cycles; and menopause. It also introduces subtle changes according to external rhythms; for example, varying melatonin levels over the course of the year result in higher estrogen in the spring and summer and higher progesterone in the fall and winter.

Human lymphocytes synthesize and release large amounts of melatonin. This melatonin appears to play a central role in the regulation of the human immune system, possibly by acting as an intracrine, autocrine, and paracrine substance. Receptors have been reported on T and B lymphocytes, and melatonin has demonstrated immune-enhancing properties in many animal studies. Physiologically, melatonin opposes the degeneration caused by elevated levels of endogenous corticosteroids (e.g., protein catabolism, suppressed immune function, and altered blood glucose metabolism). The immunosuppressive activity of exogenous corticosteroids may also be moderated by melatonin.

Various studies have shown a correlation among melatonin, aging, and life span. One proposed rationale is that the ratio of serotonin to melatonin increases as a person ages, increasing the production of various chemicals that are linked with aging. Onset of melatonin's rhythmic patterns starts at approximately 3 months of age, and young children have the highest levels of nighttime melatonin. Levels rise and then gradually start to decline during adolescence. Adults generally exhibit a 37% decline, approximately, in daily melatonin output between 20 and 70 years of age. However, controversy surrounds whether such declines are as prominent in healthy adults. These secretion patterns may contribute to sleep disruption and the tendency to shift to earlier sleep in the evening and earlier rising in the morning in the elderly population.

Numerous researchers and clinicians have suggested that the increased use of artificial light and resulting extension of the daily photoperiod of light exposure over the past century has depressed melatonin secretion and elevated the incidence of cancer in industrialized societies. 1,2

Melatonin also functions as a powerful antioxidant, particularly in neutralizing hydroxyl, the most damaging of all oxygen-based free radicals. Administration for this purpose may be inappropriate, however, because the antioxidant effects may be offset by hormonal disruption caused by taking large doses.

Studies have also shown that melatonin decreases the internal carotid pulsability index of premenopausal women 3 and, applied topically, can reduce skin damage inflicted by ultraviolet (UV) radiation. 4 Research does not support administration as a remedy for the effects of aging; it is probably more beneficial to protect oneself from influences that inhibit melatonin.

nutrient in clinical practice

Known or Potential Therapeutic Uses

As a self-prescribed nutraceutical, melatonin is primarily used to induce sleep or adjust sleep cycles, especially with travel and schedule changes. Practitioners of nutritional therapeutics, particularly within the context of integrative medicine, often prescribe melatonin in the treatment of some forms of depression and hyperactivity, at low dosages, and as part of multimodality cancer treatment protocols, using high dosages.

Historical/Ethnomedicine Precedent

None known.

Possible Uses

Age-related cognitive decline, Angelman's syndrome (sleep disturbances only), attention deficit–hyperactivity disorder (ADHD), breast cancer, cluster headaches, colon cancer, coronary heart disease, depression, epilepsy, essential hypertension, glaucoma, insomnia, jet lag, lung cancer, migraine headaches, multiple sclerosis, myoclonus, nocturnal hypertension, oxidative stress in dialysis patients (preventive), postmenopausal osteoporosis, prostate cancer, sarcoidosis, seasonal affective disorder (SAD), sudden infant death syndrome (SIDS), sleep cycle disruption, tardive dyskinesia, tinnitus.

Deficiency Symptoms

Insomnia 5 and other sleep disturbances.

Dietary Sources

Melatonin appears in foods only in trace amounts.

Nutrient Preparations Available

Time-release forms may best approximate normal physiological secretion of melatonin, 6 which typically occurs over several hours during the night. Further, a limitation of non-time-release forms is that the half-life of oral melatonin is approximately 30 to 50 minutes.

Dosage Forms Available

Capsule, tablet, sublingual tablet, time-release tablet and capsule.

Source Materials for Nutrient Preparations

Melatonin used in preparations for oral administration is derived from animals or produced synthetically.

Dosage Range

Adult

Supplemental/Maintenance: Melatonin is usually not taken on a long-term basis as a general nutritional supplement, that is, outside situational appropriateness or therapeutic strategy.

