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Melatonin, a versatile indoleamine hormone synthesized by the pineal glands of mammals and also found in plants, possesses diverse physiological functions in virtually every cell in the organism: sleep and circadian rhythm regulation, vasomotor control, anti-excitatory actions, regulation of mitochondrial functions and protection against mitochondrial impairment, immunomodulatory free scavenger and antioxidant functions, anti-viral properties, and it is also hypothesized to possess anti-tumor as well as anti-aging brain protective properties.

Following is a systemic review of current literature to determine the therapeutic actions as well as the usage, dosage, efficacy, safety and contra-indications of melatonin. This review is based on English written articles sourced in PubMed with publication dates restricted to ‘’5 years’’ (not older than March 2010), ‘’human species studies’’, and ‘’full text availability’’. Articles were sourced using the keywords ‘’melatonin’’, ‘’review’’, ‘’efficacy’’, ‘’safety’’, ‘’treatment’’, ‘’therapeutic’’, ‘’applications’’.


Melatonin (N-acetyl-5-methoxytryptamine), discovered by Lerner in 1958, is a hormone synthesized from tryptophan mainly in the pineal gland (10). Due to its small size and lipophilicity melatonin it is quickly released into the bloodstream and other body fluids (bile, cerebrospinal fluid, saliva, semen, ovarian follicular fluid) and can easily cross the blood brain barrier (2). It is estimated that the half-life of melatonin in serum varies between 30 and 57 minutes (2).

Melatonin is also synthesized in other organs, including the gastrointestinal tract, retina, thymus, bone marrow and by leucocytes. However, unlike pineal melatonin, this melatonin is not synthesized in a circadian manner nor is it released into the blood in any significant amount11 and it functions as an antioxidant and regulator of intracellular events in these organs. In fact, retinal melatonin is believed to act only locally within the eye (2, 8).

In humans and other vertebrates, melatonin is secreted rhythmically in a circadian fashion, with nighttime darkness a requirement for maximal production. Exposure to light interrupts synthesis and is associated with lower melatonin levels (4, 11). Blood concentrations normally begin to rise during the evening, peak between 02:00 am and 04:00 am and return to baseline levels during late morning (8). Because of this, melatonin is referred to as ‘’the chemical expression of darkness (11).


The antioxidant effects of melatonin include

  • prevention of lipid peroxidation LPO (6)

  • Improvement of mitochondrial respiration due to a reduction in mitochondrial hydroperoxide levels and electron leakage (6,11)

  • restoration of GSH homeostasis (6)

  • reduction in kappa-light-chain enhancer of activated B cells (transcription factors, strongly implicated in promoting cancer, that mediate and regulate innate and adaptive immunity through the initiation of inflammation as a response to cellular stress) binding to DNA (6, 11)

  • reduction of pro-inflammatory cytokines and chemokines and reduction of polymorphonuclear leucocytes to inflammatory sites (6, 17)

The importance of melatonin as an antioxidant is so great that to date there is no knowledge of an organism that has lost the ability to synthesize this indoleamine (as is the case with other free radical scavengers such as vitamin C. In fact, certain genetically modified plants have been engineered to produce increased quantities of melatonin to help protect against environmental stressors, such as droughts, diseases and weather extremes, and the free radicals they generate (11).

Melatonin’s actions as an antioxidant and free radical scavenger are exerted both directly and indirectly:

1. Melatonin has been shown to directly scavenge and detoxify reactive oxygen species (ROS), reactive nitrogen species (RNS), singlet oxygen (O2), OH, H2O2, the peroxynitrite anion (ONOO-) and inhibit lipid peroxidation (LPO). (2,6,11)

2. Melatonin and its metabolites are indirect antioxidants by upregulating antioxidant enzymes including: superoxide dismutase (SOD), catalase (CAT) glutathion peroxidase (GSH-Px), glutathion reductase (GR) as well as increasing levels of intracellular glutathion (GSH)) 2, 6 and downregulates pro-oxidant enzymes: nitric oxide synthases and lipoxygenases (6)


Because of its antioxidant & free-radical scavenging functions as well as its capacity to regulate immune function melatonin is an effective anti-viral molecule. Furthermore, because of its activity on the central nervous system (CNS) it is thought capable of protecting against excessive inflammatory response resulting from infections induced by encephalitis viruses (8).

