Clinical Uses of Melatonin: Evaluation of Human Trials
Abstract
During the last 20 years, numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. The objective of this article is to review, in depth, the science regarding clinical trials performed to date. The efficacy of melatonin has been assessed as a treatment of ocular diseases, blood diseases, gastrointestinal tract diseases, cardiovascular diseases, diabetes, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, infectious diseases, neurological diseases, sleep disturbances, aging and depression. Melatonin has been also used as a complementary treatment in anaesthesia, hemodialysis, in vitro fertilization and neonatal care. The conclusion of the current review is that the use of melatonin as an adjuvant therapy seems to be well founded for macular degeneration, glaucoma, protection of the gastric mucosa, irritable bowel syndrome, arterial hypertension, diabetes, side effects of chemotherapy and radiation in cancer patients or hemodialysis in patients with renal insufficiency and, especially, for sleep disorders of circadian etiology (jet lag, delayed sleep phase syndrome, sleep deterioration associated with aging, etc.) as well as in those related with neurological degenerative diseases (Alzheimer, etc.,) or Smith-Magenis syndrome. The utility of melatonin in anesthetic procedures has been also confirmed. More clinical studies are required to clarify whether, as the preliminary data suggest, melatonin is useful for treatment of fibromyalgia, chronic fatigue syndrome, infectious diseases, neoplasias or neonatal care. Preliminary data regarding the utility of melatonin in the treatment of ulcerative colitis, Crohns disease, rheumatoid arthritis are either ambiguous or negative. Although in a few cases melatonin seems to aggravate some conditions, the vast majority of studies document the very low toxicity of melatonin over a wide range of doses. Keywords: Melatonin, macular degeneration, glaucoma, gastric mucosa, irritable bowel syndrome, ulcerative colitis, Crohn's disease, rheumatoid arthritis, arterial hypertension, diabetes, fibromyalgia, chronic fatigue syndrome, infectious diseases, neurological diseases, Smith-Magenis syndrome, sleep disturbances, jet lag, shift work, aging, depression, anesthesia, hemodialysis, in vitro fertilization, neonatal care, clinical trials
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Many in vitro experiments under different experimental conditions confirmed the good antioxidant activity of melatonin, however, levels of melatonin in certain body organs might not be high enough to exhibit antioxidant properties.
“Many in vitro experiments under different experimental conditions confirmed the good antioxidant activity of melatonin, however, levels of melatonin in certain body organs might not be high enough to exhibit antioxidant properties (Sanchez-Barcelo et al. 2010).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Sanchez-Barcelo et al. 2010
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Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates
Carloni, S., Proietti, F., Rocchi, M., Longini, M., Marseglia, L. M., D’Angelo, G., Balduini, W., Gitto, E., & Buonocore, G. (2017) · Molecules · doi:10.3390/molecules22122115 · Cited by 75 · see citing works
“Clinical studies have proven the therapeutic benefits of melatonin in different fields of medicine, in both adults [29] and neonates [19–22,24].”
BackgroundMelatonin: Protection against age-related cardiac pathology
Favero, G., Franceschetti, L., Buffoli, B., Moghadasian, M. H., Reiter, R. J., Rodella, L. F., & Rezzani, R. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.11.007 · Cited by 76 · see citing works
Self-citationMelatonin sensitizes human hepatoma cells to endoplasmic reticulum stress–induced apoptosis
Zha, L., Fan, L., Sun, G., Wang, H., Ma, T., Zhong, F., & Wei, W. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00946.x · Cited by 74 · see citing works
“Although some clinical trials have already utilized melatonin against cancer [50], and other diseases such as neurological disorders [51], cardiovascular diseases [52] and diabetes [53], the clinical utilization of melatonin in future studies still remains controversial and is already well discussed in previous review…”
BackgroundRondanelli, M., Faliva, M. A., Perna, S., & Antoniello, N. (2013) · Aging Clinical and Experimental Research · doi:10.1007/s40520-013-0118-6 · Cited by 73 · see citing works
“Clinical studies in cancer patients show that [91]:”
BackgroundInfluentialIncreasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry
Morris, G., Walker, A. J., Walder, K. R., Berk, M., Marx, W., Carvalho, A. F., Maes, M. H. J., & Puri, B. K. (2021) · Molecular Neurobiology · doi:10.1007/s12035-020-02212-w · Cited by 74 · see citing works
Melatonin induces autophagy via an mTOR ‐dependent pathway and enhances clearance of mutant‐TGFBIp
Choi, S., Kim, K. S., Oh, J., Jin, J., Lee, G., & Kim, E. K. (2012) · Journal of Pineal Research · doi:10.1111/jpi.12039 · Cited by 72 · see citing works
“On the basis of these findings, several clinical trials have investigated the usefulness of melatonin for treating age-related macular degeneration and glaucoma [47, 48].”
BackgroundCarter, C. (2017) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-170017 · Cited by 70 · see citing works
“Melatonin [237, 238], estrogen [239–241], and memantine [242] also have reported benefits in AD.”
