The Therapeutic Potential of Melatonin: A Review of the Science

Samir Malhotra, MD; Girish Sawhney, MD; Promila Pandhi, MD

In This Article

Toxicology and Potential for Harm

The acute toxicity of melatonin as seen in both animal and human studies is extremely low. Melatonin may cause minor adverse effects, such as headache, insomnia, rash, upset stomach, and nightmares. In animals, an LD50 (lethal dose for 50% of the subjects) could not be established. Even 800 mg/kg bodyweight (high dose) was not lethal.[138] Studies of human subjects given varying doses of melatonin (1-6.6 g/day) for 30-45 days, and followed with an elaborate battery of biochemical tests to detect potential toxicity, have concluded that, aside from drowsiness, all findings were normal at the end of the test period.[139,140]

Animal studies suggest that melatonin can downregulate the pituitary/gonadal axis resulting in hypogonadism and/or delayed puberty. However chronic administration of low-dose melatonin in men did not alter blood levels of testosterone or luteinizing hormone.[141] One case of extremely high melatonin levels associated with delayed puberty and hypogonadism has been reported.[142] Pubertal development and resolution of the hypogonadism occurred spontaneously as melatonin levels declined over several years. Recent experimental evidence demonstrates that melatonin reduces sperm motility[143] and that long-term administration inhibits testicular aromatase levels.[144]

Melatonin has also been suggested for use as a contraceptive for women,[145] which might raise the question of whether melatonin damages the female reproductive system. Notably, no side effects were reported in a report of a phase 2 clinical trial in which 1400 women were treated with 75 mg of melatonin nightly for 4 years.[145]

Preliminary animal studies suggest that melatonin may accelerate the development of autoimmune conditions.[146] Melatonin transiently exacerbated neurologic symptoms in 1 patient with multiple sclerosis.[147]

Although melatonin is a potential adjunctive agent in the treatment of cancer and immune deficiency, poorly timed administration can produce opposite effects. Melatonin injections given in the morning stimulate tumor growth,[46,148] whereas the same doses in midafternoon have no effect but in the evening have a retarding effect. And although some people with depression may suffer from a "low melatonin syndrome,"[27] melatonin administration that unduly prolongs the nocturnal melatonin rise, or that is given throughout the day, may exacerbate SAD[82] and bipolar and classic depression.[83] Finally, animal studies have shown that moderately large doses of melatonin (equivalent in one study to about 30 mg in adult humans) increased light-induced damage to retinal photoreceptors.[149]

There is also some concern regarding increased atherosclerosis in the aorta in hypercholesterolemic rats caused by melatonin.[150] Moreover, in these animals LDLs were less well recognized by LDL-receptor metabolic pathways when melatonin was administered.

Melatonin is widely available as an over-the-counter supplement marketed by different companies. These supplements may not be similar in dosage and/or composition, and some of them may contain additional vitamins. Moreover, melatonin may interact with other over-the-counter drugs, although such interactions have not been systematically evaluated and, therefore, remain unreported.


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