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Cited by 176Circadian rhythm and melatoninVitamin D Research Studiesmelanin and skin pigmentation

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

Open access
Minich, Deanna M., Henning, Melanie, Darley, Catherine, Fahoum, Mona, Schuler, Corey B., Frame, James·2022·Nutrients
DOI 10.3390/nu14193934PMC PMC9571539
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Abstract

Melatonin has become a popular dietary supplement, most known as a chronobiotic, and for establishing healthy sleep. Research over the last decade into cancer, Alzheimer’s disease, multiple sclerosis, fertility, PCOS, and many other conditions, combined with the COVID-19 pandemic, has led to greater awareness of melatonin because of its ability to act as a potent antioxidant, immune-active agent, and mitochondrial regulator. There are distinct similarities between melatonin and vitamin D in the depth and breadth of their impact on health. 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 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. The trend toward greater use of melatonin supplements has resulted in concern about its safety, especially higher doses, long-term use, and application in certain populations (e.g., children). This review aims to evaluate the recent data on melatonin’s mechanisms, its clinical uses beyond sleep, safety concerns, and a thorough summary of therapeutic considerations concerning dietary supplementation, including the different formats available (animal, synthetic, and phytomelatonin), dosing, timing, contraindications, and nutrient combinations.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues melatonin resembles vitamin D as a pleiotropic, light/dark-responsive hormone and reviews its mechanisms, clinical uses beyond sleep, safety, and supplement considerations. It emphasizes that melatonin is not simply a sleep aid, that dosing should generally be low and personalized, and that phytomelatonin may outperform synthetic melatonin in some in vitro assays.

Key findings

  • The pineal gland produces about 0.1–0.9 mg melatonin daily, while gut enterochromaffin cells contain roughly 400 times more melatonin than the pineal gland, with gut levels 10–100 times greater than serum levels; production declines with age.
  • In vitro, phytomelatonin showed 646% stronger COX-2 inhibition, 267–470% more potent free-radical scavenging, and 100% greater efficacy in reducing cellular ROS in a human skin cell line compared with synthetic melatonin.
  • Clinical studies cited include 3 mg melatonin reducing migraine frequency comparably to amitriptyline; 10 mg nightly reducing endometriosis pain by about 40% and pain-medication use by 80%; six months of melatonin in PCOS decreasing androgens, free testosterone, hydroxyprogesterone, anti-Mullerian hormone, and LDL, with menstrual irregularities decreasing in 95%; and controlled-release melatonin reducing asleep systolic blood pressure by 3.57 mm Hg.
  • Supplement quality and safety concerns include 31 over-the-counter melatonin products ranging from −83% to +478% of label claim, limited safety studies for high-dose melatonin (≥10 mg/day), and evidence that 0.3 mg restored sleep efficiency without the hypothermia and daytime melatonin elevation seen with 3 mg.

Methods

  • Narrative review; no systematic search strategy or review protocol is reported.
  • It synthesizes mechanistic, preclinical, and clinical literature on melatonin mechanisms, clinical uses, safety, dietary sources, supplement formats, dosing, timing, contraindications, and nutrient combinations.
  • Evidence discussed includes in vitro cellular assays, animal studies, randomized controlled trials, meta-analyses, systematic reviews, cohort studies, and clinical guidelines; no new primary data are presented.

Limitations

  • Stated: there are limited studies to conclude safety of high-dose melatonin (≥10 mg/day); there is a lack of significant data on nutrient combinations; bioavailability of different formats and sources remains unanswered; and in the bone-health combination trial, melatonin cannot be inferred to be responsible for the effects.
  • Stated/evident: several clinical areas rely on small, older, or mixed studies—for example, endometriosis results are mixed, shift-work findings are inconsistent or show essentially no benefit, and most jet-lag dosing research is 10–20 years old or older.
  • Evident: as a narrative review without systematic search or risk-of-bias assessment, selection and interpretation may be subject to bias; laboratory assessment of melatonin is also confounded by light exposure, timing, diet, season, physical activity, age, sex, genetics, and posture.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/nu14193934

Cites

320 of 320 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 253 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    In a human skin cell line, phytomelatonin had 100% greater efficacy in reducing cellular ROS than synthetic melatonin.

