Most people who use dietary supplements are probably familiar with Melatonin as a sleep aid —for which it is indeed effective. But not everyone is aware that sublingual Melatonin (a small lozenge type tablet placed under the tongue and allowed to dissolve and enter the blood stream through diffusion) is likely more effective than a standard Melatonin capsule or tablet. This article will discuss the research on sublingual melatonin: but first let’s review the general science behind Melatonin as a sleep aid.

Melatonin Overview
Melatonin is a hormone secreted by the pineal gland.1 It is produced from tryptophan, which after being metabolized, is converted to serotonin, and ultimately to Melatonin.2 Melatonin’s primary role is regulation of the body’s circadian rhythm, endocrine secretions, and sleep patterns.3,4 The way it works is that light inhibits Melatonin secretion and darkness stimulates secretion. Therefore, at night Melatonin is secreted which initiates sleep. However, people who suffer from an insufficient amount of environmental light, such as office workers in windowless buildings5 and the elderly who do not get outside very much, often have decreased endogenous Melatonin secretion.6 Furthermore, research suggests that some individuals may have inadequate levels of Melatonin to promote sleep. This includes elderly people7,8 (who may make less melatonin), people with chronic fatigue syndrome9 and others.10,11,12,13

In addition, Melatonin is a potent antioxidant; with 6–10 times the antioxidant activity of vitamin E.14 It acts as an oxygen free radical scavenger and prevents several enzymatic reactions that generate reactive oxygen species (ROS).15

Difficulty Sleeping in Adults
In adults with difficulty sleeping, short-term use of Melatonin modestly reduce the time it takes to fall asleep (sleep latency).16 In addition, some patients report minor improvement in subjective feelings of sleep quality.17,18,19 Furthermore, research has shown that Melatonin supplementation is effective in adults with difficulty sleeping, secondary to other causes.20 For example, Melatonin may improve difficulty sleeping secondary to mood and mental health issues21,22,23 age-related decline in memory function24, hospitalization25, and difficulty sleeping relating to “ICU syndrome”—referring to sleep disturbances while in the intensive care unit.26 A pooled analysis of studies using Melatonin for difficulty sleeping, secondary to other causes, suggests that it modestly increase sleep efficiency.27

In individuals with a circadian rhythm sleep disorder; supplementation with Melatonin improves difficulty falling asleep and other quality of life factors such as mental health, vitality, and bodily pain.28,29,30 In addition, taking Melatonin also helps improve circadian rhythm sleep disorders in blind children and adults. Melatonin has FDA orphan drug status for this indication.31,32,33,34,35

Difficulty Sleeping In Children
In children with delayed onset of sleep, Melatonin seems to shorten the time that it takes to fall asleep and increase the duration of sleep.36 Clinical research also demonstrates Melatonin may improve insomnia in children with attention deficithyperactive disorder (ADHD) who are taking stimulants.37,38

Furthermore taking Melatonin is helpful for sleep-wake cycle disturbances in children and adolescents with mental retardation, autism, and other central nervous system disorders.39,40,41,42,43

Melatonin also improves the time to fall asleep in children with developmental disabilities, including cerebral palsy, autism, and mental retardation.44 Melatonin supplementation seems to subjectively improve difficulty sleeping, secondary to other causes, associated with various sleep-wake cycle disturbances.45,46,47,48

Drug Withdrawal and Related Sleep Issues
Supplementation with Melatonin has been shown to be beneficial for facilitating benzodiazepine withdrawal in elderly people with sleep difficulties.49,50 Likewise, Melatonin supplementation 3.5 hours after nicotine withdrawal in smokers reduced subjective symptoms of anxiety, restlessness, irritability, depression, and cigarette craving over the next 10 hours.51 Although not related to withdrawal issues, beta-blockers such as atenolol and propranolol decrease Melatonin levels. Naturally, this may result in sleep difficulties. Supplementation with Melatonin supplement can decrease sleep difficulties caused by betablockers.52,53

Jet Lag
Flying from one time zone to another can result in jet lag. Research shows that supplementation with Melatonin modestly improves some symptoms of jet lag such as alertness and psychomotor performance. In addition, Melatonin mildly improves daytime sleepiness and fatigue.54 A range of doses from 0.5 to 5 mg appear to be equally effective, and 2 to 3 mg of Melatonin is particularly useful when taken at local bedtime on the day of arrival and for two to five nights thereafter in those traveling eastward through five or more time zones. The usefulness of Melatonin for westward travel or over fewer time zones is less clear.55,56,57,58,59,60,61,62

Sublingual Melatonin
With all of the aforementioned research, it is clear that Melatonin is effective as a sleep aid when used in the form of standard dietary supplement dosing (capsules and tablets). However, additional research shows that a sublingual form of Melatonin appears to be the preferred way to use this supplement.

