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.

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.

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).

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.

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