Effect on endogenous production of melatonin by exogenous administration

Fråga: Which doses, and after how long can endogenous production of melatonin be affected after exogenous administration?

Sammanfattning: The few available studies, in which exogenous melatonin in higher doses and/or in longer periods than the recommend were investigated, report lack of the suppressing effect on its endogenous production.

Svar: Melatonin is a neurohormone produced by the pineal gland during the dark hours of the day-night cycle. The regulating system of melatonin secretion is complex; signals originating in the retina generated by the light/dark cycle as well as cyclic endogenous signals arising in the suprachiasmatic nucleus (SCN) of the hypothalamus are believed to be the primary regulating factors of melatonin blood levels, (a retina-SCN-pineal circuit) (1,2).

The SCN in the hypothalamus has a high density of melatonin receptors suggesting a negative feedback circuit for controlling the amplitude of endogenous melatonin production (2). In the few studies that are published, suspected feedback inhibition of endogenous melatonin production, a mechanism of regulation that is common in other hormonal systems, could not be confirmed.

In Sweden, Circadin is the only registered medicine containing melatonin. Circadin is indicated as monotherapy for short-term treatment of primary insomnia in patients 55 years of age and older. The recommended dose of melatonin is 2 mg once daily, 1-2 hours before bedtime for 13 weeks (3).

In an old study (Mallo C 1988), an oral preparation of 8 mg melatonin was administered on 4 consecutive days at 22.00 h to 6 healthy volunteers. A 24-h plasma melatonin curve was obtained on three occasions, the first before treatment (day 0), the second on day 1 (day 5) and the third on day 3 (day 7) after withdrawal of a 4-day melatonin course. For the plasma melatonin profile, only the acrophase (The time at which the peak of a rhythm occurs) of day 7 was significantly advanced whereas the daily mean levels and the amplitude were similar to those of day 0 and day 5(4).

In another study (Matsumoto M 1997) melatonin (0.5 mg) or placebo was given for seven days at bedtime to night-shift workers (n=21) during their off-week. The second part of the study was done on a totally blind man where melatonin (50 mg) was given at bedtime for 37 days. In both parts of the study, exogenous administration was discontinued one day prior to admission to the Clinical Research Center, where hourly samples were drawn for 24 hours. For both the shift-worker group and in the blind subject, the average peak melatonin concentration was within the expected range prior to exogenous melatonin administration, and was unchanged following treatment (5).

Studies using the rhythm of the main catabolite of melatonin, 6-sulphatoxymelatonin (6-SMT) in the urine as evidence for endogenous melatonin production had comparable results.

In a study (Lissoni P 1999) where 7 healthy volunteers received melatonin at a dose of 10 mg/day orally in the evening hours for 30 consecutive days, urinary samples of 24 hours (separate urinary collections during daylight and night periods) were collected at the beginning of the study, as a control, and a day after the last exogenous administration of melatonin. As expected, the subjects presented circadian variation in their urinary excretion of 6-SMT, with lower values in the daytime samples and higher in those collected during the hours of darkness. The average excretion of both day and night 6-MTS observed after exogenous administration of melatonin was not significantly different from the one detected before (6).

Similarly, in a relative recent study (Lemoine P1, 2011), the 6 months administration of 2 mg prolonged-release melatonin did not cause suppression of endogenous melatonin production in a group of 15 of insomnia patients as evident by the rhythm in 6-SMT in the urine assessed 2 weeks after withdrawal of the drug(7). Wurtman R, Physiology and available preparations of melatoin. UptoDate (cited 2018-05-18). Pandi-Perumal SR, Cardinali DP editors. Melatonin: From Molecules to Therapy, chapter VII Regulation of Melatonin Synthesis: Animal versus Human Studies, New York: Nova Science Publishers; 2007: 117-134. Produktresume Circadin (melatonin). Takeda Pharma (citerad 2018-08-16). Mallo C, Zaidan R, Faure A, Brun J, Chazot G, Claustrat B. Effects of a four-day nocturnal melatonin treatment on the 24 h plasma melatonin, cortisol and prolactin profiles in humans. Acta endocrinologica. 1988;119(4):474-480. Matsumoto M, Sack RL, Blood ML, Lewy AJ. The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans. Journal of pineal research. 1997;22(1):42-44. Lissoni P, Rovelli F, Pittalis S, Casati M, Giani L, Barni S, et al. [Therapy with melatonin does not suppress its endogenous production in healthy volunteers]. Recenti Prog Med. 1999;90(2):84-85. Lemoine P, Garfinkel D, Laudon M, Nir T, Zisapel N. Prolonged-release melatonin for insomnia - an open-label long-term study of efficacy, safety, and withdrawal. Therapeutics and clinical risk management. 2011;7:301-311.