Melatonin For Cancer Treatment Side Effects: Safe Aid In Cancer

MELATONIN

Trials have been aimed at systemic benefits of this hormone, melatonin can penetrate most of the bodies tissues and is a vital part of natural immune system activity. Meta-analyses across research studies report lowered risks for progression in multiple cancer types mostly for doses in the 20 to 40mg range but can be a lot higher. For instance, recent research in lung cancer has shown meaningful effects in pilot phase. A 2020 study showed significantly lower overall risk levels for advanced prostate cancers, researchers suggesting that benefits are more defined in advanced disease stages.

Some phase II trials report results in the palliative care phase with aggressive, mostly metastatic, cancers including brain, pancreatic and breast cancers. High dose melatonin stabilized disease progress for quite a few months in about half of the patients. And almost a quarter – saw over 10 months of stable disease. Side effects were minimal, some drowsiness. These levels are many times the amount of melatonin recommended as RDA, but had no recorded negative effects. A recent 2023 trial in 45 patients with varied late stage cancers showed an average 28% reduction in tumor sizes, and increased complete response to oncology treatments of 22% vs only 4.5% in the control . Doses varied up to 40 or even 60mg (see References). So far, higher doses have seen nothing significant in the way of negative side effects. some researchers comment pointedly on the lack of investments into broader melatonin testing. The lack of registered clinical trials is repeatedly highlighted in reports as surprising. There are multiple trials reporting reductions in a range of treatment side effects from improved immune sytem and blood markers to sleep and anxiety

In types 2 diabetes clinical trials, there is evidence of metabolic and heart health improvements. And, is also known to enhance circadian rhythm, to modulate the immune system and for neuro-protective actions. Researchers point out very clearly these proven protective effects, for instance in cardiovascular health, clearly encourage more trials. There is a large amount of pre-clinical evidence for anti-metastatic activity, but for now that can only be inferred as part of the benefits seen in slower progression.

Research links declining levels of melatonin with age as one factor in cancer. Pre-clinical analysis has shown cancer cell activity is suppressed by melatonin, often cancer patients have only 20 to 30% of the serum levels found in control groups. For example, Icelandic researchers linked melatonin levels to incidence of prostate cancers (see references), making this an understudied possibility for prevention. Around a third of men over 60 developing prostate cancer rising to nearly half over 70 years of age. Some research has shown very strong associations of low melatonin to cortisol ratios to prostate cancer, with and without raised PSA levels. Ovarian. colorectal and oral cancers have similar data. In breast cancer, evidence is more mixed but research on the whole indicates links to postmenopausal incidence (see Examples) . Cancer patients usually have depressed levels which can worsen during treatment, and increase the risk of multiple side effects.

TYPICAL ABSORPTION LEVELS

High

EXAMPLES OF IMPROVED OUTCOMES

YES

PRE-DIAGNOSIS OR PREVENTION

YES

Highlighted Studies

This meta-analysis shows a significant positive effect for cancer patients with the use of oral MLT, alone and in combination with chemotherapy. Benefits were seen on survival rates, treatment response rates, and disease progression and on the toxicity profile of a number of chemotherapy agents. It is important to note that these benefits were observed despite the fact that the analysis combined a wide variety of biologically and clinically distinct cancer types, across which MLT nonetheless ...

…overall survival [lung cancer] was enhanced only among those patients randomized to receive evening melatonin (HR = 0.39). Survival benefit in the PM [evening dose] melatonin arm was optimized in patients who reported normal sleep quality. After adjusting for significant covariates at baseline, we found an overall survival advantage for PM melatonin when compared against placebo. Moreover, PM melatonin’s therapeutic effect was optimal in patients who self-reported normal sleep qualit...

In the group of patients with poor prognosis [prostate cancer], we see the opposite picture….a clear positive effect of melatonin administration on long-term survival rates. At a 5-year median follow-up, patients who received melatonin had an overall survival rate that, on average, was 13 months longer as compared to the control group. This conclusion was proven by a multi-factor analysis, where treatment with melatonin served as an independent predictive factor and reduced the risk of ...

..a preliminary study with a very high dose of MLT, consisting of 1000 mg/once day in the evening, in untreatable cancer patients, who failed to respond to the conventional anticancer therapies, and for whom the only available treatment was the palliative therapy. The treatment was well tolerated, and a disease control was achieved in 54% patients. These preliminary results would justify further clinical studies to generate ...

