Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements

In the paper

“Of note, when melatonin is taken 4 h before the sleep midpoint, i.e., at bedtime, the low dose of 0.5 mg does not shift the circadian rhythm, while the 3.0 mg dose will cause a phase delay.”

In the paper

“Both doses improved sleep efficiency, but the higher dose impacted the biological day and night sleep patterns, the duration of non-REM sleep, and awakening time [93].”

What the sources say

• Not checked yetcites [93] Duffy, 2022, High dose melatonin increases sleep duration during nighttime and daytime sleep episodes in older adults, J. Pineal Res. source

In the paper

“A randomized study of people with delayed sleep-wake phase disorder found that a low dose of melatonin (0.5 mg) an hour before the desired bedtime, along with behavioral strategies for four weeks, resulted in earlier sleep onset, improved sleep efficiency during the first third of the night, and reduced subjective complaints [72].”

What the sources say

• Not checked yetcites [72] Sletten, T.L., Magee, M., Murray, J.M., Gordon, C.J., Lovato, N., Kennaway, D.J., Gwini, S.M., Bartlett, D.J., Lockley, S.W., and Lack, L.C. (2018). Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: A double-blind, randomised clinical trial. PLoS Med., 15. source

In the paper

“A 2017 systematic review [92] identified 5030 studies on melatonin and sleep, but only twelve were included to meet their criteria for randomized, controlled, and single or double-blind studies.”

What the sources say

• Not checked yetcites [92] Auld, 2017, Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders, Sleep Med. Rev. source

In the paper

“Melatonin had a statistically significant effect on reducing sleep latency and increasing total sleep time.”

What the sources say

• Not checked yetcites [1] Wunsch, N.-G. (2022, July 31). Sales of Melatonin 2020. Available online: https://www.statista.com/statistics/1267421/sales-of-melatonin-in-the-united-states/.
• Not checked yetcites [91] Qawasmi, 2018, Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders, Focus source

In the paper

“In a Cochrane review, nine out of ten trials found that melatonin effectively reduced jet lag symptoms in travelers, especially if traveling eastward or over five time zones [74].”

What the sources say

• Not checked yetcites [74] Herxheimer, 2002, Melatonin for the prevention and treatment of jet lag, Cochrane Database Syst. Rev.

In the paper

“In a small pilot study of elderly patients with a mild cognitive deficit, the ability to remember previously learned items improved, and depression decreased with melatonin [105].”

What the sources say

• Not checked yetcites [105] Zizi, 1998, Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment, J. Pineal Res. source

In the paper

“Levels from infancy to adolescence increase and plateau in association with Tanner stages of puberty and then slowly decline with age starting in the late twenties [9,10].”

What the sources say

• Not checked yetcites [9] Crowley, 2012, Human puberty: Salivary melatonin profiles in constant conditions, Dev. Psychobiol. source
• Not checked yetcites [10] Grivas, 2007, Melatonin the “light of night” in human biology and adolescent idiopathic scoliosis, Scoliosis source

In the paper

“From a basic mechanistic perspective, both have widespread effects on multiple systems and are found extensively throughout the body.”

In the paper

“Breastfed babies have the benefit of melatonin from their mother’s milk [8].”

What the sources say

• Not checked yetcites [8] Caba, 2022, Breast Milk and the Importance of Chrononutrition, Front. Nutr. source

In the paper

“Both act as hormones, affect multiple systems through their immune-modulating, anti-inflammatory functions, are found in the skin, and are responsive to sunlight and darkness.”

In the paper

“Like vitamin D, melatonin could plausibly be treated as a required dietary nutrient, with certain individuals necessitating less, more, or fine-tuning to personalized needs for lifestyle requirements (e.g., exposure to artificial blue light at night, jet lag, shift work) or alterations in physiology, such as gene variants in melatonin receptors or metabolic response [2,3].”

What the sources say

• Not checked yetcites [2] Celestin, 2021, Impact of Changes in Free Concentrations and Drug-Protein Binding on Drug Dosing Regimens in Special Populations and Disease States, J. Pharm. Sci. source
• Not checked yetcites [3] Garaulet, 2015, Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans, Metabolism source

In the paper

“On average, the pineal gland produces between 0.1 and 0.9 mg of melatonin per day [4,6].”

What the sources say

• Not checked yetcites [4] Srinivasan, 2006, Melatonin: Nature’s most versatile biological signal?, Febs. J. source
• Not checked yetcites [6] Mahmood, 2019, Pleiotropic Effects of Melatonin, Drug Res. source

In the paper

“Melatonin production and circadian rhythms do not develop in babies until around three months [7].”

What the sources say

• Not checked yetcites [7] Rivkees, 1997, Developing circadian rhythmicity. Basic and clinical aspects, Pediatr. Clin. N. Am. source

In the paper

“In fact, there may be similarities between the widespread concern about vitamin D deficiency as a “sunlight deficiency” and reduced melatonin secretion as a result of “darkness deficiency” from overexposure to artificial blue light.”

In the paper

“Ultraviolet (UV)-B radiation is required to convert 7-dehydrocholesterol in the skin to vitamin D3 [21].”

