Article from Townsend Letter

Melatonin: More Than Just the Hormone That Regulates Sleep

by Pamela W. Smith, MD, MPH, MS

Melatonin is a hormone produced in the pineal gland, retina, GI tract, and white blood cells that is associated with sleep. In addition, there are melatonin receptors expressed all over the body, for example, in the intestines, fat tissue, kidneys, liver, lungs, adrenals, and other organs. The amount of melatonin the body produces decreases as one ages and depends on the activity of an enzyme called serotonin-N-acetyltransferase (NAT). The body’s production of NAT, on the other hand, depends on its storage of vitamin B6.

Functions of Melatonin1-5

Signs and Symptoms of Melatonin Deficiency

Causes of Melatonin Deficiency

There are many etiologies of melatonin deficiency. Perhaps the most common cause of melatonin deficiency in today’s world is electromagnetic fields. Other causes include the following:

Therapeutic Benefits

The therapeutic benefits of melatonin are numerous. Melatonin is a hormone that does more than regulate the sleep cycle.

Hypertension. Melatonin has been shown to decrease blood pressure in patients with hypertension.6-7  In fact, a study revealed that evening controlled-release melatonin, 2 mg for one month, significantly reduced nocturnal systolic blood pressure in patients with nocturnal hypertension.8

Heart Health. Patients with coronary artery disease tend to have low nocturnal serum melatonin levels. In addition, patients who developed adverse effects post myocardial infarction were shown to have lower nocturnal melatonin levels than patients without adverse effects. Melatonin is cardioprotective due to its vasodilator actions and free radical scavenger properties, and it also inhibits oxidation of LDL-C.9-10  Likewise, melatonin has been shown to reduce hypoxia and prevent reoxygenation-induced damage in patients with cardiac ischemia and ischemic stroke.11

The MARIA study was a prospective, randomized, double-blind, placebo-controlled trial that used IV melatonin in patients following an acute MI that were having angioplasty. It decreased CRP and IL-6, two major markers of inflammation. Melatonin also attenuated tissue damage from reperfusion, decreased V tach and V fib after reperfusion, and reduced cellular and molecular damage from ischemia.12 Another study revealed that there is an inverse correlation between melatonin levels and CRP levels after acute MI.13  Moreover, melatonin has been shown to protect cardiac myocyte mitochondria after doxorubicin use.14

Insulin Regulation and Obesity. Melatonin is necessary for the proper synthesis, secretion, and action of insulin. In addition, melatonin acts by regulating GLUT4 expression, via its G-protein-coupled membrane receptors, the phosphorylation of the insulin receptor, and its intracellular substrates that mobilize the insulin-signaling pathway. Furthermore, melatonin is responsible for the establishment of adequate energy balance by regulating energy flow and expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue. Likewise, melatonin is a powerful chronobiotic, meaning that it helps regulate the body’s internal clock. Consequently, the reduction in melatonin production that may occur with aging, shift work, or illuminated environments during the night commonly induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian changes that commonly lead to weight gain.15  A study using laboratory animals showed that melatonin supplementation daily at middle age decreased abdominal fat and lowered plasma insulin to youthful levels.16  A low melatonin level is a frequently overlooked cause for an individual’s inability to effectively lose weight.

Neurodegenerative Disorders. Studies have shown that low melatonin levels are associated with an increased risk of developing neurodegenerative diseases.17-20

Alzheimer’s Disease. Some of the symptoms of low melatonin levels are also common to patients with Alzheimer’s disease: disruption of the circadian rhythm of the body, mood changes, and delirium.21-22  One medical trial showed that melatonin levels in the cerebrospinal fluid (CSF) in patients over the age of 80 were one-half the level of younger, healthier patients. Individuals in this study with Alzheimer’s disease had even lower levels, only 20% of the amount observed in young healthy people.23 Fortunately, numerous studies have shown that supplementing with melatonin helps to protect against Alzheimer’s disease.24-30  In addition, in animal and human trials a benefit in melatonin replacement in patients with early Alzheimer’s disease was seen, even before it was clinically evident.31-32  In fact, when melatonin was replaced early, the participants did not show pathological changes nor have symptoms of cognitive decline.33 In addition, melatonin supplementation has been shown to decrease the damage caused by amyloid beta proteins and tau proteins.34-38 Moreover, medical trials revealed that using melatonin in patients with Alzheimer’s disease that they had better sleep patterns, less sundowning, and slower progression of cognitive loss.39  Likewise, melatonin has also been shown to guard against the harmful effects of aluminum, which has been shown to cause oxidative changes in the brain that are similar to those seen in Alzheimer’s disease.40-41

