I'm on HRT Too: The Case for Melatonin
Updated: Sep 14, 2020
Citations for my review on melatonin follow. You can watch the video here.
A. Melatonin was first isolated from a cow’s pineal gland tissue in 1958 by Aaron Lerner.
B. Melatonin is a very ancient molecule: it is produced by vertebrates, invertebrates, fungi, algae, and unicells.
C. Humans have two G protein-coupled melatonin receptors named MT1 and MT2, first identified by Reppert et al. These receptors are found in the retinas, across the brain, in the adrenal cortex, in reproductive organs, in the cardiovascular system, and in organs that modulate immune function.
D. MT1 activity is associated with suppression of neuronal firing in the suprachiasmatic nucleus (SCN) whereas MT2 activity is associated with circadian phase shifts, and the density of these receptors varies according to the circadian rhythm.
E. In addition to its dedicated receptors, melatonin also binds to quinone reductase 2, calmodulin, calreticulin, the retinoic acid and retinoid x receptors, and in brain mitochondria.
F. Melatonin is metabolized extensively, with some of its metabolites (e.g. AMK) having an even greater antioxidant potential than melatonin.
G. Summary of some effects: By improving circadian rhythms, melatonin suppresses oxidative damage. Melatonin prevents excitotoxic calcium overload in the nervous system. Melatonin modulates the immune system. Melatonin downregulates steroid receptors such as the glucocorticoid receptors, preventing apoptosis. Melatonin downregulates nitric oxide formation. In pharmacologic doses, melatonin potently neutralizes reactive oxygen and reactive nitrogen species, terminating radical reactive chains. See citation for a great overview.
MELATONIN AND THE BRAIN
A. Melatonin has neurotrophic effects. It co-localizes with the expression of BDNF and GDNF in some cells and to stimulate their expression in stem cells, allowing them to diversify into mature cells.
B. For a review of melatonin’s neuroprotective character, see this citation.
C. There is much evidence for melatonin being particularly neuroprotective against the pathology of Parkinson’s disease.
D. Melatonin is being investigated for the treatment of Alzheimer’s disease (see this amazing review).
E. Melatonin appears particularly useful for alleviating methamphetamine toxicity. It may do the same for alcohol (not just in the brain).
MELATONIN AND AGING
A. Pharmacologic melatonin may improve aging.
B. Melatonin delays senescence.
C. Melatonin modulates sirtuin activity.
MELATONIN AND BLOOD PRESSURE
A. A meta-analysis of 5 controlled trials found that supplemental melatonin significantly reduced systolic and diastolic blood pressure. This falls in line with theoretical evidence for melatonin and angiotensin modulating each other.
MELATONIN AND LIPIDS
A. A meta-analysis of 8 randomized controlled trials found that melatonin supplementation produced a large and significant reduction in serum triglycerides and a significant reduction in total serum cholesterol.
MELATONIN AND THE IMMUNE SYSTEM
A. Melatonin is immunomodulatory. It is synthesized by lymphocytes and the thymus. It stimulates natural killer cells and governs the release of T-helper 1 cells, B lymphocytes, and cytokine release.
B. In a randomized, double-blind, controlled study, 6 mg of melatonin reduced the TNF-alpha, interleukin-6, and C-reactive protein of obese women, indication a reduction in inflammation and oxidative stress.
MELATONIN AND CANCER
A. Melatonin is known to inhibit cancer development and cancer metastasis.
B. Melatonin selectively triggers apoptosis in a variety of cancer cells.
C. Melatonin has been shown to inhibit breast cancer development, and it is thought that the reason night shift workers develop breast cancers more frequently is due to reduced melatonin synthesis.
D. Melatonin produces an anti-angiogenic effect by inhibits VEGF in liver cancer cells.
MELATONIN, INSULIN RESISTANCE, DIABETES, OBESITY, AND NAFLD
A. Melatonin regulates insulin sensitivity, producing insulin sensitivity early in the day and inducing insulin resistance when it is transmitted in the latter day. It also influences GLUT4 expression, lipolysis, lipogenesis, fatty acid uptake, pancreatic islet function, and modulates IGF-1 activity.
