The use of melatonin preparations in sleep disorders

The role in the body and the biological significance of the pineal hormone melatonin is discussed. Data are presented on the effect on biological rhythms in humans and animals, as well as on the sleep in general. In diurnal humans and animals, melatonin acts on the suprachiasmatic nuclei of the hypothalamus to dampen the wake-stimulating signal of the internal clock, thereby promoting sleep. Data are presented on the clinical use of melatonin in sleep disorders: Circadian Rhythm Sleep-Wake Disorders (jet lag syndrome, delayed sleep phase syndrome, irregular cycle), parasomnias (Rapid-Eye Movements Sleep Behavior Disorder) and insomnia. A significant effect of melatonin preparations with a high level of evidence was confirmed in Circadian Rhythm Sleep-Wake Disorders, less pronounced in Parasomnias. The effects of melatonin, used as a drug for jet lag, have the greatest degree of evidence. The melatonin preparation is recommended to be taken both before the flight and at the new place of stay in accordance with the time of its evening secretion in this time zone. In delayed sleep phase syndrome, the onset of melatonin secretion is delayed, reflecting a general lag in the body’s internal clock. Taking melatonin preparations leads to a shift in the sleep-wake cycle to an earlier time. In REM sleep behavior disorder, melatonin preparations to reduce excessive motor activity are preferred over benzodiazepines, since this disorder manifests itself in people of older age groups, and an undesirable effect on cognitive functions should be avoided. In chronic insomnia, the effect of melatonin significantly exceeds the placebo effect and is most pronounced in people of older age groups.

1. Tordjman S., Chokron S., Delorme R., Charrier A., Bellissant E., Jaafari N. Fougerou C. Melatonin: Pharmacology, Functions and Therapeutic Benefits. Current Neuropharmacology. 2017;15(3):434–443. https://doi.org/10.2174/1570159X14666161228122115.

2. Pandi-Perumal S.R., Srinivasan V., Maestroni G.J.M., Cardinali D.P., Poeggeler B., Hardeland R. Melatonin: Nature’s most versatile biological signal? FEBS J. 2006;273(13):2813–2838. https://doi.org/10.1111/j.1742-4658.2006.05322.x.

3. Pevet P., Challet E. Melatonin: both master clock output and internal time-giver in the circadian clock network. J Physiology-Paris. 2011;105(4–6):170–182. https://doi.org/10.1016/j.jphysparis.2011.07.001.

4. Arendt J. Melatonin and human rhythms. Chronobiol Int. 2006;23(1–2)9:21–37. https://doi.org/10.1080/07420520500464361.

5. Miller S.C., Pandi-Perumal S.R., Esquifino A.I., Cardinali D.P. The role of melatonin in immunoenhancement: Potential application in cancer. Int J Exp Pathol. 2006;87(2):81–87. https://doi.org/10.1111/j.09599673.2006.00474.x.

6. Srinivasan V., Pandi-Perumal S.R., Maestroni G.J.M., Esquifino A.I., Hardeland R., Cardinali D.P. Role of melatonin in neurodegenerative diseases. Neurotox Res. 2005;7(4):293–318. https://doi.org/10.1007/BF03033887.

7. Hardeland R., Pandi-Perumal S.R. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutr Metab. 2005;(2):1–15. https://doi.org/10.1186/1743-7075-2-22.

8. Guzman-Marin R., Suntsova N., Methippara M., Greiffenstein R., Szymusiak R., McGinty D. Sleep deprivation suppresses neurogenesis in the adult hippocampus of rats. Eur J Neurosci. 2005;22(8):2111–2116. https://doi.org/10.1111/j.1460-9568.2005.04376.x.

9. Kong X., Li X., Cai Z., Yang N., Liu Y., Shu J., Pan L., Zuo P. Melatonin regulates the viability and differentiation of rat midbrain neural stem cells. Cell Mol Neurobiol. 2008;28(4):569–579. https://doi.org/10.1007/s10571-007-9212-7.