    “Phytomelatonin was found to have 646% stronger COX-2 inhibition (see Figure 3), 267–470% more potent free-radical scavenging ability (see Figure 4), and 100% greater efficacy in reducing cellular ROS in a human skin cell line (see Figure 5) when compared to synthetic melatonin”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • Findingcitation

    In human cell line assays, phytomelatonin had 267-470% more potent free-radical scavenging ability than synthetic melatonin.

    “Phytomelatonin was found to have 646% stronger COX-2 inhibition (see Figure 3), 267–470% more potent free-radical scavenging ability (see Figure 4), and 100% greater efficacy in reducing cellular ROS in a human skin cell line (see Figure 5) when compared to synthetic melatonin”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Findingcitation

    In human cell line assays, phytomelatonin had 646% stronger COX-2 inhibition than synthetic melatonin.

    “Phytomelatonin was found to have 646% stronger COX-2 inhibition (see Figure 3), 267–470% more potent free-radical scavenging ability (see Figure 4), and 100% greater efficacy in reducing cellular ROS in a human skin cell line (see Figure 5) when compared to synthetic melatonin”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Findingcitation

    In one study, Akkermansia muciniphila and Lactobacilli species were increased in the melatonin-treated animals.

    “In one of the studies, Akkermansia muciniphila and Lactobacilli species were increased in the melatonin-treated animals [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Park, 2020, Melatonin in the colon modulates intestinal microbiota in response to stress and sleep deprivation, Intest Res. source

      Not checked in the free run.

  • Findingcitation

    Both 0.5 mg and 3.0 mg doses of melatonin taken in the morning, approximately 6 h after the sleep midpoint, will cause a phase delay.

    “Both doses of melatonin taken in the morning, approximately 6 h after the sleep midpoint, will cause a phase delay.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 90
  • Classified as probably not a substantial claim. 46
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingnone given

    When melatonin is taken 4 h before the sleep midpoint, the low dose of 0.5 mg does not shift the circadian rhythm, while the 3.0 mg dose will cause a phase delay.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The higher dose (5 mg) impacted the biological day and night sleep patterns, the duration of non-REM sleep, and awakening time.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Duffy, 2022, High dose melatonin increases sleep duration during nighttime and daytime sleep episodes in older adults, J. Pineal Res. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    A 2017 systematic review 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Auld, 2017, Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders, Sleep Med. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

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

    “Melatonin had a statistically significant effect on reducing sleep latency and increasing total sleep time.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [91] Qawasmi, 2018, Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders, Focus source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Herxheimer, 2002, Melatonin for the prevention and treatment of jet lag, Cochrane Database Syst. Rev.

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Zizi, 1998, Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment, J. Pineal Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Crowley, 2012, Human puberty: Salivary melatonin profiles in constant conditions, Dev. Psychobiol. source

      Not checked in the free run.

    • cites [10] Grivas, 2007, Melatonin the “light of night” in human biology and adolescent idiopathic scoliosis, Scoliosis source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Both melatonin and vitamin D have widespread effects on multiple systems and are found extensively throughout the body.

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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Breastfed babies have the benefit of melatonin from their mother's milk.

    “Breastfed babies have the benefit of melatonin from their mother’s milk [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Caba, 2022, Breast Milk and the Importance of Chrononutrition, Front. Nutr. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

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

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Melatonin could plausibly be treated as a required dietary nutrient, with certain individuals necessitating less, more, or fine-tuning to personalized needs.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [3] Garaulet, 2015, Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans, Metabolism source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    On average, the pineal gland produces between 0.1 and 0.9 mg of melatonin per day.

    “On average, the pineal gland produces between 0.1 and 0.9 mg of melatonin per day [4,6].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Srinivasan, 2006, Melatonin: Nature’s most versatile biological signal?, Febs. J. source

      Not checked in the free run.

    • cites [6] Mahmood, 2019, Pleiotropic Effects of Melatonin, Drug Res. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Melatonin production and circadian rhythms do not develop in babies until around three months.