In one study on mice infected with encephalomyocarditis virus melatonin was shown to prevent paralysis and death8. Another study on mice inoculated intranasally with respiratory syncytial virus (RSV), which commonly causes severe bronchiolitis in infants less than 3 yrs of age, showed a marked reduction of acute lung oxidative injury when the mice were pretreated with melatonin suggesting that in RSV infection melatonin might help reduce injury to the airway structure (8). Finally, in human infant studies, melatonin has been shown effective in reducing excessive inflammation reactions and oxidative damage in newborns with sepsis and preterm infants with respiratory distress syndrome (8).


Several studies have demonstrated a relationship between aging, increased oxidative damage and mitochondrial dysfunction. Oxidative injury occurs in mitochondrial DNA (mtDNA), proteins and membranes (9). Based on these findings ‘’the free radical theory of aging’’ states that organisms age because cells accumulate free radical damage over time.

The mammalian brain’s has high energy demands need very large amounts of oxygen (20% of the amount inhaled (9) and very active mitochondria for optimal function. However, this generates large amounts of ROS free radicals in the brain which could cause damage resulting in brain aging and the development of neurodegenerative diseases. Age related disorders such as Parkinson’s disease (PD), Alzheimer’s (AD) (22), Huntington’s disease (HD) (21) and Amyotrophic lateral sclerosis (ALS) may share mitochondrial dysfunction, oxidative stress and apoptosis in particular brain areas (9).

Since mitochondria are directly related to cell health and fate they should be targeted for treatment in case of neurodegenerative disease. Melatonin, quickly and readily available to the brain after oral ingestion, exerts important antioxidant, anti-inflammatory and regulatory functions on the mitochondria. It supports mitochondrial homeostasis and increases the activity of the respiratory chain and ATP production. Studies and investigations on mouse models of PD, AD, HD, and ALS as well as on human patients have demonstrated improvement of symptoms as well as protective actions against further deterioration of these conditions (9, 20, 21, 22, 23, 24).


NAFLD is the most common chronic hepatic pathology in the developed world (3). Oxidative stress and apoptosis of hepatocytes appear to be implicated in the progression the disease and its transformation to cirrhosis (27). Melatonin, a scavenger of free radicals, appears to be a possible treatment.

A study, in November 2008, of 74 patients diagnosed with NAFLD (by liver biopsy) randomly assigned them to three groups:

  • Group 1 received 300 mg of phospholipids tid and tryptophan 2x500 mg qd over 14 months

  • Group 2 received 300 mg of phospholipids tid and melatonin 2x5 mg qd over 14 months

  • Group 3 received 300 mg of phospholipids tid over 14 months

After 14 months of treatment, liver biopsies were performed. Results indicate that melatonin and its precursor tryptophan could be useful in NAFLD. Melatonin improved metabolic parameters of NAFLD and lowered plasma levels of TNF-α and other pro-inflammatory cytokines IL-1, Il-6. Melatonin and tryptophan reduced inflammation in liver tissue in patients with non-alcoholic steatohepatitis (NASH) (3).


Several studies have demonstrated that melatonin secretion is impaired in patients suffering from certain cancers such as breast, endometrial or colorectal1. This is further corroborated by the fact that night-shift workers including nurses suffer from a higher rate of breast cancer (BC) incidence (15) implying then that melatonin might be considered a deterrent against the initiation, promotion and progression of cancer (1), (29). It has also been noted in one study that blind women, whose eyes cannot detect light and so have a high production of melatonin, have a lower than average BC rate (14).