10. Moriya T., Horie N., Mitome M., Shinohara K. Melatonin influences the proliferative and differentiative activity of neural stem cells. J Pineal Res. 2007;42(4):411–418. https://doi.org/10.1111/j.1600-079X.2007.00435.x.

11. Reiter R.J. Neuroendocrine effects of light. Int J Biometeorol. 1991;35(3):169–175. https://doi.org/10.1007/BF01049063.

12. Iwasaki S., Nakazawa K., Sakai J., Kometani K., Iwashita M., Yoshimura Y., Maruyama T. Melatonin as a local regulator of human placental function. J Pineal Res. 2005;39(3):261–265. https://doi.org/10.1111/j.1600079X.2005.00244.x.

13. Kennaway D.J. Melatonin and development: physiology and pharmacology. Semin Perinatol. 2000;24(4):258–266. https://doi.org/10.1053/sper.2000.8594.

14. Niles L.P., Armstrong K.J., Rincón Castro L.M., Dao C.V., Sharma R., McMillan C.R. et al. Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT1 receptor with neuronal and glial markers. BMC Neurosci. 2004;(5):1–9. https://doi.org/10.1186/1471-2202-5-41.

15. Ladizesky M.G., Cutrera R.A., Boggio V., Somoza J., Centrella J.M., Mautalen C., Cardinali D.P. Effect of melatonin on bone metabolism in ovariectomized rats. Life Sci. 2001;70(5):557–565. https://doi.org/10.1016/S0024-3205(01)01431-X.

16. Roth J.A., Kim B.G., Lin W.L., Cho M.I. Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem. 1999;274(31):22041–22047. https://doi.org/10.1074/jbc.274.31.22041.

17. Koyama H., Nakade O., Takada Y., Kaku T., Lau K.H. Melatonin at pharmacologic doses increases bone mass by suppressing resorption throught downregulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res. 2002;17(7):1219–1229. https://doi.org/10.1359/jbmr.2002.17.7.1219.

18. Nakade O., Koyama H., Ariji H., Yajima A., Kaku T. Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro. J Pineal Res. 1999;27(2):106–110. https://doi.org/10.1111/j.1600-079X.1999.tb00603.x.

19. Dibner C., Schibler U. Circadian timing of metabolism in animal models and humans. J Intern Med. 2015;277(5):513–527. https://doi.org/10.1111/joim.12347.

20. Peschke E. Melatonin, endocrine pancreas and diabetes. J Pineal Res. 2008;44(1):26–40. https://doi.org/10.1111/j.1600-079X.2007.00519.x.

21. Aleandri V., Spina V., Morini A. The pineal gland and reproduction. Hum Reprod Update. 1996;2(3):225–235. https://doi.org/10.1093/humupd/2.3.225.

22. Barrell G.K., Thrun L.A., Brown M.E., Viguie C., Karsch F.J. Importance of photoperiodic signal quality to entrainment of the circannual reproductive rhythm of the Ewe. Biol Reprod. 2000;63(3):769–774. https://doi.org/10.1095/biolreprod63.3.769.

23. Kauppila A., Kivela A., Pakarinien A., Vakkuri O. Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity. J Clin Endocrinol Metab. 1987;65(5):823–828. https://doi.org/10.1210/jcem-65-5-823.

24. Fargason R.E., Fobian A.D., Hablitz L.M., Paul J.R., White B.A., Cropsey K.L., Gamble K.L. Correcting Delayed Circadian Phase with Bright Light Therapy Predicts Improvement in ADHD Symptoms: A Pilot Study. J Psychiatr Res. 2017;(91):105–110. https://doi.org/10.1016/j.jpsychires.2017.03.004.

25. Ferri L., Filardi M., Moresco M., Pizza F., Vandi S., Antelmi E. et al. Non-24Hour Sleep-Wake Rhythm Disorder and Melatonin Secretion Impairment in a Patient with Pineal Cyst. J Clin Sleep Med. 2017;13(11):1355–1357. https://doi.org/10.5664/jcsm.6816.