B. A randomized, double-blind controlled trial found that 6 mg of melatonin significantly but minorly improved HbA1c, fasting blood glucose, and HDL-cholesterol among type 2 diabetics.
C. A randomized, double-blind controlled trial found that 10 mg of melatonin significantly improved insulin sensitivity, HDL-cholesterol, systolic and diastolic blood pressure, C-reactive protein, and metrics of oxidative stress among type 2 diabetics with coronary heart disease.
D. In a randomized, controlled trial, 10 mg of melatonin improved body weight reduction, antioxidant defense, and adipokine (cytokines released from adipose tissue, like leptin) secretion among obese dieters.
E. In a double-blind, controlled, crossover study, 8 mg of melatonin significantly improved some metrics of the metabolic syndrome.
F. Melatonin is particularly attractive for nonalcoholic fatty liver disease and liver injury. In a randomized, controlled trial, 10 mg of melatonin improved liver grade and C-reactive protein among sufferers of nonalcoholic fatty liver disease.
THOUGHTS FOR A PROTOCOL
A. At higher doses, melatonin becomes profoundly neuroprotective.
B. High doses protect against cardiac ischemia-reperfusion injury.
C. 300 mg of rectal melatonin was successfully used to normalize oxidative damage in a group of 31 ALS patients.
D. 50 mg of oral melatonin was well-tolerated in a study on Parkinson’s patients.
E. Oral melatonin has a:
a. 15% average absolute bioavailability. The low bioavailability is due to extensive first-pass metabolism.
b. One study found 2 mg of melatonin reached peak concentrations in plasma/serum at 15 minutes while 10 mg did in 210 minutes. Another study found the peak concentration of 10 mg of melatonin at 41 minutes with a half-life of 54 minutes.
F. Oral extended-release melatonin has a:
a. 10-56% absolute bioavailability with an average of 15%.
b. Half-life of 3.5-4 hours.
c. A maximum serum concentration at 0.75-3 hours.
d. 60% of it binds to proteins, mainly albumin, alpha1-acid, and HDL
e. Is metabolized by CYP1A1, CYP1A2, and potentially CYPC19.
f. Its affinity for MT1 is 0.081 Ki (nM) and MT2 is 0.383 Ki (nM).
G. Interestingly, high-dose intravenous administration has been studied, as has low-dosed intranasal administration. Transdermal and oral transmucosal administration has also been studied.
a. Intravenous melatonin has a linear elimination graph.
H. Intuitively, twice a day dosing appears to damage sex hormone production by interfering with gonadotropin releasing hormone.
I. It is believed that a loss of response to melatonin supplementation is due to slow metabolism, particularly, to reduced activity of the CYP1A2 enzyme (found in 12-14% of people).