    “Melatonin production and circadian rhythms do not develop in babies until around three months [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Rivkees, 1997, Developing circadian rhythmicity. Basic and clinical aspects, Pediatr. Clin. N. Am. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    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 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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    UV-B radiation is required to convert 7-dehydrocholesterol in the skin to vitamin D3.

    “Ultraviolet (UV)-B radiation is required to convert 7-dehydrocholesterol in the skin to vitamin D3 [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Wacker, 2013, Sunlight and Vitamin D: A global perspective for health, Dermato-Endocrinology source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Vitamin D and melatonin may work synergistically in the skin.

    “Specifically, vitamin D and melatonin may work synergistically in the skin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Melatonin synthesis is reduced by exposure to light, with artificial light reducing a person's melatonin production and increasing disease risk.

    “Its synthesis is reduced by exposure to light, with artificial light reducing a person’s melatonin production and increasing disease risk [4,6].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Srinivasan, 2006, Melatonin: Nature’s most versatile biological signal?, Febs. J. source

      Not checked in the free run.

    • cites [6] Mahmood, 2019, Pleiotropic Effects of Melatonin, Drug Res. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Ferder, 2020, Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin, J. Steroid Biochem. Mol. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

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

  • May combine two claims.

    Premisecitation

    Concurrent with 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Ferder, 2020, Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin, J. Steroid Biochem. Mol. Biol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

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

    “Newer, in vitro data on phytomelatonin would suggest superior antioxidant, anti-radical, and anti-inflammatory effects over synthetic melatonin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Melatonin is involved with mitochondrial homeostasis, genomic regulation, modulation of inflammatory and immune cytokines, and systemic and acute anti-inflammatory properties.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Tan, 2015, Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism, Molecules source

      Not checked in the free run.

    • cites [26] Loh, D., and Reiter, R.J. (2021). Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders. Antioxidants, 10. source

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  • May combine two claims.

    Premisecitation

    Melatonin's dual actions can inhibit pro-oxidative enzymes (e.g., xanthine oxidase) while also potentiating critical antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase, and catalase.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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.

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    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

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

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

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    Premisecitation

    Melatonin can stimulate the regeneration of epithelial cells and has protective antioxidant effects on the lining of the GI tract.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Kanova, M., and Kohout, P. (2021). Tryptophan: A Unique Role in the Critically Ill. Int. J. Mol. Sci., 22. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The gut-brain axis is a network of complex interactions between the nervous and GI systems with major contributions from intestinal microbiota.

    “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.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Unlike pinealocytes, enterochromaffin cells are not regulated by light and dark but appear affected by food intake and digestion.

    “Unlike pinealocytes, enterochromaffin cells are not regulated by light and dark but appear affected by food intake and digestion [39,40].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [40] Yasmin, 2021, Gut melatonin: A potent candidate in the diversified journey of melatonin research, Gen. Comp. Endocrinol. source

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  • May combine two claims.

    Interpretationcitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [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

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    • cites [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

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    • cites [56] Maffei, M.E. (2020). 5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology. Int. J. Mol. Sci., 22. source

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    • cites [57] Reiter, 2010, Neurotoxins: Free radical mechanisms and melatonin protection, Curr. Neuropharmacol. source

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    • cites [58] Brinkmann, 2019, The Aryl Hydrocarbon Receptor (AhR) in the Aging Process: Another Puzzling Role for This Highly Conserved Transcription Factor, Front. Physiol. source

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  • May combine two claims.

    Premisecitation

    Levels of melatonin are 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Tan, 2015, Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism, Molecules source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

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

    “Elderly individuals may also be more susceptible to serotonergic and melatonergic system errors due to known lower amounts of biota diversity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Chen, 2011, Distribution, function and physiological role of melatonin in the lower gut, World J. Gastroenterol. source

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    • cites [41] Fowler, 2022, Circadian Rhythms and Melatonin Metabolism in Patients With Disorders of Gut-Brain Interactions, Front. Neurosci. source

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  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Melatonin is derived from serotonin using 5-hydroxytryptophan (5-HTP) and tryptophan.

    “Melatonin is derived from serotonin using 5-hydroxytryptophan (5-HTP) and tryptophan [32,55].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Quinolinic acid is a neurotoxin, while kynurenic acid has neuroprotective properties.