TABLE OF REFERENCES

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URL	Rating	Category	Highlight	Highlight 2	Dose mg/kg
https://journals.sagepub.com/doi/10.1177/1534735411425484	5	Meta-analysis	In trials combining MLT with chemotherapy, adjuvant MLT decreased 1-year mortality (RR = 0.60) and improved outcomes of complete response, partial response, and stable disease..., MLT also significantly reduced asthenia, leucopenia, nausea and vomiting, hypotension, and thrombocytopenia. Conclusion. MLT 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.	Regarding results for chemotherapy-associated toxicities, all trials in which chemotherapy was included as treatment were reviewed for the incidence of toxicity-induced comorbidities. Consistent outcomes amenable to meta-analysis included asthenia, leucopenia, nausea and vomiting, hypotension, and thrombocytopenia. The pooled RR for these outcomes that demonstrated benefit are 0.45, 0.65 , 0.84, 0.21 , and 0.17, respectively
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566809/	5	Meta-analysis	n the group of patients with poor prognosis, we see the opposite picture. Multi-sided statistical analysis demonstrated a clear positive effect of melatonin administration on long-term survival rates. At a 5-year median follow-up, patients who received melatonin had an overall survival rate that, on average, was 13 months longer as compared to the control group. This conclusion was proven by a multi-factor analysis, where treatment with melatonin served as an independent predictive factor and reduced the risk of death in patients with PCa by more than 2 times.	The analysis of the overall survival of patients with PCa with both favorable and intermediate prognosis did not reveal any significant differences depending on the long-term use of melatonin drugs. These categories of patients after radical treatment had high rates of cancer effectiveness and were characterized by long-term overall survival (median overall survival was not achieved in any of the groups with an average follow-up period of more than 10 years)
https://www.tandfonline.com/doi/full/10.1080/09291016.2021.1899485	4.5	Human study - adjunct	After adjusting for covariates, the Cox proportional hazards regression analysis found that the overall survival was enhanced only among those patients randomized to receive evening melatonin (p = 0.031 HR = 0.39). Survival benefit in the PM melatonin arm was optimized in patients who reported normal sleep quality. After adjusting for significant covariates at baseline, we found an overall survival advantage for PM melatonin when compared against placebo. Moreover, PM melatonin’s therapeutic effect was optimal in patients who self-reported normal sleep quality	Nonetheless, a daily oral dosage of 20 mg of evening melatonin but not morning melatonin, nor twice daily placebo, correlated with improved survival of advanced NSCLC patients with no perceptible side effects. Evening and morning melatonin produced salutary effects upon nighttime sleep quality and diminished intensity of shortness of breath, which are also important patient benefits. These results suggest that oncologists should investigate the clinical benefits of interventions that restore circadian organization of patients with advanced cancer
https://www.primescholars.com/articles/five-yearsurvival-with-highdose-melatonin-and-other-antitumor-pineal-hormones-in-advanced-cancer-patients-eligible-for-t-108325.html	4.5	Human study	This preliminary study, by showing a possible increase in the survival time in patients with untreatable tumors and life expectancy less than 1 year, then suitable for the only supportive care by the simple administration of the immunostimulating pineal hormones would suggest that the separation between palliative and curative has to be abrogated by the existence in the nature of several non-toxic anticancer agents, namely within the same human body, which could be administered to untreatable cancer patients with respect to the only palliative therapy. Moreover, further studies by evaluating other immune parameters, such as tumor infiltrating lymphocytes, will be required to better define the immunomodulating effects of pineal therapy.	the percentage of 9-month survival achieved in progressed patients, who continued the pineal therapy, was significantly longer than that found in those, who interrupted the endocrine treatment (14/44 (32%) vs. 0/57, P<0.05). Finally, abnormally low LMR values prior to therapy were seen in 70/101 (69%) patients with PD. The 9-month survival percentage observed in patients with PD but normal pretreatment values of LMR was significantly longer than that found in progressed patients with abnormally low values of LMR prior to therapy (9/31 (29%) vs. 5/70 (7%), P<0.05). The treatment was well tolerated, and most patients experienced a clear subjective benefit in mood, anxiety, sleep quality and asthenia.