Mild Cognitive Impairment. Mild cognitive impairment (MCI) is impairment that precedes actual dementia.42 In fact, 12% of people with MCI proceed to develop dementia each year.43  Studies have shown that people who supplemented with melatonin (3-24 mg daily) for 15-60 months did much better on cognitive tests.44-46

Longevity. Lab trials have shown that melatonin replacement increases SIRT1, which is a longevity protein. SIRT1 is also activated by caloric restriction.47

Parkinson’s Disease. Melatonin replacement has been shown to decrease the risk of developing Parkinson’s disease.48-50 In fact, animal trials have shown that melatonin can prevent and to some extent may even help reverse the motor and behavior changes that are associated with this disease process.51-53

In Parkinson’s disease there is an accumulation of a protein called alpha-synuclein.54  Melatonin supplementation also attacks alpha-synuclein and makes it more available to be removed by the body.55-56  In addition, a lab study showed that melatonin can reverse the inflammatory changes that occur in Parkinson’s disease.57 Moreover, an animal trial also showed that melatonin helps to restore the normal activity of a key enzyme that is involved in the synthesis of dopamine.58-59  Furthermore, in lab studies melatonin supplementation was shown to increase the survival of dopamine-producing cells.60-62 Consequently, more research needs to be done concerning melatonin’s use in Parkinson’s disease.

Cerebral Vascular Accident (CVA). If the patient has a low melatonin level, they have an increased risk of developing a stroke. The odds rise more than 2% for every 1 pg/mL decline in melatonin.63 In fact, in individuals with a calcified pineal gland, the risk of developing a CVA is increased by 35%.64 Moreover, melatonin supplementation has been shown to shrink the size of an infarct area in a patient with acute CVA. This may be due to melatonin’s ability to neutralize free radical production.65-70 Melatonin may also decrease the risk of CVA by significantly lowering cholesterol and also decreasing blood pressure.71 Furthermore, melatonin supplementation in lab animals decreased the damage after stroke and decreased seizure occurrence.72 In addition, melatonin has been shown to increase plasticity of neurons after CVA.73  Likewise, in animal studies, melatonin reduced the damage caused by stroke by decreasing the activation of “protein-melting” enzymes.74-75 Melatonin has also been shown to tighten the blood-brain barrier, reduce tissue swelling, and prevent hemorrhagic transformation in animal trials with experimentally induced stroke.76-79

Closed Head Injury (CHI)/Traumatic Brain Injury (TBI). Supplementation with melatonin has been shown to minimize the brain swelling and dysfunction that occurs after a closed head injury.80-85  Melatonin supplementation has also been shown to help protect the brain in the case of traumatic brain injury.86-87  Likewise, studies employing lab animals have shown that giving melatonin after a TBI had the following results: maintained the integrity of the blood-brain barrier, prevented dangerous brain swelling in the hours and days after injury, and shrank the size of the bruised and injured tissue.88  Melatonin, likewise, reduced the mortality rate after burst aneurysm in laboratory studies.89-90

Sleep Hygiene. Melatonin has long been known to be beneficial for sleep. Melatonin has been shown to synchronize the circadian rhythms and improve the onset, duration, and quality of sleep. The good news is that exogenous melatonin supplementation is well tolerated and has no obvious short- or long-term adverse effects when used in small doses to improve sleep hygiene.91-92

Pre-Op Anxiety. When compared to placebo, melatonin given as premedication (tablets or sublingually) can reduce preoperative anxiety in adults. In fact, melatonin may be equally as effective as the standard treatment with midazolam in reducing preoperative anxiety. The effect of melatonin on postoperative anxiety in adults is mixed but suggests an overall attenuation of the effect compared to preoperatively.93

COVID-19. Melatonin is now being used as an adjuvant treatment for COVID-19 since it has been shown to limit virus-related diseases. It has also been demonstrated to be protective against acute lung injury and adult respiratory distress syndrome caused by viruses and other pathogens due to its anti-inflammatory and anti-oxidative effects.94-96 Unfortunately, COVID-19 tends to take a more severe course in individuals with chronic metabolic diseases such as obesity, diabetes mellitus, and hypertension. Since COVID-19 complications frequently involve severe inflammation and oxidative stress in this population, melatonin is being suggested as an add-on therapy for patients that are diabetic and overweight.97