What the sources say

• Not checked yetcites [21] Wacker, 2013, Sunlight and Vitamin D: A global perspective for health, Dermato-Endocrinology source

In the paper

“Specifically, vitamin D and melatonin may work synergistically in the skin.”

In the paper

“Its synthesis is reduced by exposure to light, with artificial light reducing a person’s melatonin production and increasing disease risk [4,6].”

What the sources say

• Not checked yetcites [4] Srinivasan, 2006, Melatonin: Nature’s most versatile biological signal?, Febs. J. source
• Not checked yetcites [6] Mahmood, 2019, Pleiotropic Effects of Melatonin, Drug Res. source

In the paper

“It has been proposed that both vitamin D and melatonin orchestrate many of their functions, especially related to redox status, at the level of the mitochondria [27].”

What the sources say

• Not checked yetcites [27] Ferder, 2020, Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin, J. Steroid Biochem. Mol. Biol. source

In the paper

“Numerous studies have identified melatonin as a powerful free-radical scavenger with potential protective properties against neurodegenerative disorders, epilepsy, and certain cancers.”

In the paper

“Concurrent with the age-related depletions in levels of vitamin D and melatonin, there is mitochondrial dysfunction, which has implications in a variety of clinical conditions that present differently through the seasons with changing light exposure [27].”

What the sources say

• Not checked yetcites [27] Ferder, 2020, Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin, J. Steroid Biochem. Mol. Biol. source

In the paper

“Newer, in vitro data on phytomelatonin would suggest superior antioxidant, anti-radical, and anti-inflammatory effects over synthetic melatonin.”

In the paper

“Finally, melatonin is involved with multiple activities that include mitochondrial homeostasis, genomic regulation, modulation of inflammatory and immune cytokines, directly impacting both systemic and acute anti-inflammatory properties as well as indications around its potential role in phase separation [25,26].”

What the sources say

• Not checked yetcites [25] Tan, 2015, Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism, Molecules source
• Not checked yetcites [26] Loh, D., and Reiter, R.J. (2021). Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders. Antioxidants, 10. source

In the paper

“Melatonin’s dual actions can inhibit pro-oxidative enzymes (e.g., xanthine oxidase) while also acting to potentiate the critical antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase, and catalase, aiding in the body’s first line of immune defense and metabolic detoxification [31,32].”

What the sources say

• Not checked yetcites [31] Ighodaro, 2018, First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid, Alex. J. Med.
• Not checked yetcites [32] Chitimus, D.M., Popescu, M.R., Voiculescu, S.E., Panaitescu, A.M., Pavel, B., Zagrean, L., and Zagrean, A.M. (2020). Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules, 10. source

In the paper

“Of interest, research has indicated that the sheer amplitude of plasma melatonin may not have as much to do with chronological age but more with the degree of pineal calcification and associated melatonin secretion [16].”

What the sources say

• Not checked yetcites [16] Tan, D.X., Xu, B., Zhou, X., and Reiter, R.J. (2018). Pineal Calcification, Melatonin Production, Aging, Associated Health Consequences and Rejuvenation of the Pineal Gland. Molecules, 23. source

In the paper

“Melatonin assists in mitochondrial redox balance through its ability to reduce the superoxide anion molecule from the electron transport chain and to directly scavenge free radicals [36].”

What the sources say

• Not checked yetcites [36] Reiter, R.J., Tan, D.X., Rosales-Corral, S., Galano, A., Zhou, X.J., and Xu, B. (2018). Mitochondria: Central Organelles for Melatonin’s Antioxidant and Anti-Aging Actions. Molecules, 23. source

In the paper

“The established serotonergic and melatonergic systems may be vulnerable before establishing a stable global biota in infancy.”

In the paper

“It can stimulate the regeneration of epithelial cells [43] and has also been shown to have protective antioxidant effects on the lining of the GI tract [43].”

What the sources say

• Not checked yetcites [43] Kanova, M., and Kohout, P. (2021). Tryptophan: A Unique Role in the Critically Ill. Int. J. Mol. Sci., 22. source

In the paper

“It is suspected that the gut-brain axis is a network of complex interactions between the nervous and GI systems with major contributions from intestinal microbiota.”

In the paper

“Unlike pinealocytes, enterochromaffin cells are not regulated by light and dark but appear affected by food intake and digestion [39,40].”

What the sources say

• Not checked yetcites [39] Rezzani, R., Franco, C., Franceschetti, L., Gianò, M., and Favero, G. (2022). A Focus on Enterochromaffin Cells among the Enteroendocrine Cells: Localization, Morphology, and Role. Int. J. Mol. Sci., 23. source
• Not checked yetcites [40] Yasmin, 2021, Gut melatonin: A potent candidate in the diversified journey of melatonin research, Gen. Comp. Endocrinol. source

In the paper

“Low levels of melatonin may trigger an upregulation in the kynurenine pathway, and kynurenine production, as well as trigger the aryl hydrocarbon receptor (AhR) located on the outer membrane of the mitochondria [32,55,56,57,58].”