https://www.oncotarget.com/article/27757/text/	4.5	Human study - adjunct	The overall survival rate of PCa patients with favorable and intermediate prognoses treated or not treated with melatonin was not statistically significantly different. In the poor prognosis group, the median overall survival in patients taking the drug was 153.5 months versus 64.0 months in patients not using it (p < 0.0001). The 5-year overall survival rates in the research and control groups were 66.8 ± 1.9 and 53.7 ± 2.6 (p < 0.0001) respectively. In a multivariate analysis, melatonin administration proved to be an independent prognostic factor and reduced the risk of death of PCa patients by more than twice (	The results of our study are in agreement with the data on favorable antitumor effect melatonin treatment of patients with advanced cancer of various localization, mainly in the breast, uterus, colon, etc., [1, 19–22]. Taking into consideration the optimistic conclusions obtained in our work, based on large clinical material, it is advisable to conduct prospective randomized studies with an assessment of survival rates in patients with PCa of various prognosis groups.	3mg per day
https://ojs.omniscient.sg/index.php/TrendsinOncology/article/view/988	4	Human study - adjunct	a preliminary study with a very high dose of MLT, consisting of 1000 mg/once day in the evening, was carried out in untreatable cancer patients, who failed to respond to the conventional anticancer therapies, and for whom the only available treatment was the palliative therapy. The treatment was well tolerated, and a disease control was achieved in 54% patients. These preliminary results would justify further clinical studies to generate a new interpretation of cancer control, consisting of the pharmacological reproduction of the same mechanisms responsible for the natural resistance against cancer development.	this preliminary study may also suggest that very high-dose MLT has no toxicity also in cancer patients with a poor clinical status, as well as in the healthy subjects [23]. Then, with respect to the previous results reported in the healthy subjects, who received high-dose MLT for no more than 30 days[23], this study shows that MLT at 1000 mg/day may be administered for a longer period of time until more than 11 months without any toxicity, despite the poor clinical status of patients.Therefore, in the successive clinical studies performed in untreatable advanced cancer patients	100 to 1000mg per day
https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=7ec018abac93e145d9c000f20eeef0bf908899bdhttps://pubmed.ncbi.nlm.nih.gov/18505083/	4	Human study - adjunct, Human study	The MLT alone was able to induce a significant increase of disease stabilization and survival time with respect to supportive care alone. The association of lL-2 with MLT provided a further improvement in the percentage of tumor regressions and of 3-year survival with respect to MLT alone	The simple administration of the pineal hormone MLT, in an attempt to correct the main cancer-related endocrine deficiency, appears to be able to prolong the survival time, which may be further improved by the correction of the major cancer-related immune deficiency, namely the progressive decline in the endogenous production of IL-2. It is thus probable that more interesting therapeutic results may be achieved by the correction of other important neuroendocrine alterations, such as diminished activity of the endocannabinoid system
https://jscholaronline.org/articles/JOCR/The-Nighttime-Hormones-Role-in-Cancer-Control-and-Immunity-Enhancement.pdf	4	Human study - adjunct	The study comprised 45 oncological patients with varying types and stages IV of cancer, and grade G3 tumors...After 11 months of treatment with melatonin, the patient group exhibited a statistically significant reduction in tumor size compared to the baseline (mean percentage change ± SD: -28.3%). In contrast, the control group showed no such reduction, as expec	Melatonin's intervention led to a noteworthy decrease in tumor size, particularly in patients with advanced-stage breast and prostate cancers. These outcomes not only suggest the direct antitumor effects of melatonin but also indicate its role in sensitizing cancer cells to conventional treatments. The increasing urinary melatonin sulfate levels observed post-treatment imply improved melatonin uptake and metabolism, which correlates with the therapeutic benefits seen in our patient cohort. While the results are promising, they also underscore the complexity of cancer as a multifaceted disease that requires a concerted approach to therapy. Melatonin's role in cancer biology is intricate and involves a symphony of biochemical and immunological pathways that are yet to be fully deciphered. The study's findings represent a step forward in the quest to enhance cancer therapy but also remind us of the journey still ahead in achieving a comprehensive understanding of cancer treatment.