26. Flynn-Evans E.E., Lockley S.W. A Pre-Screening Questionnaire to Predict Non-24-Hour Sleep-Wake Rhythm Disorder (N24HSWD) among the Blind. J Clin Sleep Med. 2016;12(5):703–710. https://doi.org/10.5664/jcsm.5800.

27. Fukuda T., Haraguchi A., Takahashi M., Nakaoka T., Fukazawa M., Okubo J. et al. A Randomized, Double-Blind and Placebo-Controlled Crossover Trial on the Effect of l-Ornithine Ingestion on the Human Circadian Clock. Chronobiol Int. 2018;35(10):1445–1455. https://doi.org/10.1080/07420528.2018.1490315.

28. Ghaziuddin N., Shamseddeen W., Bertram H., McInnis M., Wilcox H.C., Mitchell P.B. et al. Salivary Melatonin Onset in Youth at Familial Risk for Bipolar Disorder. Psychiatry Res. 2019;274:49–57. https://doi.org/10.1016/j.psychres.2019.02.013.

29. Palagini L., Manni R., Aguglia E., Amore M., Brugnoli R., Bioulac S. et al. International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders. Front Psychiatry. 2021;(12):1–15. https://doi.org/10.3389/fpsyt.2021.688890.

30. Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018;175(16):3190–3199. https://doi.org/10.1111/bph.14116.

31. Steele T.A., Louis E.K., Videnovic A., Auger R.R. Circadian Rhythm Sleep– Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease. Neurotherapeutics. 2021;18(1):53–74. https://doi.org/10.1007/s13311-021-01031-8.

32. Auger R.R., Burgess H.J., Emens J.S., Deriy L.V., Sherene T.M., Sharkey K.M. Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015. J Clin Sleep Med. 2015;11(10):1199–1236. https://doi.org/10.5664/jcsm.5100.

33. Sletten T.L., Magee M., Murray J.M., Gordon C.J., Lovato N., Kennaway D.J. et al. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: A double-blind, randomized clinical trial. PLoS Med. 2018;15(6):1–24. https://doi.org/10.1371/journal.pmed.1002587.

34. Serfaty M., Kennell-Webb S., Warner J., Blizard R., Raven P. Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Int J Geriatr Psychiatry. 2002;17(12):1120–1127. https://doi.org/10.1002/gps.760.

35. Singer C., Tractenberg R.E., Kaye J., Schafer K., Gamst A., Grundman M. et al. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep. 2003;26(7):893–901. https://doi.org/10.1093/sleep/26.7.893.

36. Weissová K., Škrabalová J., Skálová K., Cervená K., Bendová Z., Miletínová E. et al. Circadian rhythms of melatonin and peripheral clock gene expression in idiopathic REM sleep behavior disorder. Sleep Med. 2018;52:1–6. https://doi.org/10.1016/j.sleep.2018.07.019.

37. Jiménez-Jiménez F.J., Alonso-Navarro H., García-Martín E., Agúndez, J.A. Current Treatment Options for REM Sleep Behaviour Disorder. J Pers Med. 2021;11(11):1–21. https://doi.org/10.3390/jpm11111204.

38. McGrane I.R., Leung J.G., St. Louis E.K., Boeve B.F. Melatonin therapy for REM sleep behavior disorder: a critical review of evidence. Sleep Medicine. 2015;16(1):19–26. https://doi.org/10.1016/j.sleep.2014.09.011.

39. Riemann D., Baglioni C., Bassetti C., Bjorvatn B., Groselj L.D., Ellis J.G. et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26(6):675–700. https://doi.org/10.1111/jsr.12594.

40. Котова О.В., Акарачкова Е.С., Беляев А.А., Бородулина И.В., Павлова С.В. Эффективность и безопасность комбинированного препарата СонНорм Дуо у пациентов с инсомнией: результаты открытого рандомизированного сравнительного клинического исследования. Эффективная фармакотерапия. 2022;18(36):60–65. Режим доступа: https://umedp.ru/articles/effektivnost_i_bezopasnost_kombinirovannogo_preparata_sonnorm_duo_u_patsientov_s_insomniey_rezultaty.html?sphrase_id=110601.