What the sources say

• Not checked yetcites [32] Chitimus, D.M., Popescu, M.R., Voiculescu, S.E., Panaitescu, A.M., Pavel, B., Zagrean, L., and Zagrean, A.M. (2020). Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules, 10. source
• Not checked yetcites [55] Ferlazzo, N., Andolina, G., Cannata, A., Costanzo, M.G., Rizzo, V., Currò, M., Ientile, R., and Caccamo, D. (2020). Is Melatonin the Cornucopia of the 21st Century?. Antioxidants, 9. source
• Not checked yetcites [56] Maffei, M.E. (2020). 5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology. Int. J. Mol. Sci., 22. source
• Not checked yetcites [57] Reiter, 2010, Neurotoxins: Free radical mechanisms and melatonin protection, Curr. Neuropharmacol. source
• Not checked yetcites [58] Brinkmann, 2019, The Aryl Hydrocarbon Receptor (AhR) in the Aging Process: Another Puzzling Role for This Highly Conserved Transcription Factor, Front. Physiol. source

In the paper

“Levels of melatonin are known to be higher in mitochondria compared with blood levels, most likely due to the greater antioxidant requirements with the copious amounts of free radicals generated through the electron transport chain [25].”

What the sources say

• Not checked yetcites [25] Tan, 2015, Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism, Molecules source

In the paper

“Elderly individuals may also be more susceptible to serotonergic and melatonergic system errors due to known lower amounts of biota diversity.”

In the paper

“The release of melatonin in the gut acts in a paracrine manner to increase activity and circulation in the gastric mucosa and enhances GI motility [5,41].”

What the sources say

• Not checked yetcites [5] Chen, 2011, Distribution, function and physiological role of melatonin in the lower gut, World J. Gastroenterol. source
• Not checked yetcites [41] Fowler, 2022, Circadian Rhythms and Melatonin Metabolism in Patients With Disorders of Gut-Brain Interactions, Front. Neurosci. source

In the paper

“Ultimately, the gut microbiota may influence CNS function and, over time, could cause neurological diseases, including Alzheimer’s disease, mood and anxiety disorders, multiple sclerosis (MS), Parkinson’s disease, and migraines.”

In the paper

“It may be that declining melatonin levels with age and, thus, less protection of the mitochondria from oxidative stress may be contributors to preclinical changes and, ultimately clinical symptoms.”

In the paper

“Melatonin is derived from serotonin using 5-hydroxytryptophan (5-HTP) and tryptophan [32,55].”

What the sources say

• Not checked yetcites [32] Chitimus, D.M., Popescu, M.R., Voiculescu, S.E., Panaitescu, A.M., Pavel, B., Zagrean, L., and Zagrean, A.M. (2020). Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules, 10. source
• Not checked yetcites [55] Ferlazzo, N., Andolina, G., Cannata, A., Costanzo, M.G., Rizzo, V., Currò, M., Ientile, R., and Caccamo, D. (2020). Is Melatonin the Cornucopia of the 21st Century?. Antioxidants, 9. source

In the paper

“Quinolinic acid is a neurotoxin, while kynurenic acid has neuroprotective properties [32,55,56,57,58].”

What the sources say

• Not checked yetcites [32] Chitimus, D.M., Popescu, M.R., Voiculescu, S.E., Panaitescu, A.M., Pavel, B., Zagrean, L., and Zagrean, A.M. (2020). Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules, 10. source
• Not checked yetcites [55] Ferlazzo, N., Andolina, G., Cannata, A., Costanzo, M.G., Rizzo, V., Currò, M., Ientile, R., and Caccamo, D. (2020). Is Melatonin the Cornucopia of the 21st Century?. Antioxidants, 9. source
• Not checked yetcites [56] Maffei, M.E. (2020). 5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology. Int. J. Mol. Sci., 22. source
• Not checked yetcites [57] Reiter, 2010, Neurotoxins: Free radical mechanisms and melatonin protection, Curr. Neuropharmacol. source
• Not checked yetcites [58] Brinkmann, 2019, The Aryl Hydrocarbon Receptor (AhR) in the Aging Process: Another Puzzling Role for This Highly Conserved Transcription Factor, Front. Physiol. source

In the paper

“Circadian rhythm sleep-wake disorders are either intrinsic or extrinsic.”

In the paper

“Many neurological disorders feature elements of the kynurenine pathway of tryptophan, specifically the dysregulation of tryptophan metabolism and subsequent melatonin production.”

In the paper

“This dosing regimen may contribute to the occasional complaints of a paradoxical effect of melatonin supplements on sleep.”

In the paper

“Melatonin is both water- and lipid-soluble (‘amphiphilic’); thereby, it can freely flow among all bodily tissues, especially across the selective blood–brain barrier, making it likely one of the most formidable antioxidants within the central nervous system [60].”

What the sources say

• Not checked yetcites [60] Escames, 2010, The role of mitochondria in brain aging and the effects of melatonin, Curr. Neuropharmacol. source

In the paper

“Melatonin supplements can be used therapeutically for both conditions [67].”