Since melatonin is a hormone produced during hours of darkness and its production is closely dependent on sleep duration, nightshift work which disrupts sleep pattern decreases levels of melatonin. The ‘Nurses’ Health Study’ demonstrated that BC is significantly and inversely proportional to urinary melatonin levels (15). Another Italian study consisting of 178 post-menopausal women with invasive BC as well as 710 healthy controls demonstrated a positive correlation between melatonin’s major metabolite (aMT6s) and BC.

Melanoma, a very aggressive type of skin cancer, has a highly unfavorable prognosis once metastasized in part because of its resistance to cytotoxic agents. Furthermore, NO synthase (iNOS) and its product NO (free-radical action) as well as COX-2 (inflammatory action) molecules appear to be over expressed in melanoma (5). Fisetin, a flavonoid extracted from fruits and vegetables, exerts antitumor effects against several cancers; however, its effectiveness is limited by the emergence of side effects at therapeutic doses.

A study using human melanoma cell lines designed to determine whether melatonin could

potentiate Fisetin’s anti-tumor effect. The results demonstrated that melatonin could potentiate Fisetin-mediated antitumor activity through activating cytochrome-c/capsase-dependent-apoptotic pathway, downregulating expression of COX-2 and iNOS and abolishing their binding on COX-2 promoter. In conclusion this study found that the combined effects of Fisetin and melatonin in the treatment of melanoma improved therapeutic efficiency.

Insomnia is highly prevalent in cancer patients, because of various reasons including psychological distress, steroid producing tumors as well as chemotherapy and other cancer treatments (28). This may exacerbate cancer-associated symptoms as well as increased daytime sedation. Melatonin offers a treatment choice that is both safe and validated as successful through several tests.

In conclusion, whether for cancer prevention or cancer treatment, melatonin appears to:

  1. Exert anti-proliferative, proapoptotic, and anti-angiogenic properties (1, 2, 5, 19, 24, 29)

  2. Lower the toxicity of various chemotherapeutic agents including: cisplatin, Etoposide, antrhracyclines and 5-fluorouracil, Fisetin (1, 5, 24)

  3. Lower the chances of treatment side-effects such: myelosuppression, neurotoxicity, nephrotoxicity, cardiotoxicity and asthenia, therefore reducing mortality rates (1, 2)

  4. Offers effective radioprotective actions when used as an adjuvant in radiation therapy and may decrease normal tissue damage (2, 24)

  5. Has few severe side-effects or adverse events listed (1)


Many children diagnosed with autism spectrum disorder (ASD) appear to suffer from irregular sleep patterns (40-80% rate) in comparison with typically developing children (10-20% rate) (7). This has been linked to irregular and diminished levels of melatonin secretion leading to nighttime wakefulness and daytime sleepiness accompanied by an exacerbation of symptoms of autism symptoms. Numerous studies involving melatonin interventions in ASD children were reviewed and showed significant improvement in sleep/wake patterns and daytime behavior (7, 26)


Infant brains are more vulnerable to hypoxic ischemic injury than adult brains. Fetal brain injury in infants, particularly preterm, is a major contributor in morbidity and the cause of long-term neurological disabilities (6, 18). Melatonin appears to have a neuroprotective action in newborn mouse models (6). One study on human newborns found that melatonin treatment significantly reduced the products of lipid peroxidation in the serum of asphyxiated infants as compared with non-melatonin treated infants.

Free radical damage is a major cause of lung damage and respiratory disorders of newborns. Oxygen therapy essential to the treatment of such infants leads to hyperoxic exposure inducing excessive production of ROS/RNS free radicals in the respiratory system leading to ventilator-associated lung injury (6). Melatonin intervention in these newborns resulted in a reduction of pro-inflammatory cytokines and better clinical outcomes in terms of developing chronic lung disease6.

Retinopathy of prematurity (ROP) is a disease of the retinal vasculature in premature infants and a major cause of blindness in newborns (6). Incidence is more common in premature infants exposed to high concentrations of oxygen with resulting excessive free radical formation (6). Supplementation with melatonin may exert a beneficial antioxidant effect and improve outcomes (25).

