Melatonin

What Is It?

Melatonin is a hormone mainly produced in the pineal gland of the brain, and is present at various quantities in foods such as meat, eggs, milk, fruits, and nuts$^{1}$. It is known for the physiological regulation of circadian rhythms and body cycles, as well as its indirect effects on cardiovascular function, neurogenerative processes, and immune system function$^{1}$. However, some studies have shown that melatonin has properties that make it potentially anti-carcinogenic and thus a vital component of anticancer nutritional research$^{2}$. There is evidence that melatonin can suppress the effects of induced carcinogenesis (development of cancer due to external carcinogens) as well as decrease the mortality rate of advanced cancer patients, rendering it a promising avenue for future anticancer research$^{2,3}$.

What Are Its Other Names?

Melatonin is also recognised as 5-methoxy-N-acetyltryptamine, and is derived from the pineal gland. Its IUPAC name is N-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-acetamide$^{4}$. There are various plant and animal sources of melatonin.

What Foods Have It?

*DW = dry weight FW = fresh weight

[Source: Meng et al (2017)]

What Are Its Main Benefits?

Treatment of Insomnia

Melatonin is produced in the body to regulate the 24-hour sleep-wake cycle, and thus can be used as an initial treatment for chronic insomnia$^{5}$. When people have trouble sleeping during normal hours or suffer from delayed sleep-wake phase disorder (DSWPD)$^{5}$, taking melatonin 30-45 minutes prior to an intended bedtime may be effective in initiating circadian regulation since it reduces the time between going to bed and falling sleep. 

Jet Lag Treatment

A widely regarded sleep-aid, taking melatonin during flights can help with adjusting to changes in time zones while travelling, and can help avoid disruption of bodily functions. However, the time at which one should use the sleep aid differs based on whether they are travelling eastbound or westbound$^{6}$.

Anxiety and Sedation during Surgical Procedures

Taking melatonin before a procedure in adults reduces the need for multiple sedatives and can work well with general anaesthesia to reduce confusion and fear in patients. For children receiving sevoflurane (anaesthetic), melatonin can help with post-operative agitation$^{7}$.

Benefits for Cancer Treatment

Many in vitro (cell line) studies and human clinical trials are being conducted to analyse the effect of melatonin (along with chemotherapy) in reducing tumour growth. Promising results have been seen for many hormone-based cancers such as breast cancer, prostate cancer, oral cancer, and gastric cancer$^{8}$. While it has yet to be studied in human cells, a large part of the effectiveness of melatonin in dealing with cancer symptoms is through its direct molecular action on cells$^{7,8}$. This includes increased autophagy (regulated destruction of cells), and free-radical detox (a metabolic process to remove harmful free radicals that can damage DNA)$^{9}$. While some preclinical and clinical studies have indicated that melatonin may have potential anticancer properties, this evidence is only preliminary and no anticancer drugs with melatonin are currently on the market. Melatonin is offered as over-the-counter medication for insomnia, sleep disorders, and sedation, and is available in regular doses (0.5mg to 10mg) in pharmacies$^{5}$.

What Are Its Main Drawbacks?

While melatonin shows promise in cancer prevention, it faces important limitations. Notably, melatonin supplementation can potentially interfere with the body's natural circadian rhythm production by leading to dependency on supplements and reduced endogenous melatonin synthesis over time$^{11}$. Additionally, the dosing and timing of melatonin for cancer prevention is difficult to optimize since factors like individual metabolism, other medications, and cancer type all affect its therapeutic efficacy, rendering it challenging to establish standardized preventive protocols$^{5,10}$. 

How Does It Work?

Melatonin has some prominent anticancer effects on hormone-induced cancers, specifically breast cancer and prostate cancer. These effects are achieved via antioxidant properties, downregulating proliferative cell-signalling, increasing apoptosis, and by counteracting tumour-driven immune suppressions$^{8,10}$. Due to extensive research on its impact on endocrine physiology, melatonin research on breast cancer has generated the most in vitro results. 

What Are Its Mechanisms of Action?

1. Antioxidant Properties: Due to its electron-rich structure and amphipathic nature (i.e. it possesses both hydrophilic and hydrophobic properties), melatonin has strong antioxidant effects. For instance, melatonin can sequester free radical OH- ions at a much greater capacity than vitamin E$^{11}$. Moreover, melatonin is considered responsible for the synthesis of various other antioxidant enzymes in cells, managing the mitochondrial electron transport chain (which regulates the number of ions in circulation), and can be metabolized under oxidative stress (via enzymatic degradation cascades that neutralize many radical products)$^{10,11}$. 
2. Impact on Proliferative Cell Signalling: Cancer cells are recognized for their ability to overexpress, proliferate uncontrollably, and hijack protein synthesis and cell signalling pathways. Melatonin, along with 5-fluorouracil (a chemotherapy drug), is experimentally recognized to have an anti-proliferative effect on colon cancer cells by downregulating important signalling pathways (like PI3K, NFκB and iNOS)$^{12}$.  NFκB is a pro-inflammatory transcription factor that is implicated in cancer growth as it blocks apoptosis, induces cell proliferation, and promotes angiogenesis$^{15}$. In various other cancer cell lines, melatonin has inhibitory effects against the accumulation of certain growth factors, and upregulates proteins such as p21 and p27 which are responsible for regulating cell proliferation and inhibiting the cyclin-kinase pathway, overall leading to increased cancer cell apoptosis$^{13,14}$. 
3. Effect on Tumour-Associated Immune Evasion:  Various models and studies have shown that melatonin may help stimulate T-cells and Natural Killer cells of the immune system. This was experimentally determined by testing the dysregulation of the Foxp3 gene in cell lines, and it was concluded that melatonin demonstrated in vivo anti-gastric cancer effects (due to its direct anti-inflammatory action on stomach gastric mucosa)$^{16}$. A study on the anticancer potential of melatonin in conjunction with thymoquinone (a phytochemical with anticancer effects) also concluded that there was a positive synergistic impact on breast cancer cell implants and a reduction of tumour size within mice models, and this response was mediated by inducing apoptosis, and activating the T-helper-1 cell’s anticancer immune response$^{17}$. 
4. Effect on Tissue Metastasis of Cancer: In experiments conducted on tumour metastases and ways of preventing cancer progression, it was concluded that melatonin exhibited anti-metastatic properties. This included prevention of secondary tumours and metastasis by interrupting inter-cell communication within tumours, as well as by modulating cell adhesions, extracellular matrices, and cell-cell interactions between cancer cells$^{18}$. In some cell lines (such as breast cancer cells), administering melatonin at tumour target sites reduced levels of proteins required for cell migration, thus providing a barrier against cancer cell metastasis$^{18}$. This data can be applied in clinical experiments to further understand the mechanism of melatonin and its overall impact in various stages of cancers.