What the sources say

• Not checked yetcites [67] Auger, 2015, Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline, J. Clin. Sleep Med. source

In the paper

“Studies using melatonin have explored how shift work, particularly night work with its exposure to light at night, may increase the risk of cancer, aggravate both gastrointestinal and cardiovascular disease, complicate pregnancy, and interfere with drug therapy [68].”

What the sources say

• Not checked yetcites [68] Iguichi, 1982, Age-dependent reduction in serum melatonin concentrations in healthy human subjects, J. Clin. Endocrinol. Metab. source

In the paper

“The AhR is responsible for modulating mitochondrial metabolism, melatonergic pathways, acetyl-coenzyme A, and COX-2 prostaglandin.”

In the paper

“The melatonin-serotonin pathway accounts for approximately five percent of dietary tryptophan degradation, while the kynurenic pathway accounts for approximately 95 percent of dietary tryptophan degradation [32,56].”

What the sources say

• Not checked yetcites [32] Chitimus, D.M., Popescu, M.R., Voiculescu, S.E., Panaitescu, A.M., Pavel, B., Zagrean, L., and Zagrean, A.M. (2020). Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules, 10. source
• Not checked yetcites [56] Maffei, M.E. (2020). 5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology. Int. J. Mol. Sci., 22. source

In the paper

“The summary concluded that melatonin is indicated for the following [92]:Insomnia: Immediate release 1–3 mg, 30 min before bed; slow-release can be used for sleep maintenance problemsRegulating sleep in blind individuals who often experience non-24 h sleep-wake rhythm disorder;Replicating the normal endogenous pattern;Delayed sleep phase.”

What the sources say

• Not checked yetcites [92] Auld, 2017, Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders, Sleep Med. Rev. source

In the paper

“Dysfunctional sleep does not have one mechanism, such as reduced melatonin, but potentially several causes, some or all, may be impacting melatonin levels.”

In the paper

“Relatively smaller amounts of melatonin are produced in the retina compared with the pineal gland [96].”

What the sources say

• Not checked yetcites [96] Ostrin, 2019, Ocular and systemic melatonin and the influence of light exposure, Clin. Exp. Optom. source

In the paper

“Importantly, iRBD is a prodrome biomarker for Parkinson’s disease.”

In the paper

“Thus, at a larger, more macroscopic level, as mentioned previously, imbalances in melatonin may be associated with what might be referred to as a “darkness deficiency,” or a lack of adequate evening darkness to initiate the secretion of melatonin by the pineal gland.”

In the paper

“However, interest has been expressed for inflammatory conditions such as ocular neuritis and uveitis [97].”

What the sources say

• Not checked yetcites [97] Aranda, 2017, Melatonin as a Therapeutic Resource for Inflammatory Visual Diseases, Curr. Neuropharmacol. source

In the paper

“Many studies support melatonin’s use in reducing the ill effects of jet lag and speeding up the normalization of circadian rhythms [73].”

What the sources say

• Not checked yetcites [73] Srinivasan, 2008, Jet lag: Therapeutic use of melatonin and possible application of melatonin analogs, Travel. Med. Infect. Dis. source

In the paper

“Patients with iRBD will retain muscle tone during REM sleep and can act out their dreams, posing a danger to themselves and others.”

In the paper

“Moreover, there may be an association between environmental toxins such as heavy metals (e.g., arsenic) and sleep disturbance [82,83].”

What the sources say

• Not checked yetcites [82] Rahman, 2022, Association of urinary arsenic and sleep disorder in the US population: NHANES 2015-2016, Environ. Sci. Pollut. Res. Int. source
• Not checked yetcites [83] Shiue, 2017, Urinary arsenic, pesticides, heavy metals, phthalates, polyaromatic hydrocarbons, and polyfluoroalkyl compounds are associated with sleep troubles in adults: USA NHANES, 2005-2006, Environ. Sci. Pollut. Res. Int. source

In the paper

“Some researchers suggest that glaucoma may be a therapeutic target for melatonin [98,99].”

What the sources say

• Not checked yetcites [98] Martínez-Águila, A., Martín-Gil, A., Carpena-Torres, C., Pastrana, C., and Carracedo, G. (2021). Influence of Circadian Rhythm in the Eye: Significance of Melatonin in Glaucoma. Biomolecules, 11. source
• Not checked yetcites [99] Gubin, 2022, Melatonin, circadian rhythms and glaucoma: Current perspective, Neural Regen. Res. source

In the paper

“Overall, children diagnosed with ASD and positive family history had higher serum melatonin and nitric oxide levels, with significantly lower malondialdehyde/melatonin ratios, suggesting greater impaired oxidant-antioxidant metabolism and balance in children with ASD [117].”

What the sources say

• Not checked yetcites [117] Rana, 2021, The Assessment and Treatment of Sleep Abnormalities in Children and Adolescents with Autism Spectrum Disorder: A Review, J. Can. Acad. Child Adolesc. Psychiatry

In the paper

“Overall, clinical data suggest that melatonin supplementation improves sleep and neurotransmission and reduces sundowning in those with Alzheimer’s disease.”