Pharmacological/Therapeutic: 0.5 to 6.0 mg nightly; up to 40 mg per day in cancer therapy.

Toxic: Melatonin is generally considered nontoxic when used in accordance with proper dosing guidelines for appropriate conditions.

Pediatric (<18 Years)

Supplemental/Maintenance: Melatonin is generally not appropriate for children, other than short-term situational use (e.g., travel, jet lag).

Pharmacological/Therapeutic: Generally not appropriate, except with managed therapeutic protocols.

Toxic: Melatonin is generally considered nontoxic for children when used in accordance with proper dosing guidelines for appropriate conditions.

Laboratoary Values

Salivary melatonin concentration, urinary 6-hydroxymelatonin sulphate excretion rate, serum melatonin concentration. 7

Note: Melatonin in a physiological setting is problematic to study, because a blood sample needs to be obtained between 3 and 4AMwithout exposing the patient to light, in order to obtain a relevant measurement. Accurate interpretation of the assay requires a collection of normal levels arranged by age.

safety profile

Overview

Melatonin use is generally considered safe when used for appropriate conditions in accordance with standard dosage levels. Although certain predictable effects may occur, no substantive and consistent patterns of adverse effects or toxicity, based on clinical trials or qualified case reports, have been confirmed in the scientific literature. Long-term human studies on toxicity or subtle adverse effects have not been conducted. Evidence is lacking at this time of a feedback loop in which augmentation or replacement causes suppression. Nevertheless, as with administration of any exogenous hormone, regular use of melatonin over an extended period may interfere with self-regulatory mechanisms in hormonal systems.

Nutrient Adverse Effects

General Adverse Effects

Drowsiness is an expected outcome of taking melatonin, and being drowsy at inopportune times represents the most common adverse effect. Overuse or incorrect use of melatonin may disrupt circadian rhythms and sleep cycles. Morning sedation or drowsiness may indicate that the dosage used is excessive; if so, a lower dosage should reduce adverse symptoms. Somnambulism, disorientation, and vivid dreams have also been reported. Sleep disruption was observed in one small study. 8 Anxiety and irritability may occur in some individuals. Nocturnal asthma may be aggravated. 9,10

Scattered and unqualified case reports have suggested exogenous melatonin intake as a factor in a variety of adverse phenomena, including transient psychosis, headache, abdominal cramps, decreased libido, infertility, and painful gynecomastia. 11-14Subsequent investigation has yet to document and confirm significant patterns of adverse effects consistent with these reported individual reactions. 15-17

Pregnancy and Nursing

Melatonin readily crosses the placenta, and its fetal effects are unknown; therefore, melatonin is not recommended during pregnancy. Given the intimate relationships between melatonin and reproductive hormones, use of melatonin by women who are pregnant is further contraindicated, pending substantive evidence of safety. The lack of research on the effects and safety of melatonin in infants warrants avoidance by mothers who are breastfeeding.

Infants and Children

An increased incidence of seizures in children with neurological disorders after melatonin administration has been reported but not confirmed. 18 Monitoring by a qualified health care professional is warranted when use in such populations is otherwise appropriate.

Contraindications

Driving and operation of machinery should be avoided while under the influence of melatonin. Daytime use may result in fatigue and decreased alertness; other contraindications include pregnancy and nursing; fibromyalgia (if elevated melatonin), 19 insulin sensitivity or diabetes, 3 and SAD.

Some highly experimental animal trials suggest that melatonin may be contraindicated for patients with autoimmune disorders such as rheumatoid arthritis, lupus, or multiple sclerosis.

Precautions and Warnings

General

Caution is advised given the limited knowledge of hormones and their interactions and the multiple influences melatonin exerts on other regulatory hormones.

Regular use for extended periods is not advised without supervision by a health care professional experienced in nutritional therapies.

Specific Populations

Elevated melatonin levels may inhibit ovulation; prudence suggests that melatonin should generally be avoided by women attempting to conceive.