In conclusion, since free radical damage appears to play a major role in the pathogenesis of several infant diseases the use of antioxidant therapies, including melatonin, could help counteract oxidative damage and improve outcomes for these newborns (18).


Dose and timing is important in determining efficacy of melatonin treatment. Doses used for circadian rhythm regulation are usually lower than doses for free radical control and cancer patients (11). Furthermore, when melatonin is used to treat irregular sleep patterns it should be administered in the evening before sleep but when it is used to harness free radicals it is more effective if given when the free radical event occurs regardless of the time of day (11).

According to studies/observations, in the case of radiotherapy, the optimal dose for a melatonin protocol is (2):

  • Low-dose pre-treatment, preferably in the evening one week or 10 days prior to irradiation (2)

  • High-dose administration half an hour before exposure to irradiation or radiation treatment (2)

  • Low-dose administration in the evening until the follow-up of patient after radiotherapy (2)


  • A dose of 0.3 mg at night appears to be effective for the treatment of insomnia in the elderly (10)

  • Doses of 0.3 mg to 6.0 mg/day have been used to treat chronic sleep disorders in children (10)

  • Doses of 3 mg to 40 mg/ day have been used for the prevention and treatment of various conditions (10)



  • Melatonin is ‘’likely safe’’ for all adults when taken by mouth or applied to the skin (13)

  • Melatonin has been used safely for 2 years in some people. However, possible side effects (13) include: headaches, short-term feelings of depression, daytime sleepiness, dizziness, stomach cramps, and irritability (13, 30)

  • Pregnancy and Breastfeeding: not enough known, melatonin might interfere with ovulation

  • Children: melatonin might affect other hormones and interfere with development during adolescence

  • Do not drive or use machinery for four or five hours after taking melatonin

Adverse Effects

  • In healthy volunteers, a single dose of melatonin of 10, 20, 40, 80 mg or even as low as 0.1 to 1.0 mg, slowed reaction time and increased fatigue, confusion and sleepiness (10)

  • Melatonin treatment has been associated with increased seizure frequency in some epileptic patients and a decrease in others, since it is unpredictable it must be used with caution (10, 13)

  • In case reports, oligospermia developed in 2 young men, with low-normal sperm count, while taking melatonin 3mg/day for 3 months possibly due to the reduction of aromatase at the testicular level (10)

  • Caution: melatonin might make bleeding worse in patients with bleeding disorders, may increase blood pressure when taken with certain HBP medications, might increase blood sugar in people with diabetes, can make symptoms of depression worse and can increase immune function and interfere with immunosuppressive therapy in transplant patients

Drug Interactions

  • Benzodiazepines: 2 mg of controlled release melatonin 2 hours before bedtime for 6 weeks appeared to facilitate withdrawal from benzodiazepines in patients with insomnia (10)

  • Chemotherapy: in patients with metastatic solid tumors, 20 mg/ of melatonin orally in the evening reduced frequency of chemotherapy-induced thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis, and asthenia (10)

  • Fluvoxamine (SSRI): co-administration of melatonin markedly increased bioavailability of melatonin in healthy male volunteers and might increase the effects of melatonin (10, 13) Nifedipine (CCB for HBP): administration of melatonin at night increased blood pressure of patients taking Nifedipine in the morning (10, 13)

  • Sedative medications (CNS depressants) interact with melatonin, concomitant use Taking might cause too much sleepiness (10, 13)

  • Diabetes medications: melatonin might increase blood sugar, dose change might be needed

  • Immunosuppressants’ effectiveness might be suppressed by melatonin intake (10, 13)

  • Anticoagulant / Antiplatelet drugs: Melatonin might slow blood clotting and increase the chances of bruising and bleeding (10, 13)

  • Birth control pills increase endogenous production of melatonin (13)

  • Other interactions: melatonin secretion may be suppressed by certain medications including aspirin, ibuprofen and beta blockers (10)

  • Caffeine interacts with melatonin and might decrease melatonin levels in the body


Melatonin is a multitasking molecule acting as a direct free radical scavenger and an indirect antioxidant. Its small size and lipophilicity make it easily and quickly absorbed into the bloodstream and other body fluids as well as able to cross the blood brain barrier. Its beneficial effects have been observed on various parts of the body including the mitochondria and CNS. Its ability to regulate the circadian rhythm is crucial for optimal physiology and function of the human body and its ability to protect against free radical injury is indispensable for optimal cellular function.

