The Influence of Melatonin on the Human Circadian Clock

  • Alfred J. Lewy
  • Robert L. Sack
  • Saeeduddin Ahmed
  • Vance K. Bauer
  • Mary L. Blood
Part of the NATO ASI Series book series (NSSA, volume 277)


Now that it has been established that experimental administration of melatonin has circadian phase-shifting effects in humans, we can speculate about its endogenous function. More specifically, melatonin in physiologic amounts can produce effects that are described by a phase response curve (PRC) (Lewy et al., 1990a; Lewy et al., 1992; Lewy et al., 1991; Lewy et al., 1990b; Lewy et al., 1991; Zaidan et al., 1994) that is about 12 hours out of phase with the PRCs to light (Czeisler et al., 1989; Honma and Honma, 1988; Minors et al., 1991; Wever, 1989). Therefore, it appears that the most likely role of endogenous melatonin production in humans is to augment phase-shifting and entrainment of the endogenous circadian pacemaker (ECP) by the light-dark cycle. This is accomplished through the suppressant effect of light on melatonin production (Lewy et al., 1980).


Phase Advance Melatonin Level Melatonin Treatment Circadian Time Phase Response Curve 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arendt, J., Aldhous, M., English, J., Marks, V., Arendt, J.H., Marks, M. and Folkard, S., 1987, Some effects of jet-lag and their alleviation by melatonin, Ergonomics 30:1379.CrossRefGoogle Scholar
  2. Arendt, J., Aldhous, M. and Marks, V., 1986, Alleviation of “jet lag” by melatonin: preliminary results of controlled double blind trial, Br. Med. J. 292:1170.CrossRefGoogle Scholar
  3. Arendt, J., Aldhous, M. and Wright, J., 1988, Synchronisation of a disturbed sleep-wake cycle in a blind man by melatonin treatment [letter], Lancet i:772.CrossRefGoogle Scholar
  4. Arendt, J., Bojkowski, C., Folkard, S., Franey, C., Marks, V., Minors, D., Waterhouse, J., Wever, R.A., Wildgruber, C. and Wright, J., 1985, Some effects of melatonin and the control of its secretion in humans, in: “Photoperiodism, Melatonin and the Pineal,” D. Evered and S. Clark, eds., Pitman, London.Google Scholar
  5. Arendt, J. and Marks, V., 1982, Physiological changes underlying jet lag, Br. Med. J. 284:144.CrossRefGoogle Scholar
  6. Armstrong, S.M. and Chesworth, M.J., 1987, Melatonin phase shifts a mammalian circadian clock, in: “Fundamentals and Clinics in Pineal Research,” G.P. Trentini, C. de Gaetani and P. Pévet, eds., Raven Press, New York.Google Scholar
  7. Czeisler, C.A., Kronauer, R.E., Allan, J.S., Duffy, J.F., Jewett, M.E., Brown, E.N. and Ronda, J.M., 1989, Bright light induction of strong (Type O) resetting of the human circadian pacemaker, Science 244:1328.PubMedCrossRefGoogle Scholar
  8. Dawson, D. and Lack, L., 1988, Can the position of the X oscillator be shifted while the sleep-wake cycle is held constant?, Sleep Res. 17:370.Google Scholar
  9. Dollins, A.B., Zhdanova, I.V., Wurtman, R.J., Lynch, H.J. and Deng, M.H., 1994, Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance, Proc. Natl. Acad. Sci. U.S.A. 91:1824.PubMedCrossRefGoogle Scholar
  10. Folkard, S., Arendt, J., Aldhous, M. and Kennett, H., 1990, Melatonin stabilises sleep onset time in a blind man without entrainment of Cortisol or temperature rhythms, Neurosci. Lett. 113:193.PubMedCrossRefGoogle Scholar