Individuals diagnosed with depression, diabetes, fibromyalgia, or schizophrenia, especially when not deficient; adolescents; individuals undergoing corticosteroid therapy for anti-inflammatory or immune suppressive effects; individuals with nocturnal asthma may experience increased inflammation with elevated melatonin levels.

Many clinicians have observed a paradoxical effect, causing alertness and insomnia, from melatonin administration in approximately 5% of patients. With those individuals, melatonin can often be successfully dosed in the morning with no adverse effects (i.e., no drowsiness).

interactions review

Strategic Considerations

In most clinical settings, and in the vast majority of self-prescribed use by the general public, melatonin is used to treat sleep disorders (3 mg time-release form) or regulate sleep cycles (e.g., travel across multiple time zones, changing work shift). Assays for deficiency status (or excess) are available, but most experienced practitioners use sleep quality (after correcting sleep hygiene as much as possible, and ruling out sleep apnea/nocturnal myoclonic leg jerks as problems) and response to melatonin (3 mg time-release form) as the primary criteria in clinical evaluation for melatonin sufficiency.

Although consideration of its physiological role raises suspicions that many medications may interfere with melatonin secretion, human research into such effects and their clinical implications is sparse and early in its evolution. Depletion of melatonin by some pharmaceutical agents can be easily corrected with coadministration, usually at low doses, if deficiency results. In a more proactive sense, melatonin may play an important role as a component of integrative care strategies in the treatment of hormone-related cancers and sleep disturbances.

nutrient-drug interactions
Benzodiazepines
Beta-1-Adrenoceptor Antagonists (Beta-1-Adrenergic Blocking Agents)
Chemotherapy and Radiotherapy
Including: Cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ), cyclophosphamide (Cytoxan, Neosar), docetaxel (Taxotere), doxorubicin (Adriamycin, Rubex), etoposide (Eposin, Etophos, VePesid, VP-16), fluorouracil (5-FU; Adrucil, Efudex, Efudix, Fluoroplex), gemcitabine (Gemzar), irinotecan (camptothecin-11, CPT-11; Campto, Camptosar), methotrexate (Folex, Maxtrex, Rheumatrex), paclitaxel (Paxene, Taxol), tumor necrosis factor alpha (TNF-α). See also Interleukin 2 (IL-2), Tamoxifen, and Triptorelin.
Prevention or Reduction of Drug Adverse Effect
Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base: Emerging

Effect and Mechanism of Action

Melatonin, at high dosages (typically 10-20 mg/day, often as high as 50 mg/day), has been used in combination with a variety of chemotherapeutic agents to ameliorate adverse drug effects and enhance chemotherapy cytotoxicity. At this point, published research indicates that melatonin's activity is attributable to its ability to reduce oxidative stress and inflammation, directly influence the neuroendocrine-immune system regulatory axis, promote apoptosis of cancer cells, and cause release of immunomodulating cytokines by activated T cells and monocytes. 29-34

Research

Neri et al. 35 (1994) conducted a 12-month clinical trial in which 22 patients with metastatic renal cell carcinoma were treated with the combination of human lymphoblastoid interferon (IFN), 3 mega units (MU) intramuscularly three times per week, and melatonin, 10 mg/day orally, and then evaluated for response and toxicity. Three complete and four partial remissions (33%) were reported among the 21 evaluable patients, and nine achieved stable disease; five progressed. General toxicity was mild, with adverse effects generally of moderate severity and reversible. Several years later, these Italian researchers conducted immunoradiometric assays for tumor necrosis factor alpha (TNF-α); interleukins 1, 2, and 6 (IL-1, IL-2, IL-6); and interferon gamma (IFN-γ) after administering melatonin, 10 mg/day orally, for 3 months to 31 patients with advanced solid tumors (7 gastric, 9 enteric, 8 renal, 5 bladder, 2 prostate) who were unresponsive to chemotherapy and radiotherapy. After 3 months of therapy, marked by an absence of adverse reactions, 12 patients (39%) reported an improvement in their general well-being, demonstrated significant decrease of IL-6 circulating levels, and showed disease stabilization with no further growth of either the primary tumor or metastases. 31