    “Quinolinic acid is a neurotoxin, while kynurenic acid has neuroprotective properties [32,55,56,57,58].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [57] Reiter, 2010, Neurotoxins: Free radical mechanisms and melatonin protection, Curr. Neuropharmacol. source

      Not checked in the free run.

    • cites [58] Brinkmann, 2019, The Aryl Hydrocarbon Receptor (AhR) in the Aging Process: Another Puzzling Role for This Highly Conserved Transcription Factor, Front. Physiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

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

    “Circadian rhythm sleep-wake disorders are either intrinsic or extrinsic.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

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

    “Many neurological disorders feature elements of the kynurenine pathway of tryptophan, specifically the dysregulation of tryptophan metabolism and subsequent melatonin production.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

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

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

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Escames, 2010, The role of mitochondria in brain aging and the effects of melatonin, Curr. Neuropharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin supplements can be used therapeutically for both intrinsic and extrinsic circadian rhythm sleep-wake disorders.

    “Melatonin supplements can be used therapeutically for both conditions [67].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Iguichi, 1982, Age-dependent reduction in serum melatonin concentrations in healthy human subjects, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “The AhR is responsible for modulating mitochondrial metabolism, melatonergic pathways, acetyl-coenzyme A, and COX-2 prostaglandin.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The melatonin-serotonin pathway accounts for approximately five percent of dietary tryptophan degradation, while the kynurenic pathway accounts for approximately 95 percent.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin is indicated for insomnia (immediate release 1-3 mg, 30 min before bed; slow-release can be used for sleep maintenance problems), regulating sleep in blind individuals who often experience non-24 h sleep-wake rhythm disorder, replicating the normal endogenous pattern, and delayed sleep phase.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Auld, 2017, Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders, Sleep Med. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

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

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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Relatively smaller amounts of melatonin are produced in the retina compared with the pineal gland.

    “Relatively smaller amounts of melatonin are produced in the retina compared with the pineal gland [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Ostrin, 2019, Ocular and systemic melatonin and the influence of light exposure, Clin. Exp. Optom. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    iRBD is a prodrome biomarker for Parkinson's disease.

    “Importantly, iRBD is a prodrome biomarker for Parkinson’s disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Imbalances in melatonin may be associated with a "darkness deficiency," or a lack of adequate evening darkness to initiate the secretion of melatonin by the pineal gland.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Interest has been expressed for melatonin in inflammatory eye conditions such as ocular neuritis and uveitis.

    “However, interest has been expressed for inflammatory conditions such as ocular neuritis and uveitis [97].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Aranda, 2017, Melatonin as a Therapeutic Resource for Inflammatory Visual Diseases, Curr. Neuropharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many studies support melatonin's use in reducing the ill effects of jet lag and speeding up the normalization of circadian rhythms.

    “Many studies support melatonin’s use in reducing the ill effects of jet lag and speeding up the normalization of circadian rhythms [73].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Srinivasan, 2008, Jet lag: Therapeutic use of melatonin and possible application of melatonin analogs, Travel. Med. Infect. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

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

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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There may be an association between environmental toxins such as heavy metals (e.g., arsenic) and sleep disturbance.

    “Moreover, there may be an association between environmental toxins such as heavy metals (e.g., arsenic) and sleep disturbance [82,83].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some researchers suggest that glaucoma may be a therapeutic target for melatonin.

    “Some researchers suggest that glaucoma may be a therapeutic target for melatonin [98,99].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [99] Gubin, 2022, Melatonin, circadian rhythms and glaucoma: Current perspective, Neural Regen. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In children with ASD and positive family history, serum melatonin and nitric oxide levels were higher and malondialdehyde/melatonin ratios significantly lower, suggesting impaired oxidant-antioxidant metabolism.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical data suggest that melatonin supplementation improves sleep and neurotransmission and reduces sundowning in those with Alzheimer's disease.

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

  • May combine two claims.

