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REVIEW ARTICLE

Utility of exogenous melatonin in patients with breast cancer: A systematic review

Ji Yu1† ,  Junfei Xu1†*
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1 Department of Thyroid and Breast Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu , China
†These authors contributed equally to this work.
Received: 9 June 2026 | Revised: 5 August 2026 | Accepted: 1 September 2026 | Published online: 16 September 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Fatigue, sleep disturbance, menopausal symptoms and impaired quality of life remain common and poorly controlled in breast cancer. Exogenous melatonin is an inexpensive, plausible supportive-care option that has not yet been systematically appraised. PubMed, Web of Science and the Cochrane Library were searched to May 15, 2026 for controlled studies of oral melatonin in patients with breast cancer or survivors (full-text English only). Screening, extraction, and Cochrane Risk of Bias 2 assessment were performed in duplicate; results were synthesized narratively (Synthesis Without Meta-analysis), stratified by daily dose, with post hoc sensitivity analyses. Eleven trials (849 participants) were included, spanning chemotherapy, radiotherapy, endocrine therapy, adjuvant follow-up and survivorship rehabilitation, at 1–20 mg/day for 10 days to three years. Sleep quality was the most reproducible benefit: both trials assessing it reported improvement at low risk of bias. Benefit was also reported for endocrine therapy-related symptoms, sexual function, quality of life and fatigue (3 of 5 trials), although a phase III radiotherapy trial was negative. No effect was seen on estradiol or insulin-like growth factor-axis biomarkers, body composition, or fitness. Six Iranian trials formed two clusters with overlapping authors; their removal left the fatigue and quality-of-life signals unsupported, but the sleep signal persisted. Oral melatonin is well tolerated (no grade 3/4 toxicity) and reproducibly improves sleep quality (moderate certainty), with less certain signals for endocrine therapy-related symptoms, quality of life, and fatigue (low certainty), justifying adequately powered, symptom-stratified trials. It is not supported as an antitumor therapy or a routine adjunct to exercise-based rehabilitation.

Keywords
Breast cancer
Melatonin
Cancer-related fatigue
Sleep disturbance
Quality of life
Endocrine therapy
Supportive care
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Huang YR, Xing HQ, Yan YR, et al. Quality of life in breast cancer survivors: a meta-analysis of case-control studies. Psychooncology. 2026;35(2):e70398. doi: 10.1002/pon.70398
  2. Muthanna FMS, Hassan BAR, Karuppannan M, Ibrahim HK, Mohammed AH, Abdulrahman E. Prevalence and impact of fatigue on quality of life (QOL) of cancer patients undergoing chemotherapy: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2023;24(3):769-781. doi: 10.31557/APJCP.2023.24.3.769
  3. Gray L, Sindall P, Pearson SJ. Does resistance training ameliorate cancer-related fatigue in cancer survivors? A systematic review with meta-analysis. Disabil Rehabil. 2024;46(11):2213-2222. doi: 10.1080/09638288.2023.2226408
  4. Anandavadivelan P, Mijwel S, Wiklander M, et al. Five-year follow-up of the OptiTrain trial on concurrent resistance and high-intensity interval training during chemotherapy for patients with breast cancer. Sci Rep. 2024;14(1):15333. doi: 10.1038/s41598-024-65436-z
  5. Cooper JT, Svoboda E, Prochazka AV, Ha DM. Effects of cognitive-behavioral therapy for insomnia compared with controls among cancer survivors: a systematic review and meta-analysis of randomized trials. BMC Cancer. 2025;25(1):871. doi: 10.1186/s12885-025-14192-y
