Melatonin

Our assessments of evidence for each medical benefit fall into one of these categories:

• Strong evidence: consistent, significant effects in several large (or at least one very large) well designed clinical studies or at least two meta-analysesa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of clinical studies of moderate or better quality (or one large meta-analysis) finding similar results
• Good evidence: significant effects in one large or several mid-sized and well-designed clinical studies ( randomized controlled trialsa study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects with an appropriate placebo or other strong comparison control or observational studies that control for confounds)
• Modest evidence: significant effects in at least three small but well-designed randomized controlled trials (RCTs), or one or more well-designed, mid-sized clinical studies of reasonably good quality (RCTs or observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies), or several small studies aggregated into a meta-analysis
• Preliminary evidence: significant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect
• Weak evidence: one or more case studies, supported by animal evidence OR small treatment effects of limited clinical significance OR studies with no controls OR weak trends of effects
• Insufficient evidence: preclinical evidence only OR clinical studies with such poor or unclear methodology that no conclusion can be drawn OR conflicting findings across clinical studies with no preponderance of evidence in one direction; conflicting evidence occurs when studies find conflicting effects (positive effect vs no effect or negative effect) with the same treatment and the same general study population (same cancer type, for example)

• Lower toxicity of chemotherapy drugs including cisplatin, etoposide, anthracyclines, and 5-fluorouracil among people treated with melatonin in a review of clinical trials²⁰Sánchez-Barceló EJ, Mediavilla MD, Tan DX, Reiter RJ. Clinical uses of melatonin: evaluation of human trials. Current Medicinal Chemistry. 2010;17(19):2070-95.
• Better chemotherapy tolerance among people with metastatic non-small cell lung cancer treated with 20 mg oral melatonin per day in the evening compared to chemotherapy alone in a mid-sized RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects²¹Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. Journal of Pineal Research. 2003 Aug;35(1):12-5.
• No evidence of an effect on adverse events after cancer resection among people with non-small cell lung cancer treated with 20 mg melatonin nightly for 1 year after surgery compared to placebo in a large RCT²²Seely D, Legacy M et al. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): a randomized placebo controlled clinical trial. EClinicalMedicine. 2021 Feb 27;33:100763.

• No evidence of an effect on anxiety after cancer resection among people with non-small cell lung cancer treated with 20 mg melatonin nightly for 1 year after surgery compared to placebo in a large RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects²³Seely D, Legacy M et al. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): a randomized placebo controlled clinical trial. EClinicalMedicine. 2021 Feb 27;33:100763.

• Dramatically decreased treatment-related low platelet counts (thrombocytopenia) during chemotherapy or radiotherapy among people with solid tumor cancers treated with 20 mg oral melatonin compared to controls in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 8 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects²⁴Wang YM, Jin B et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemotherapy and Pharmacology. 2012 May;69(5):1213-20.
• Smaller reduction in blood cell counts (platelets, white blood cells, lymphocytes, and neutrophils, but not red blood cells) during radiotherapy among people with rectal cancer treated with 20 mg melatonin 5 days a week for 28 days compared to placebo in a small RCT²⁵Kouhi Habibi N, Shabestani Monfared A et al. The protective effects of melatonin on blood cell counts of rectal cancer patients following radio-chemotherapy: a randomized controlled trial. Clinical and Translational Oncology. 2019;21(6):745-752.
• No evidence of an effect on toxicity of red blood cells, platelets and neutrophils during chemotherapy among people with stage 3–4 inoperable lung cancer treated with 40 mg oral melatonin in the evening for 21 days starting 2 days before chemotherapy compared to placebo in a small RCT²⁶Ghielmini M, Pagani O et al. Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer. British Journal of Cancer. 1999 Jun;80(7):1058-61.