    Premisecitation

    Melatonin supplementation decreased TNF-alpha, IL-6, and C-reactive protein, with more significant lowering of TNF-alpha and IL-6 in studies of at least twelve weeks and at least 10 mg/day.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [175] Zarezadeh, 2020, Melatonin supplementation and pro-inflammatory mediators: A systematic review and meta-analysis of clinical trials, Eur. J. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Theoretical safety concerns exist related to the 1989 Eosinophilia-Myalgia Syndrome outbreak from L-tryptophan contaminants because melatonin's indole structure closely resembles tryptophan, although the dose of melatonin tends to be about 1000 times lower than that of tryptophan.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [264] Williamson, 1997, Contaminants in commercial preparations of melatonin, Mayo Clin. Proc. source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [266] Allen, 2011, Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan, Arthritis Rheum. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autistic patients have low melatonin levels caused by a primary deficit in ASMT gene activity.

    “It was found that autistic patients have low melatonin levels caused by a primary deficit in ASMT gene activity [116].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Melke, 2008, Abnormal melatonin synthesis in autism spectrum disorders, Mol. Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Age-related macular degeneration theoretically could benefit from melatonin administration, although significant clinical research is currently lacking.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100] Rastmanesh, 2011, Potential of melatonin to treat or prevent age-related macular degeneration through stimulation of telomerase activity, Med. Hypotheses source

      Not checked in the free run.

    • cites [101] Mehrzadi, 2020, Mitochondrial dysfunction in age-related macular degeneration: Melatonin as a potential treatment, Expert Opin. Ther. Targets source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High doses of melatonin were effective in arresting tumor growth and improving quality of life in patients with solid metastatic tumors.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [178] Lissoni, 1991, Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies, Oncology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Melatonin may decrease the progression of Alzheimer's 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.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [102] Lin, 2013, Melatonin in Alzheimer’s disease, Int. J. Mol. Sci. source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [104] Li, 2020, Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer’s disease, Biomed. Pharmacother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Migraines can also be correlated with many autoimmune disorders tied to melatonin regulation failure, including Hashimoto's thyroiditis with associated hypothyroidism, rheumatic diseases, and antiphospholipid syndrome.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Ribeiro, 2016, Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention, J. Neurol. Neurosurg. Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

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

    “Migraine headaches are comorbid with several health conditions, including neurological, psychiatric, cardiovascular, cerebrovascular, GI, metaboloendocrine, and immunological disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A review found that patients with autism had improved sleep parameters, better daytime behavior, and minimal side effects with melatonin use.

    “A review article found that patients with autism had improved sleep parameters, better daytime behavior, and minimal side effects with melatonin use [118].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Rossignol, 2011, Melatonin in autism spectrum disorders: A systematic review and meta-analysis, Dev. Med. Child. Neurol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

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

    “For jet lag, recent studies are lacking in detailing the most efficacious dose.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

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

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Herxheimer, 2002, Melatonin for the prevention and treatment of jet lag, Cochrane Database Syst. Rev.

      Not checked in the free run.

    • Rests on an assumption: Melatonin may not be effective for everyone.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There have been reports of vivid dreams or nightmares while using melatonin supplements.

    “There have also been reports of vivid dreams or nightmares while using melatonin supplements [164].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Siah, 2014, Melatonin for the treatment of irritable bowel syndrome, World J. Gastroenterol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Zhdanova et al., the control group (not insomniacs) also had low melatonin levels, but melatonin did not improve sleep.

    “Interestingly, the control group (not insomniacs) also had low melatonin levels, but melatonin did not improve sleep.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [278] Zhdanova, 2001, Melatonin treatment for age-related insomnia, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Lewy et al. concluded that too much melatonin may negatively affect the melatonin phase-response curve.

    “They concluded that that too much melatonin may negatively affect the melatonin phase-response curve [281].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [281] Lewy, 2002, Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period, Chronobiol. Int. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some jet lag studies used a protocol in which melatonin supplementation was initiated three days before travel started.

    “Some studies used a protocol in which melatonin supplementation was initiated three days before travel started [284,285].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [284] Petrie, 1989, Effect of melatonin on jet lag after long haul flights, Br. Med. J. source

      Not checked in the free run.

