‘Vitamin’ D and melatonin are pluripotent compounds. Some think of them as vitamins, but they are more convincingly classified as hormones. These two molecules interact with each other in an incredibly complex circadian dance (1), a dance that affects us profoundly. Due to modern lifestyles, more and more of us are out of step, and suffering ill health as a result.
‘Vitamin’ D is the hormone of sunlight, and melatonin is its dark twin. Both molecules appear very early in the evolutionary tree, and both play key roles in defending the cell’s ability to generate biologically useful energy in the mitochondria, around the clock. This goes some way to explaining the importance of D and melatonin to our health, and their involvement in many diseases.
‘Vitamin’ D protects mitochondria in various ways. These include a possible direct antioxidant effect in mitochondrial membrane (2) and the up-regulation of antioxidant enzymes such as glutathione peroxidase (3). D also up-regulates various anti-ageing and mito-protective proteins including Klotho (4-5), the sirtuins (6, 7) and the Heat Shock Proteins (HSP’s) (8, 9).
The D receptor (VDR) occurs in mitochondrial outer membrane (10) where it regulates the permeability transition pore (11). D is thus involved not only in mitochondrial survival but also the life and death of the cell housing those mitochondria (12-15).
The age-related decline in Klotho, sirtuin and HSP synthesis drives symptoms of ageing such as loss of muscle volume and function (16-19); and the age-related decline in mitochondrial function exerts multiple adverse effects in many tissues (20). Against this background, ‘Vitamin’ D can legitimately be regarded as a gero-suppressant.
While the effects of D supplements on mitochondrial function are subtle and complex, and vary depending on dose and duration (21), they are generally protective. Overall, D deficiency impairs mitochondrial function and D repletion restores it (22-25), in muscle and probably other tissues. ‘Vitamin’ D will not build and maintain muscle and other tissues on its own, but is a necessary element in that process.
Unlike D, which is formed exclusively in skin, melatonin is synthesized in the mitochondria of all animal, plant, fungal and bacterial cells, and in the chloroplasts of plants (26-30).
Melatonin’s ubiquity is unsurprising. Chloroplasts and mitochondria were originally prokaryotes which needed antioxidant defenses against free radicals produced by photosynthesis and oxidative phosphorylation respectively. The original free-living prokaryote species (cyanobacteria and purple non-sulphur bacteria) still produce melatonin in a clockwise manner (31, 32), and our eukaryotic cells have learned to capitalize on it (33-36).
Melatonin and its metabolites are highly effective in scavenging reactive oxygen and reactive nitrogen species, and modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. Like D, melatonin up-regulates Klotho (34), the sirtuins (35) and the HSP’s (36), creating a powerful mito-protective effect; and like D, melatonin is a gerosuppressant (37).
This translates into protective effects against neurodegeneration (38, 39), myocardial damage (40, 41), renal fibrosis (42) and various cancers (43); especially when combined with vitamin D and pre-transitional nutrition.
Unfortunately, our indoors lifestyles and lack of exposure to daylight has created wide-spread hypovitaminosis D, even in the sub-tropics (44). Hypomelatonism, which is induced by the widely used beta blocker metoprolol (45), non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen (46), alcohol (47) and even the dim light emitted by LED screens at night (48), must be equally common.
Our D and melatonin rhythms are out of sync too.
Most human activities display circadian rhythms. We are generally more active during daylight hours and require higher levels of mitochondrial function – one reason why our mitochondria have maintained circadian rhythms similar to those of their prokaryote ancestors (49, 50). This creates circadian rhythms in insulin sensitivity, and is the key to time-restricted eating (See below).
Once those prokaryotic bacteria had infected eukaryotes and then higher life forms with their circadian clocks, our timing machinery required daily re-setting in order to take circannual changes into account. In humans, light sets a master clock in the supra-chiasmatic nucleus which entrains cellular clocks in other tissues, linking inner requirements to external cues and resources. The opposing light / dark rhythms in D and melatonin are an important part of this.
Getting out of sync – ie shift working, eating at night, staying up very late – disrupts these links and is another way in which the modern lifestyle contributes to today’s appalling public health. Animal studies show that the equivalent of night work and recurrent jet lag trigger weight gain (51-53) and metabolic syndrome (54).