What Are Typical Doses and Durations?

Based on the human clinical trial data compiled below, it can be concluded that the average dose of melatonin administered was between 10mg to 20mg/day. Usually, this amount was given orally either with or without chemicals like dimethyl sulfoxide. While there is no official upper limit, consuming more than 2-3 mg/hr of melatonin in quick succession or 20 mg/day can cause severe nausea and dizziness. The dosage must be regulated further for patients undergoing combinations of treatments such as drugs and chemo-radiation, as they may experience severe lethargy and nausea with higher dose treatments. The duration of dosage depends entirely on the type and aggressiveness of a cancer, and the type of administered treatment (solely melatonin, or melatonin in combination with other chemicals or radiation). Based on the trials examined, the patients could be administered melatonin for anywhere between a week to about 6 months, with the average duration yielding positive results being roughly 3 months. It must be noted, however, that this data on dosage and duration is based on clinical trials and preliminary data in various cancer patients. It should only be implemented in diets after consultation with a medical professional.

Summary of Data

Melatonin for Cancer A total of 25 human clinical studies or randomized controlled trials were identified from PubMed that investigated melatonin as a means of preventing or treating cancer. A summary of the results for each cancer type is as follows:

Melatonin for the Side Effects of Cancer Treatment 24 human clinical studies or randomized control trials were identified from PubMed that considered melatonin as a means of ameliorating various side effects of cancer treatments. A summary of the results for each type of side effect is as follows:

📄 Detailed Melatonin human clinical trial study notes analyzed by Anticancer.ca

References

1. Meng, X. et al. Dietary sources and bioactivities of melatonin. Nutrients 9 at https://doi.org/10.3390/nu9040367 (2017).
2. Anisimov, V. N. et al. Melatonin as antioxidant, geroprotector and anticarcinogen. Biochimica et Biophysica Acta - Bioenergetics 1757 573–589 at https://doi.org/10.1016/j.bbabio.2006.03.012 (2006).
3. Mills, E., Wu, P., Seely, D. & Guyatt, G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. Journal of Pineal Research 39, 360–366 (2005).
4. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 896, Melatonin; [cited 2024 July 9]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Melatonin
5. Melatonin: What You Need To Know | NCCIH. https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know.
6. Jet lag disorder - Diagnosis and treatment - Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/jet-lag/diagnosis-treatment/drc-20374031.
7. Melatonin: MedlinePlus Supplements. https://medlineplus.gov/druginfo/natural/940.html.
8. Li, Y. et al. Melatonin for the prevention and treatment of cancer. vol. 8 www.impactjournals.com/oncotarget (2017).
9. Tordjman, S. et al. Melatonin: Pharmacology, Functions and Therapeutic Benefits.
10. Talib, W. H., Alsayed, A. R., Abuawad, A., Daoud, S. & Mahmod, A. I. Melatonin in cancer treatment: Current knowledge and future opportunities. Molecules 26 at https://doi.org/10.3390/molecules26092506 (2021).
11. Claustrat, B. & Leston, J. Melatonin: Physiological effects in humans. Neurochirurgie 61, 77–84 (2015).
12. Cho, S. Y. et al. Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1α inactivation in hypoxic PC-3 prostate cancer cells. Journal of pineal research 51, 87–93 (2011).
13. Lin, P. H. et al. Melatonin activates cell death programs for the suppression of uterine leiomyoma cell proliferation. Journal of pineal research 68, (2020).
14. Liu, H. et al. Role of CD4+ CD25+ regulatory T cells in melatonin-mediated inhibition of murine gastric cancer cell growth in vivo and in vitro. Anatomical record (Hoboken, N.J. : 2007) 294, 781–788 (2011).
15. Sethi G, Tergaonkar V. Potential pharmacological control of the NF-ΚB pathway. Trends in Pharmacological Sciences. 2009;30:313–21
16. Odeh, L. H., Talib, W. H. & Basheti, I. A. Synergistic effect of thymoquinone and melatonin against breast cancer implanted in mice. Journal of cancer research and therapeutics 14, S324–S330 (2018).
17. Su, S. C. et al. Cancer metastasis: Mechanisms of inhibition by melatonin. Journal of pineal research 62, (2017).
18. do Nascimento Gonçalves, N. et al. Effect of melatonin in epithelial mesenchymal transition markers and invasive properties of breast cancer stem cells of canine and human cell lines. PLoS ONE 11, (2016).

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• Melatonin
• What Is It?
• What Are Its Other Names?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• How Does It Work?
• What Are Its Mechanisms of Action?
• What Are Typical Doses and Durations?
• Summary of Data
• References
• About This Article
• Disclaimer