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(19940201)73:3%3C699::AID-CNCR2820730332%3E3.0.CO;2-L	4	Human study - adjunct	The survival at 1 year, free-from-brain-progression period, and mean survival time were significantly higher in patients treated with melatonin than in those who received the supportive care alone. Conversely, steroid-induced metabolic and infective complications were significantly more frequent in patients treated with supportive care alone than in those concomitantly treated with melatonin.	In our previous studies, we have observed that melatonin may antagonize some macrophage functions related to tumorgrowth." Therefore, we hypothesize that melatonin may counteract brain metastasis growth by regulating glial cell activities. In addition, the documented antitumor cytostatic action of melatonin5 may also explain the potential efficacy of the pineal hormone in patients with brain metastases
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00043-2/fulltext	4		Adjuvant melatonin following resection of NSCLC does not affect DFS for patients with resected early stage NSCLC, yet may increase DFS in patients with late stage disease. Further study is needed to confirm this positive result. No beneficial effects were seen in QOL, symptoms, or immune function.	709 patients across eight centres were randomized to melatonin (n = 356) versus placebo (n = 353). At two years, melatonin showed a relative risk of 1·01 DFS. At five years.... When stratified by cancer stage (I/II and III/IV), a hazard reduction of 25% in five-year DFS [disease free survival] was seen for participants in the treatment arm with advanced cancer (stage III/IV). No meaningful differences were seen in any other outcomes.
https://pmc.ncbi.nlm.nih.gov/articles/PMC5503661/	4	Meta-analysis	According to a clinical trial, treatment of low-dose subcutaneous interleukin-2 (3 million IU/day for 6 days/week for 4 weeks) plus melatonin (40 mg/day orally) significantly increased 1 year survival rate of patients with metastatic colorectal cancer, compared with supportive care alone (9/25 vs. 3/25, p < 0.05) [188]. In a phase-II study including 14 patients with metastatic breast cancer, an oral 20 mg/day of melatonin starting 7 days before tamoxifen therapy achieved a partial response in 4/14 (28.5%) patients, caused a relief of anxiety in most patients, and did not enhance the toxicity of tamoxifen.	The underlying mechanisms include several molecular pathways, which are associated with antioxidant activity, modulation of melatonin receptors MT1 and MT2, regulation of apoptosis, pro-survival signaling and tumor metabolism, inhibition of angiogenesis, invasion and metastasis, and induction of epigenetic alteration. Melatonin also showed the potential to be utilized as adjuvant of cancer therapies, through reinforcing the therapeutic effects and reducing the side effects of chemotherapies or radiation. In clinical trials, melatonin showed the ability to enhance the therapeutic effect of various anticancer drugs, and might help improving the sleep and life quality of cancer patients. Overall, the impressive efficacy and safety of melatonin support it as a promising agent for the prevention and treatment of cancers.
https://www.nature.com/articles/srep29606	4	Human study	We measured their major metabolites in urine collected from 120 newly diagnosed prostate cancer patients and 240 age-matched controls from January 2011 to April 2014. Compared with patients with lower urinary melatonin-sulfate or melatonin-sulfate/cortisol (MT/C) ratio levels, those with above-median levels were significantly less likely to have prostate cancer (adjusted OR (aOR) = 0.59, 95% CI = 0.35–0.99; aOR = 0.46, 95% CI: 0.27–0.77) or advanced stage prostate cancer (aOR = 0.49, 95% CI = 0.26–0.89; aOR = 0.33, 95% CI = 0.17–0.62). The combined effect of both low MT/C ratios and PSA levels exceeding 10 ng/ml was an 8.82-fold greater likelihood of prostate cancer and a 32.06-fold greater likelihood of advanced stage prostate cancer	After adjusting for other covariates, we found that subjects with high urinary melatonin-sulfate or MT/C ratios were significantly less likely to have prostate cancer compared to those with low urinary melatonin-sulfate or MT/C ratios (adjusted OR (aOR) = 0.59, 95% CI = 0.35–0.99 and aOR = 0.46, 95% CI = 0.27–0.77, respectively) (Table 2). In addition, subjects with both high MT/C ratio and a pre-operative PSA level exceeding 10 ng/ml were 3.61 fold more likely (95% CI = 1.62–8.07) to have prostate cancer, when compared to those with both high MT/C ratio and a pre-operative PSA level less than 10 ng/ml. (Table 2). The risk was even higher in the group with low MT/C ratios and pre-operative PSA levels exceeding 10 ng/ml (aOR = 8.82),