In the paper

“In a systematic review and meta-analysis of thirteen clinical trials, melatonin supplementation was found to decrease inflammatory compounds (TNF-alpha, IL-6, C-reactive protein), although with a more significant lowering effect on TNF-alpha and IL-6, especially with studies ≥ twelve weeks and at a dosage ≥ 10 mg/day [175].”

What the sources say

• Not checked yetcites [175] Zarezadeh, 2020, Melatonin supplementation and pro-inflammatory mediators: A systematic review and meta-analysis of clinical trials, Eur. J. Nutr. source

In the paper

“Moreover, with the indole structure of melatonin closely resembling that of tryptophan, there could be theoretical safety concerns related to the Eosinophilia-Myalgia Syndrome (EMS) outbreak in 1989 from the intake of at least six contaminants in an L-tryptophan dietary supplement [264,265,266], although the dose of melatonin tends to be about 1000 times lower than that of tryptophan.”

What the sources say

• Not checked yetcites [264] Williamson, 1997, Contaminants in commercial preparations of melatonin, Mayo Clin. Proc. source
• Not checked yetcites [265] Williamson, 1998, Structural characterization of contaminants found in commercial preparations of melatonin: Similarities to case-related compounds from L-tryptophan associated with eosinophilia-myalgia syndrome, Chem. Res. Toxicol. source
• Not checked yetcites [266] Allen, 2011, Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan, Arthritis Rheum. source

In the paper

“It was found that autistic patients have low melatonin levels caused by a primary deficit in ASMT gene activity [116].”

What the sources say

• Not checked yetcites [116] Melke, 2008, Abnormal melatonin synthesis in autism spectrum disorders, Mol. Psychiatry source

In the paper

“Age-related macular degeneration is another serious ophthalmic condition that theoretically could benefit from melatonin administration, although significant clinical research is currently lacking [100,101].”

What the sources say

• Not checked yetcites [100] Rastmanesh, 2011, Potential of melatonin to treat or prevent age-related macular degeneration through stimulation of telomerase activity, Med. Hypotheses source
• Not checked yetcites [101] Mehrzadi, 2020, Mitochondrial dysfunction in age-related macular degeneration: Melatonin as a potential treatment, Expert Opin. Ther. Targets source

In the paper

“Most notable is early research conducted on patients with solid metastatic tumors, in which it was demonstrated that high doses of melatonin were effective in arresting tumor growth and improving quality of life markers [178].”

What the sources say

• Not checked yetcites [178] Lissoni, 1991, Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies, Oncology source

In the paper

“At a mechanistic level, it may decrease the progression of the disease through its protection of neuronal cells from amyloid-beta, possibly due to the facilitation of its degradation and transport from the brain matter through the glymphatic fluid [102,103,104].”

What the sources say

• Not checked yetcites [102] Lin, 2013, Melatonin in Alzheimer’s disease, Int. J. Mol. Sci. source
• Not checked yetcites [103] Roy, J., Tsui, K.C., Ng, J., Fung, M.L., and Lim, L.W. (2021). Regulation of Melatonin and Neurotransmission in Alzheimer’s Disease. Int. J. Mol. Sci., 22. source
• Not checked yetcites [104] Li, 2020, Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer’s disease, Biomed. Pharmacother. source

In the paper

“Migraines can also be correlated with many autoimmune disorders tied to melatonin regulation failure. These conditions include Hashimoto’s thyroiditis with associated hypothyroidism, rheumatic diseases, and antiphospholipid syndrome [109].”

What the sources say

• Not checked yetcites [109] Ribeiro, 2016, Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention, J. Neurol. Neurosurg. Psychiatry source

In the paper

“Migraine headaches are comorbid with several health conditions, including neurological, psychiatric, cardiovascular, cerebrovascular, GI, metaboloendocrine, and immunological disorders.”

In the paper

“A review article found that patients with autism had improved sleep parameters, better daytime behavior, and minimal side effects with melatonin use [118].”

What the sources say

• Not checked yetcites [118] Rossignol, 2011, Melatonin in autism spectrum disorders: A systematic review and meta-analysis, Dev. Med. Child. Neurol. source

In the paper

“For jet lag, recent studies are lacking in detailing the most efficacious dose.”

In the paper

“Melatonin may not be effective for everyone but could be well-suited for those individuals with a history of jet lag and/or for those flying across ≥ five time zones to the East [74].”

What the sources say

• Not checked yetcites [74] Herxheimer, 2002, Melatonin for the prevention and treatment of jet lag, Cochrane Database Syst. Rev.

In the paper

“There have also been reports of vivid dreams or nightmares while using melatonin supplements [164].”

What the sources say

• Not checked yetcites [164] Siah, 2014, Melatonin for the treatment of irritable bowel syndrome, World J. Gastroenterol. source

In the paper

“Interestingly, the control group (not insomniacs) also had low melatonin levels, but melatonin did not improve sleep.”

What the sources say

• Not checked yetcites [278] Zhdanova, 2001, Melatonin treatment for age-related insomnia, J. Clin. Endocrinol. Metab. source

In the paper

“They concluded that that too much melatonin may negatively affect the melatonin phase-response curve [281].”

What the sources say

• Not checked yetcites [281] Lewy, 2002, Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period, Chronobiol. Int. source

In the paper

“Some studies used a protocol in which melatonin supplementation was initiated three days before travel started [284,285].”