  6. Li M, Wang T, Liu XL, et al. Somatic acupressure for the management of the fatigue-sleep disturbance-depression symptom cluster in breast cancer survivors: a study protocol for a phase III randomized controlled trial. BMJ Open. 2025;15(3):e089515. doi: 10.1136/bmjopen-2024-089515
  7. Greeley KM, Rash J, Tulk J, et al. Impact and mechanisms of cognitive behavioral therapy for insomnia on fatigue among cancer survivors: a secondary analysis of a randomized controlled trial. Sleep. 2025;48(6):zsaf014. doi: 10.1093/sleep/zsaf014
  8. Merceur M, Reilly KT, Bonan I, et al. A systematic review of rehabilitation programs for cognitive impairment related to breast cancer: different programs at different times? Ann Phys Rehabil Med. 2024;67(5):101832. doi: 10.1016/j.rehab.2024.101832
  9. Wang R, Wang Y, Fang L, et al. Efficacy and safety of traditional Chinese medicine in the treatment of menopause-like syndrome for breast cancer survivors: a systematic review and meta-analysis. BMC Cancer. 2024;24(1):42. doi: 10.1186/s12885-023-11789-z
  10. Mayer EL, Dueck AC, Martin M, et al. Quality-of-life and symptom severity in the PALLAS randomized trial of palbociclib with adjuvant endocrine therapy in early breast cancer (AFT-05, ABCSG-42, BIG-14-03, PrE0109). ESMO Open. 2025;10(6):105120. doi: 10.1016/j.esmoop.2025.105120
  11. Shainhouse J, Hwang PSY, Fontes M, Bao T. Integrative medicine in breast cancer survivorship care. Ann Palliat Med. 2025;14(3):283-294. doi: 10.21037/apm-24-176
  12. Cardinali DP, Pandi-Perumal SR, Brown GM. Melatonin as a chronobiotic and cytoprotector in non-communicable diseases: more than an antioxidant. Subcell Biochem. 2024;107:217-244. doi: 10.1007/978-3-031-66768-8_11
  13. Azzeh FS, Kamfar WW, Ghaith MM, et al. Unlocking the health benefits of melatonin supplementation: a promising preventative and therapeutic strategy. Medicine. 2024;103(38):e39657. doi: 10.1097/MD.0000000000039657
  14. Barbarossa A, Carrieri A, Carocci A. Melatonin and related compounds as antioxidants. Mini Rev Med Chem. 2024;24(5):546-565. doi: 10.2174/1389557523666230627140816
  15. Álvarez-López AI, Cruz-Chamorro I, Lardone PJ, et al. Melatonin, an antitumor necrosis factor therapy. J Pineal Res. 2025;77(1):e70025. doi: 10.1111/jpi.70025
  16. Li DD, Zhou T, Gao J, Wu GL, Yang GR. Circadian rhythms and breast cancer: from molecular level to therapeutic advancements. J Cancer Res Clin Oncol. 2024;150(9):419. doi: 10.1007/s00432-024-05917-w
  17. Hosseinzadeh A, Alinaghian N, Sheibani M, Seirafianpour F, Naeini AJ, Mehrzadi S. Melatonin: current evidence on protective and therapeutic roles in gynecological diseases. Life Sci. 2024;344:122557. doi: 10.1016/j.lfs.2024.122557
  18. Mukhopadhyay ND, Khorasanchi A, Pandey S, et al. Melatonin supplementation for cancer-related fatigue in patients with early stage breast cancer receiving radiotherapy: a double-blind placebo-controlled trial. Oncologist. 2024;29(2):e206-e212. doi: 10.1093/oncolo/oyad250
  19. Sadeghi Yazdankhah S, Javadinia SA, Welsh JS, Mosalaei A. Efficacy of melatonin in alleviating radiotherapy-induced fatigue, anxiety, and depression in breast cancer patients: a randomized, triple-blind, placebo-controlled trial. Integr Cancer Ther. 2025;24. doi: 10.1177/15347354251371705
  20. Sedighi Pashaki A, Sheida F, Moaddab Shoar L, et al. A randomized, controlled, parallel-group trial on the long-term effects of melatonin on fatigue associated with breast cancer and its adjuvant treatments. Integr Cancer Ther. 2023;22. doi: 10.1177/15347354231168624
  21. Zetner D, Kamby C, Gülen S, et al. Quality-of-life outcomes following topical melatonin application against acute radiation dermatitis in patients with early breast cancer: a double-blind, randomized, placebo-controlled trial. J Pineal Res. 2023;74(1):e12840. doi: 10.1111/jpi.12840