Cancer. Many studies have shown that melatonin is an effective therapy for breast cancer as an adjunct to traditional care.98-102  It has also been shown to be effective for the prevention and reduction of some of the side effects of chemotherapy and radiation including mouth ulcers, dry mouth, weight loss, nerve pain, weakness, and thrombocytopenia (low platelet count).103  Moreover, melatonin has been used as a therapy for other cancer forms such as brain, lung, prostate, head and neck, and gastrointestinal cancer.104

Immune Builder. Melatonin has been shown to be a major regulator of the immune system. Consequently, disease states affecting a wide range of organ systems have been reported as benefiting from melatonin administration.105-106

Gastrointestinal Diseases. The enterochromaffin cells of the gastrointestinal tract secrete 400 times as much melatonin as the pineal gland. Consequently, it is not surprising that numerous studies have found that melatonin plays an important role in GI functioning. As previously mentioned, melatonin is a powerful antioxidant that resists oxidative stress due to its capacity to directly scavenge reactive species, increase the activities of antioxidant enzymes, and to stimulate the innate immune response through its direct and indirect actions. In the gastrointestinal tract, the activities of melatonin are mediated by melatonin receptors, serotonin, and cholecystokinin B receptors, as well as, via receptor-independent processes.107-109

Melatonin and the GI Tract

Let us now examine the use of melatonin in several disease processes of the GI tract. The prevalence of gastroesophageal reflux disease (GERD) is increasing with individuals experiencing symptoms such as heartburn, regurgitation, dysphagia, coughing, hoarseness, or chest pain. Fortunately, melatonin has been shown to have inhibitory activities on gastric acid secretion and nitric oxide biosynthesis. Nitric oxide has an important role in transient lower esophageal sphincter relaxation, which is a major etiology of reflux in people with this disease process. A study revealed that a combination of melatonin, l-tryptophan, vitamin B6, folic acid, vitamin B12, methionine and betaine was beneficial for patients with GERD. In addition, the other components of the formula exhibit anti-inflammatory and analgesic effects. All patients that took the combination of nutrients and melatonin reported a complete regression of symptoms after 40 days of treatment. However, only 65.7% of the omeprazole reported regression of symptoms in the same period.110  Numerous other studies have also revealed that melatonin has a role in the improvement of gastro-esophageal reflux disease when used alone or in combination with omeprazole.111-112

In addition, melatonin can protect the GI mucosa from ulceration by its antioxidant action, stimulation of the immune system, limitation of gastric mucosal injury, and promoting epithelial regeneration. Melatonin can also reduce the secretion of pepsin and hydrochloric acid and influence the activity of the myoelectric complexes of the gut via its action in the central nervous system.113-116 This hormone furthermore attenuates acute gastric lesions and accelerates ulcer healing via its interaction with melatonin receptors due to an enhancement of the gastric microcirculation.117

Similarly, melatonin is a promising therapeutic agent for irritable bowel syndrome (IBS) with activities independent of its effects on sleep, anxiety, or depression due to its important role in gastrointestinal physiology. It regulates gastrointestinal motility, has local anti-inflammatory reaction, as well as moderates visceral sensation. Studies have consistently showed improvement in abdominal pain; some trials even revealed improvement in quality of life in these individuals.118-121 In fact, studies have regularly publicized that alteration of the circadian rhythm is associated with the development of digestive pathologies that are linked to dysmotility or changes in microbiota composition in irritable bowel syndrome and similar conditions.122-123

Moreover, disruption of circadian physiology, due to sleep disturbance or shift work, may result in various gastrointestinal diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, or peptic ulcer disease. In addition, circadian disruption accelerates aging and promotes tumorigenesis in the liver and GI tract. Furthermore, identification of the role that melatonin plays in the regulation of circadian rhythm allows researchers and clinicians to approach gastrointestinal diseases from a chronobiological perspective. Recently, it has been postulated that disruption of circadian regulation may lead to obesity by shifting food intake schedules.124-125Likewise, a study suggests that sensing of bacteria through toll-like receptor 4 (TLR4) and regulation of bacteria through altered goblet cells and antimicrobial peptides is involved in the anti-colitic effects of melatonin. Consequently, melatonin may have use in therapeutics for inflammatory bowel disease.126

Lastly, foods that are high in melatonin (phytomelatonin) have recently been shown to be considered important in preventing diseases of the liver. Currently, more studies are needed to examine the potential beneficial effects of supplemental melatonin, and foods rich in melatonin, in liver diseases and to better clarify the molecular mechanisms of action.127

Other Sources of Melatonin

The following are common foods that contain the most melatonin.