BackgroundNasiri, E., Alizadeh, A., Roushandeh, A. M., Gazor, R., Hashemi-Firouzi, N., & Golipoor, Z. (2019) · Metabolic Brain Disease · doi:10.1007/s11011-019-00421-4 · Cited by 66 · see citing works
Usefulness of Antioxidants as Adjuvant Therapy for Septic Shock: A Randomized Clinical Trial
Aisa-Álvarez, A., Soto, M. E., Guarner‐Lans, V., Camarena-Alejo, G., Franco-Granillo, J., Martínez-Rodríguez, E. A., Ávila, R. G., Pech, L. M., & Pérez-Torres, I. (2020) · Medicina · doi:10.3390/medicina56110619 · Cited by 64 · see citing works
Yang, Y., Chiou, P.-C., Chen, P., et al. (2018) · Environmental Toxicology · doi:10.1002/tox.22674 · Cited by 64 · see citing works
“Reassuringly, melatonin treatment has been utilized in various clinical settings and has largely demonstrated a very low toxicity profile over a wide range of doses.(44) In clinical oncology, the use of melatonin as a complementary treatment enhances the efficacy and attenuates the side effects of chemoradiotherapies.”
The emergence of melatonin in oncology: Focus on colorectal cancer
Gil‐Martín, E., Egea, J., Reiter, R. J., & Romero, A. (2019) · Medicinal Research Reviews · doi:10.1002/med.21582 · Cited by 67 · see citing works
“this regard, on the bases of animal's studies, but human reports as well, the regular administration of melatonin defers the onset of some age‐related diseases, for example, neurodegenerative conditions, cancer, cardiovascular disease, etc.(16) Up to our knowledge, the administration to mammals(361,362) and humans,(16…”
BackgroundSelf-citationHigh levels of melatonin generated during the brewing process
Garcia‐Moreno, H., Calvo, J. R., & y Aibar, M. D. M. (2012) · Journal of Pineal Research · doi:10.1111/jpi.12005 · Cited by 64 · see citing works
“The combined actions of melatonin and its derivatives greatly increase the efficacy of melatonin in protecting against free radical damage and in reducing the likelihood of human disease [29].”
BackgroundNutraceuticals for older people: Facts, fictions and gaps in knowledge
González‐Sarrías, A., Larrosa, M., García‐Conesa, M., Tomás-Barberán, F. A., & Espı́n, J. C. (2013) · Maturitas · doi:10.1016/j.maturitas.2013.05.006 · Cited by 66 · see citing works
Melatonin: shedding light on infertility? - a review of the recent literature
Fernando, S., & Rombauts, L. J. F. (2014) · Journal of Ovarian Research · doi:10.1186/s13048-014-0098-y · Cited by 62 · see citing works
“These unique characteristics have made melatonin the subject of investigation into medical conditions in which oxidative stress has been implicated, including diabetes, glaucoma, irritable bowel syndrome and even in curtailing the side effects of chemo- and radiotherapy [48,49].”
BackgroundMelatonin: does it have utility in the treatment of haematological neoplasms?
Li, T. X., Yang, Z. Z., Jiang, S., et al. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13966 · Cited by 62 · see citing works
“As mentioned above, numerous studies have shown that melatonin inhibits carcinogenesis in both human and animals (Tanaka et al., 2009; Sanchez-Barcelo et al., 2010).”
BackgroundSelf-citationD’Angelo, G., Manti, S., Aversa, S., et al. (2015) · American Journal of Perinatology · doi:10.1055/s-0035-1547328 · Cited by 60 · see citing works
Self-citationChoi, S., Dadakhujaev, S., Ryu, H., et al. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00866.x · Cited by 60 · see citing works
“On the basis of these findings, several clinical trials have investigated the usefulness of melatonin for treating agerelated macular degeneration and glaucoma [40, 41].”
BackgroundAlamili, M., Bendtzen, K., Lykkesfeldt, J., Rosenberg, J., & Gögenür, I. (2013) · Journal of Critical Care · doi:10.1016/j.jcrc.2013.09.006 · Cited by 59 · see citing works
“Furthermore, the inhibiting effect of melatonin on the inflammatory response has also been documented [8-20].”
BackgroundReina, M., & Martı́nez, A. (2017) · Computational and Theoretical Chemistry · doi:10.1016/j.comptc.2017.11.017 · Cited by 59 · see citing works
Spadoni, G., Bedini, A., Lucarini, S., Mari, M., Caignard, D., Boutin, J. A., Delagrange, P., Lucini, V., Scaglione, F., Lodola, A., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01066 · Cited by 59 · see citing works
Mechanisms of Yogic Practices in Health, Aging, and Disease
Kuntsevich, V. I., Bushell, W. C., & Theise, N. D. (2010) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20214 · Cited by 57 · see citing works
Therapeutic uses of melatonin and melatonin derivatives: a patent review (2012 – 2014)
Rivara, S., Pala, D., Bedini, A., & Spadoni, G. (2015) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2014.1001739 · Cited by 58 · see citing works
“Several clinical trials have been set up to evaluate its efficacy, alone or in combination with other drugs, in different clinical settings [5].”