 Lerner, A. B., Case, J. D., Takahashi, Y., Lee, T. H., & Mori, W. (1958). Isolation of melatonin, the pineal gland factor that lightens melanocyteS1. Journal of the American Chemical Society, 80(10), 2587-2587.  Hardeland, R. (1997). New actions of melatonin and their relevance to biometeorology. International journal of biometeorology, 41(2), 47-57.  Reppert, S. M., Weaver, D. R., & Ebisawa, T. (1994). Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron, 13(5), 1177-1185.  Reppert, S. M., Godson, C., Mahle, C. D., Weaver, D. R., Slaugenhaupt, S. A., & Gusella, J. F. (1995). Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proceedings of the National Academy of Sciences, 92(19), 8734-8738.  Mazzucchelli, C., Pannacci, M., Nonno, R., Lucini, V., Fraschini, F., & Stankov, B. M. (1996). The melatonin receptor in the human brain: cloning experiments and distribution studies. Molecular Brain Research, 39(1-2), 117-126.  Torres-Farfan, C., Richter, H. G., Rojas-García, P., Vergara, M., Forcelledo, M. L., Valladares, L. E., ... & Serón-Ferré, M. (2003). mt1 Melatonin receptor in the primate adrenal gland: inhibition of adrenocorticotropin-stimulated cortisol production by melatonin. The Journal of Clinical Endocrinology & Metabolism, 88(1), 450-458.  Steffens, F., Zhou, X. B., Sausbier, U., Sailer, C., Motejlek, K., Ruth, P., ... & Wieland, T. (2003). Melatonin receptor signaling in pregnant and nonpregnant rat uterine myocytes as probed by large conductance Ca2+-activated K+ channel activity. Molecular Endocrinology, 17(10), 2103-2115.  Ekmekcioglu, C., Thalhammer, T., Humpeler, S., Mehrabi, M. R., Glogar, H. D., Hölzenbein, T., ... & Marktl, W. (2003). The melatonin receptor subtype MT2 is present in the human cardiovascular system. Journal of pineal research, 35(1), 40-44.  Carrillo-Vico, A., Garcia-Perganeda, A., Naji, L., Calvo, J. R., Romero, M. P., & Guerrero, J. M. (2003). Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cellular and Molecular Life Sciences CMLS, 60(10), 2272-2278.  Hunt, A. E., Al-Ghoul, W. M., Gillette, M. U., & Dubocovich, M. L. (2001). Activation of MT2 melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. American Journal of Physiology-Cell Physiology, 280(1), C110-C118.  Waly, N. E., & Hallworth, R. (2015). Circadian pattern of melatonin MT1 and MT2 receptor localization in the rat suprachiasmatic nucleus. Journal of circadian rhythms, 13.  Nosjean, O., Ferro, M., Cogé, F., Beauverger, P., Henlin, J. M., Lefoulon, F., ... & Boutin, J. A. (2000). Identification of the Melatonin-binding SiteMT 3 as the Quinone Reductase 2. Journal of Biological Chemistry, 275(40), 31311-31317.  Soto‐Vega, E., Meza, I., Ramírez‐Rodríguez, G., & Benitez‐King, G. (2004). Melatonin stimulates calmodulin phosphorylation by protein kinase C. Journal of pineal research, 37(2), 98-106.  Macías, M., Escames, G., Leon, J., Coto, A., Sbihi, Y., Osuna, A., & Acuña‐Castroviejo, D. (2003). Calreticulin–melatonin: An unexpected relationship. European journal of biochemistry, 270(5), 832-840.  Carlberg, C., & Wiesenberg, I. (1995). The orphan receptor family RZR/ROR, melatonin and 5‐lipoxygenase: An unexpected relationship: Mini Review. Journal of pineal research, 18(4), 171-178.  Hardeland, R., & Poeggeler, B. (2007). Actions of melatonin, its structural and functional analogs in the central nervous system and the significance of metabolism. Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Central Nervous System Agents), 7(4), 289-303.  Ressmeyer, A. R., Mayo, J. C., Zelosko, V., Sáinz, R. M., Tan, D. X., Poeggeler, B., ... & Hardeland, R. (2003). Antioxidant properties of the melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK): scavenging of free radicals and prevention of protein destruction. Redox report, 8(4), 205-213.  