Side Effects and Contraindications

Melatonin is an immune stimulator. Therefore, it should be used with caution in patients that have an autoimmune disease and individuals who are pregnant, breastfeeding, taking steroids, or who have a mental illness, leukemia, or lymphoma.

Signs and Symptoms of Elevated Levels

The most common reason that a person has an elevated level of melatonin is that they take too

large a dose or take melatonin and they do not need it. Likewise, an individual may also have high levels of melatonin if they eat too many foods that contain melatonin. Some medications such as clorgiline, desipramine, fluvoxamine, thorazine, tranylcypromine, and others may also raise melatonin levels as can St. John’s wort supplementation. The herb Vitex agnus-castus (chaste tree) can also elevate melatonin levels. If melatonin levels are high, serotonin levels tend to decline. Therefore, it is very important to measure melatonin levels, by salivary testing, if taking more than one mg of melatonin at night.

Melatonin Dosing Schedules

Generally, women are more sensitive to melatonin than men if melatonin is being suggested for insomnia. Some women may need only a very low dose, and hence the melatonin may need to be compounded. In addition, medical studies have also suggested that as patients age, they may need less melatonin for insomnia.128-130  As previously mentioned, large doses of melatonin are used to treat breast cancer and other cancers. Likewise, very large doses of melatonin are now being employed as co-therapies for COVID-19.131  Measuring melatonin levels by salivary testing, before and after implementing melatonin therapy, for patients who are not hospitalized for COVID is recommended. For patients who are hospitalized for COVID, no testing methods have yet been standardized.

The following are common dosage ranges for patients. Changes in dosing may need to be employed depending on the results of follow-up salivary testing.

Conclusion

Melatonin is a wonderful hormone that has so many functions in the body aside from regulating sleep. As you have seen, it has been shown to be an effective therapy for many disease processes along with a beneficial method to build the immune system.

References:

  1. Smith, S., What You Must Know About Women’s Hormones. Garden City Park, NY: Square One Publishers, 2010.
  2. Reiter, R., “Melatonin: clinical relevance,” Best Pract Res Clin Endocrinol Metab 2003; 17(2):273-85.
  3. Sinatra, S., “Melatonin shows promise against age-related disorders,” Heart Health and Nutrition 2007; 13(9):6-7
  4. Tan, D., et al., “Melatonin: a potent endogenous hydroxyl radical scavenger,” Endocrin Jour 1993; 1:57-60.
  5. Tordjman, S., et al., “Melatonin: pharmacology, functions and therapeutic benefits,” Curr Neuropharmacol 2017; 15(3):434-43.
  6. Arangino, S., et al., “Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men,”
    Amer Jour Cardiol 1999; 83:1417.
  7. Scheer, F., et al., “Daily night-time melatonin reduces blood pressure in male patients with essential hypertension,” Hypertension 2004; 43:192-97.
  8. Grossman, E., et al., “Melatonin reduces night blood pressure in patients with nocturnal hypertension,” Amer Jour Med 2006; 119(10):898-902.
  9. Dominguez-Rodriguez, A., et al., “Prognostic value of nocturnal melatonin levels as a novel marker in patients with ST-segment elevation my in myocardial infarction,” Amer Jour Cardiol 2006; 97(8):1162-64.
  10. Dominguez-Rodriguez, A., et al., “Melatonin and circadian biology in human cardiovascular disease,” Jour Pineal Res 2010; 49(1):14-22.
  11. Reiter, R., et al., Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart,” Cardiovasc Res 2003; 58(1):10-9.
  12. Dominguez-Rodriguez, A., et al., “Clinical aspects of melatonin in the acute coronary syndrome,” Curr Vasc Pharmacol 2009; 7(3):367-73.
  13. Dominguez-Rodriguez, A., et al., “Relation of nocturnal melatonin levels to c- reactive protein concentration in patients with T-segment elevation myocardial infarction,” Amer Jour Cardiol 2006; 91(1):10-2.
  14. Xu, M., et al., “Melatonin protection against lethal myocyte injury induced by doxorubicin as reflected by effects on mitochondrial membrane potential,” Jour Mol Cell Cardiol 2003; 34(1):75-9.
  15. Cipolla-Neto, J., et al., “Melatonin, energy metabolism, and obesity: a review,” Jour Pineal Res 2014; 56(4):371-81.
  16. Wolden-Hanson, T., et al., “Daily melatonin administration to middle-aged rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin: independent of food intake and total body fat,” Endocrinology 2000; 141(2):487-97.
  17. Pandi-Perumal, S., et al., “Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes,” Neurotox Res 2013; 23(3):267-300.
  18. Gupta, Y., et al., “Neuroprotective role of melatonin in oxidative stress vulnerable brain,” Indian Jour Physiol Pharmacol 2003; 47(4):373-86.
  19. Bondy, S., et al., “Retardation of brain aging by chronic treatment with melatonin,” Ann NY Acad Sci 2004; 1035:197-215.
  20. Lahiri, D., et al., “Melatonin, metals, and gene expression: implications in aging and neurodegenerative disorders,” Ann NY Acad Sci 2004; 1035:216-30.
  21. De Rooij, S., et al., “Melatonin deficiency hypothesis in delirium. A synthesis of current evidence,” Rejuvenation Res 2013; April 13.
  22. Fredericks, S., “Melatonin: The brain hormone,” Life Extension, Sep 2013, p. 40-9.
  23. Liu, R., et al., “Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging,” Alzheimer’s disease, and apolipoprotein E-epsilon 4/4 genotype,” Jour Clin Endocrinol Metab 1999; 84(1):323-27.
  24. , Pandi-Perumal.
  25. , Lahiri.
  26. Ma, J., et al., “Does melatonin help save dopaminergic cells in MPTP-treated mice?” Parkinsonism Relat Disord 2009; 15(4):307-14.
  27. Borah, A., et al., “Melatonin inhibits 6-hydroxydopamine production in the brain to protect against experimental parkinsonism in rodents,” Jour Pineal Res 2009; 47(4):293-300.
  28. Reiter, R., et al., “Melatonin ameliorates neurologic damage and neurologic damage and neurophysiologic deficits in experimental models of stroke,” Ann NY Acad Sci 2003; 993:35-47.
  29. Bondy, S., et al., “Retardation of brain aging by chronic treatment with melatonin,” Ann NY Acad Sci 2004; 1035:197-215.
  30. Feng, Z., et al., “Early melatonin supplementation alleviates oxidative stress in a transgenic-mouse model of Alzheimer’s disease,” Free Radic Biol Med 2006; 40(1):101-09.
  31. Cardinali, D., et al., “The use of melatonin in Alzheimer’s disease,” Neuro Endocrinol Lett 2002; 23(Suppl 1):20-3.
  32. Cardinali, D., et al., “The use of chronobiotics in the synchronization of the sleep/wake cycle. Therapeutic application in the early phases of Alzheimer’s disease,” Recent Pat Endocr Metab Immune Drug Discov 2011; 5(2):80-90.
  33. Feng, Z., et al., “Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic-mouse model of Alzheimer’s disease,” Jour Pineal Res 2004; 37(2):129-36.
  34. Wang, J., et al., “Role of melatonin in Alzheimer-like neurodegeneration,” Acta Pharmacol 2006; 27(1):41-9.
  35. Zhu, L., et al., “Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat,” Jour Pineal Res 2004; 37(2):71-7.
  36. Daniels, W., et al., “Melatonin prevents beta-amyloid-induced lipid peroxidation,” Jour Pineal Res 1998; 24(2):78-82.
  37. Lahiri, D., et al., “Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in murine cerebral cortex,” Jour Pineal Res 2004; 36(4);224-31.
  38. Feng, Z., et al., “Early melatonin supplementation alleviates oxidative stress in a transgenic-mouse model of Alzheimer’s disease,” Free Radic Biol Med 2006; 40(1):101-09.
