MD, PhD, FMedSci, FRSB, FRCP, FRCPEd.

Melatonin is an indolamine hormone which is secreted from the human pineal gland during night-time acting as physiological regulator. In many countries, dietary supplements containing synthetically produced melatonin are available. Melatonin is being promoted as a treatment of a range of conditions, including virtually all types of cancer.

One website, for instance, states that the anti-cancer benefits of melatonin aren’t just indirect; this miracle molecule is also classified as a directly cytotoxic hormone and anti-cancer agent. Studies have referred to melatonin as a “full-service anti-cancer agent” due to its ability to inhibit the initiation of cell mutation and cancer growth, and to halt the progression and metastasis of cancer cell colonies.

Such statements sound far too good to be true. So, let’s have a look and find out what the evidence tells us. Test-tube experiments suggest that melatonin has anti-cancer effects.[1] Its actions include the advancement of apoptosis, the arrest of the cell cycle, inhibition of metastasis, and antioxidant activity.[2]

A review of 21 clinical trials of melatonin for cancer found positive effects for complete response, partial response, and stable disease. In trials combining melatonin with chemotherapy, adjuvant melatonin therapy decreased 1-year mortality and improved outcomes of complete response, partial response, and stable disease. In these studies, melatonin also significantly reduced asthenia, leukopenia, nausea and vomiting, hypotension, and thrombocytopenia. The authors concluded that melatonin may benefit cancer patients who are also receiving chemotherapy, radiotherapy, supportive therapy, or palliative therapy by improving survival and ameliorating the side effects of chemotherapy.[3]

A further systematic review of RCTs of melatonin in solid tumour cancer patients evaluated its effect on one-year survival. Ten trials were included of melatonin as either sole treatment or as adjunct treatment. Melatonin reduced the risk of death at 1 year. Effects were consistent across melatonin dose, and type of cancer. No severe adverse events were reported.[4]

A 2012 systematic review confirmed these findings by concluding that Melatonin as an adjuvant therapy for cancer led to substantial improvements in tumor remission, 1-year survival, and alleviation of radiochemotherapy-related side effects.[5]

Finally, a 2020 review concluded that melatonin in combination with anticancer agents may improve the efficacy of routine medicine and survival rate of patients with cancer. [6] Apart from its direct anticancer potential, melatonin also seems to reduce chemotherapy toxicity, while improving its therapeutic efficacy.[7]

So, is this evidence compelling? While all this does indeed sound encouraging, it is necessary to mention several important caveats:

  • The primary studies of melatonin suffer from several methodological shortcomings.
  • Their vast majority originate from one single research group.
  • In recent years, there have been no further clinical studies trying to replicate the initial findings.

This means that definitive trials are still missing, and it would seem wise to interpret the existing evidence with great caution.

References

[1] Kong X, Gao R, Wang Z, Wang X, Fang Y, Gao J, Reiter RJ, Wang J. Melatonin: A Potential Therapeutic Option for Breast Cancer. Trends Endocrinol Metab. 2020 Sep 3:S1043-2760(20)30155-7. doi: 10.1016/j.tem.2020.08.001. Epub ahead of print. PMID: 32893084.

[2] Samanta S. Melatonin: an endogenous miraculous indolamine, fights against cancer progression. J Cancer Res Clin Oncol. 2020 Aug;146(8):1893-1922. doi: 10.1007/s00432-020-03292-w. Epub 2020 Jun 24. PMID: 32583237.

[3] Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, Mills E. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2012 Dec;11(4):293-303. doi: 10.1177/1534735411425484. Epub 2011 Oct 21. PMID: 22019490.

[4] Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005 Nov;39(4):360-6. doi: 10.1111/j.1600-079X.2005.00258.x. PMID: 16207291.

[5] Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012 May;69(5):1213-20. doi: 10.1007/s00280-012-1828-8. Epub 2012 Jan 24. PMID: 22271210.

[6] Pourhanifeh MH, Mehrzadi S, Kamali M, Hosseinzadeh A. Melatonin and gastrointestinal cancers: Current evidence based on underlying signaling pathways. Eur J Pharmacol. 2020 Nov 5;886:173471. doi: 10.1016/j.ejphar.2020.173471. Epub 2020 Aug 30. PMID: 32877658.

[7] Iravani S, Eslami P, Dooghaie Moghadam A, Moazzami B, Mehrvar A, Hashemi MR, Mansour-Ghanaei F, Mansour-Ghanaei A, Majidzadeh-A K. The Role of Melatonin in Colorectal Cancer. J Gastrointest Cancer. 2020 Sep;51(3):748-753. doi: 10.1007/s12029-019-00336-4. PMID: 31792737.

5 Responses to Melatonin: a “full-service anti-cancer agent”?

  • I am unsure what to make of this. It is only relatively recently that medical researchers have found that the timing of drug administration can have quite a profound effect on both efficacy toxicity due to circadian changes in the levels of many enzymes. To anybody who has experienced jet-lag (not everybody does) this should come as no surprise. Melatonin is certainly involved in the control of circadian rhythms, and I can well believe that concurrent administration might well alter the body’s response to chemotherapy.

    However, I see no reason to expect the effect to be the same with different drugs, nor for it necessarily to be beneficial. I can possibly envisage a role if it turns out that certain cytotoxics are best given in the middle of the night, and melatonin could shift this to more social hours, but a lot of research would be needed before we could draw even tentative conclusions here.

    I have always been surprised at the number of oral preparations of melatonin that seem to be sold (not in the UK, where a single modified-release preparation, Circadin, is available by prescription only, licensed for short-term use as a hypnotic and for jet-lag). It is an oligopeptide, so I would expect it to be digested into its component amino acids rather than absorbed (I don’t know about the modified-release version – if it is released low enough in the digestive tract it might avoid that fate). Nasal sprays and sub-lingual or buccal preparations are available in some countries and I would expect these to get into the system more effectively.

    There is also no information about its safety in kidney disease, nor in pregnancy, though it passes into breast milk so should be avoided by nursing mothers, nor about interactions with other drugs. The British National Formulary lists common side-effects, such as headache and joint pain, and a lot of rare but more serious ones (such as angina and leucopenia), though this probably means that although they have been reported they are not necessarily caused by melatonin.

    • I am also uncertain.
      I was hoping you could shed some light why the series of clinical trials stopped.
      one would have thought that, with a subject looking this promising, oncologists would be keen to determine the truth.
      it almost looks to me as though there was something dodgy with the Italian/Polish trials.

  • It would seem to me that, if one is concerned about melatonin levels, the first step should be to ensure one has proper darkness at night, not go and spend money on an unproven supplement. See, for example:
    https://owncloud.iac.es/index.php/s/WcdR7Z8GeqfRWxG/download?path=%2F&files=Draft%20Report%20Bio-Environment.pdf

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