‘Wrong’ meal timing pushes nutrients into the blood when the mitochondria are in resting phase, and less able to deal with them. This dysrhythmia is made worse by a high-fat (ie ultra-processed) diet (55, 56), and these factors help to explain why urbanization (57) and particularly shift working increases the risks of obesity, diabetes and cardiovascular disease (58, 59).
It also explains why clinical trials show that time-restricted eating, which brings food intake and mitochondrial function back into sync, provides weight-loss and major metabolic benefits even without calorie restriction (60, 61).
In the real world, however, the problems of dysrhythmia are further exacerbated by sleep-deprivation which leaves our tired brains over-responsive to food stimuli (62, 63), making us eat more. In a final twist of the screw today’s ultra-processed diet, rich in sugars and fats but low in fruit and vegetables, creates a negative feedback loop which damages sleep further (64-66). Polyphenol depletion is implicated (66).
Back to the lifestyle-related problems of hypovitaminosis D and hypomelatonism.
The evolutionary process has built so many buffering systems into us that on their own, they would probably not cause serious harm. But these endocrine abnormalities are super-imposed on a population already experiencing chronic inflammatory stress, glycative stress, Type B Malnutrition and, critically, dysbiosis.
The microbiome is also on the clock, and displays bacterial and chemical shifts which affect host rhythms and are affected by them (67). Dysbiosis likely worsens the impact of circadian disruption, increasing the risk of inflammation, insomnia, depression, diabetes, cancer, infections, auto-immunity and other problems (68-69).
D and melatonin supplements are therefore a potentially good idea, if used appropriately. Sadly, hypovitaminosis D is generally not alleviated by the arbitrarily tiny doses of D permitted in the EU. Nor is hypomelatonism helped by melatonin supplements, which have negligible bioavailability due to low absorption and first pass metabolism (70).
Sub-lingual tablets avoid first pass but are, simply, awkward. Trans-mucosal delivery systems such as bio-adhesive gel strips make perfect delivery systems (71, 72), and their low payload is not a problem with the doses relevant to D and melatonin.
Day and night strips containing D and melatonin respectively make sense to me. Apart from any health benefits they would help many to sleep better at night, feel more awake the next day (73), improve their memory (74) and even lose a little weight (75). And here, I will stop the clock.
Next week: radiant smiles, yellow nails and white icing sugar.
- Mocayar Marón FJ, Ferder L, Reiter RJ, Manucha W. Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin. J Steroid Biochem Mol Biol. 2020 May;199:105595.
- Wiseman H. Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action. FEBS Lett. 1993 Jul 12;326(1-3):285-8.
- Ansari MGA, Sabico S, Clerici M, Khattak MNK, Wani K, Al-Musharaf S, Amer OE, Alokail MS, Al-Daghri NM. Vitamin D Supplementation is Associated with Increased Glutathione Peroxidase-1 Levels in Arab Adults with Prediabetes. Antioxidants. 2020; 9(2):118.
- Forster RE, Jurutka PW, Hsieh JC, Haussler CA, Lowmiller CL, Kaneko I, Haussler MR, Kerr Whitfield G. Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells. Biochem. Biophys. Res. Commun. 414 (2011) 557–562.
- Chen Z, Zhou Q, Liu C, Zeng Y, Yuan S. Klotho deficiency aggravates diabetes-induced podocyte injury due to DNA damage caused by mitochondrial dysfunction. Int J Med Sci. 2020 Sep 28;17(17):2763-2772.
- Chandel N, Ayasolla K, Wen H, Lan X, Haque S, Saleem MA, Malhotra A, Singhal PC. Vitamin D receptor deficit induces activation of renin angiotensin system via SIRT1 modulation in podocytes. Exp. Mol. Pathol. 102 (2017) 97–105.
- Manna P, Achari AE, Jain SK. Vitamin D supplementation inhibits oxidative stress and upregulate SIRT1/AMPK/GLUT4 cascade in high glucose-treated 3T3L1 adipocytes and in adipose tissue of high fat diet-fed diabetic mice. Arch. Biochem. Biophys. 615 (2017) 22–34.