    • cites [285] Petrie, 1993, A double-blind trial of melatonin as a treatment for jet lag in international cabin crew, Biol. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Zhdanova et al., the pharmacological dose (3 mg), like the lowest dose (0.1 mg), improved sleep but induced hypothermia and caused plasma melatonin to remain elevated into daylight hours.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [278] Zhdanova, 2001, Melatonin treatment for age-related insomnia, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Doses used in melatonin studies tended to be supraphysiological or based on previous studies that did not have an explicit rationale for choosing the amount.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

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

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [279] (1995). National Center for Biotechnology Information. Methods of Inducing Sleep Using Melatonin. (US5449683A), U.S. Patent.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

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

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

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [275] Benedict, 2022, Melatonin’s Potential Side Effects: It May Be in Your Genes, Mayo Clin. Proc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Zhdanova et al., the physiological dose (0.3 mg) restored sleep efficiency and elevated plasma melatonin levels to normal during early adulthood.

    “The physiological dose (0.3 mg) restored sleep efficiency and elevated plasma melatonin levels to normal during early adulthood.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [278] Zhdanova, 2001, Melatonin treatment for age-related insomnia, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Phytomelatonin may have advantages over synthetic melatonin related to improved bioavailability and efficacy, although more research comparing synthetic and plant-based sources is needed.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    There is a lack of significant scientific evidence that long-term high-dose melatonin causes dependence, and if it does, the conditions and susceptible individuals are unknown.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lissoni et al.'s cancer research demonstrated that 20 mg melatonin given intramuscularly followed by oral daily doses of 10 mg was effective in arresting tumor growth and improving quality of life markers.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [178] Lissoni, 1991, Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies, Oncology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fluvoxamine is a known inhibitor of CYP1A2 and can result in potentiation of melatonin levels by reducing its degradation.

    “This pharmaceutical is a known inhibitor of CYP1A2 and can result in the potentiation of melatonin levels due to reducing its degradation [304].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [304] Wang, 2001, Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin, J. Clin. Psychopharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [306] Therapeutic Research (2022, July 31). Melatonin. Available online: https://naturalmedicines.therapeuticresearch.com/.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A few human clinical studies published more than two decades ago suggest that vitamin B12 supplementation increased the phase advance effect of morning light and decreased nocturnal melatonin levels.

    “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]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [310] Hashimoto, 1996, Vitamin B12 enhances the phase-response of circadian melatonin rhythm to a single bright light exposure in humans, Neurosci. Lett. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “Neither the parents nor children monitored their melatonin use but relied on the initial study proposal, so dosing varied widely.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [290] Hoebert, 2009, Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia, J. Pineal Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Combining melatonin supplementation with actives that influence melatonin pharmacokinetics may cause side effects.

    “As stated above, combining melatonin supplementation with actives that influence melatonin pharmacokinetics may cause side effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [293] Braam, 2010, Loss of response to melatonin treatment is associated with slow melatonin metabolism, J. Intellect. Disabil. Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [290] Hoebert, 2009, Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia, J. Pineal Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

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

    “Compliance nearly four years later was at 65%, presumably due to the satisfaction of use.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [290] Hoebert, 2009, Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia, J. Pineal Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [290] Hoebert, 2009, Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia, J. Pineal Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lewy suggests that dosing for sleep requires a minimum of twelve hours of wakefulness.

    “Lewy suggests that dosing for sleep requires a minimum of twelve hours of wakefulness [281].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [281] Lewy, 2002, Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period, Chronobiol. Int. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The dramatic increase in the use of supplemental melatonin in children is unwarranted because children endogenously produce more melatonin than adults.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Grivas, 2007, Melatonin the “light of night” in human biology and adolescent idiopathic scoliosis, Scoliosis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin in tablet or capsule form is generally not very bioavailable (1 to 74%) and can be influenced by multiple variables.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [295] Savage, R.A., Zafar, N., Yohannan, S., and Miller, J.M.M. (2022). Melatonin. StatPearls, StatPearls Publishing LLC.. StatPearls Publishing. Copyright © 2022.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin administered in tablet or capsule forms follows first-order or concentration-dependent kinetics, implying that kinetic absorption is not saturable and larger doses produce higher plasma concentrations.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [297] Vasey, C., McBride, J., and Penta, K. (2021). Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin. Nutrients, 13. source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisenone given