Tan, D. X., Manchester, L. C., Terron, M. P., Flores, L. J., & Reiter, R. J. (2007). One molecule, many derivatives: a never‐ending interaction of melatonin with reactive oxygen and nitrogen species?. Journal of pineal research, 42(1), 28-42.  Hardeland, R., & Poeggeler, B. (2008). Melatonin beyond its classical functions. The Open Physiology Journal, 1, 1-22.  Niles, L. P., Armstrong, K. J., Castro, L. M. R., Dao, C. V., Sharma, R., McMillan, C. R., ... & Kirkham, D. L. (2004). Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT 1 receptor with neuronal and glial markers. BMC neuroscience, 5(1), 1-9.  Rincón Castro, L. M., Gallant, M., & Niles, L. P. (2005). Novel targets for valproic acid: up‐regulation of melatonin receptors and neurotrophic factors in C6 glioma cells. Journal of neurochemistry, 95(5), 1227-1236.  Kong, X., Li, X., Cai, Z., Yang, N., Liu, Y., Shu, J., ... & Zuo, P. (2008). Melatonin regulates the viability and differentiation of rat midbrain neural stem cells. Cellular and molecular neurobiology, 28(4), 569-579.  Alghamdi, B. S. (2018). The neuroprotective role of melatonin in neurological disorders. Journal of neuroscience research, 96(7), 1136-1149.  Srinivasan, V., Cardinali, D. P., Srinivasan, U. S., Kaur, C., Brown, G. M., Spence, D. W., ... & Pandi-Perumal, S. R. (2011). Therapeutic potential of melatonin and its analogs in Parkinson’s disease: focus on sleep and neuroprotection. Therapeutic advances in neurological disorders, 4(5), 297-317.  Shukla, M., Govitrapong, P., Boontem, P., Reiter, R. J., & Satayavivad, J. (2017). Mechanisms of melatonin in alleviating Alzheimer's disease. Current neuropharmacology, 15(7), 1010-1031.  Nopparat, C., Porter, J. E., Ebadi, M., & Govitrapong, P. (2010). The mechanism for the neuroprotective effect of melatonin against methamphetamine‐induced autophagy. Journal of pineal research, 49(4), 382-389.  Al Kury, L. T., Zeb, A., Abidin, Z. U., Irshad, N., Malik, I., Alvi, A. M., ... & Shah, F. A. (2019). Neuroprotective effects of melatonin and celecoxib against ethanol-induced neurodegeneration: a computational and pharmacological approach. Drug Design, Development and Therapy, 13, 2715.  Mishra, A., Paul, S., & Swarnakar, S. (2011). Downregulation of matrix metalloproteinase-9 by melatonin during prevention of alcohol-induced liver injury in mice. Biochimie, 93(5), 854-866.  Poeggeler, B. (2005). Melatonin, aging, and age-related diseases. Endocrine, 27(2), 201-212.  Wang, P., Yin, L., Liang, D., Li, C., Ma, F., & Yue, Z. (2012). Delayed senescence of apple leaves by exogenous melatonin treatment: toward regulating the ascorbate–glutathione cycle. Journal of pineal research, 53(1), 11-20.  Mayo, J. C., Sainz, R. M., Gonzalez Menendez, P., Cepas, V., Tan, D. X., & Reiter, R. J. (2017). Melatonin and sirtuins: a “not‐so unexpected” relationship. Journal of pineal research, 62(2), e12391.  Cristòfol, R., Porquet, D., Corpas, R., Coto‐Montes, A., Serret, J., Camins, A., ... & Sanfeliu, C. (2012). Neurons from senescence‐accelerated SAMP8 mice are protected against frailty by the sirtuin 1 promoting agents melatonin and resveratrol. Journal of pineal research, 52(3), 271-281.  Dezfouli, M. A., Zahmatkesh, M., Farahmandfar, M., & Khodagholi, F. (2019). Melatonin protective effect against amyloid β-induced neurotoxicity mediated by mitochondrial biogenesis; involvement of hippocampal Sirtuin-1 signaling pathway. Physiology & behavior, 204, 65-75.  