First-pass metabolism is a phenomenon whereby the concentration of a drug, or in some cases a nutraceutical, is greatly reduced by clearance in the liver before it reaches the systemic circulation. This is also true of Melatonin. Research shows that 44–90 percent of a standard Melatonin supplement absorbed into the blood is cleared by the liver in a single passage.63 Conversely, other research64 shows that the amount of Melatonin absorbed in the mouth (i.e. sublingual) and reaching systemic circulation was 80 percent greater than the standard oral tablet, and the peak concentration of Melatonin was 50 percent higher as well.

In addition to bioavailability, there are other advantages associated with the use of sublingual Melatonin over the standard delivery form.

Research has shown that, surprisingly, Melatonin has both receptor-mediated and receptor-independent actions in cells of the oral cavity. Functions of Melatonin in the oral cavity are likely to relate primarily to its anti-inflammatory and antioxidant activities. According to one study published in the Journal of Periodontal Research, “These actions may suppress inflammation of the gingiva and periodontium, reduce alveolar bone loss, abrogate herpes lesions, enhance osteointegration of dental implants, limit oral cancer, and suppress disorders that have a free radical component. Sublingual Melatonin tablets or oral Melatonin sprays and topical Melatonin-containing gel, if used on a regular basis, may improve overall oral health and reduce mucosal lesions.”65

Furthermore, research has demonstrated that sublingual Melatonin has anti-anxiety effects. Two studies66,67 examined the effects of sublingual Melatonin in patients prior to surgery. The results were that sublingual Melatonin exerted a significant anti-anxiety effect.

Another study68 used sublingual Melatonin on emergency physicians who worked night shifts and slept during the day. Results showed that sublingual Melatonin improved day sleep and night alertness. The improvement in night alertness was probably a function of getting adequate sleep during the day. These effects suggest that sublingual Melatonin is likely able to help night workers adapt better to the shift in normal sleeping patterns.

Conclusion
As a dietary supplement, Melatonin has been shown to offer benefit in a number of situations and populations who need an effective sleep aid. This is true whether or not Melatonin is used as a capsule, tablet or as a sublingual lozenge (sometimes referred to as a mini-tablet, mini-lozenge or dot). Still, research shows that the sublingual form of Melatonin may have greater bioavailability and offer additional benefits beyond those of standard supplementation forms. In any case, a good dosage range is 3–6 mg for most people.