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

    “Dyssomnia, ADHD, and ASD have been studied and reviewed, all confirming effectiveness and safety of melatonin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Oral melatonin reaches peak plasma concentration after forty-one minutes of administration, although pharmacokinetics varied greatly between individuals.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [297] Vasey, C., McBride, J., and Penta, K. (2021). Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin. Nutrients, 13. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [296] Andersen, 2015, Clinical pharmacokinetics of melatonin: A systematic review, Eur. J. Clin. Pharmacol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

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

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

  • May combine two claims.

    Premisecitation

    Caffeine is metabolized through CYP1A2 and can increase melatonin levels.

    “Similarly, caffeine is also metabolized through CYP1A2 and can increase melatonin levels [305].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Studies of melatonin in children were of various lengths, with some as short as two weeks and the longest-lasting study six months.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

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

    “Indiscriminate, long-term dosing may lead to unnecessary dependence and even perturbations in puberty onset when nocturnal levels of melatonin tend to decline [291].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [291] Boafo, 2019, Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician’s perspective, Nat. Sci. Sleep source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the case of methylcobalamin specifically, vitamin B12 may result in less need for sleep and impart better sleep quality.

    “and in the case of methylcobalamin specifically, may even result in less need for sleep and impart better sleep quality [311]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [311] Mayer, 1996, Effects of vitamin B12 on performance and circadian rhythm in normal subjects, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The timing of eating and time of sleep may influence melatonin levels, as can intermittent fasting.

    “Furthermore, the timing of eating and time of sleep may influence melatonin levels, as can intermittent fasting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Melatonin has systemic effects through its mechanisms of action, ultimately having the potential for a significant impact on the etiologies of multiple chronic diseases.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [320] Bennett, 2009, Use of modified spectacles and light bulbs to block blue light at night may prevent postpartum depression, Med. Hypotheses source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Phytomelatonin may have greater efficacy and present a more sustainable, low-toxic option compared with synthetic formats of melatonin.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisenone given

    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 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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Lifestyle habits such as proper exposure to light and darkness and less blue light at night are helpful for establishing healthy melatonin levels.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

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

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

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [321] Shechter, 2018, Blocking nocturnal blue light for insomnia: A randomized controlled trial, J. Psychiatr. Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Melatonin acts as a powerful antioxidant that can cross the blood-brain barrier, inhibit inflammation, and interact with the gut microbiome.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    There could be an interrelationship between the collective antioxidant activities of glutathione, vitamin D, and melatonin.

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

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Various research studies have confirmed individual associations between melatonin and glutathione, and between glutathione and vitamin D.

    “Various research studies have confirmed that there are individual associations between melatonin and glutathione [165], and glutathione and vitamin D [316].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    To reduce 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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Routine laboratories do not tend to offer melatonin testing, and of the specialty labs that offer these assessments, there are confounding factors to consider.

    “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:”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Routine laboratories do not tend to offer melatonin testing.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Melatonin imbalance may indicate "darkness deficiency" in much the same way that vitamin D may infer whether or not someone has a "light deficiency".

    “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”.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Melatonin test results will be variable and potentially influenced by light conditions; in normal home lighting the test will simply reflect suppressed levels expected in electric lighting.

    “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.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The circadian release of melatonin is strongly suppressed by light, particularly blue light.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationnone given

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

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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Glutathione is one of the major antioxidant systems in the body and is susceptible to changes in redox status and nutrient supply.

    “Glutathione is one of the major antioxidant systems in the body and is susceptible to changes in redox status and nutrient supply [315].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [315] Minich, D.M., and Brown, B.I. (2019). A Review of Dietary (Phyto)Nutrients for Glutathione Support. Nutrients, 11. source

      Not checked in the free run.

124 of 124

  • The paper relies on this without support.

    Oxidative stress is one of the leading causes of age-related brain dysfunction by impairing neurogenesis.

    “Oxidative stress is one of the leading causes of age-related brain dysfunction by impairing neurogenesis.”

  • The paper relies on this without support.