- Kim YO, Li C, Sun BK, Kim JS, Lim SW, Choi BS, Kim YS, Kim J, Bang BK, Yang CW. Preconditioning with 1,25-dihydroxyvitamin D3 protects against subsequent ischemia- reperfusion injury in the rat kidney. Nephron Exp Nephrol. 2005; 100(2):e85-94.
- Leu JI, Barnoud T, Zhang G, Tian T, Wei Z, Herlyn M, Murphy ME, George DL. Inhibition of stress-inducible HSP70 impairs mitochondrial proteostasis and function. Oncotarget. 2017 Jul 11;8(28):45656-45669.
- Silvagno F, De Vivo E, Attanasio A, Gallo V, Mazzucco G, Pescarmona G. Mitochondrial localization of vitamin d receptor in human platelets and differentiated megakaryocytes. PLoS One 5 (2010) e8670.
- Silvagno F, Consiglio M, Foglizzo V, Destefanis M, Pescarmona G. Mitochondrial translocation of vitamin d receptor is mediated by the permeability transition pore in human keratinocyte cell line. PLoS One 8 (2013) e54716.
- Tanwar J, Singh JB, Motiani RK. Molecular machinery regulating mitochondrial calcium levels: The nuts and bolts of mitochondrial calcium dynamics. Mitochondrion. 2020 Dec 11;57:9-22.
- Wang H, Liu C, Zhao Y, Gao G. Mitochondria regulation in ferroptosis. Eur J Cell Biol. 2020 Jan;99(1):151058.
- Tadokoro T, Ikeda M, Ide T, Deguchi H, Ikeda S, Okabe K, Ishikita A, Matsushima S, Koumura T, Yamada KI, Imai H, Tsutsui H. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight. 2020 May 7;5(9):e132747.
- Sun L, Dong H, Zhang W, Wang N, Ni N, Bai X, Liu N. Lipid Peroxidation, GSH Depletion, and SLC7A11 Inhibition are Common Causes of EMT and Ferroptosis in A549 Cells, but Different in Specific Mechanisms. DNA Cell Biol. 2020 Dec 22. doi: 10.1089/dna.2020.5730. Epub ahead of print.
- Sahu A, Mamiya H, Shinde SN, Cheikhi A, Winter LL, Vo NV, Stolz D, Roginskaya V, Tang WY, St Croix C, Sanders LH, Franti M, Van Houten B, Rando TA, Barchowsky A, Ambrosio F. Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. Nat Commun. 2018 Nov 19;9(1):4859
- Lee SH, Lee JH, Lee HY, Min KJ. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019 Jan;52(1):24-34.
- Sahu A, Mamiya H, Shinde SN, Cheikhi A, Winter LL, Vo NV, Stolz D, Roginskaya V, Tang WY, St Croix C, Sanders LH, Franti M, Van Houten B, Rando TA, Barchowsky A, Ambrosio F. Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. Nat Commun. 2018 Nov 19;9(1):4859.
- Bozaykut P, Sozen E, Kaga E, Ece A. Ozaltin E, Ek B, Ozer NK, Grune T, Bergquist J, Karademir B. The role of heat stress on the age related protein carbonylation. J. Proteom. 2013, 89, 238–254.
- Haas RH. Mitochondrial Dysfunction in Aging and Diseases of Aging. Biology (Basel). 2019 Jun 17;8(2):48.
- Blajszczak CC, Nonn. Vitamin D regulates prostate cell metabolism via genomic and non-genomic mitochondrial redox-dependent mechanisms. J. Steroid Biochem. Mol. Biol. 195 (2019) 105484.
- Dzik KP, Skrobot W, Kaczor KB, Flis DJ, Karnia MJ, Libionka W, Antosiewicz J, Kloc W, Kaczor JJ. Vitamin d deficiency is associated with muscle atrophy and reduced mitochondrial function in patients with chronic low back pain. Oxid. Med. Cell. Longev. (2019), 6835341.
- Montenegro KR, Carlessi R, Cruzat V, Newsholme P. Effects of vitamin D on primary human skeletal muscle cell proliferation, differentiation, protein synthesis and bioenergetics. J. Steroid Biochem. Mol. Biol. 193 (2019) 105423.