  22. Scafuri L, Buonerba C, Strianese O, et al. Impact of dietary supplements on clinical outcomes and quality of life in patients with breast cancer: a systematic review. Nutrients. 2025;17(6):981. doi: 10.3390/nu17060981
  23. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71
  24. Campbell M, McKenzie JE, Sowden A, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ. 2020;368:l6890. doi: 10.1136/bmj.l6890
  25. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomized trials. BMJ. 2019;366:l4898. doi: 10.1136/bmj.l4898
  26. McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021;12(1):55-61. doi: 10.1002/jrsm.1411
  27. Guyatt GH, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383-394. doi: 10.1016/j.jclinepi.2010.04.026
  28. Schernhammer ES, Giobbie-Hurder A, Gantman K, et al. A randomized controlled trial of oral melatonin supplementation and breast cancer biomarkers. Cancer Causes Control. 2012;23(4):609-616. doi: 10.1007/s10552-012-9927-8
  29. Palmer ACS, Zortea M, Souza A, et al. Clinical impact of melatonin on breast cancer patients undergoing chemotherapy; effects on cognition, sleep and depressive symptoms: a randomized, double-blind, placebo-controlled trial. PLoS ONE. 2020;15(4):e0231379. doi: 10.1371/journal.pone.0231379
  30. Sedighi Pashaki A, Mohammadian K, Afshar S, et al. A randomized, controlled, parallel-group trial on the effects of melatonin on fatigue associated with breast cancer and its adjuvant treatments. Integr Cancer Ther. 2021;20. doi: 10.1177/1534735420988343
  31. Keshtpour Amlashi Z, Sheida F, Anbiaee R, et al. The effect of melatonin on increasing the health related quality of life in non-metastatic breast cancer patients: three-year follow up a clinical trial. Integr Cancer Ther. 2024;23. doi: 10.1177/15347354241237520
  32. Nimee F, Gioxari A, Papandreou P, et al. The effect of melatonin supplementation on cancer-related fatigue during chemotherapy treatment of breast cancer patients: a double-blind, randomized controlled study. Cancers. 2024;16(4):802. doi: 10.3390/cancers16040802
  33. Vaziri N, Shakourifar M, Sattari P, et al. Melatonin aids in treating mood and sleep problems resulting from hormonal therapy in breast cancer patients: a randomized, double-blinded, placebo-controlled trial. Iran J Pharm Res. 2025;23(1):e156581. doi: 10.5812/ijpr-156581
  34. Sattari P, Shakourifar M, Jafarian K, et al. Exploring the efficacy of melatonin in alleviating menopausal symptoms in breast cancer survivors: a randomized, double-blind, placebo-controlled study. Adv Biomed Res. 2025;14(1):114. doi: 10.4103/abr.abr_352_22
  35. Celorrio San Miguel AM, Cacharro LM, Santamaría G, et al. Adjuvant melatonin therapy during exercise prescription in breast cancer survivors on physical and anthropometric parameters, quality of life, and hormonal response: a randomized controlled trial. Front Sports Act Living. 2025;7:1594733. doi: 10.3389/fspor.2025.1594733
  36. Ramos E, Egea J, López-Muñoz F, Gil-Martín E, Romero A. Therapeutic potential of melatonin counteracting chemotherapy-induced toxicity in breast cancer patients: a systematic review. Pharmaceutics. 2023;15(6):1616. doi: 10.3390/pharmaceutics15061616
  37. Yu ZY, Peng RY, Cheng N, et al. Melatonin in cancer treatment. Cochrane Database Syst Rev. 2025;2025(4):CD010145. doi: 10.1002/14651858.CD010145.pub2
  38. Fan R, Bu X, Yang S, et al. Effect of melatonin on quality of life and symptoms in patients with cancer: a systematic review and meta-analysis of randomized controlled trials. BMJ Open. 2022;12(9):e060912. doi: 10.1136/bmjopen-2022-060912
  39. Seo K, Kim JH, Han D. Effects of melatonin supplementation on sleep quality in breast cancer patients: a systematic review and meta-analysis. Healthcare. 2023;11(5):675. doi: 10.3390/healthcare11050675
  40. Pontinen J, Lemke E. Melatonin for the management of cancer-related fatigue in breast cancer: an integrative review. J Adv Pract Oncol. 2026;17(1):25-32. doi: 10.6004/jadpro.2026.17.1.3