What the sources say

• Not checked yetcites [284] Petrie, 1989, Effect of melatonin on jet lag after long haul flights, Br. Med. J. source
• Not checked yetcites [285] Petrie, 1993, A double-blind trial of melatonin as a treatment for jet lag in international cabin crew, Biol. Psychiatry source

In the paper

“The pharmacological dose (3 mg), like the lowest dose (0.1 mg), also improved sleep; however, it induced hypothermia and caused plasma melatonin to remain elevated into the daylight hours.”

What the sources say

• Not checked yetcites [278] Zhdanova, 2001, Melatonin treatment for age-related insomnia, J. Clin. Endocrinol. Metab. source

In the paper

“Much has been written about melatonin’s therapeutic value, but the doses used in studies tended to be supraphysiological or based on previous studies that did not have an explicit rationale for choosing the amount.”

In the paper

“The dose of melatonin was patented up to 1 mg based on this earlier research [279], excluding dietary supplement manufacturers from selling this dose and thus, using higher doses.”

What the sources say

• Not checked yetcites [279] (1995). National Center for Biotechnology Information. Methods of Inducing Sleep Using Melatonin. (US5449683A), U.S. Patent.

In the paper

“Melatonin’s action of lowering body temperature is important to monitor and may give significant clues to the appropriate dosage.”

In the paper

“In clinical applications, too much melatonin or various extended-release formats have been documented to produce side effects such as amnesia or a “melatonin hangover” the next day, finding it harder to fall asleep, or sleeping well for three to four hours and then waking up and not being able to go back to sleep [275].”

What the sources say

• Not checked yetcites [275] Benedict, 2022, Melatonin’s Potential Side Effects: It May Be in Your Genes, Mayo Clin. Proc. source

In the paper

“The physiological dose (0.3 mg) restored sleep efficiency and elevated plasma melatonin levels to normal during early adulthood.”

What the sources say

• Not checked yetcites [278] Zhdanova, 2001, Melatonin treatment for age-related insomnia, J. Clin. Endocrinol. Metab. source

In the paper

“Although more research is needed comparing synthetic and plant-based sources of melatonin, there is some initial indication that phytomelatonin may have advantages related to improved bioavailability and efficacy.”

What the sources say

• Not checked yetcites [34] Kukula-Koch, W., Szwajgier, D., Gaweł-Bęben, K., Strzępek-Gomółka, M., Głowniak, K., and Meissner, H.O. (2021). Is Phytomelatonin Complex Better Than Synthetic Melatonin? The Assessment of the Antiradical and Anti-Inflammatory Properties. Molecules, 26. source
• Not checked yetcites [267] Pérez-Llamas, F., Hernández-Ruiz, J., Cuesta, A., Zamora, S., and Arnao, M.B. (2020). Development of a Phytomelatonin-Rich Extract from Cultured Plants with Excellent Biochemical and Functional Properties as an Alternative to Synthetic Melatonin. Antioxidants, 9. source

In the paper

“While a theoretical concern, there is a lack of significant scientific evidence that this dependence can develop, and if it does, under which conditions and individuals may be most susceptible.”

In the paper

“Lissoni et al.’s cancer research from over twenty years ago demonstrated that 20 mg given intramuscularly followed by oral daily doses of 10 mg was effective in arresting tumor growth and improving quality of life markers [178].”

What the sources say

• Not checked yetcites [178] Lissoni, 1991, Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies, Oncology source

In the paper

“This pharmaceutical is a known inhibitor of CYP1A2 and can result in the potentiation of melatonin levels due to reducing its degradation [304].”

What the sources say

• Not checked yetcites [304] Wang, 2001, Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin, J. Clin. Psychopharmacol. source

In the paper

“In summary, while not a comprehensive listing, melatonin can interact or be influenced by pharmaceuticals, nutrients, or herbs with blood thinning, blood sugar-lowering, blood pressure reducing, anti-convulsing, sedative, anti-depressant, and/or immunosuppressive activities [306].”

What the sources say

• Not checked yetcites [306] Therapeutic Research (2022, July 31). Melatonin. Available online: https://naturalmedicines.therapeuticresearch.com/.

In the paper

“A few human clinical studies published more than two decades ago would suggest that vitamin B12 supplementation increased the phase advance effect of morning light and decreased nocturnal melatonin levels [309,310]”

What the sources say

• Not checked yetcites [309] Honma, 1992, Effects of vitamin B12 on plasma melatonin rhythm in humans: Increased light sensitivity phase-advances the circadian clock?, Experientia source
• Not checked yetcites [310] Hashimoto, 1996, Vitamin B12 enhances the phase-response of circadian melatonin rhythm to a single bright light exposure in humans, Neurosci. Lett. source

In the paper

“Neither the parents nor children monitored their melatonin use but relied on the initial study proposal, so dosing varied widely.”

What the sources say

• Not checked yetcites [290] Hoebert, 2009, Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia, J. Pineal Res. source

In the paper

“As stated above, combining melatonin supplementation with actives that influence melatonin pharmacokinetics may cause side effects.”