In a randomized preliminary study, Brackowski et al. 36 investigated the effects of TNF-α versus combined TNF-α and melatonin in the treatment of 14 advanced-cancer patients with metastatic solid tumors for whom no effective conventional therapy was available. Those patients receiving melatonin were administered 40 mg/day orally, starting 7 days before the TNF-α. Five consecutive days of intravenous (IV) recombinant human TNF-α was then administered at 0.75 mg/day. Although many adverse effects of TNF-α therapy were common to both groups, lymphocyte mean number observed at the end of TNF-α infusion was significantly higher and asthenia and hypotension significantly less frequent in subjects receiving both agents. The authors concluded that this small trial suggested that melatonin coadministration offered a strong possibility of modulating TNF-α toxicity and biological activity. Nevertheless, while this study utilizing TNF-α is theoretically interesting, TNF-α as a therapy is strictly in the experimental phase and not being used clinically.

Over more than a decade, Lissoni et al. 37-42 have conducted a series of clinical trials investigating potential roles for melatonin within emerging integrative approaches to cancer care, with a focus on patients in a poor clinical state. Initially, they looked at using melatonin in conjunction with radiotherapy in treating patients with brain glioblastomas, reporting that this “radioneuroendocrine strategy…may prolong the survival time and improve the quality of life of patients” affected by this condition known for very poor prognosis. 37 In a small, randomized, controlled study involving 50 patients with unresectable brain metastases caused by solid neoplasms were treated with steroids and anticonvulsants as supportive care alone or in combination with 20 mg melatonin each evening. Among subjects receiving only steroids and anticonvulsants, 88% (21 of 26) died within 1 year, compared with 63% (15 of 24) in the group who also received melatonin. The survival at 1 year, free-from-brain-progression period, and mean survival time were significantly higher in patients who had received the melatonin, whereas steroid-induced metabolic and infective complications were significantly more frequent in those treated only with steroids and anticonvulsants. 38 In 1997, Lissoni et al. 39 published the results of a randomized study comparing combination cisplatin and etoposide chemotherapy versus cisplatin, etoposide and melatonin, “chemoendocrine therapy” as they have termed it, as a first-line treatment of advanced non–small cell lung cancer (NSCLC) patients. Although higher in patients receiving melatonin, improvement in the tumor response rate was not statistically significant. However, compared to subjects who received chemotherapy alone, patients treated with concomitant chemotherapy and melatonin demonstrated a significantly higher percentage of 1-year survival and greater tolerance of chemotherapy, particularly a significantly lower incidence of myelosuppression, neuropathy, and cachexia. Also in 1997, Lissoni et al. 40 conducted a clinical trial of 80 individuals with a range of advanced metastatic solid tumors and found that combining 20 mg melatonin each evening with various chemotherapeutic regimens measurably reduced several common chemotherapy-induced adverse effects. Subsequently, this same team of Italian researchers reported decreased toxicity and increased efficacy of cancer chemotherapy using melatonin in a randomized trial involving 250 patients with metastatic solid tumors. Chemotherapy consisted of cisplatin plus etoposide or gemcitabine alone for lung cancer; doxorubicin alone, mitoxantrone alone, or paclitaxel alone for breast cancer; 5-FU plus folinic acid for gastrointestinal tumors; and 5-FU plus cisplatin for head and neck cancers. Compared to patients treated with antineoplastic agents alone, those treated with melatonin (20 mg/day orally) and chemotherapy concomitantly demonstrated significantly higher 1-year survival rate and objective tumor regression rate, as well as reduced frequency of thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis, and asthenia. 41 Subsequent studies using melatonin in conjunction with conventional chemotherapy (e.g., irinotecan, etoposide, cisplatin) have carried these research findings into further development. 42,43

More recent animal research has noted that melatonin may provide a protective effect against doxorubicin (Adriamycin) toxicity, cisplatin-induced acute renal injury, and doxorubicin-induced cardiotoxicity. 44-46