Hadi, A., Ghaedi, E., Moradi, S., Pourmasoumi, M., Ghavami, A., & Kafeshani, M. (2019). Effects of melatonin supplementation on blood pressure: a systematic review and meta-analysis of randomized controlled trials. Hormone and Metabolic Research, 51(03), 157-164.  Campos, L. A., Cipolla-Neto, J., Amaral, F. G., Michelini, L. C., Bader, M., & Baltatu, O. C. (2013). The angiotensin-melatonin axis. International Journal of Hypertension, 2013.  Mohammadi-Sartang, M., Ghorbani, M., & Mazloom, Z. (2018). Effects of melatonin supplementation on blood lipid concentrations: a systematic review and meta-analysis of randomized controlled trials. Clinical Nutrition, 37(6), 1943-1954.  Mohamed, M., Srinivasan, V., Maestroni, G., Rosenstein, R. E., & Oter, S. (2014). Melatonin and immune function: clinical significance. In Melatonin and Melatonergic Drugs in Clinical Practice (pp. 143-157). Springer, New Delhi.  Alamdari, N. M., Mahdavi, R., Roshanravan, N., Yaghin, N. L., Ostadrahimi, A. R., & Faramarzi, E. (2015). A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Hormone and Metabolic Research, 47(07), 504-508.  Reiter, R. J., Rosales-Corral, S. A., Tan, D. X., Acuna-Castroviejo, D., Qin, L., Yang, S. F., & Xu, K. (2017). Melatonin, a full service anti-cancer agent: inhibition of initiation, progression and metastasis. International journal of molecular sciences, 18(4), 843.  Su, S. C., Hsieh, M. J., Yang, W. E., Chung, W. H., Reiter, R. J., & Yang, S. F. (2017). Cancer metastasis: Mechanisms of inhibition by melatonin. Journal of pineal research, 62(1), e12370.  Bizzarri, M., Proietti, S., Cucina, A., & Reiter, R. J. (2013). Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert opinion on therapeutic targets, 17(12), 1483-1496.  Hill, S. M., Belancio, V. P., Dauchy, R. T., Xiang, S., Brimer, S., Mao, L., ... & Frasch, T. (2015). Melatonin: an inhibitor of breast cancer. Endocrine-related cancer, 22(3), R183-R204.  Carbajo-Pescador, S., Ordoñez, R., Benet, M., Jover, R., García-Palomo, A., Mauriz, J. L., & González-Gallego, J. (2013). Inhibition of VEGF expression through blockade of Hif1α and STAT3 signalling mediates the anti-angiogenic effect of melatonin in HepG2 liver cancer cells. British journal of cancer, 109(1), 83-91.  Cipolla‐Neto, J., Amaral, F. G., Afeche, S. C., Tan, D. X., & Reiter, R. J. (2014). Melatonin, energy metabolism, and obesity: a review. Journal of pineal research, 56(4), 371-381.  Rezvanfar, M. R., Heshmati, G., Chehrei, A., Haghverdi, F., Rafiee, F., & Rezvanfar, F. (2017). Effect of bedtime melatonin consumption on diabetes control and lipid profile. International Journal of Diabetes in Developing Countries, 37(1), 74-77.  Raygan F, Ostadmohammadi V, Bahmani F et al. Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: A randomized, double-blind, placebo-controlled trial  Szewczyk-Golec, K., Rajewski, P., Gackowski, M., Mila-Kierzenkowska, C., Wesołowski, R., Sutkowy, P., ... & Woźniak, A. (2017). Melatonin supplementation lowers oxidative stress and regulates adipokines in obese patients on a calorie-restricted diet. Oxidative medicine and cellular longevity, 2017.  Goyal, A., Terry, P. D., Superak, H. M., Nell-Dybdahl, C. L., Chowdhury, R., Phillips, L. S., & Kutner, M. H. (2014). Melatonin supplementation to treat the metabolic syndrome: a randomized controlled trial. Diabetology & metabolic syndrome, 6(1), 124.  Zhou, H., Du, W., Li, Y. E., Shi, C., Hu, N., Ma, S., ... & Ren, J. (2018). Effects of melatonin on fatty liver disease: The role of NR 4A1/DNA‐PK cs/p53 pathway, mitochondrial fission, and mitophagy. Journal of Pineal Research, 64(1), e12450.  Zhang, J. J., Meng, X., Li, Y., Zhou, Y., Xu, D. P., Li, S., & Li, H. B. (2017). Effects of melatonin on liver injuries and diseases. International Journal of Molecular Sciences, 18(4), 673.  