The scientific research lineage of utilizing melatonin supplementation in those with cancer dates back at least three decades. Most notable is early research conducted on patients with solid metastatic tumors, in which it was demonstrated that high doses of melatonin were effective in arresting tumor growth and improving quality of life markers (1). Lissoni’s group, well-recognized pioneers in the field of psycho-immune-neuroendocrinology (2), provided several reports on this dose throughout the 1990s (3) with subsequent studies confirming his findings (4–7). Of particular mention, one of Lissoni’s studies indicated that melatonin supplementation (20 mg daily, starting seven days before chemotherapy) was helpful in chemotherapy response rate in fifty metastatic non-small cell lung cancer patients (8). Interestingly, there was an interaction between melatonin’s efficacy and the spirituality of the patient, with greater effects noted in those with spiritual faith (8). This intriguing finding relates to the dynamic nature of how various therapies like melatonin supplementation can be enhanced through mindset or a belief system, which is a relevant topic for immune system functioning; hence, the field of psycho-immune-neuroendocrinology.
Melatonin may help to re-establish altered circadian rhythm in cancer. Patients with breast and colorectal cancers were observed to have altered circadian rhythms associated with flattened cortisol levels throughout the day (9). Mortality was positively associated with erratic circadian rhythm and poor sleep. Normally, cortisol levels are lowest in the evening hours and start to rise in the morning. Cortisol and melatonin work inversely, so as cortisol rises, melatonin decreases and vice versa (10). These two endocrine messengers provide some clinical information, albeit somewhat indirectly, about the function of both the hypothalamic-pituitary-adrenal axis and the pineal gland, which is pivotal for disease outcomes like cancer where there is neuroimmune involvement (3). Lissoni et al. also suggested that the pineal gland produces other indole hormones that could be therapeutic in cancer (11).
Under states of stress and high cortisol, tryptophan’s conversion to serotonin and melatonin is shunted to kynurenine. Often, patients with cancer experience chronic fatigue, anemia, depression, and overall decreased quality of life. Researchers recognized that individuals with solid tumors have an initial immune response involving pro-inflammatory cytokines as the body recognizes self from non-self (12). During this process, the kynurenic pathway is accelerated, causing inflammation-mediated tryptophan catabolism, fatigue, anemia, and depression (13). In such cases, supplementation with melatonin may be an effective way to augment the standard of care and mitigate the inflammatory cascade that ultimately leads to decreased quality of life.
In night-shift workers, circadian disruption is prevalent due to light exposure at night (14). Upon review of human clinical trials specific to breast cancer risk in night-shift workers, researchers reported melatonin’s ability to suppress the aerobic metabolism of tumors (known as the Warburg effect) while suppressing the tumor cells’ proliferation, tumor cells’ survival, metastasis, and potential drug resistance. In human models, circadian rhythm disruption due to artificial light exposure at night significantly increased breast cancer risk (15,16). A meta-analysis examined the role of melatonin in forty-six different microRNAs found in breast, oral, gastric, colorectal, prostate, and glioblastoma cancers. The microRNAs associated with breast, gastric and oral cancers were most responsive to melatonin treatments. Researchers identified the actions of melatonin to upregulate genes correlated to immune and apoptotic responses, where melatonin downregulated tumor cell survival involved in metastasis and angiogenesis (17).
Authors: Deanna Minich, Ph.D., Melanie Henning, ND, Catherine Darley, ND, Mona Fahoum, ND, Corey B. Schuler, DC, James Frame
Reviewer: Peer-review in Nutrients Journal
Last updated: September 22, 2022
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