https://www.mdpi.com/1422-0067/18/4/843	4	Meta-analysis	Melatonin, in numerous experimental paradigms, has been shown to mitigate acute, normal cell damage, e.g., oral mucositis due to ionizing radiation [379] as well as the cardio-hepatic and renal toxicity of many drugs [105,380]. Relative to chronic consequences, the cardiac damage resulting from chemotherapy administration may lead to compromised long-term heart function. Since melatonin protects the heart from multiple adverse processes [381,382,383,384,385,386], it is highly likely that chronic, life threatening heart failure may be averted. Despite findings such as these, the application of this information to clinical situations has been questionably and possibly unethically slow. Melatonin is essentially a non-toxic endogenously-produced molecule that is available at a pharmaceutical grade purity for use in humans and it should be put to immediate use, or minimally, immediate testing, in situations where collateral normal tissue damage occurs. There are many individuals who could potentially benefit from such co-treatments.	Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4860800/	4	Human study	The serum levels of melatonin were significantly lower in women with ovarian cancer compared with healthy women (p<0.05). However there was no difference in melatonin levels in perimenopausal and postmenopausal patients. In addition, there is no statistically significant difference in seasonal distribution of birth between ovarian cancer patients and the control group. The melatonin levels in ovarian cancer patients and controls were not associated with the season of birth. Our results demonstrate the lower serum levels of melatonin in ovarian cancer patients which may contribute to the pathogenesis of ovarian cancer.	The serum levels of melatonin were significantly reduced in women with ovarian cancer In order to investigate whether melatonin is involved in the development of ovarian cancer, the serum levels of melatonin in women with ovarian cancer (n=96) were measured. The circulating levels of melatonin were significantly lower in women with ovarian cancer (41.8pg/ml ranging from 1.52 to 223.2pg/ml) compared with healthy women (82.4 pg/ml ranging from 9.7-241.5pg/ml)
https://journals.lww.com/ctg/fulltext/2021/08000/use_of_melatonin_is_associated_with_lower_risk_of.6.aspx	4	Human study	The incidence rate of CRC was 10.40 per 10,000 person-years for melatonin users, whereas the rate was 12.82 per 10,000 person-years in the nonusers. We found a significant negative association between melatonin use and risk of CRC (adjusted hazard ratio, 0.82; 95% confidence interval, 0.72–0.92). A test for trend showed a significant dose-response correlation (P < 0.001). The decrease of CRC risk was independent of tumor location and stage at diagnosis. When stratified by age groups, the inverse association was significant only among individuals aged 60 years and older.	Melatonin use was inversely associated with CRC risk among older adults, with an adjusted HR of 0.82. We found the inverse association was slightly stronger for rectal cancer (adjusted HR, 0.73) compared with distal colon cancer and proximal colon cancer and for earlier stages (adjusted HR, 0.78) compared with advanced stages (adjusted HR, 0.82)
https://pubmed.ncbi.nlm.nih.gov/18544743/	4	Meta-analysis	Increased melatonin levels were associated with a statistically significantly lower risk of invasive breast cancer in postmenopausal women (for women in the highest quartile of total overnight 6-sulfatoxymelatonin output vs the lowest quartile, multivariable OR also adjusted for testosterone = 0.56, 95% confidence interval [CI] = 0.33 to 0.97; Ptrend = .02). This association was strongest among never and past smokers (OR = 0.38, 95% CI = 0.20 to 0.74; Ptrend = .001) and after excluding women who were diagnosed with invasive breast cancer within 4 years after urine collection (OR = 0.34, 95% CI = 0.15 to 0.75; Ptrend = .002). We did not observe substantial variation in relative risks by hormone receptor status of breast tumors.	The inverse association between 6-sulfatoxymelatonin and breast cancer risk remained by and large unchanged when we restricted the analysis to women with estrogen receptor–positive breast tumors (for highest vs lowest quartile of urinary 6-sulfatoxymelatonin, multivariable OR = 0.59, 95% CI = 0.30 to 1.13) and was virtually the same when we restricted the analysis to women with HER2-negative tumors (for highest vs lowest quartile of urinary 6-sulfatoxymelatonin, multivariable OR = 0.60, 95% CI = 0.32 to 1.13). Although there were only six case subjects in the highest quartile of 6-sulfatoxymelatonin, the risk of estrogen receptor–negative breast cancer appeared lowest among women in the highest quartile of 6-sulfatoxymelatonin concentration
https://www.spandidos-publications.com/10.3892/ol.2019.11215?text=fulltext	4	Human study	In addition, the serum melatonin levels had a high predictive accuracy for discriminating patients with OSCC with T-depth of invasion (DOI) II from the healthy controls (89.1%), as well as in discriminating patients with OSCC with nodal metastasis from those without nodal metastasis (83.8%). On the whole, the findings of this study suggest that the serum melatonin concentrations are closely related to the severity of OSCC and may thus be used to assess the different stages of oral cancer objectively and accurately. The present study also supports the conclusion that melatonin may be a potential therapeutic agent for use in the treatment of patients with OSCC.	