Melatonin: Range of Effects and Therapeutic Applications

In the 60 years since Aaron Lerner and colleagues isolated melatonin, the hormone has been found to affect every system of the body. Although it is primarily synthesized by the pineal gland, melatonin is also produced in peripheral tissues and serves numerous critical physiological functions.¹ In mammals, its synthesis in the pineal gland is timed by the suprachiasmatic nucleus via projections to the paraventricular hypothalamic nucleus. Melatonin is most well-known for its role in regulating circadian rhythm and sleep-wake cycles.¹

Pineal melatonin production mainly occurs at night and is dependent on darkness, as light blocks its release. In addition to its immediate effects such as sleep induction, reductions in body temperature and blood pressure, induction of insulin resistance and glucose intolerance, and blockade of cortisol secretion, melatonin also leads to prospective effects that manifest throughout the following day.¹

“During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent,” explained a paper published in Endocrine Reviews.¹ These include increased pancreatic sensitivity to glucose and incretins-induced insulin secretion, induction of insulin sensitivity, regulation of blood pressure, and energy balance.^1,2

Melatonin “regulates energy metabolism, acting in every step of the energy balance, including energy intake (eating), energy flow to and from storages, and energy expenditure…[and] synchronizes energy metabolism requirements to the daily and annual rhythmic environmental photoperiod,” the review authors wrote.¹ As this suggests, the influence of melatonin extends beyond its immediate or short-term effects, given that the “annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come.”

In addition, maternal melatonin, the only source of melatonin for the mammalian fetus and newborn until pineal melatonin production begins after birth, programs the future physiology and behavior of the fetus to enable coping with environmental day/night fluctuations. Thus, melatonin is a “biological time-domain molecule acting on the circadian, seasonal, and transgenerational timescales.”¹

Along with its effects on the endocrine system, melatonin is involved in regulating certain parameters of the cardiovascular system, including heart rate, blood pressure, and vascular resistance. Research has indicated that melatonin may play a role in cardiovascular events such as ischemia, pulmonary hypertension, and valvular heart diseases.¹ The central nervous system (CNS), too, is a major target of melatonin. Melatonin has direct access to the CNS because of its presence in cerebrospinal fluid, and 1 of its most important functions in the CNS is neuroprotection through several mechanisms including antioxidant action.^1,3 Some findings suggest a possible correlation between the cerebrospinal fluid melatonin profile/concentration and neurologic disorders such as traumatic brain injury,⁴ mood disorders,⁵ and delirium.⁶ Use of melatonin as an adjuvant therapy in neurodegenerative disorders is also supported, as pineal melatonin production is dramatically reduced in patients with neurologic disorders.¹