New research show the impressive health benefits including neuroprotective benefits, cancer fighting potential, circadian rhythm regulation and healthy sleep promotion, and a very powerful antioxidant effect. Furthermore, there is little or no evidence of any major toxicities with melatonin, even at high doses (15)


  1. Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: review and remarks. Mariangela Rondanelli, Milena Anna Faliva, Simone Perna, and Neldo Antoniello. Aging Clin Exp Res. 2013; 25(5): 499–510.

  2. Can Melatonin Help Us in Radiation Oncology Treatments? Ehsan Mihandoost, 1 Alireza Shirazi, 2 ,* Seied Rabie Mahdavi, 3 and Akbar Aliasgharzadeh 4. Biomed Res Int. 2014; 2014: 578137.

  3. Effects of treatment with melatonin and tryptophan on liver enzymes, parameters of fat metabolism and plasma levels of cytokines in patients with non-alcoholic fatty liver disease--14 months follow up. Celinski K1, Konturek PC, Slomka M, Cichoz-Lach H, Brzozowski T, Konturek SJ, Korolczuk A. J Physiol Pharmacol. 2014 Feb;65(1):75-82.

  4. Individual variations in serum melatonin levels through time: implications for epidemiologic studies. Nogueira LM1, Sampson JN1, Chu LW2, Yu K1, Andriole G3, Church T4, Stanczyk FZ5, Koshiol J1, Hsing AW2

  5. Melatonin Enhances the Anti-Tumor Effect of Fisetin by Inhibiting COX-2/iNOS and NF-κB/p300 Signaling Pathways. DOI: 10.1371/journal.pone.0099943. Canhui Yi, Yong Zhang, Zhenlong Yu, Yao Xiao, Jingshu Wang, Huijuan Qiu, Wendan Yu, Ranran Tang, Yuhui Yuan, Wei Guo, Wuguo Deng

  6. Protective role of melatonin in neonatal diseases. Gitto E1, Marseglia L1, Manti S2, D'Angelo G1, Barberi I1, Salpietro C2, Reiter RJ3.

  7. Pediatric School Psychology: Melatonin Imbalance and Sleep Dysfunction in Children With Autism By Katelyn Rose & Paul C. MacCabe.

  8. Melatonin: its possible role in the management of viral infections--a brief review. Silvestri M1, Rossi GA. Melatonin: its possible role in the management of viral infections--a brief review. Silvestri M1, Rossi GA

  9. Melatonin, Neurogenesis and Aging Brain. Lopez, Escames, Lopes, Garcia, Doerrier and Catroviejo -

  10. Alan R. Gaby, M.D. Nutritional Medicine, Fritz Perlberg Publishing, Concord, NH. Copyright © 2011

  11. Melatonin: Exceeding Expectations. Russel J. Reiter , Dun Xian Tan , Annia Galano - Physiology Published 1 September 2014 Vol. 29 no. 5, 325-333 DOI: 10.1152/physiol.00011.201

  12. Melatonin as add-on treatment for epilepsy. Brigo F1, Del Felice A.

  13. WebMD, Melatonin -

  14. Reduced cancer incidence among the blind. Feychting M1, Osterlund B, Ahlbom A. Epidemiology. 1998 Sep;9(5):490-4

  15. Rotating Night Shifts and Risk of Breast Cancer in Women Participating in the Nurses' Health Study. Eva S. Schernhammer, Francine Laden, Frank E. Speizer, Walter C. Willett, David J. Hunter,Ichiro Kawachi and Graham A. Colditz; Oxford Journals. Medicine & Health, NCI J Natl Cancer Inst, Volume 93, Issue 20;


  17. Involvement of the circadian rhythm and inflammatory cytokines in the pathogenesis of rheumatoid arthritis. Yoshida K1, Hashimoto T2, Sakai Y3, Hashiramoto A4. J Immunol.doi: 10.1155/2014/282495. Epub 2014 May 8.