In the paper

“In one report, clinicians observed that the initial response to melatonin had disappeared weeks after starting treatment, and that the favorable response returned with dose reduction [293].”

What the sources say

• Not checked yetcites [293] Braam, 2010, Loss of response to melatonin treatment is associated with slow melatonin metabolism, J. Intellect. Disabil. Res. source

In the paper

“Historically, much of the research related to sleep has indicated melatonin supplementation thirty to sixty minutes before bed; yet, some studies have shown that it can be taken up to four hours prior and be effective.”

In the paper

“In an average of 3.7 years of follow-up from previous clinical trial participation of pharmacological doses of melatonin, 65% of children were still using melatonin as prescribed in the study, but only 9% were able to discontinue use [290].”

What the sources say

• Not checked yetcites [290] Hoebert, 2009, Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia, J. Pineal Res. source

In the paper

“Compliance nearly four years later was at 65%, presumably due to the satisfaction of use.”

What the sources say

• Not checked yetcites [290] Hoebert, 2009, Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia, J. Pineal Res. source

In the paper

“Only one questionnaire-based study investigated long-term melatonin use in children with ADHD and chronic insomnia and, by its design, was based on subjective symptom reports.”

What the sources say

• Not checked yetcites [290] Hoebert, 2009, Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia, J. Pineal Res. source

In the paper

“Lewy suggests that dosing for sleep requires a minimum of twelve hours of wakefulness [281].”

What the sources say

• Not checked yetcites [281] Lewy, 2002, Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period, Chronobiol. Int. source

In the paper

“The authors would like to emphasize that the dramatic increase in the use of supplemental melatonin in children is unwarranted because they endogenously produce more melatonin than adults [10].”

What the sources say

• Not checked yetcites [10] Grivas, 2007, Melatonin the “light of night” in human biology and adolescent idiopathic scoliosis, Scoliosis source

In the paper

“It is well accepted that melatonin in tablet or capsule form is generally not very bioavailable (1 to 74%) and can be influenced by multiple variables [295].”

What the sources say

• Not checked yetcites [295] Savage, R.A., Zafar, N., Yohannan, S., and Miller, J.M.M. (2022). Melatonin. StatPearls, StatPearls Publishing LLC.. StatPearls Publishing. Copyright © 2022.

In the paper

“From a pharmacokinetic standpoint, Vasey, McBride, and Penta [297] indicated that melatonin administered in tablet or capsule forms follows first-order or concentration-dependent kinetics. This implies that the kinetic absorption of melatonin is, in fact, not saturable, meaning that larger doses would produce higher plasma concentrations.”

What the sources say

• Not checked yetcites [297] Vasey, C., McBride, J., and Penta, K. (2021). Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin. Nutrients, 13. source

In the paper

“Dyssomnia, ADHD, and ASD have been studied and reviewed, all confirming effectiveness and safety of melatonin.”

In the paper

“Oral melatonin has been studied to reach peak plasma concentration after forty-one minutes of administration, although it was reported that melatonin pharmacokinetics varied greatly between individuals [297].”

What the sources say

• Not checked yetcites [297] Vasey, C., McBride, J., and Penta, K. (2021). Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin. Nutrients, 13. source

In the paper

“A systematic review by researchers at the University of Copenhagen cited an average of 15% bioavailability from oral melatonin, which was highly variable (range: 9–33%) and affected by age, illness, caffeine, smoking, and medications [296].”

What the sources say

• Not checked yetcites [296] Andersen, 2015, Clinical pharmacokinetics of melatonin: A systematic review, Eur. J. Clin. Pharmacol. source

In the paper

“Historically, due to the lack of safety data, melatonin supplementation was not recommended for women who are pregnant or nursing.”

In the paper

“Similarly, caffeine is also metabolized through CYP1A2 and can increase melatonin levels [305].”

What the sources say

• Not checked yetcites [305] Ursing, 2003, Caffeine raises the serum melatonin level in healthy subjects: An indication of melatonin metabolism by cytochrome P450(CYP)1A2, J. Endocrinol. Investig. source

In the paper

“It should be noted that studies were of various lengths, with some as short as two weeks, and the longest-lasting study was six months.”

In the paper

“Indiscriminate, long-term dosing may lead to unnecessary dependence and even perturbations in puberty onset when nocturnal levels of melatonin tend to decline [291].”

What the sources say

• Not checked yetcites [291] Boafo, 2019, Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician’s perspective, Nat. Sci. Sleep source

In the paper

“and in the case of methylcobalamin specifically, may even result in less need for sleep and impart better sleep quality [311]”

What the sources say

• Not checked yetcites [311] Mayer, 1996, Effects of vitamin B12 on performance and circadian rhythm in normal subjects, Neuropsychopharmacology source

In the paper

“Other factors: Season, physical activity, age, gender, genetic factors related to the volume of the active pineal gland, and possibly posture at the time of sample collection may all influence melatonin levels [323].”