  11. Gwinner, E. and Benzinger, I., 1978, Synchronization of a circadian rhythm in pinealectomized European starlings by injections of melatonin, J. Comp. Physiol. 127:209.CrossRefGoogle Scholar
  12. Hoban, T.M., Lewy, A.J., Sack, R.L. and Singer, CM., 1991, The effects of shifting sleep two hours within a fixed photoperiod, J. Neural Trans. 85:61.CrossRefGoogle Scholar
  13. Honma, K. and Honma, S., 1988, A human phase response curve for bright light pulses, Jap. J. Psychiat. 42:167.Google Scholar
  14. Hughes, R.J., Badia, P., French, J., Santiago, L. and Plenzler, S., 1994, Melatonin induced changes in body temperature and daytime sleep, Sleep Res. 23:496.Google Scholar
  15. James, S.P., Mendelson, W.B., Sack, D.A., Rosenthal, N.E. and Wehr, T.A., 1987, The effect of melatonin on normal sleep, Neuropsychopharmacol. 1:41.CrossRefGoogle Scholar
  16. Johnson, C.H., 1990, “An Atlas of Phase Response Curves for Circadian and Circatidal Rhythms,” Department of Biology, Vanderbilt University, Nashville, Tennessee.Google Scholar
  17. Knauth, P., Emde, E., Rutenfranz, J., Kiesswetter, E. and Smith, P., 1981, Re-entrainment of body temperature in field studies of shiftwork, Int. Arch. Occup. Environ. Health 49:137.CrossRefGoogle Scholar
  18. Kronauer, R.E., Duffy, J.F. and Czeisler, CA., 1993, Inversion of the sleep/wake cycle in a dim light environment has no significant effect on the circadian pacemaker, Sleep Res. 22:626.Google Scholar
  19. Lewy, A., Sack, R. and Latham, J., 1990a, Circadian phase shifting of blind and sighted people with exogenous melatonin administration: evidence for a phase response curve., Soc. Light Treatment Biol. Rhythms Abst. 2:22.Google Scholar
  20. Lewy, A.J., 1983, Biochemistry and regulation of mammalian melatonin production, in: “The Pineal Gland,” R.M. Relkin, ed., Elsevier North-Holland, New York.Google Scholar
  21. Lewy, A.J., Ahmed, S., Jackson, J.M.L. and Sack, R.L., 1992, Melatonin shifts circadian rhythms according to a phase-response curve, Chronobiol. Int. 9:380.PubMedCrossRefGoogle Scholar
  22. Lewy, A.J., Sack, R.L., Blood, M.L., Bauer, V.K., Cutler, N.L. and Thomas, K.H., 1994, in: “Circadian Clocks and Their Adjustment. Ciba Foundation Symposium 183,” John Wiley, New York.Google Scholar
  23. Lewy, A.J., Sack, R.L. and Latham, J., 1991, A phase response curve for melatonin administration in humans, Sleep Res. 20:461.Google Scholar
  24. Lewy, A.J., Sack, R.L. and Latham, J.M., 1990b, Exogenous melatonin administration shifts circadian rhythms according to a phase response curve [Abstract 021]., in: “The Vth Colloquium of the European Pineal Study Group,” Guilford, England.Google Scholar
  25. Lewy, A.J., Sack, R.L. and Latham, J.M., 1991, Melatonin and the acute suppressant effect of light may help regulate circadian rhythms in humans, in: “Advances in Pineal Research,” J. Arendt and P. Pevét, eds., John Libbey, London.Google Scholar
  26. Lewy, A.J., Sack, R.L., Miller, S. and Hoban, T.M., 1987, Antidepressant and circadian phase-shifting effects of light, Science 235:352.PubMedCrossRefGoogle Scholar
  27. Lewy, A.J., Wehr, T.A., Goodwin, F.K., Newsome, D.A. and Markey, S.P., 1980, Light suppresses melatonin secretion in humans, Science 210:1267.PubMedCrossRefGoogle Scholar
  28. Mallo, C., Zaidan, R., Faure, A., Brun, J., Chazot, G. and Claustrat, B., 1988, Effects of a four-day nocturnal melatonin treatment on the 24 h plasma melatonin, Cortisol and prolactin profiles in humans, Acta Endocrinol. (Copenh.) 119:474.Google Scholar
