Melatonin

What is

Melatonin is a hormone produced by a gland in our brain called the “pineal” or epiphysis.

The production of this hormone is regulated by light: during the day, when light hits the retina, an impulse is transmitted to the pineal gland, which blocks the production of melatonin; conversely, during the night in the absence of light its production increases exponentially.

It is an important regulator of the circadian rhythm, that is, the sleep-wake cycle: in fact, its main function is to prepare the body for sleep. Not surprisingly, its production occurs during the night.

Melatonin production varies with age: in children its production is very low, with increasing age it increases and then decreases again with old age.

In addition to sunlight, studies show that melatonin production is also regulated by meditation practices. This highlights how meditation represents an important regulator of the circadian cycle (1).

Nutritional characteristics

Melatonin is also present, in fair amounts, in various herbs and plants, within which it is intended to protect them from environmental stress, including oxidative stress.

Dietary sources of melatonin are:

• • • St. John’s Wort (Hypericum)
    • coffee
    • black pepper
    • white radish
    • turmeric
    • grape
    • almonds
    • fennel
    • melon
    • cardamom
    • linseed
    • anise
    • celery
    • coriander
    • poppy seeds
    • walnuts
    • milk thistle
    • lupines
    • oat seeds
    • corn seed
    • tomato

Pharmacological properties of melatonin

The best known function of melatonin is its ability to regulate circadian rhythm.

Once produced, however, it is distributed to the rest of the body where it is able to activate numerous intracellular signaling pathways through which melatonin is able to regulate energy metabolism, blood lipid profile, cardiovascular system, endocrine system, bone growth, neural development, and relieve pain (2).

Melatonin is a powerful antioxidant capable of (3):

• • • Directly eliminate reactive oxygen and nitrogen species
    • Enhance the activity of antioxidant enzymes
    • Limiting the production of free radicals during electron transport in the mitochondrial respiratory chain
    • Generate a cascade of “scavengers” of radicals that further contribute to the elimination of ROS

Melatonin also possesses immunomodulatory and anti-inflammatory properties as (4):

• • • Inhibits cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), enzymes responsible for the inflammatory cascade
    • through blocking the transcription factor NK-kB, inhibits the production of pro-inflammatory cytokines
    • Stimulates the activity of NK cells
    • Stimulates chemotaxis and phagocytic capacity of leukocytes
    • Stimulates the proliferation of B cells
    • stimulates Th1 lymphocytes

Melatonin and oncology

Several studies, both in vivo and in vitro, have shown that melatonin exerts various antineoplastic effects (5):

• • • Induces cancer cell apoptosis (programmed cell death) by modulation of COX-2/PGE2, NF-kB, PI3K/Akt, Apaf-1 and bcl-2/bax signaling pathways.
    • Inhibits tumor cell proliferation by upregulating cyclin-dependent kinases (CDKs) and thereby blocking the cell cycle
    • Inhibits the production of the aromatase enzyme, thereby exerting an antiestrogenic effect through inhibition of the aromatase gene CYP19A1
    • Inhibits cancer cell invasion and metastasis formation by blocking the activity of MMP-2 and MMP-9 and by down-regulating the p38 pathway
    • Inhibits angiogenesis, that is, the formation of new blood vessels, by downregulating the expression of VEGF and HIF factors
    • increases levels of reactive oxygen species in cancer cells by decreasing their cell viability

Melatonin could also increase the radiosensitivity of cancer cells. According to a 2015 study, pretreatment with melatonin on breast cancer cells one week before radiation could sensitize cancer cells to the ionizing effects of radiation (6)

It would also appear to be able to reduce the side effects of chemotherapy drugs (7) and potentiate their effect, particularly cisplatin (8), doxorubicin (9), gefitinib (10) and tamoxifen (11).