  18. Pharmacological neuroprotective strategies in neonatal brain injuy. Sandra E. Juul, M.D., PhD. And Donna M. Ferriero, M.D. Published online 2013 Dec 12. doi: 10.1016/j.clp.2013.09.004;

  19. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. Jardim-Perassi BV1, Arbab AS2, Ferreira LC1, Borin TF3, Varma NR2, Iskander AS2, Shankar A2, Ali MM2, de Campos Zuccari DA3. 2014 Jan 9;9(1):e85311. doi: 10.1371/journal.pone.0085311. eCollection 2014.

  20. Treatment of the sleep disorders associated with Parkinson's disease. Trotti LM1, Bliwise DL. 2014 Jan;11(1):68-77. doi: 10.1007/s13311-013-0236-z

  21. Neuroprotective Effects of Psychotropic Drugs in Huntington’s Disease. Int J Mol Sci. 2013 Nov; 14(11): 22558–22603.

  22. Melatonin in Alzheimer's disease. Lin L1, Huang QX, Yang SS, Chu J, Wang JZ, Tian Q. 2013 Jul 12;14(7):14575-93. doi: 10.3390/ijms140714575.

  23. Oxidative stress and immunosenescence: therapeutic effects of melatonin. Espino J1, Pariente JA, Rodríguez AB.2012;2012:670294. doi: 10.1155/2012/670294. Epub 2012 Dec 31.

  24. Melatonin enhances DNA repair capacity possibly by affecting genes involved in DNA damage responsive pathways. Liu R1, Fu A, Hoffman AE, Zheng T, Zhu Y. 2013 Jan 7;14:1. doi: 10.1186/1471-2121-14-1.

  25. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Robertson NJ1, Faulkner S, Fleiss B, Bainbridge A, Andorka C, Price D, Powell E, Lecky-Thompson L, Thei L,Chandrasekaran M, Hristova M, Cady EB, Gressens P, Golay X, Raivich G. 2013 Jan;136(Pt 1):90-105. doi: 10.1093/brain/aws285. Epub 2012 Nov 26.

  26. The use of MElatonin in children with neurodevelopmental disorders and impaired sleep: a randomised, double-blind, placebo-controlled, parallel study (MENDS). Appleton RE1, Jones AP, Gamble C, Williamson PR, Wiggs L, Montgomery P, Sutcliffe A, Barker C, Gringras P. 2012;16(40):i-239. doi: 10.3310/hta16400.

  27. Serotonin and melatonin secretion and metabolism in patients with liver cirrhosis. Chojnacki C1, Walecka-Kapica E, Klupińska G, Wachowska-Kelly P, Żylińska K, Winczyk K, Chojnacki J. 2012;122(9):392-7. Epub 2012 Jul 19.

  28. Circadian rhythm disruption in cancer biology. Savvidis C1, Koutsilieris M. 2012 Dec 6;18:1249-60. doi: 10.2119/molmed.2012.00077.

  29. Circadian disruption, sleep loss, and prostate cancer risk: a systematic review of epidemiologic studies. Sigurdardottir LG1, Valdimarsdottir UA, Fall K, Rider JR, Lockley SW, Schernhammer E, Mucci LA. 2012 Jul;21(7):1002-11. doi: 10.1158/1055-9965.EPI-12-0116. Epub 2012 May 7.

  30. Melatonin, Michael D. Carter, PhD and David N. Juurlink, MD PhD. CMAJ. 2012 Nov 20; 184(17): 1923.

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