Birdsall et al. 47 and Cancer Treatment Centers of America conducted an exploratory trial to investigate effects of concomitant naturopathic therapies on clinical tumor response to external beam radiation therapy for early-stage prostate cancer (tumor stages 1b through 2, N0,M0). External beam radiation therapy of up to 72 Gy was given to 22 patients on a conventional 8-week treatment regimen while the 13 patients in the naturopathic group received at least one antioxidant preparation, with the most frequent antioxidant naturopathic treatments including green tea extract, melatonin, and a high-potency multivitamin, vitamin C, or vitamin E. “All patients were monitored for at least 12 months (range 12-42) and no patient received concomitant hormonal therapy.” The investigators reported that in the patients “who did not receive naturopathic [antioxidant] treatments, the median pretreatment PSA level was 5.4 ng/mL, the median PSA nadir was 0.66 ng/mL, and the median time to PSA nadir was 16.0 months,” while in the “patients who did receive naturopathic treatments, the corresponding values were 5.8 ng/mL; 0.59 ng/mL; and 16.0 months.” One tumor treatment failure occurred in the nonnaturopathic group “based on PSA elevation >2 ng from nadir which occurred at 14 months”; there were no treatment failures in the patients who received concomitant naturopathic regimens ( PSA, prostate-specific antigen; CAM,complementary and alternative medicine). The authors noted as “also significant that 9/9 patients in the non-CAM group were considered to be low risk (based on pretreatment PSA levels of 4-10 ng) whereas 3 patients in the CAM group were classified as intermediate risk (PSA >10-20 ng) and 1 patient as high risk (PSA >20 ng).” Thus, the authors concluded that “concomitant naturopathic treatment does not appear to inhibit the capacity of external beam radiation therapy to control localized prostate cancer, and does not interfere with either the magnitude of the response, the velocity of the response, or its durability for at least 1 year.” They added that these “results provide definitive evidence that antioxidant-based CAM modalities, designed to improve patient tolerance, quality of life, and possibly improve survival, do not inhibit tumor responses that depend on oxidative [tumor] killing mechanisms elicited by external beam radiation therapy.” 47 Although encouraging, this small, retrospective study did not have sufficient power to draw any statistically significant conclusions. Similar studies involving much larger groups of patients receiving radiotherapy are warranted.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Further research with large, well-designed clinical trials is essential, but melatonin is already playing a role in many cancer treatment protocols employing multiple therapeutic modalities within an integrative clinical strategy. Many clinicians working with difficult cases have been offering this option to patients facing poor prognoses. Emerging clinical practices have begun to produce operative interventions based on collaboration of oncologists and other health care professionals experienced in both conventional pharmacology and nutritional therapeutics.

In many clinics providing integrative oncology care, melatonin has become part of therapeutic protocols used in the treatment of almost every cancer type and chemotherapy regimen, to mitigate adverse effects and enhance efficacy. Many such care facilities consider the human clinical trial data compelling enough to extrapolate using melatonin in most patients. The only patient population for whom many experienced practitioners do not routinely use melatonin is with hematological malignancies, because immune stimulation is potentially contraindicated.

The usual dosage of melatonin ranges from moderate (10 mg daily) to extremely high (>40 mg daily) and inherently requires close supervision and regular monitoring. Physicians and other health care professionals may consider reviewing the potential for such synergistic therapies with appropriate patients and provide referral information to centers specializing in such integrative approaches.

Corticosteroids, Oral
Fluoxetine
Fluvoxamine
Haloperidol and Related Antipsychotic Medications
Interleukin-2 (IL-2)
Mirtazapine
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Acetylsalicylic Acid (Aspirin)
Tamoxifen
Triptorelin
Verapamil
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Anticoagulants
Bupropion, Desipramine, Tranylcypromine
Clonidine; Methoxamine
Cyclosporine
Cytochrome 1A2 lsoenzyme Substrates
Cytochrome 2C9 lsoenzyme Substrates
Estrogens, Progestins, and Estrogen-Progestin Combinations
Indomethacin
Vitamin B 6 –Depleting Drugs
Sedative Medications
nutrient-nutrient interactions
Alcohol/Ethanol
Tryptophan
Vitamin B 6 , Pyridoxine
Vitamin B 12
herb-nutrient interactions
Hypnotic Herbs
Citations and Reference Literature
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