Endnotes

  1. Nurnberger JI Jr, Adkins S, Lahiri DK, et al. Melatonin suppression by light in euthymic bipolar and unipolar patients. Arch Gen Psychiatr 2000;57:572–9.
  2. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186–95.
  3. Ibid.
  4. Lissoni P, Barni S, Meregalli S, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus Melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer 1995;71:854–6.
  5. ‘White’ light suppresses the body’s production of melatonin. September 12, 2011. Medical Press. Retrieved February 12, 2015 from http://medicalxpress.com/news/2011-09-whitesuppresses-body-production-melatonin.html.
  6. Mishima K, Okawa M, Shimizu T, Hishikawa Y. Diminished Melatonin secretion in the elderly caused by insufficient environmental illumination. J Clin Endocrinol Metab 2001;86:129–34.
  7. Garfinkel D, et al. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995;346:541–44.
  8. Brusco LI, Fainstein I, Marquez M, et al. Effect of Melatonin in selected populations of sleep-disturbed patients. Biol Signals Recept 1999;8:126–31.
  9. van Heukelom RO, Prins JB, Smits MG, Bleijenberg G. Influence of Melatonin on fatigue severity in patients with chronic fatigue syndrome and late Melatonin secretion. Eur J Neurol 2006;13:55–60.
  10. Tjon Pian Gi CV, Broeren JP, Starreveld JS, A Versteegh FG. Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study. Eur J Pediatr 2003;162:554–5.
  11. Weiss MD, Wasdell MB, Bomben MM, et al. Sleep hygiene and Melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry 2006;45:512–9.
  12. McArthur AJ, Budden S. Sleep dysfunction in Rett syndrome: a trial of exogenous Melatonin treatment. Dev Med Child Neurol 1998;40:186–92.
  13. Sack RL, Lewy AJ, Blood ML, et al. Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms 1991;6:249–61.
  14. Shamir E, Barak Y, Shalman I, et al. Melatonin treatment for tardive dyskinesia: A double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry 2001;58:1049–52.
  15. Cuzzocrea S, Reiter RJ. Pharmacological action of Melatonin in shock, inflammation and ischemia/reperfusion injury. Eur J Pharmacol 2001;426:1–10.
  16. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous Melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 2005;20:1151–8.
  17. Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res 1996;5:61–5.
  18. James SP, Sack DA, Rosenthal NE, Mendelson WB. Melatonin administration in insomnia. Neuropsychopharmacol 1990;3:19–23.
  19. Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for treatment of sleep disorders. Summary, Evidence Report/Technology Assessment #108. (Prepared by the Univ of Alberta Evidence-based Practice Center, under Contract#290-02-0023.) AHRQ Publ #05-E002-2. Rockville, MD: Agency for Healthcare Research & Quality. November 2004.
  20. Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous Melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: metaanalysis. BMJ 2006;332:385–93.
  21. Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatr 1998;155:1119–21.
  22. Brusco LI, Fainstein I, Marquez M, et al. Effect of Melatonin in selected populations of sleep-disturbed patients. Biol Signals Recept 1999;8:126–31.
  23. Shamir E, Laudon M, Barak Y, et al. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry 2000;61:373–7.
  24. Brusco LI, Fainstein I, Marquez M, et al. Effect of Melatonin in selected populations of sleep-disturbed patients. Biol Signals Recept 1999;8:126–31.
  25. Andrade C, Srihari BS, Reddy KP, Chandramma L. Melatonin in medically ill patients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2001;62:41–5.
  26. Shilo L, Dagan Y, Smorjik Y, et al. Effect of Melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int 2000;17:71–6.
  27. Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous Melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: metaanalysis. BMJ 2006;332:385–93.
  28. Nagtegaal JE, Laurant MW, Kerkhof GA, et al. Effects of Melatonin on the quality of life in patients with delayed sleep phase syndrome. J Psychosom Res 2000;48:45–50.
  29. Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for treatment of sleep disorders. Summary, Evidence Report/Technology Assessment #108. (Prepared by the Univ of Alberta Evidence-based Practice Center, under Contract#290-02-0023.) AHRQ Publ #05-E002-2. Rockville, MD: Agency for Healthcare Research & Quality. November 2004.
  30. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous Melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 2005;20:1151–8.
  31. Sack RL, Lewy AJ, Blood ML, et al. Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms 1991;6:249–61.
  32. FDA. List of orphan designations and approvals. Office of Orphan Products Development. Available at: www.fda.gov/orphan/designat/list.htm.
  33. Palm L, Blennow G, Wetterberg L. Long-term Melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Dev Med Child Neurol 1997;39:319–25.
  34. Skene DJ, Lockley SW, Arendt J. Melatonin in circadian sleep disorders in the blind. Biol Signals Recept 1999;8:90–5.
  35. Sack RL, Brandes RW, Kendall AR, et al. Entrainment of freerunning circadian rhythms by Melatonin in blind people. N Engl J Med 2000;343:1070–7.
  36. Smits MG, Nagtegaal EE, van der Heijden J, et al. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. J Child Neurol 2001;16:86–92.
  37. Tjon Pian Gi CV, Broeren JP, Starreveld JS, A Versteegh FG. Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study. Eur J Pediatr 2003;162:554–5.
  38. Weiss MD, Wasdell MB, Bomben MM, et al. Sleep hygiene and Melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry 2006;45:512–9.