  41. Martella S, Proserpio P, Guerrieri ME, et al. Insomnia in women surviving breast and gynecological cancers: a narrative review to address the hormonal factor. Cancers. 2025;17(24):4022. doi: 10.3390/cancers17244022
  42. Hauer M, Rossi AM, Wertheim BC, Kleppel HB, Bea JW, Funk JL. Dietary supplement use in women diagnosed with breast cancer. J Nutr. 2023;153(1):301-311. doi: 10.1016/j.tjnut.2022.12.007
  43. Ahmad SB, Ali A, Bilal M, et al. Melatonin and health: insights of melatonin action, biological functions, and associated disorders. Cell Mol Neurobiol. 2023;43(6):2437-2458. doi: 10.1007/s10571-023-01324-w
  44. Pardi PC, Turri JAO, Bayer LHCM, et al. Biological action of melatonin on target receptors in breast cancer. Rev Assoc Med Bras. 2024;70(3):e20231260. doi: 10.1590/1806-9282.20231260
  45. Das N, Mukherjee S, Das A, Gupta P, Bandyopadhyay A, Chattopadhyay S. Intra-tumor ROS amplification by melatonin interferes in the apoptosis-autophagy-inflammation-EMT collusion in the breast tumor microenvironment. Heliyon. 2024;10(1):e23870. doi: 10.1016/j.heliyon.2023.e23870
  46. Barboza G, Oliveira J, Ferreira A, Lopes R, Cupertino M. Prolonged exposure to artificial light and carcinogenesis: a systematic review of oncostatic mechanisms associated with melatonin pathways. Photochem Photobiol. 2026;102(4):780-796.doi: 10.1111/php.70040
  47. Luo Z, Liu Z, Chen H, Liu Y, Tang N, Li H. Light at night exposure and risk of breast cancer: a meta-analysis of observational studies. Front Public Health. 2023;11:1276290. doi: 10.3389/fpubh.2023.1276290
  48. Prajapati N, Praud D, Perrin C, et al. Outdoor exposure to artificial light at night and breast cancer risk: a case-control study nested in the E3N-Generations cohort. Environ Health Perspect. 2025;133(5):057015. doi: 10.1289/EHP15105
  49. Vivarelli S, Formica T, Puliatti Y, Spatari G, Fenga C. Night shift work and breast cancer: from etiopathology to precision risk analysis. npj Breast Cancer. 2026;12(1):7.doi: 10.1038/s41523-025-00863-3
  50. Li X, Hu Y, Aslanbeigi F. Genetic and epigenetic alterations in night shift nurses with breast cancer: a narrative review. Cancer Cell Int. 2025;25(1):20. doi: 10.1186/s12935-025-03649-6
  51. Zhang B, Tang M, Li X. A narrative review of sleep and breast cancer: from epidemiology to mechanisms. Cancer Causes Control. 2025;36(5):457-472. doi: 10.1007/s10552-024-01951-8
  52. Franco PIR, do Carmo Neto JR, Milhomem AC, Machado JR, Miguel MP. Antitumor effect of melatonin on breast cancer in experimental models: a systematic review. Biochim Biophys Acta Rev Cancer. 2023;1878(1):188838. doi: 10.1016/j.bbcan.2022.188838
  53. Alves MS, Damous LL, Ferreira IDS, et al. Melatonin’s oncostatic effects in experimental breast cancer: a systematic review of dose-response and apoptotic mechanisms in animal models. Clinics. 2026;81:100888. doi: 10.1016/j.clinsp.2026.100888
  54. He Y, Hu C, Hu F, et al. Natural compound melatonin suppresses breast cancer development by regulating circadian rhythm. Nutrients. 2025;17(21):3386. doi: 10.3390/nu17213386
  55. Pourbarkhordar V, Rahmani S, Roohbakhsh A, Hayes AW, Karimi G. Melatonin effect on breast and ovarian cancers by targeting the PI3K/Akt/mTOR pathway. IUBMB Life. 2024;76(12):1035-1049. doi: 10.1002/iub.2900
  56. Demirkesen S, Iriagac Y, Seber ES, Aral C. Melatonin enhances everolimus efficacy in breast cancer by suppressing mTOR pathway activation and promoting apoptosis and mitochondrial function. BMC Pharmacol Toxicol. 2025;26(1):100. doi: 10.1186/s40360-025-00907-1
  57. Lai YW, Liu ZW, Lin MH, et al. Melatonin increases olaparib sensitivity and suppresses cancer-associated fibroblast infiltration via suppressing the LAMB3-CXCL2 axis in TNBC. Pharmacol Res. 2024;209:107429. doi: 10.1016/j.phrs.2024.107429