The circulating levels of melatonin were significantly lower in the patients with OSCC than in the healthy controls (18.2 vs. 47.6 pg/ml, P<0.001). Furthermore, within the OSCC group (Table II), the melatonin concentrations were significantly lower in the T-DOI II subgroup than in the T-DOI I group (P=0.012) and were also lower in the positive lymph nodes subgroup than in the negative lymph node one (P<0.001). No statistically significant differences were observed in the serum levels of melatonin between the G1, G2 or G3 subgroups of patients.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3036562/	4	Meta-analysis	An increased concentration of urinary aMT6s was statistically significantly associated with a lower risk of breast cancer (odds ratio [OR] for the highest versus lowest quartile of morning urinary 6-sulfatoxymelatonin = 0.62, 95% confidence interval [CI] = 0.41 to 0.95; P[trend] = .004). There was no apparent modification of risk by hormone receptor status of breast tumors, age, body-mass index, or smoking status.	Although there were only ten case patients in the upper quartile, the risk of estrogen receptor-negative breast cancer appeared lowest among women in the highest quartile of 6-sulfatoxymelatonin concentration (for highest versus lowest quartile of urinary 6-sulfatoxymelatonin, multivariable OR = 0.64, 95% CI = 0.31 to 1.32). For a subgroup of women (71%), information on HER2 receptor status was also available. Of these, only 39 women had HER2 positive breast tumors. Although with limited power, in stratified analyses, results appeared similar regardless of HER2 receptor status
https://cancerci.biomedcentral.com/articles/10.1186/s12935-019-0853-7	3.5	Meta-analysis	Based on the published reports, melatonin is an appropriate complementary treatment that should be considered to enhance the clinical benefits in NSCLC therapy and to improve poor outcomes. Melatonin acts by affecting the related gene expression, apoptotic pathways and the proliferation of tumor cells (Fig. 3). In summary, several clinical trials have been designed to assess the potential beneficial effects of melatonin supplementation in the treatment of lung cancer and NSCLC, in particular. Additional RCTs should be carried out to determine the effectiveness of melatonin as a co-treatment for NSCLC.	The role of melatonin, produced in and released from the pineal gland, has been documented as a potential therapy for NSCLC. Melatonin prevents tumor metastasis via inducing apoptosis processes and restraining the autonomous cell proliferation. Moreover, melatonin inhibits the progression of tumors due to its oncostatic, pro-oxidant and anti-inflammatory effects. As a result, the combined treatment with melatonin and chemotherapy may have a synergistic effect, as with some other tumors, leading to a prolonged survival and improved quality of life in patients with NSCLC
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318783/	3.5	Human study	A total of 111 men were diagnosed with incident PCa, including 24 with advanced disease. Men who reported sleep problems at baseline had lower morning 6-STM levels compared with those who reported no sleep problems. Men with morning 6-STM levels below the median had a fourfold statistically significant increased risk for advanced disease compared with men with levels above the median (hazard ratio: 4.04)	In summary, men with lower morning 6-STM levels were at increased risk for advanced or lethal PCa. These results require replication in larger prospective cohort studies with longer follow-up and more detailed clinical information. Given that disruption of melatonin levels is potentially avoidable, further studies of melatonin and PCa risk should be a priority.
https://onlinelibrary.wiley.com/doi/10.1111/cas.16103	3.5	Meta-analysis	Compared with subjects in the lowest tertile of melatonin intake, those in the middle and highest tertiles had decreased risks of liver cancer, with a significant linear trend after multivariate adjustments (hazard ratios: 0.64 and 0.65, respectively, trend p = 0.023). There was no significant interaction by sex (interaction p = 0.54). This initial finding, which needs to be confirmed by further studies, suggests that consuming melatonin-containing foods might play a role in the prevention of liver cancer	In this prospective study in Japan, we observed a significant association between increased melatonin intake and a decreased risk of liver cancer, with no significant difference between men and women. This is the first report to suggest that melatonin intake might have a beneficial impact on the risk of developing liver cancer.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460067/	3.5	Meta-analysis	Different studies have showed that melatonin administered with radiotherapy is able to enhance its therapeutic effects and can protect normal cells against side effects of this treatment. Several mechanisms are involved in the radiosensitization induced by melatonin: increase of reactive oxygen species production, modulation of proteins involved in estrogen biosynthesis, impairment of tumor cells to DNA repair, modulation of angiogenesis, abolition of inflammation, induction of apoptosis ...All findings point to melatonin as an effective adjuvant molecule to radiotherapy in cancer treatment.	