The Therapeutic Potential of Melatonin: A Review of the Science

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

Disclosures
In This Article

Endocrine Function and Immunity

A close, reciprocal relationship exists between the pineal and the pituitary/adrenal axis. Melatonin modulates the activity of this axis and the peripheral actions of corticoids. One study found that melatonin releases vasotocin, which lowers corticoid levels;[13] however, this work has never been confirmed, and recently, another study found that melatonin reduces the basal release of vasotocin.[23] In this latter study, substance P-induced secretion of vasotocin was also found to be inhibited.

The different responses observed in these studies may have been the result of the different doses used. Forsling and Williams[24] elegantly demonstrated that the increase in vasotocin secretion during hypertonic saline infusion and exercise was attenuated by high doses (5 mg) but augmented by low doses (0.5 mg) of melatonin. Pinealectomy causes adrenal hypertrophy, which is reversed by melatonin administration.[25] Some have proposed that melatonin acts as a corticotropin-releasing factor inhibitor, and that disinhibition of the pituitary/adrenal axis in major depression, in which melatonin levels are low,[26] results from a lack of this modulating influence by the pineal gland.[27] Melatonin levels are low in patients with Cushing's disease,[26] a pathologic variety of hyperadrenocorticism.

Melatonin antagonizes several effects of exogenous corticoids: immune depression[28] and hypercatabolism, thymic involution, and adrenal suppression.[29] These findings have led to the suggestion that melatonin might work as an antiadrenocortical or antistress factor.[29] The melatonin/corticoid relationship is significant because chronic hypercortisolemia has been linked to several aspects of aging and age-associated phenomena, including glucose intolerance, atherogenesis, impaired immune function, and cancer.[30]

In addition to high absolute levels of corticoids, disorganization of the normal rhythm of corticoid release is also pathogenic. Corticoids are normally high in the early morning and daytime, and low at night. Properly timed exogenous melatonin may entrain, or reorganize, this critical endocrine rhythm, resulting in long-term systemic benefit. Indeed, the immune-enhancing and anticorticoid effects of melatonin, or putative mediators of melatonin action, appear to depend on nocturnal administration.[28,31] This may represent an integral immune-recovery mechanism by which melatonin acts as a kind of buffer against the harmful effects of stress on immune homeostasis.[28]

Beta-adrenoceptor blockers, which depress melatonin secretion, exert immunosuppressive effects, but only when given in the evening.[32,33] This is when blood melatonin (and the immunoenhancing effect of melatonin) is highest. Exogenous melatonin reverses beta-blocker-induced immunosuppression and enhances immune parameters in animals. A preliminary report of patients with AIDS who took melatonin 20 mg daily in the evening revealed uneven but generally beneficial effects on immune parameters.[34] It has been recommended that the dose be timed not only periodically within each day (at night only) but also periodically within the month, with treatment periods of 3-4 weeks, followed by a week-long "washout" period.[33]

Immunomodulatory effects of melatonin were also observed recently in healthy subjects and patients with bronchial asthma.[35] Melatonin increased production of interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha, indicating the possibility of an adverse effect of exogenous melatonin in patients with asthma. On the other hand, in a model of adjuvant-induced arthritis, both prophylactic and therapeutic melatonin administrations inhibited the inflammatory response.[36] This inhibition was accompanied by enhanced thymocyte proliferation and IL-2 production by melatonin. In another animal study, melatonin was shown to possess both cellular and humoral immunoenhancing effects, and immune responses were augmented even in the absence of previous immunosuppression.[37] Melatonin-receptor immunoreactivity has also been detected in the human eye,[38] the physiologic function of which remains unclear.

Predictably, melatonin-induced corticoid antagonism and immune enhancement may not always be desirable. Melatonin should be used cautiously, if at all, in patients with autoimmune conditions and in those with known or suspected adrenocortical insufficiency. The effects of melatonin on the immune system are complex, occasionally contradictory, and depend on several factors, including the dose of melatonin, the immune status of the animal (as well as its age, sex, and species), the season during which the immune system is studied, circadian rhythm of immunity, pineal gland status, and presence of a stressful condition.[39]

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