  39. Cardinali, D., et al., “Clinical aspects of melatonin intervention in Alzheimer’s disease progression,” Curr Neuropharmacol 2010; 8(3):218-27.
  40. , Daniels.
  41. Lahiri, D., et al., “Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases,” Ann NY Acad Sci 2005; 1056:430-49.
  42. Cardinali, D., et al., “Therapeutic application of melatonin in mild cognitive impairment,” Amer Jour Neurodegener Dis 2012; 1(3):280-91.
  43. , Fredericks
  44. , Cardinali, 2010.
  45. Cardinali, D., et al., “Therapeutic application of melatonin in mild cognitive impairment,” Amer Jour Neurodegener Dis 2012; 1(3):280-91.
  46. Furio, A., et al., “Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study,” Jour Pineal Res 2007; 43(4):404-09.
  47. Chang, H., et al., “Melatonin preserves longevity protein (sirtuin 1): expression in the hippocampus of total sleep-deprived rats,” Jour Pineal Res 2009; 47(3):211-20.
  48. Ayer, R., et al., “Effects of melatonin in early brain injury following subarachnoid hemorrhage,” Actu Neurochir Suppl 2008; 102:327-30.
  49. , Wang.
  50. , Pandi-Perumal.
  51. Patki, G., et al., “Melatonin protects against neurobehavioral and mitochondrial deficits in a chronic mouse model of Parkinson’s disease,” Pharmacol Biochem Behav 2011; 99(4):704-11.
  52. Gutierrez-Valdez, A., et al., “Effects of chronic L-dopa or melatonin treatments after dopamine deafferentation in rats: dyskinesia, motor performance, and cytological analysis,” ISRN Neurol 2012; 2012:360379.
  53. , Ma.
  54. Ono, K., et al., “Effect of melatonin on alpha-synuclein self-assembly and cytotoxicity,” Neurobiol Aging 2012; 33(9):2172-85.
  55. , Ono.
  56. Sae-Ung, K., et al., “Melatonin reduces the expression of alpha-synuclein in the dopamine containing neuronal regions of amphetamine-treated postnatal rats,” Jour Pineal Res 2012; 52(1):128-37.
  57. Brito-Armas, J., et al., “Melatonin prevents dopaminergic cell loss induced by lentiviral vectors expressing A3OP mutant alpha-synuclein,” Histol Histopathol 2013; Feb 27.
  58. Niranjan, R., et al., “The mechanism of action of MPTO-induced neuroinflammation and its modulation by melatonin in rat astrocytoma cells,” C6 Free Radic Res 2010; 44(11):1304-16.
  59. , Cardinali, 2002.
  60. , Niranjan.
  61. , Ma.
  62. , Borah.
  63. Atanassova, P., et al., “Impaired nocturnal melatonin in acute phase of ischaemic stroke: cross-sectional matched case-control analysis,” Jour Neuroendocrinol 2009; 21(7):657-63.
  64. Kitkhuandee, A., et al., “Pineal calcification is associated with symptomatic cerebral infarction,” Jour Stroke Cerebrovasc Dis 2013; Feb. 20.
  65. , Pandi-Perumal.
  66. , Lahiri.
  67. , Feng.
  68. , Niranjan.
  69. , Ma.
  70. Deykun, K., et al., “Modulations of behavioral consequences of minor cortical ischemic lesion by application of free radical scavengers,” Gen Physiol Biophys 2011; 30(3):263-70.
  71. Sewerynek, E., et al., “Melatonin and the cardiovascular system,” Neuro Endocrinol Lett 2002; 23(Supp l):79-83.
  72. Maney, H., et al., “Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats,” FASEB Jour 1996; 10(13):1546-51.
  73. Chen, H., et al., “Melatonin improves presynaptic protein, SNAP-25, expression and dendritic spin density and enhances functional and electrophysiological recovery following transient focal cerebral ischemia in rats,” Jour Pineal Res 2009; 47(3):260-70.
  74. Hung, Y., et al., “Melatonin decreases matrix metalloproteinase-9 activation and expression and attenuates reperfusion-induced hemorrhage following transient focal cerebral ischemia in rats,” Jour Pineal Res 2008; 45(4):459-67.
  75. Jang, J., et al., “Melatonin reduced the elevated matrix metalloproteinase-9 level in a rat photothrombotic stroke model,” Jour Neuro Sci 2012; 15:323(1-2):221-27.
  76. , Reiter.
  77. , Hung.
  78. , Jang.
  79. Reiter, R., et al., “When melatonin gets on your nerves: its beneficial actions in experimental models of stroke,” Exp Biol Med (Maywood) 2005; 230(2):104-17.
  80. , Pandi-Perumal.
  81. , Feng.
  82. , Ma.
  83. , Reiter.
  84. , Niranjan.
  85. , Lahiri.
  86. Tsai, M., et al., “Melatonin attenuates brain contusion-induced oxidative insult, inactivation of signal transducers and activators of transcription 1, and up-regulation of suppressor of cytokine signalin-3 in rats,” Jour Pineal Res 2011; 51(2):233-45.
  87. Ismailoglu, O., et al., “The therapeutic effects of melatonin and nimodipine in rats after cerebral cortical injury,” Turk Neurosurg 2012; 22(6):740-46.
  88. , Ismailoglu.
  89. Ayer, R., et al., “Effects of melatonin in early brain injury following subarachnoid hemorrhage,” Actu Neurochir Suppl 2008; 102:327-30.
  90. , Wang.
  91. Xie, Z., et al., “A review of sleep disorders and melatonin,” Neurol Res 2017; 29(6):559-65.
  92. Auld, F., et al., “Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders,” Sleep Med Rev 2017; 34:10-22.
  93. Hansen, M., et al., “Melatonin for pre-and postoperative anxiety in adults,” Cochrane Database Syst Rev 2015; 2015(4):CD009861.
  94. Zhang, R., et al., “COVID-19: Melatonin as a potential adjuvant treatment,” Life Sci 2020; 250:117583.
  95. Salles, C., et al., “Correspondence COVID-19: Melatonin as a potential adjuvant treatment,” Life Sci 2020; 253:117716.
  96. Juybari, K., et al., “Melatonin potentials against viral infections including COVID- 19: Current evidence and new findings,” Virs Res 2020; 287:198108.