- Ryan ZC, Craig TA, Folmes CD, Wang X, Lanza IR, Schaible NS, Salisbury JL, Nair KS, Terzic A, Sieck GC, Kumar R. 1α,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells. J Biol Chem. 2016 Jan 15;291(3):1514-28.
- Sinha A, Hollingsworth KG, Ball S, Cheetham T. Improving the vitamin D status of vitamin D deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle. J. Clin. Endocrinol. Metab. 98 (2013) E509–513.
- Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell. Mol. Life Sci. 74 (2017) 3863–3881.
- Venegas C, García JA, Escames G, Ortiz F, López A, Doerrier C, García-Corzo L, López LC, Reiter RJ, Acuña-Castroviejo D. Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J. Pineal Res. 52 (2012) 217–227.
- Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM, Mayo JC, Fuentes-Broto L, Reiter RJ. The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness. Biol Rev Camb Philos Soc. 2010 Aug;85(3):607-23.
- Wang L, Feng C, Zheng X, Guo Y, Zhou F, Shan D, Liu X, Kong J. Plant mitochondria synthesize melatonin and enhance the tolerance of plants to drought stress. J Pineal Res. 2017 Oct;63(3).
- Zheng X, Tan DX, Allan AC, Zuo B, Zhao Y, Reiter RJ, Wang L, Wang Z, Guo Y, Zhou J, Shan D, Li Q, Han Z, Kong J. Chloroplastic biosynthesis of melatonin and its involvement in protection of plants from salt stress. Sci Rep. 2017 Feb 1;7:41236.
- Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, Vriend J, Tan DX, Reiter RJ. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015 Nov;59(4):403-19.
- Mahmood D. Pleiotropic effects of melatonin. Drug Res (Stuttg) 69 (2019) 65–74.
- Slominski AT, Zmijewski MA, Semak I, Kim TK, Janjetovic Z, Slominski RM, Zmijewski JW. Melatonin, mitochondria, and the skin. Cell. Mol. Life Sci. 74(2017) 3913–3925.
- Ko JW, Shin NR, Jung TY, Shin IS, Moon C, Kim SH, Lee IC, Kim SH, Yun WK, Kim HC, Kim JC. Melatonin attenuates cisplatin-induced acute kidney injury in rats via induction of anti-aging protein, Klotho. Food Chem Toxicol. 2019 Jul;129:201-210.
- Sahan A, Akbal C, Tavukcu HH, Cevik O, Cetinel S, Sekerci CA, Sener TE, Sener G, Tanidir Y. Melatonin prevents deterioration of erectile function in streptozotocin-induced diabetic rats via sirtuin-1 expression. Andrologia. 2020 Oct;52(9):e13639.
- Belenichev IF, Bila YV, Kamyshniy AM. Study of the expression pattern of mRNA Hsp70 and the level of HSP70 protein in experimental subtotal ischemiaand in the contrast of pharmacological correction of HSP70 modulators. Biol Mark Guid Ther (2018), 5(1):75–84.
- Menendez JA, Cufí S, Oliveras-Ferraros C, Vellon L, Joven J, Vazquez-Martin A. Gerosuppressant metformin: less is more. Aging (Albany NY). 2011 Apr;3(4):348-62.
- Sarlak G, Jenwitheesuk A, Chetsawang B, Govitrapong P. Effects of melatonin on nervous system aging: neurogenesis and neurodegeneration. J. Pharmacol. Sci.123 (2013) 9–24.
- Dezfouli MA, Zahmatkesh M, Farahmandfar M, Khodagholi F. Melatonin protective effect against amyloid β-induced neurotoxicity mediated by mitochondrialbiogenesis; involvement of hippocampal Sirtuin-1 signaling pathway. Physiol. Behav. 204 (2019) 65–75.
- Savran M, Asci H, Ozmen O, Erzurumlu Y, Savas HB, Sonmez Y, Sahin Y. Melatonin protects the heart and endothelium against high fructose corn syrup consumption-induced cardiovascular toxicity via SIRT-1 signaling. Hum. Exp. Toxicol. 38 (10) (2019) 1212–1223
- Ding M, Feng N, Tang D, Feng J, Li Z, Jia M, Liu Z, Gu X, Wang Y, Fu F, Pei J. Melatonin prevents Drp1-mediated mitochondrial fission in diabetic hearts through SIRT1-PGC1α pathway. J. Pineal Res. 65 (2018) e12491.