BackgroundMelatonin and Synthetic Melatonergic Agonists: Actions and Metabolism in the Central Nervous System
Hardeland, R., & Pöeggeler, B. (2012) · Central Nervous System Agents in Medicinal Chemistry · doi:10.2174/187152412802430129 · Cited by 56 · see citing works
Circadian Rhythms in Gastrointestinal Health and Diseases
Bishehsari, F., Lévi, F., Turek, F. W., & Keshavarzian, A. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.07.036 · Cited by 57 · see citing works
“Finally, Dr Reiter discussed the potential role of melatonin in treating GI diseases.(20) Melatonin helps to synchronize circadian rhythmicity between central and peripheral clocks.”
BackgroundBonomini, F., Borsani, E., Favero, G., Rodella, L. F., & Rezzani, R. (2018) · Nutrients · doi:10.3390/nu10091135 · Cited by 56 · see citing works
“Many of its reported beneficial properties have been linked also with its antioxidant [16,148] and anti-inflammatory effects [111] which improve neurological function, retard processes linked to aging and slow the onset of different diseases such as neurodegenerative diseases, heart disease and diabetes [135,137,138,1…”
BackgroundMożdżan, M., Możdżan, M., Chałubiński, M., Wojdan, K., & Broncel, M. (2014) · Archives of Medical Science · doi:10.5114/aoms.2014.44858 · Cited by 55 · see citing works
“However, as a drug, it is not only used in restoring the normal circadian rhythm, but it can also be useful in preventive and anti-cancer therapies as well as in andropause symptoms relief [1–3].”
BackgroundEbola Hemorrhagic Shock Syndrome-on-a-Chip
Junaid, A., Tang, H., van Reeuwijk, A., Abouleila, Y., Wuelfroth, P., van Duinen, V., Stam, W., van Zonneveld, A. J., Hankemeier, T., & Mashaghi, A. (2019) · iScience · doi:10.1016/j.isci.2019.100765 · Cited by 56 · see citing works
Ge, D., Dauchy, R. T., Liu, S., Zhang, Q., Mao, L., Dauchy, E. M., Blask, D. E., Hill, S. M., Rowan, B. G., Brainard, G. C., et al. (2013) · Journal of Pineal Research · doi:10.1111/jpi.12084 · Cited by 53 · see citing works
“Melatonin plays an important role in many physiological and pathological processes; thus, it has been tested in the treatments of a variety of diseases [5].”
BackgroundDoes the use of melatonin overcome drug resistance in cancer chemotherapy?
Asghari, M. H., Ghobadi, E., Moloudizargari, M., Fallah, M., & Abdollahi, M. R. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.01.024 · Cited by 52 · see citing works
“Moreover, the efficacy of melatonin treatment is wellevidenced in metabolic disorders such as obesity and diabetes complications [16] and in cardiovascular disorders notably hypertension, myocardial infarction, and coronary heart diseases [56].”
Background
- Authors
- Sanchez-Barcelo, E. J., Mediavilla, M. D., Tan, D. X., & Reiter, R. J.
- Affiliations
- Universidad de Cantabria (ES)
- ORCID
- Reiter, R.J.
- Venue
- Current Medicinal Chemistry
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2010-07-01
- Volume
- 17
- Issue
- 19
- Pages
- 2070-2095
- ISSN
- 0929-8673 (ISSN-L)
- OpenAlex
- W2121858140
- Cited by
- 301
- References
- 0
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 12 · 2023: 12 · 2022: 16 · 2021: 21 · 2020: 24 · 2019: 20 · 2018: 16 · 2017: 27 · 2016: 17 · 2015: 14 · 2014: 23 · 2013: 33 · 2012: 28
- FWCI
- 13.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Keywords
- melatonin, clinical efficacy, eye diseases, macular degeneration, glaucoma, gastrointestinal diseases, irritable bowel syndrome, ulcerative colitis, Crohn's disease, rheumatoid arthritis, cardiovascular disease, hypertension, diabetes mellitus, fibromyalgia, chronic fatigue syndrome, infectious diseases, neurological disorders, Alzheimer's disease, Smith-Magenis syndrome, sleep disorders, jet lag, shift work, aging, depression, anesthesia, hemodialysis, in vitro fertilization, neonatal care, adjuvant therapy
- MeSH terms
- Cardiovascular Diseases, Clinical Trials as Topic, Communicable Diseases, Endocrine System Diseases, Eye Diseases, Gastrointestinal Diseases, Hematologic Diseases, Humans, Melatonin, Muscular Diseases, Neoplasms, Nervous System Diseases, Fatigue Syndrome, Chronic
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