  97. El-Missiry, M., et al., “Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of COVID-19,” Eur Jour Pharmacol 2020; 882:173329.
  98. Barcelo, S., et al., “Breast cancer therapy based on melatonin,” Recent Pat Endocr Metab Immune Drug Discov 2012; 6(2):108-16.
  99. Cos, S., et al., “Melatonin as a selective estrogen enzyme modulator,” Curr Cancer Curr Cancer Drug Targets 2008; 8(8):691-702.
  100. Proietti, S., et al., “Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFB-1-dependent growth inhibition of breast cancer cells,” Jour Pineal Res 2011; 50(2):150-58.
  101. Thaiz-Ferraz, B., et al., “Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression,” Jour Pineal Res 2015; Aug. 21.
  102. do Nascimento Goncalves, N., et al., “Effect of melatonin in epithelial mesenchymal transition markers and invasive properties of breast cancer stem cells of canine and human cell lines,” PLoS One 2016; 11(3):e0150407.
  103. Sanchez-Barcelo, E., et al., “Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation,” Expert Opin Investig Drugs 2012; 21(6):819-31.
  104. Mills, E., et al., “Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis,” Jour Pineal Res 2005; 39(4):360-66.
  105. Csaba, G., “The pineal regulation of the immune system: 40 years since the discovery,” Acta Microbiol Immunol Hung, 2013; 60(2):77-91.
  106. Bondy, S., et al., “Melatonin and regulation of immune function: Impact on numerous diseases,” Curr Aging Sci 2020; Jul 11. doi: 10.2174/1874609813666200711153223, on-line ahead of print.
  107. Esteban-Zubero, E., et al., “Melatonin’s role as a co-adjuvant treatment in colonic disease: A review,” Life Sci 2017; 170:72-81.
  108. Konturek, S., et al., “Role of melatonin in upper gastrointestinal tract,” Jour Physiol Pharmacol 2007; 58(Suppl 6):23-52.
  109. Konturek, S., et al., “Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT),” Jour Physiol Pharmacol 2007; 58(3):381-405.
  110. de Souza Pereira, R., “Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and amino acids: comparison with omeprazole,” Jour Pineal Res 2006; 41:195–200.
  111. Kandil, T., et al., “The potential therapeutic effect of melatonin in gastroesophageal reflux disease,” BMC Gastroenterol 2010; 10:7.
  112. Werbach, M., “Melatonin for the treatment of gastroesophageal reflux disease,” Altern Ther Health Med 2008, 14(4):54–8.
  113. Bubenik, G., et al., “Localization, physiological significance and possible clinical implication of gastrointestinal melatonin,” Biol Signals Recept 2001; 10(6):350-66.
  114. Brzozowska, J., et al., “Mucosal strengthening activity of central and peripheral melatonin in the mechanism of gastric defense,” Jour Physiol Pharmacol 2009; 60(Suppl 7):47-56.
  115. Brzozowski, T., et al., “Importance of the pineal gland, endogenous prostaglandins and sensory nerves in the gastroprotective actions of central and peripheral melatonin against stress-induced damage,” Jour Pineal Res 2005; 39(4):375-85.
  116. Brzozowska, I., et al., “Mechanisms of esophageal protection, gastroprotection and ulcer healing by melatonin. Implications for the therapeutic use of melatonin in gastroesophageal reflux disease (GERD) and peptic ulcer disease,” Curr Pharm Des 2014; 20(30):4807-15.
  117. Brzozowski, T., et al., “Role of circadian rhythm and endogenous melatonin in pathogenesis of acute gastric bleeding erosions induced by stress,” Jour Physiol Pharmacol 2007; 58(Suppl 6):53-64.
  118. Thor, P., et al., “Melatonin and serotonin effects on gastrointestinal motility,” Jour Physiol Pharmacol 2007; 58(Suppl 6):97-103.
  119. , Esteban-Zubero.
  120. Bubenik, G., “Thirty-four years since the discovery of gastrointestinal melatonin,” Jour Physiol Pharmacol 2008; 59(Suppl 2):33-51.
  121. Siah, K., et al., “Melatonin for the treatment of irritable bowel syndrome,” World Jour Gastroenterol 2014; 20(10):2492-98.
  122. Duboc, H., et al., “Disruption of circadian rhythms and gut motility: An overview of underlying mechanisms and associated pathologies,” Jour Clin Gastroenterol 2020; 54(5):405-14.
  123. Franch, P., et al., “Circadian rhythms in the pathogenesis of gastrointestinal diseases,” World Jour Gastroenterol 2018; 24(38):4297-303.
  124. Konturck, P., et al., “Gut clock: implication of circadian rhythms in the gastrointestinal tract,” Jour Physiol Pharmacol 2011; 62(2):139-50.
  125. Fatima, N., et al., “Metabolic implications of circadian disruption,” Pflugers Arch 2020; 472(5):513-26.
  126. Kim, S., et al., “Melatonin controls microbiota in colitis by goblet cell differentiation and antimicrobial peptide production through Toll-like receptor 4 signalling,” Sci Rep 2020; 10:2232.
  127. Bonomini, F., et al., “Dietary melatonin supplementation could be a promising preventing/therapeutic approach for a variety of liver diseases,” Nutrients 2018; 10(9):1135.
  128. Pierce, M., et al., “Optimal melatonin dose in older adults: A clinical review of the literature,” Sr Care Pharm 2019; 34(7):419-31.
  129. Viral, E., et al., “Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature,” Drugs Aging 2014; 31(6):441-51.
  130. Gooneratne, N., et al., “Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults,” Jour Pineal Res 2012; 52(4):437-5.
  131. Reiter, R., et al., “Therapeutic algorithm for use of melatonin in patients with COVID-19,” Front Med (Lausanne) 2020; 7:226.
  132. Ibid., Reiter.