  39. McArthur AJ, Budden S. Sleep dysfunction in Rett syndrome: a trial of exogenous Melatonin treatment. Dev Med Child Neurol 1998;40:186–92.
  40. Lancioni GE, O’Reilly MF, Basili G. Review of strategies for treating sleep problems in persons with severe or profound mental retardation or multiple handicaps. Am J Ment Retard 1999;104:170–86.
  41. Jan JE, O’Donnell ME. Use of Melatonin in the treatment of paediatric sleep disorders. J Pineal Res 1996;21:193–9. 42. O’Callaghan FJ, Clarke AA, Hancock E, et al. Use of Melatonin to treat sleep disorders in tuberous sclerosis. Dev Med Child Neurol 1999;41:123–6.
  42. Jan JE, Freeman RD, Fast DK. Melatonin treatment of sleepwake cycle disorders in children and adolescents. Dev Med Child Neurol 1999;41:491–500.
  43. Dodge NN, Wilson GA. Melatonin for treatment of sleep disorders in children with developmental disabilities. J Child Neurol 2001;16:581–4.
  44. Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatr 1998;155:1119-21.
  45. Brusco LI, Fainstein I, Marquez M, et al. Effect of Melatonin in selected populations of sleep-disturbed patients. Biol Signals Recept 1999;8:126-31.
  46. Shilo L, Dagan Y, Smorjik Y, et al. Effect of Melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int 2000;17:71–6.
  47. Shamir E, Laudon M, Barak Y, et al. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry 2000;61:373–7.
  48. Garfinkel D, Zisapel N, Wainstein J, Laudon M. Facilitation of benzodiazepine discontinuation by melatonin, a new clinical approach. Arch Intern Med 1999;159:2456–60.
  49. Dagan Y, Zisapel N, Nof D, et al. Rapid reversal of tolerance to benzodiazepine hypnotics by treatment with oral melatonin: a case report. Eur Neuropsychopharmacol 1997;7:157–60.
  50. Zhdanova IV, Piotrovskaya VR. Melatonin treatment attenuates symptoms of acute nicotine withdrawal in humans. Pharmacol Biochem Behavior 2000;67:131–5.
  51. Van Den Heuvel CJ, Reid KJ, Dawson D. Effect of atenolol on nocturnal sleep and temperature in young men: reversal by pharmacological doses of melatonin. Physiol Behav 1997;61:795–802.
  52. Stoschitzky K, Sakotnik A, Lercher P, et al. Influence of beta-blockers on Melatonin release. Eur J Clin Pharmacol 1999;55:111–5.
  53. Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for treatment of sleep disorders. Summary, Evidence Report/ Technology Assessment #108. (Prepared by the Univ of Alberta Evidence-based Practice Center, under Contract#290-02-0023.) AHRQ Publ #05-E002-2. Rockville, MD: Agency for Healthcare Research & Quality. November 2004.
  54. Suhner A, Schlagenhauf P, Johnson R, et al. Comparative study to determine the optimal Melatonin dosage form for the alleviation of jet lag. Chronobiol Int 1998;15:655–6.
  55. Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of Melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatr 1993;33:526–30.
  56. Claustrat B, Brun J, David M, et al. Melatonin and jet lag: confirmatory result using a simplified protocol. Biol Psychiatr 1992;32:705–11.
  57. Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of Melatonin on jet lag after long haul flights. BMJ 1989;298:705–7.
  58. Sanders DC, Chaturvedi AK, Hordinsky JR. Melatonin: aeromedical, toxicopharmacological, and analytical aspects. J Anal Toxicol 1999;23:159–67.
  59. Suhner A, Schlagenhauf P, Johnson R, et al. Comparative study to determine the optimal Melatonin dosage form for the alleviation of jet lag. Chronobiol Int 1998;15:655-66.
  60. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev 2002;2:CD001520.
  61. Nickelsen T, Lang A, Bergau L. The effect of 6-, 9- and 11-hour time shifts on circadian rhythms: adaptation of sleep parameters and hormonal patterns following the intake of Melatonin or placebo. Adv Pineal Res 1991;5:303–6.
  62. Di W-L, Kadva A, Johnston A, Silman R. Variable Bioavailability of Oral Melatonin. N Engl J Med 1997; 336:1028–9.
  63. Bartoli AN, De Gregori S, Molinaro M, Broglia M, Tinelli C, et al. Bioavailability of a New Oral Spray Melatonin Emulsion Compared with a Standard Oral Formulation in Healthy Volunteers. J Bioequiv Availab. 2012;4:96–9.
  64. Reiter RJ1, Rosales-Corral SA, Liu XY, Acuna-Castroviejo D, Escames G, Tan DX. Melatonin in the oral cavity: physiological and pathological implications. J Periodontal Res. 2015 Feb;50(1):9–17.
  65. Khezri MB, Merate H. The effects of Melatonin on anxiety and pain scores of patients, intraocular pressure, and operating conditions during cataract surgery under topical anesthesia. Indian J Ophthalmol. 2013 Jul;61(7):319–24.
  66. Naguib M, Samarkandi AH. The comparative dose-response effects of Melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg. 2000 Aug;91(2):473–9.
  67. Jorgensen KM, Witting MD. Does exogenous Melatonin improve day sleep or night alertness in emergency physicians working night shifts? Ann Emerg Med. 1998 Jun;31(6):699-704.

Gene Bruno, MS, MHS

Gene Bruno is the Dean of Academics and Professor of Dietary Supplement Science for Huntington College of Health Sciences (a nationally accredited distance learning college offering diplomas and degrees in nutrition and other health science related subjects. Gene has two undergraduate Diplomas in Nutrition, a Bachelor’s in Nutrition, a Master’s in Nutrition, a Graduate Diploma in Herbal Medicine, and a Master’s in Herbal Medicine. As a 32 year veteran of the Dietary Supplement industry, Gene has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines, and peer-reviewed publications. Gene's latest book, A Guide to Complimentary Treatments for Diabetes, is available on Amazon.com, and other fine retailers.