Mortezaee, K., & Khanlarkhani, N. (2018). Melatonin application in targeting oxidative‐induced liver injuries: A review. Journal of Cellular Physiology, 233(5), 4015-4032.  Pakravan, H., Ahmadian, M., Fani, A., Aghaee, D., Brumanad, S., & Pakzad, B. (2017). The effects of melatonin in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Advanced biomedical research, 6.  Shokouhi, G., Tubbs, R. S., Shoja, M. M., Hadidchi, S., Ghorbanihaghjo, A., Roshangar, L., ... & Oakes, W. J. (2008). Neuroprotective effects of high-dose vs low-dose melatonin after blunt sciatic nerve injury. Child's Nervous System, 24(1), 111-117.  Ceyran, H., Narin, F., Narin, N., Akgün, H., Ceyran, A. B., Öztürk, F., & Akçalı, Y. (2008). The effect of high dose melatonin on cardiac ischemia-reperfusion Injury. Yonsei Medical Journal, 49(5), 735-741.  Weishaupt, J. H., Bartels, C., Pölking, E., Dietrich, J., Rohde, G., Poeggeler, B., ... & Schneider, A. (2006). Reduced oxidative damage in ALS by high‐dose enteral melatonin treatment. Journal of pineal research, 41(4), 313-323.  Dowling, G. A., Mastick, J., Colling, E., Carter, J. H., Singer, C. M., & Aminoff, M. J. (2005). Melatonin for sleep disturbances in Parkinson's disease. Sleep medicine, 6(5), 459-466.  DeMuro, R. L., Nafziger, A. N., Blask, D. E., Menhinick, A. M., & Bertino Jr, J. S. (2000). The absolute bioavailability of oral melatonin. The Journal of Clinical Pharmacology, 40(7), 781-784.  Di, W. L., Kadva, A., Johnston, A., & Silman, R. (1997). Variable bioavailability of oral melatonin. New England Journal of Medicine, 336(14), 1028-1029.  Harpsøe, N. G., Andersen, L. P. H., Gögenur, I., & Rosenberg, J. (2015). Clinical pharmacokinetics of melatonin: a systematic review. European journal of clinical pharmacology, 71(8), 901-909.  Andersen, L. P., Werner, M. U., Rosenkilde, M. M., Harpsøe, N. G., Fuglsang, H., Rosenberg, J., & Gögenur, I. (2016). Pharmacokinetics of oral and intravenous melatonin in healthy volunteers. BMC Pharmacology and Toxicology, 17(1), 1-5.  Williams III, W. P., McLin III, D. E., Dressman, M. A., & Neubauer, D. N. (2016). Comparative review of approved melatonin agonists for the treatment of circadian rhythm sleep‐wake disorders. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 36(9), 1028-1041.  Ceyran, H., Narin, F., Narin, N., Akgün, H., Ceyran, A. B., Öztürk, F., & Akçalı, Y. (2008). The effect of high dose melatonin on cardiac ischemia-reperfusion Injury. Yonsei Medical Journal, 49(5), 735-741.  Helfrich, E., Neef, C., & Merkus, F. W. H. M. (2002). Population pharmacokinetics of intranasally administered low dose melatonin. British Journal of Clinical Pharmacology, 53(5), 543P-544P.  Zetner, D., Andersen, L. P. H., & Rosenberg, J. (2016). Pharmacokinetics of alternative administration routes of melatonin: a systematic review. Drug Research, 66(04), 169-173.  Andersen, L. P., Werner, M. U., Rosenkilde, M. M., Harpsøe, N. G., Fuglsang, H., Rosenberg, J., & Gögenur, I. (2016). Pharmacokinetics of oral and intravenous melatonin in healthy volunteers. BMC Pharmacology and Toxicology, 17(1), 1-5.  Amano, M., Iigo, M., Ikuta, K., Kitamura, S., Okuzawa, K., Yamada, H., & Yamamori, K. (2004). Disturbance of plasma melatonin profile by high dose melatonin administration inhibits testicular maturation of precocious male masu salmon. Zoological science, 21(1), 79-85.  Braam, W., Van Geijlswijk, I., Keijzer, H., Smits, M. G., Didden, R., & Curfs, L. M. (2010). Loss of response to melatonin treatment is associated with slow melatonin metabolism. Journal of Intellectual Disability Research, 54(6), 547-555.