- Li J, Li N, Yan S, Lu Y, Miao X, Gu Z, Shao Y. Melatonin attenuates renal fibrosis in diabetic mice by activating the AMPK/PGC1α signaling pathway and rescuing mitochondrial function. Mol Med Rep. 2019 Feb;19(2):1318-1330.
- Proietti S, Cucina A, D’Anselmi F, Dinicola S, Pasqualato A, Lisi E, Bizzarri M. Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells. J Pineal Res. 2011 Mar;50(2):150-8.
- Huang C-H, Huang Y-TA, Lai Y-C, Sun C-K (2017) Prevalence and predictors of hypovitaminosis D among the elderly in subtropical region. PLoS ONE 12(7): e0181063.
- Brismar K, Hylander B, Eliasson K, Rössner S, Wetterberg L. Melatonin secretion related to side-effects of beta-blockers from the central nervous system. Acta Med Scand. 1988;223(6):525-30.
- Murphy PJ, Myers BL, Badia P. Nonsteroidal anti-inflammatory drugs alter body temperature and suppress melatonin in humans. Physiol Behav. 1996 Jan;59(1):133-9.
- Kurhaluk N, Tkachenko H. Melatonin and alcohol-related disorders. Chronobiol Int. 2020 Jun;37(6):781-803.
- Molcan L, Sutovska H, Okuliarova M, Senko T, Krskova L, Zeman M. Dim light at night attenuates circadian rhythms in the cardiovascular system and suppresses melatonin in rats. Life Sci. 2019 Aug 15;231:116568.
- de Goede P, Wefers J, Brombacher EC, Schrauwen P, Kalsbeek A. Circadian rhythms in mitochondrial respiration. J Mol Endocrinol. 2018 Apr;60(3):R115-R130.
- Ma P, Mori T, Zhao C, Thiel T, Johnson CH. Evolution of KaiC-Dependent Timekeepers: A Proto-circadian Timing Mechanism Confers Adaptive Fitness in the Purple Bacterium Rhodopseudomonas palustris. PLoS Genet. 2016 Mar 16;12(3):e1005922.
- Arble DM, Bass J, Laposky AD, Vitaterna MH, Turek FW. Circadian timing of food intake contributes to weight gain. Obesity (Silver Spring) : 2100–2102, 2009.
- Tsai L-L, Tsai Y-C, Hwang K, Huang Y-W, Tzeng J-E. Repeated light-dark shifts speed up body weight gain in male F344 rats. Am J Physiol Endocrinol Metab : E212–E217, 2005.
- Fonken LK, Workman JL, Walton JC, Weil ZM, Morris JS, Haim A, Nelson RJ. Light at night increases body mass by shifting the time of food intake. Proc Natl Acad Sci USA : 18664–18669, 2010.
- Kettner NM, Mayo SA, Hua J, Lee C, Moore DD, Fu L. Circadian dysfunction induces leptin resistance in mice. Cell Metab : 448–459, 2015.
- Bartol-Munier I, Gourmelen S, Pevet P, Challet E. Combined effects of high-fat feeding and circadian desynchronization. Int J Obes : 60–67, 2006.
- Kohsaka A, Laposky AD, Ramsey KM, Estrada C, Joshu C, Kobayashi Y, Turek FW, Bass J. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab : 414–421, 2007.
- Martins AJ, Isherwood CM, Vasconcelos SP, Lowden A, Skene DJ, Moreno CRC. The effect of urbanization on sleep, sleep/wake routine, and metabolic health of residents in the Amazon region of Brazil. Chronobiol Int. 2020 Aug 11:1-9.
- Antunes LC, Levandovski R, Dantas G, Caumo W, Hidalgo MP. Obesity and shift work: chronobiological aspects. Nutr Res Rev : 155–168, 2010.
- Knutsson A. Health disorders of shift workers. Occup Med (Lond) : 103–108, 2003.