The sensitization of cancer cells by melatonin is also exerted by an increase of apoptosis induced by ionizing radiation. In tumor microenvironment, melatonin also may modulate the response of pre-adipocytes (differentiation, aromatase activity and expression) to ionizing radiation. The inhibition of glycolysis by melatonin in cancer cells also increases the sensitivity of cancer cells to the cytotoxicity of radiation. All these actions of melatonin make it a promising agent used as adjuvant to radiotherapy.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2074765/	3.5	Human study - adjunct	Even though the low number of patients and the different tumour histotypes do not allow us to draw definite conclusions, this phase II study suggests that the neuroendocrine combination with TMX and MLT is a well-tolerated treatment, even in patients of poor clinical status, and a potentially active therapy to induce stabilisation of disease and objective tumour regressions in at least a few cases in patients unable to receive more aggressive therapies	Both drugs were given orally every day until disease progression (TMX Tamoxifem, 20 mg day-1 at noon; Melatonin, 20 mg day-1 in the evening). Three patients had a partial response (PR) (12%; 95% confidence limits 2-24%) (one cervix carcinoma; one melanoma; one unknown primary tumour). A stable disease (SD) was achieved in 13 other patients, whereas the remaining nine patients progressed. Performance status (PS) improved in 9/25 patients, whose median score increased from 50% to 70%. Finally, a survival longer than 1 year was observed in 7/25 (28%) patients. This phase II study would suggest that the neuroendocrine combination with TMX plus MLT may have some benefit in untreatable metastatic solid tumour patients, either in controlling cancer cell proliferation or improving the PS.
https://ar.iiarjournals.org/content/anticanres/34/12/7327.full.pdf	3.5	Human study - adjunct	Melatonin in combination with chemotherapy did not affect survival and adverse events of advanced patients with NSCLC, but there was a trend for better HRQoL.	ECOG score and fatigue at baseline, patients in the melatonintreated group had better HRQoL, i.e. higher estimated mean HRQoL scores, in all domains . The total FACT-L score was 65.35 in melatonin-treated groups and 55.85 in the placebo-treated group, with the average score being 9.5 points higher in the melatonin-treated groups
https://www.sciencedirect.com/science/article/pii/S2095177924000303	3.5		In conclusion, the present findings establish a clear role for melatonin in improving the hypoxic immunosuppressive microenvironment of tumors, reducing tumor progression, and enhancing the efficacy of anti-PD-L1 antibodies in treating residual tumors. Elucidating this potential mechanism further will provide a solid scientific basis for targeting the hypoxic microenvironment to prevent HCC recurrence and metastasis in clinical RFA practice.	The current study demonstrated that melatonin improved the hypoxic immunosuppressive microenvironment, promoted intratumoral CD8+ T lymphocyte infiltration, and reduced MDSCs, which are key mediators in improving the treatment of residual tumors with anti-PD-L1 antibodies. Furthermore, we established liver and lung metastasis models and evaluated the inhibitory effects of melatonin in combination with an anti-PD-L1 antibody on tumor metastasis. Our study strongly supports the possibility that melatonin enhances the efficacy of anti-PD-L1 antibodies in treating residual tumors after iRFA and effectively inhibits liver and lung metastasis.
https://www.researchgate.net/publication/378231388_Dietary_melatonin_and_liver_cancer_incidence_in_Japan_From_the_Takayama_study	3.5	Human study	During the mean follow‐up period of 13.6 years, 189 individuals developed liver cancer. Compared with subjects in the lowest tertile of melatonin intake, those in the middle and highest tertiles had decreased risks of liver cancer, with a significant linear trend after multivariate adjustments (hazard ratios: 0.64 and 0.65, respectively, trend p = 0.023). There was no significant interaction by sex (interaction p = 0.54). This initial finding, which needs to be confirmed by further studies, suggests that consuming melatonin‐containing foods might play a role in the prevention of liver cancer.	The observed association between dietary melatonin and liver cancer might have been underestimated because measure-ment errors due to such misclassifications are likely to have oc-curred independent of cancer incidence. It is possible that other components in melatonin- containing foods or synergic effects with them are responsible for the positive association between melatonin intake and liver cancer