What the sources say

• Not checked yetcites [323] Rzepka-Migut, B., and Paprocka, J. (2020). Melatonin-Measurement Methods and the Factors Modifying the Results. A Systematic Review of the Literature. Int. J. Environ. Res. Public Health, 17. source

In the paper

“Furthermore, the timing of eating and time of sleep may influence melatonin levels, as can intermittent fasting.”

In the paper

“It has been shown to have systemic effects through its mechanisms of action, ultimately having the potential for a significant impact on the etiologies of multiple chronic diseases.”

In the paper

“When worn during a 60 min light pulse at 0100 h, blue-light-blocking glasses resulted in a slight increase in melatonin levels compared to baseline, while melatonin levels decreased significantly by 46% in the control condition [320].”

What the sources say

• Not checked yetcites [320] Bennett, 2009, Use of modified spectacles and light bulbs to block blue light at night may prevent postpartum depression, Med. Hypotheses source

In the paper

“When it comes to supplemental sources, phytomelatonin may have greater efficacy and present a more sustainable, low-toxic option compared with synthetic formats of melatonin.”

What the sources say

• Not checked yetcites [34] Kukula-Koch, W., Szwajgier, D., Gaweł-Bęben, K., Strzępek-Gomółka, M., Głowniak, K., and Meissner, H.O. (2021). Is Phytomelatonin Complex Better Than Synthetic Melatonin? The Assessment of the Antiradical and Anti-Inflammatory Properties. Molecules, 26. source

In the paper

“In healthy adults without sleep or circadian disorders, using blue-light-blocking glasses from 1800 h until bedtime for a week resulted in subjective reports of earlier sleep onset, though objective measures were not improved.”

In the paper

“One recent clinical trial in type 2 diabetics found that modest vitamin D supplementation helped to increase both vitamin D and glutathione levels, while decreasing oxidative stress and inflammation [317].”

What the sources say

• Not checked yetcites [317] Gu, 2022, Effect of vitamin D on oxidative stress and serum inflammatory factors in the patients with type 2 diabetes, J. Clin. Lab. Anal. source

In the paper

“Finally, lifestyle habits such as proper exposure to light and darkness and less blue light at night are also helpful for establishing healthy melatonin levels.”

In the paper

“It remains unclear how food intake (types of foods, macronutrient distribution, timing) during the day can alter pineal gland secretion of melatonin at night;”

In the paper

“After seven nights of wearing blue blockers for two hours before bed, people with insomnia have significantly improved subjective and objective total sleep time, sleep quality, and soundness [321].”

What the sources say

• Not checked yetcites [321] Shechter, 2018, Blocking nocturnal blue light for insomnia: A randomized controlled trial, J. Psychiatr. Res. source

In the paper

“From a scientific perspective, melatonin acts as a powerful antioxidant that can cross the blood–brain barrier, inhibit inflammation, and interact with the gut microbiome.”

In the paper

“Thus, while not yet extensively researched, there could be an interrelationship between the collective antioxidant activities of glutathione, vitamin D, and melatonin.”

In the paper

“For people with Delayed Sleep-Wake Phase, wearing blue-light-blocking glasses from 2100 h to bedtime for two weeks resulted in their dim-light melatonin onset occurring 78 min earlier, while sleep onset was significantly earlier by 132 min [322].”

What the sources say

• Not checked yetcites [322] Esaki, 2016, Wearing blue light-blocking glasses in the evening advances circadian rhythms in the patients with delayed sleep phase disorder: An open-label trial, Chronobiol. Int. source

In the paper

“Various research studies have confirmed that there are individual associations between melatonin and glutathione [165], and glutathione and vitamin D [316].”

What the sources say

• Not checked yetcites [165] Muñoz-Jurado, A., Escribano, B.M., Caballero-Villarraso, J., Galván, A., Agüera, E., Santamaría, A., and Túnez, I. (2022). Melatonin and multiple sclerosis: Antioxidant, anti-inflammatory and immunomodulator mechanism of action. Inflammopharmacology, 1–28. source
• Not checked yetcites [316] Parsanathan, 2019, Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice, Sci. Rep. source

In the paper

“To reduce the risk of inaccuracies, the patient would at least need to abstain from dietary sources of melatonin; however, this is not always practical, and many foods contain melatonin.”

In the paper

“Routine laboratories do not tend to offer this type of testing, and of the specialty labs that offer these assessments, there are some confounding factors to consider:”

In the paper

“From a clinical point of view, melatonin imbalance may indicate “darkness deficiency” in much the same way that vitamin D may infer whether or not someone has a “light deficiency”.”

In the paper

“Light exposure: Results will be variable and potentially influenced by light conditions. Since melatonin is strongly suppressed by light, the test will not yield many useful data in people’s normal home lighting. It will simply reflect the suppressed levels expected in electric lighting.”

In the paper

“Overall, melatonin is an intriguing compound, not unlike vitamin D, which is pleiotropic in activity and responsive to light-dark cycles.”

In the paper

“Glutathione is one of the major antioxidant systems in the body and is susceptible to changes in redox status and nutrient supply [315].”

What the sources say

• Not checked yetcites [315] Minich, D.M., and Brown, B.I. (2019). A Review of Dietary (Phyto)Nutrients for Glutathione Support. Nutrients, 11. source