  29. Minors, D.S., Waterhouse, J.M. and Wirz-Justice, A., 1991, A human phase-response curve to light, Neurosci. Lett. 133:36.PubMedCrossRefGoogle Scholar
  30. Palm, L., Blennow, G. and Wetterberg, L., 1991, Correction of non-24-hour sleep/wake cycle by melatonin in a blind retarded boy, Ann. Neurol. 29:336.PubMedCrossRefGoogle Scholar
  31. Quay, W.B., 1970, Precocious entrainment and associated characteristics of activity patterns following pinealectomy and reversal of photoperiod, Physiol. Behav. 5:1281.PubMedCrossRefGoogle Scholar
  32. Quay, W.B., 1972, Pineal homeostatic regulation of shifts in the circadian activity rhythm during maturation and aging, Trans. N.Y. Acad. Sci. 34:239.PubMedCrossRefGoogle Scholar
  33. Redman, J., Armstrong, S. and Ng, K.T., 1983, Free-running activity rhythms in the rat: entrainment by melatonin, Science 219:1089.PubMedCrossRefGoogle Scholar
  34. Reppert, S.M., Weaver, D.R., Rivkees, S.A. and Stopa, E.G., 1988, Putative melatonin receptors are located in a human biological clock, Science 242:78.PubMedCrossRefGoogle Scholar
  35. Sack, R.L., Blood, M.L. and Lewy, A.J., 1994, Melatonin administration promotes circadian adaptation to night-shift work, Sleep Res. 23:509.Google Scholar
  36. Sack, R.L., Lewy, A.J., Blood, M.L., Stevenson, J. and Keith, L.D., 1991, Melatonin administration to blind people: phase advances and entrainment, J. Biol. Rhythms 6:249.PubMedCrossRefGoogle Scholar
  37. Sack, R.L., Lewy, A.J. and Hoban, T.M., 1987, Free-running melatonin rhythms in blind people: phase shifts with melatonin and triazolam administration, in: “Temporal Disorder in Human Oscillatory Systems,” L. Rensing, U. an der Heiden and M.C. Mackey, eds., Springer-Verlag, Heidelberg.Google Scholar
  38. Sarrafzadeh, A., Wirz-Justice, A., Arendt, J. and English, J., 1990, Melatonin stabilises sleep onset in a blind man, in: “Sleep ’90,” J.A. Horne, ed., Patenagel Press, Bochum.Google Scholar
  39. Turek, F.W., McMillan, J.P. and Menaker, M., 1976, Melatonin: effects on the circadian locomotor rhythms of sparrows, Science 194:1441.PubMedCrossRefGoogle Scholar
  40. van Loon, J.H., 1963, Diurnal body temperature curves in shift workers, Ergonomics 6:261.CrossRefGoogle Scholar
  41. Waldhauser, F., Saletu, B. and Trinchard-Lugan, I., 1990, Sleep laboratory investigations on hypnotic properties of melatonin, Psychopharmacology 100:222.PubMedCrossRefGoogle Scholar
  42. Wever, R.A., 1989, Light effects on human circadian rhythms. A review of recent Andechs experiments, J. Biol. Rhythms 4:161.PubMedCrossRefGoogle Scholar
  43. Zaidan, R., Geoffrian, M., Brun, J., Taillard, J., Bureau, C., Chazot, G. and Claustrat, B., 1994, Melatonin is able to influence its secretion in humans: description of a phase-response curve, Neuroendocrinol. 60:105.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Alfred J. Lewy
    • 1
    • 2
    • 3
  • Robert L. Sack
    • 1
  • Saeeduddin Ahmed
    • 1
  • Vance K. Bauer
    • 1
  • Mary L. Blood
    • 1
  1. 1.Sleep and Mood Disorders Laboratory, Department of PsychiatryOregon Health Sciences UniversityPortlandUSA
  2. 2.Sleep and Mood Disorders Laboratory, Department of OphthalmologyOregon Health Sciences UniversityPortlandUSA
  3. 3.Sleep and Mood Disorders Laboratory, Department of PharmacologyOregon Health Sciences UniversityPortlandUSA

Personalised recommendations