    The purity of a melatonin dietary supplement available to most consumers on the retail store shelf may be debatable or simply unknown without greater diligence to investigate the source.

    “Thus, the purity of a melatonin dietary supplement available to most consumers on the retail store shelf may be debatable or simply unknown without greater diligence to investigate the source, which is often cumbersome and time-consuming.”

  • The paper relies on this without support.

    Larger doses of melatonin do not always confer greater health benefits.

    “Larger doses do not always confer greater health benefits.”

  • The paper relies on this without support.

    The upper limits of a lethal dose of melatonin have not been clinically established.

    “The upper limits of a lethal dose of melatonin have not been clinically established.”

  • The paper relies on this without support.

    Melatonin is quickly broken down by the body.

    “Melatonin is quickly broken down by the body and should be dosed at the appropriate, personalized level for each patient.”

  • The paper relies on this without support.

    Melatonin may not be effective for everyone.

    “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].”

  • The paper relies on this without support.

    There is some indication that melatonin may be of benefit during pregnancy and nursing.

    “However, there is some indication that melatonin may be of benefit during both these stages.”

  • The paper relies on this without support.

    In certain instances, nutrients may be more effective when included with melatonin or vice versa.

    “Conversely, in certain instances, nutrients may be more effective when included with melatonin or vice versa.”

  • The paper relies on this without support.

    Type 2 diabetics may be particularly vulnerable to decreases in antioxidants and increases in inflammatory markers.

    “Type 2 diabetics may be particularly vulnerable to decreases in antioxidants and increases in inflammatory markers.”

  • The paper relies on this without support.

    The circadian release of melatonin is strongly suppressed by light, particularly blue light.

    “The circadian release of melatonin is strongly suppressed by light, particularly blue light.”

  • The paper relies on this without support.

    Assessing one's levels of systemic melatonin is difficult.

    “From a clinical perspective, assessing one’s levels of systemic melatonin is difficult.”

  • The paper relies on this without support.

    Routine laboratories do not tend to offer melatonin testing.

    “Routine laboratories do not tend to offer this type of testing”

  • The paper relies on this without support.

    Melatonin has been misunderstood as a sleep aid.

    “To some extent, melatonin has been misunderstood as a sleep aid.”
13 of 13

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • A 50 km course is labeled as 31 meters

    Minor

    Fifty kilometers is 50,000 meters, not 31 meters. The parenthetical appears to mean 31 miles.

    Reported 31 · recomputed 50000

1 of 1

Cites

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19 of the 339 references couldn’t be matched to a known paper.

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Related

Authors
Minich, D. M., Henning, M., Darley, C., Fahoum, M., Schuler, C. B., & Frame, J.
Affiliations
  • University of Western States (US)
  • University of the Rockies (US)
  • National University of Natural Medicine (US)
  • Bastyr University (US)
  • School of Nutrition, Sonoran University of Health Sciences, Tempe, AZ 85282, USA
  • Natural Health International Pty., Ltd., Sydney, NSW 2000, Australia
Corresponding author
Minich, Deanna M.
ORCID
Venue
Nutrients
Publisher
MDPI AG
Published
2022-09-22
Volume
14
Issue
19
Pages
3934
ISSN
2072-6643 (ISSN-L)
DOI
10.3390/nu14193934
PMC
PMC9571539
OpenAlex
W4296829676
Semantic Scholar
e2efdb871a3ef1f27a752431bf3a072a4deb68ea
Cited by
176
References
339
Citations by year
2026: 39 · 2025: 63 · 2024: 37 · 2023: 34 · 2022: 3
FWCI
4.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Nutrients (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Symphony Natural Health
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
Keywords
melatonin, dietary supplements, sleep, antioxidant activity, immunomodulation, anti-inflammatory activity, mitochondrial regulation, vitamin D, blue light exposure, melatonin deficiency, supplement safety, phytomelatonin, Alzheimer's disease, cancer, multiple sclerosis, polycystic ovary syndrome, fertility, COVID-19 pandemic
MeSH terms
COVID-19, Animals, Antioxidants, Circadian Rhythm, Humans, Melatonin, Vitamin D, Vitamins, Dietary Supplements, Pandemics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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