Melatonin is produced endogenously in humans by the pineal gland. Although the exact mechanism of action is unknown, it is thought to control the circadian pacemaker and promote sleep ⁽¹⁾. Small amounts of melatonin are found in fruits, nuts, olive oil, and wine. The supplemental form is used as a sleep-aid.

Clinical studies suggest that melatonin may decrease sleep latency and improve sleep duration ^{(2) (3) (4)}, although randomized trials have produced mixed data ^{(27) (28) (29)}. Meta analyses did not find any significant effects with melatonin on secondary sleep disorders associated with medical, neurological, or substance abuse disorders ⁽⁵⁾ nor on sleep quality in menopausal women ⁽⁷¹⁾, but supplementation improved subjective sleep quality in patients with traumatic brain injury ⁽⁴⁴⁾ and cognitive outcomes in patients with Alzheimer’s disease ⁽⁷²⁾. Additional studies have shown that melatonin may decrease surgery-associated anxiety and pain ⁽⁶⁾ as well as the frequency of migraine attacks ⁽⁷⁾. Data also indicate that it can reduce perioperative anxiety ^(30) (56), but there is insufficient evidence for its use to improve delirium in hospitalized patients ⁽⁵⁷⁾, to improve depression or depressive symptoms ⁽⁴⁷⁾, or for seasonal affective disorder (SAD) ⁽⁴⁸⁾. Melatonin did not improve nocturia in a small study of multiple sclerosis patients ⁽⁵³⁾ and findings of its benefits in ICU patients are conflicting ^(46) (64). Whether it can help in benzodiazepine withdrawal is also unclear ^(49) (50).

A few studies indicate that melatonin may be helpful for jet lag ^(51) (52). Data also suggest benefits of child-appropriate, prolonged-release melatonin for long-term treatment in children and adolescents with autism spectrum disorder and insomnia ⁽⁵⁹⁾. The American Academy of Neurology guidelines recommend using melatonin, starting with a low-dose, for children and adolescents with autism spectrum disorder and sleep disturbance if behavioral strategies have not been helpful, and if contributing coexisting conditions and use of concomitant medications have been addressed ⁽⁶⁰⁾.

In preclinical studies, melatonin demonstrated antioxidant ^(38) (39) and antiproliferative properties ⁽⁴⁰⁾; synergistic effects with anticancer agents ^{(8) (9) (32)}; and protective effects against adriamycin-induced cardiotoxicity ⁽³³⁾.

Clinical trials evaluating melatonin as a monotherapy or in combination with other agents, and in patients with solid tumors reported improvements in fatigue ⁽⁶⁸⁾, and quality of life and survival time ^{(10) (11) (12) (13)}. But melatonin did not improve appetite, weight, or quality of life in cancer patients with cachexia ⁽³⁵⁾. In studies of postmenopausal breast cancer survivors, short-term supplementation did not influence estradiol levels ⁽³⁶⁾ but improved sleep quality ⁽³⁷⁾. Data also suggest melatonin may help reduce incidence of chemotherapy side effects including thrombocytopenia, asthenia, and neurotoxicity ⁽⁵⁴⁾; improve cognitive function, sleep quality and depressive symptoms ⁽⁶¹⁾; minimize radiotherapy-induced reduction in blood cell counts ⁽⁵⁸⁾; protect against radiation-induced genotoxicity ⁽⁶²⁾; and reduce the incidence of oral mucositis caused by chemo- and radiotherapy ⁽⁶⁹⁾. Further, melatonin was found comparable to zolpidem in affecting sleep duration, latency, efficiency, and disturbance in colorectal cancer patients undergoing chemotherapy ⁽⁶⁵⁾. But in survivors of childhood cancers, melatonin was not associated with improved sleep or neurocognitive performance ⁽⁷⁰⁾.

According to a case report, oral melatonin may delay menopause in pre-menopausal women by modulating levels of follicle stimulating hormone (FSH) and estrogen ⁽³¹⁾.