The main forms of cancer on which the antitumor effects of melatonin have been observed are:

• • • breast cancer
    • prostate cancer
    • ovarian cancer
    • uterine cancer
    • liver cancer
    • renal tumor
    • lung cancer
    • stomach cancer
    • pancreatic cancer
    • colorectal cancer

Contraindications and side effects

The rare melatonin deficiency, which may be caused by issues in the pineal gland, is responsible for alterations in the sleep-wake cycle, metabolic and cardiovascular disorders (2).

Taking high doses of does not prove to be toxic to humans (3)

Due to the lack of studies in the literature, taking melatonin during pregnancy and lactation is not recommended.

Bioavailability

The bioavailability of melatonin, especially when taken in oral supplement form, is low due to its rapid metabolism in the liver (2).

Bibliography

1. Med Sci Monit. 2004 Mar. The effects of long meditation on plasma melatonin and blood serotonin. Solberg EE, Holen A, Ekeberg Ø, Østerud B, Halvorsen R, Sandvik L.
2. Arch Endocrinol Metab. 2018 Aug. A brief review about melatonin, a pinealhormone. Amaral FGD, Cipolla-Neto J.
3. Cells. 2019 Jul. Melatonin in Medicinal and Food Plants: Occurrence, Bioavailability, and Health Potential for Humans. Bahare Salehi, Farukh Sharopov, Patrick Valere Tsouh Fokou, Agnieszka Kobylinska, Lilian de Jonge, Kathryn Tadio, Javad Sharifi-Rad, Malgorzata M. Posmyk, Miquel Martorell, Natália Martins, Marcello Iriti
4. Int J Mol Sci. 2013 Apr. Melatonin: Buffering the Immune System. Antonio Carrillo-Vico, Patricia J. Lardone, Nuria Álvarez-Sánchez, Ana Rodríguez-Rodríguez, Juan M. Guerrero
5. Oncotarget. 2017 Jun 13. Melatonin for the prevention and treatment of cancer. Ya Li, Sha Li, Yue Zhou, Xiao Meng, Jiao-Jiao Zhang, Dong-Ping Xu, Hua-Bin Li
6. J Pineal Res. 2015 Mar. Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double-strand DNA break repair. Alonso-Gonzalez C, Gonzalez A, Martinez-Campa C, Gomez-Arozamena J, Cos S.
7. Oxid Med Cell Longev. 2020. Utilizing Melatonin to Alleviate Side Effects of Chemotherapy: A Potentially Good Partner for Treating Cancer with Aging. Zhiqiang Ma, Liqun Xu, Dong Liu, Xiaoyan Zhang, Shouyin Di, Weimiao Li, Jiao Zhang, Russel J. Reiter, Jing Han, Xiaofei Li, Xiaolong Yan
8. Cell Prolif. 2015 Feb. Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. P. Plaimee, N. Weerapreeyakul, S. Barusrux, N. P. Johns
9. J Membr Biol. 2016 Apr. Synergic Effects of Doxorubicin and Melatonin on Apoptosis and Mitochondrial Oxidative Stress in MCF-7 Breast Cancer Cells: Involvement of TRPV1 Channels. Koşar PA, Nazıroğlu M, Övey İS, Çiğ B
10. Cell Physiol Biochem. 2014. Melatonin sensitizes H1975 non-small-cell lung cancer cells harboring a T790M-targeted epidermal growth factor receptor mutation to the tyrosine kinase inhibitor gefitinib. Yun M, Kim EO, Lee D, Kim JH, Kim J, Lee H, Lee J, Kim SH
11. Mol Pharmacol. 2019 Aug. Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs. Mahmud Hasan, Mohamed Akmal Marzouk, Saugat Adhikari, Thomas D. Wright, Benton P. Miller, Margarite D. Matossian, Steven Elliott, Maryl Wright, Madlin Alzoubi, Bridgette M. Collins-Burow, Matthew E. Burow, Ulrike Holzgrabe, Darius P. Zlotos, Robert E. Stratford, Paula A. Witt-Enderby