- Adafer R, Messaadi W, Meddahi M, Patey A, Haderbache A, Bayen S, Messaadi N. Food Timing, Circadian Rhythm and Chrononutrition: A Systematic Review of Time-Restricted Eating’s Effects on Human Health. Nutrients. 2020 Dec 8;12(12):3770.
- Harvie M, Howell A. Potential Benefits and Harms of Intermittent Energy Restriction and Intermittent Fasting Amongst Obese, Overweight and Normal Weight Subjects-A Narrative Review of Human and Animal Evidence. Behav Sci (Basel). 2017 Jan 19;7(1):4.
- Rihm JS, Menz MM, Schultz H, Bruder L, Schilbach L, Schmid SM, Peters J. Sleep Deprivation Selectively Upregulates an Amygdala-Hypothalamic Circuit Involved in Food Reward. J Neurosci. 2019 Jan 30;39(5):888-899.
- Katsunuma R, Oba K, Kitamura S, Motomura Y, Terasawa Y, Nakazaki K, Hida A, Moriguchi Y, Mishima K. Unrecognized Sleep Loss Accumulated in Daily Life Can Promote Brain Hyperreactivity to Food Cue. Sleep. 2017 Oct 1;40(10).
- Noorwali E, Hardie L, Cade J. Bridging the Reciprocal Gap between Sleep and Fruit and Vegetable Consumption: A Review of the Evidence, Potential Mechanisms, Implications, and Directions for Future Work. Nutrients. 2019 Jun 19;11(6):1382.
- Cordova FV, Barja S, Brockmann PE. Consequences of short sleep duration on the dietary intake in children: A systematic review and metanalysis. Sleep Med. Rev. 2018, 42, 68–84.
- Noorwali EA, Hardie LJ, Cade JE. Fruit and Vegetable Consumption and Their Polyphenol Content Are Inversely Associated with Sleep Duration: Prospective Associations from the UK Women’s Cohort Study. Nutrients 2018, 10, 1803.
- Teichman EM, O’Riordan KJ, Gahan CGM, Dinan TG, Cryan JF. When Rhythms Meet the Blues: Circadian Interactions with the Microbiota-Gut-Brain Axis. Cell Metab. 2020 Mar 3;31(3):448-471.
- Li Y, Hao Y, Fan F, Zhang B. The Role of Microbiome in Insomnia, Circadian Disturbance and Depression. Front Psychiatry. 2018 Dec 5;9:669.
- Zhou L, Kang L, Xiao X, Jia L, Zhang Q, Deng M. “Gut Microbiota-Circadian Clock Axis” in Deciphering the Mechanism Linking Early-Life Nutritional Environment and Abnormal Glucose Metabolism. Int J Endocrinol. 2019 Aug 27;2019:5893028.
- DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS Jr. The absolute bioavailability of oral melatonin. J Clin Pharmacol. 2000 Jul;40(7):781-4.
- Bénès L, Claustrat B, Horrière F, Geoffriau M, Konsil J, Parrott KA, DeGrande G, McQuinn RL, Ayres JW. Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: a crossover study with melatonin. J Pharm Sci. 1997 Oct;86(10):1115-9.
- Todd JJ, McSorley EM, Pourshahidi LK, Madigan SM, Laird E, Healy M, Magee PJ. Vitamin D3 supplementation in healthy adults: a comparison between capsule and oral spray solution as a method of delivery in a wintertime, randomised, open-label, cross-over study. Br J Nutr. 2016 Oct;116(8):1402-1408.
- Sahakyan G. The role of Vitamin D in treatment of Chronic Insomnia with Melatonin. Neurol. (2018), 90(15-S) P5.320
- Iwashita H, Matsumoto Y, Maruyama Y, Watanabe K, Chiba A, Hattori A. The melatonin metabolite N1-acetyl-5-methoxykynuramine facilitates long-term object memory in young and aging mice. J Pineal Res. 2021 Jan;70(1):e12703.
- Genario R, Cipolla-Neto J, Bueno AA, Santos HO. Melatonin supplementation in the management of obesity and obesity-associated disorders: A review of physiological mechanisms and clinical applications. Pharmacol Res. 2020 Oct 17:105254.