https://journals.sagepub.com/doi/10.1177/1758835920931714	3		Clinical trials focus mainly on advanced cancer patients, but the best MLT administration regimen for CRC treatment is still unknown and needs further research. To deepen the knowledge about the effects of MLT in CRC treatment, animal experiments to evaluate clinically important application regimen of MLT for treatment of complex CRC and CRLM are mandatory. This will pave the way for further clinical studies probably answering the question about the optimal application regimen for MLT. In summary, there is sufficient evidence that MLT is involved in carcinogenesis, development, and progression of CRC cells by different mechanisms. Thus, further clinical trials are warranted to include MLT as a new promising therapeutic agent for CRC treatment.	Melatonin (MLT), a natural body hormone, previously demonstrated impressive protective properties against toxic effects of CTx and radiotherapy, in both experimental and clinical studies.13–15 This could pave the way for application of higher doses of CTx, resulting in improved efficacy.16 Moreover, MLT itself exerts antiproliferative, antimetastatic, and cytotoxic effects on different types of human malignancies, including CRC.17–19 Taking into consideration that this endogenously generated molecule lacks any moderate–severe side effects at even relatively high dose
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10848819/	2	Human study	While some evidence suggests a favorable impact, more extensive and rigorous studies are needed to establish its effectiveness and safety as an antihypertensive agent. As our understanding of melatonin’s mechanisms and its relationship with blood pressure continues to evolve, it holds promise as a complementary approach to managing hypertension, but cautious optimism should guide both research and clinical practice	Regarding safety and contraindications, melatonin is generally considered safe when used for short-term purposes, such as adjusting sleep patterns. However, the long-term safety of melatonin supplements, especially in high doses, is still a subject of ongoing research.15 Individuals with specific medical conditions or those taking medication should consult with healthcare professionals before starting melatonin supplementation due to potential interactions and side effects.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995760/	1.5	Human study	Melatonin supplementation for 8 weeks significantly decreased the mean levels of SBP, MAP, PP, weight, BMI, WC, HC, BAI, AVI, conicity index, and WHtR post-intervention (p < 0.05). Also, the median changes of SBP, MAP, PP, weight, BMI, WC, HC BAI, AVI, and conicity index were significantly lower in the intervention group compared with the control group (p < 0.05). A significant increase (p < 0.001) was observed in the mean levels of ABSI in the intervention group. The median changes of ABSI were significantly greater in the intervention group compared with the control group	In this study, melatonin consumption for 8 weeks significantly decreased weight, WC, HC, BMI, WHR, AVI, BAI. AVI is considered as an important indicator to evaluate fat accumulation in the abdominal region....melatonin supplementation significantly increased ABSI..while it shows a strong correlation with mortality rates
https://www.nature.com/articles/s41419-021-04006-x	1	Lab study	We found that after melatonin treatment, FUNDC1 and lnc049808 downregulated in TNBC cell lines. Knockdown of FUNDC1 and lnc049808 inhibited TNBC cell proliferation, invasion, and metastasis.... These findings indicated that melatonin inhibited TNBC progression through the lnc049808-FUNDC1 pathway and melatonin could be used as a potential therapeutic agent for TNBC.	FUNDC1 knockdown suppressed cell invasion. To further confirm the function of FUNDC1 in vivo, we established mouse xenograft models and found that FUNDC1 knockdown significantly suppressed tumor growth and lung metastasis. Our findings demonstrated that FUNDC1 knockdown inhibited TNBC progression
https://www.nature.com/articles/s41598-025-93486-4	1		Although some research indicates its anticancer activity15,16,17, its specific anticancer mechanism remains unclear. This study found that melatonin reduces PD-L1 expression, inhibits immune escape in HCC, and suppresses cancer cell proliferation, metastasis and invasion, while promoting apoptosis. Furthermore, we verified these results via in vivo experiments. We established HCC models in both nude and wild-type mice to provide a comprehensive evaluation of the effects of melatonin and to validate the consistency and reliability of the results across different models. Melatonin showed significant anticancer activity in both models, confirmed its antitumoral effects in vivo	In conclusion, our study demonstrated that melatonin reduces PD-L1 expression in HCC, exerting dual anti-cancer effects by directly inhibiting cancer cell proliferation, migration and invasion, while also suppressing immune escape to enhance anti-tumor immunity. The reduction in PD-L1 expression may occur through the inhibition of HIF-1α expression or the activation of the MAPK-JNK or MAPK-P38 pathways. This research offers new insights and approaches for HCC treatment, potentially applicable to other cancers