Author bio:

Pamela Wartian Smith, M.D., MPH, MS spent her first twenty years of practice as an emergency room physician with the Detroit Medical Center and then 26-years as an Anti-Aging/Functional Medicine specialist.  She is a diplomat of the Board of the American Academy of Anti-Aging Physicians and is an internationally known speaker and author on the subject of Personalized Medicine. She also holds a Master’s in Public Health Degree along with a Master’s Degree in Metabolic and Nutritional Medicine. She has been featured on CNN, PBS, and many other television networks, has been interviewed in numerous consumer magazines, and has hosted two of her own radio shows. Dr. Smith was one of the featured physicians on the PBS series “The Embrace of Aging” as well as the on-line medical series “Awakening from Alzheimer’s” and “Regain Your Brain”. Dr. Pamela Smith is the founder of The Fellowship in Anti-Aging, Regenerative, and Functional Medicine and is professor emeritus from the Morsani College of Medicine, University of South Florida. She is the author of eleven best-selling books. Her book: “What You Must Know About Vitamins, Minerals, Herbs, and So Much More” was published last year. Her newest book: “Max Your Immunity,” will be released shortly.

Consult your doctor before using any of the treatments mentioned in this article.

Reprinted with permission from the February/March 2021 Townsend Letter,  and Pamela W. Smith, MD, MPH, MS

Learn how you can benefit from more Townsend Letter articles.