  58. Dincer B, Yildiztekin G, Cinar I. Unlocking synergistic potential: agomelatine enhances the chemotherapeutic effect of paclitaxel in breast cancer cells through MT1 melatonin receptors and ER-alpha axis. Chem Biodivers. 2023;20(10):e202301093. doi: 10.1002/cbdv.202301093
  59. Wu CC, Yang PF, Chang SJ, et al. Melatonin inhibits FAK signaling to suppress PD-L1 expression and enhance chemosensitivity in triple-negative breast cancer. Int J Med Sci. 2026;23(3):876-888. doi: 10.7150/ijms.127669
  60. Thanawala S, Abiraamasundari R, Shah R. Comparative pharmacokinetics of sustained-release versus immediate-release melatonin capsules in fasting healthy adults: a randomized, open-label, cross-over study. Pharmaceutics. 2024;16(10):1248. doi: 10.3390/pharmaceutics16101248
  61. Iyer S, Monk V, Slater R, Baxter L. Exogenous melatonin and sleep quality: a scoping review of systematic reviews. J Clin Pharmacol. 2026;66(2):e70115. doi: 10.1002/jcph.70115
  62. Markowska A, Antoszczak M, Markowska J, Huczynski A. Gynotoxic effects of chemotherapy and potential protective mechanisms. Cancers. 2024;16(12):2288. doi: 10.3390/cancers16122288
  63. Marzouk MA, Greco S, Gbahou F, et al. Cancer cells show higher sensitivity to melatonin-tamoxifen drug conjugates than to combination of melatonin and tamoxifen. ACS Omega. 2024;9(48):47857-47871. doi: 10.1021/acsomega.4c08881
  64. Soares Junior JM, Mota BS, Nobrega GB, Filassi JR, Sorpreso ICE, Baracat EC. Breast cancer survivals and hormone therapy: estrogen and melatonin. Rev Assoc Med Bras. 2023;69(10):e6910EDI. doi: 10.1590/1806-9282.6910edi
  65. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: a critical systematic review of clinical evidence. Complement Ther Med. 2019;42:65-81. doi: 10.1016/j.ctim.2018.11.003
  66. Yue JL, Chang XW, Zheng JW, et al. Efficacy and tolerability of pharmacological treatments for insomnia in adults: a systematic review and network meta-analysis. Sleep Med Rev. 2023;68:101746. doi: 10.1016/j.smrv.2023.101746
  67. Ang SP, Chia JE, Thirupathy U, et al. Melatonin supplementation and cardiovascular outcomes: a systematic review and meta-analysis of randomized trials. J Clin Med. 2026;15(9):3444. doi: 10.3390/jcm15093444
  68. Papagiannidou E, Skene DJ, Ioannides C. Potential drug interactions with melatonin. Physiol Behav. 2014;131:17-24. doi: 10.1016/j.physbeh.2014.04.016
  69. Härtter S, Wang X, Weigmann H, et al. Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. J Clin Psychopharmacol. 2001;21(2):167-174. doi: 10.1097/00004714-200104000-00008
  70. Goetz MP, Sangkuhl K, Guchelaar HJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy. Clin Pharmacol Ther. 2018;103(5):770-777. doi: 10.1002/cpt.1007
  71. Ambrosone CB, Zirpoli GR, Hutson AD, et al. Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a cooperative group clinical trial (SWOG S0221). J Clin Oncol. 2020;38(8):804-814. doi: 10.1200/JCO.19.01203
  72. Rubio-Sastre P, Scheer FAJL, Gómez-Abellán P, Madrid JA, Garaulet M. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep. 2014;37(10):1715-1719. doi: 10.5665/sleep.4088
  73. Erland LAE, Saxena PK. Melatonin natural health products and supplements: presence of serotonin and significant variability of melatonin content. J Clin Sleep Med. 2017;13(2):275-281. doi: 10.5664/jcsm.6462
  74. Nussbaumer-Streit B, Klerings I, Dobrescu AI, et al. Excluding non-English publications from evidence-syntheses did not change conclusions: a meta-epidemiological study. J Clin Epidemiol. 2020;118:42-54. doi: 10.1016/j.jclinepi.2019.10.011
  75. Dobrescu AI, Nussbaumer-Streit B, Klerings I, et al. Restricting evidence syntheses of interventions to English-language publications is a viable methodological shortcut for most medical topics: a systematic review. J Clin Epidemiol. 2021;137:209-217. doi: 10.1016/j.jclinepi.2021.04.012
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