• Less cachexia among people with untreatable advanced solid tumors treated with supportive care and 20 mg oral melatonin per day during the dark period of the day compared to supportive care alone in a very large RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects²⁷Lissoni P. Is there a role for melatonin in supportive care? Supportive Care in Cancer. 2002 Mar;10(2):110-6.
• Lower incidence of weight loss greater than 10% of body weight, with no difference in food intake, among people with untreatable metastatic solid tumors treated with supportive care and 20 mg oral melatonin per day in the evening compared to supportive care alone in a mid-sized RCT²⁸Lissoni P, Paolorossi F et al. Is there a role for melatonin in the treatment of neoplastic cachexia? European Journal of Cancer. 1996 Jul;32A(8):1340-3.
• Less cachexia among people with advanced non-small cell lung cancer with poor clinical status treated with chemotherapy and 20 mg oral melatonin per day in the evening compared to chemotherapy alone in a small RCT²⁹Lissoni P, Paolorossi F et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. Journal of Pineal Research. 1997 Aug;23(1):15-9.
• A small degree of weight stabilization or gain among people with advanced gastrointestinal cancer treated with 18 mg melatonin per day for 4 weeks, and much larger effects with combined with fish oil in a small randomized comparison trial³⁰Persson C, Glimelius B, Rönnelid J, Nygren P. Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: a randomized pilot study. Nutrition. 2005 Feb;21(2):170-8.
• No evidence of an effect on body weight after 28 days among people with advanced cancer and cachexia treated with 20 mg melatonin compared to placebo in a small RCT³¹Del Fabbro E, Dev R, Hui D, Palmer L, Bruera E. Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. Journal of Clinical Oncology. 2013 Apr 1;31(10):1271-6.

• Less cardiotoxicity among people with metastatic cancer with chemotherapy-resistant tumor histotypes treated with chemotherapy and 20 mg oral melatonin per day during the dark period of the day compared to chemotherapy alone in a mid-sized RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects³²Lissoni P. Is there a role for melatonin in supportive care? Supportive Care in Cancer. 2002 Mar;10(2):110-6.
• Less cardiotoxicity among people with metastatic solid tumors treated with chemotherapy and 20 mg oral melatonin every day compared to chemotherapy alone in a mid-sized RCT³³Lissoni P, Barni S et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. European Journal of Cancer. 1999;35(12):1688-1692.
• Lower incidence of low blood pressure (hypotension) among people with advanced solid tumors, for whom no effective standard anticancer therapy was available, receiving a cytokine biotherapy with interleukin-2 or tumor-necrosis-factor-alpha plus 40 mg of melatonin per day in the evening, starting 7 days prior to cytokine injection, compared to cytokine alone in a mid-sized RCT³⁴Lissoni P, Pittalis S et al. Prevention of cytokine-induced hypotension in cancer patients by the pineal hormone melatonin. Supportive Care in Cancer. 1996 Jul;4(4):313-6.

• No evidence of an effect on appetite after 28 days among people with cancer cachexia treated with 20 mg melatonin compared to placebo in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects³⁵Del Fabbro E, Dev R, Hui D, Palmer L, Bruera E. Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. Journal of Clinical Oncology. 2013 Apr 1;31(10):1271-6.

• Better performance related to executive function, episodic memory (immediate and delayed), recognition, and verbal fluency during a first cycle of adjuvant chemotherapy after lumpectomy or mastectomy among people with breast cancer treated with 20 mg oral melatonin daily approximately 1 hour before bedtime for 10 days beginning 3 days before their first chemotherapy session compared to placebo in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects³⁶Palmer ACS, Zortea M 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 Apr 17;15(4):e0231379.
• Better cognitive function during hormonal or trastuzumab therapy among people with metastatic breast cancer treated with 5 mg melatonin at bedtime for 2 months compared to baseline in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design³⁷Innominato PF, Lim AS et al. The effect of melatonin on sleep and quality of life in patients with advanced breast cancer. Supportive Care in Cancer. 2016 Mar;24(3):1097-105.

• Lower depression scores during a first cycle of adjuvanttreatment applied after initial treatment for cancer, especially to suppress secondary tumor formation chemotherapy after lumpectomy or mastectomy among people with breast cancer treated with 20 mg of oral melatonin daily approximately 1 hour before bedtime for 10 days beginning 3 days before their first chemotherapy session compared to placebo in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects³⁸Palmer ACS, Zortea M 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 Apr 17;15(4):e0231379.
• Lower risk of developing symptoms of depression among women without signs of depression undergoing surgery for breast cancer treated with 6 mg oral melatonin for 3 months compared to placebo in a small RCT³⁹Hansen MV, Andersen LT et al. Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial. Breast Cancer Research and Treatment. 2014 Jun;145(3):683-95.
• Lower risk of developing depressive symptoms during 3 months after surgery among people with breast cancer treated with 6 mg oral melatonin compared to placebo in a small RCT⁴⁰Hansen MV. Chronobiology, cognitive function and depressive symptoms in surgical patients. Danish Medical Journal. 2014 Sep;61(9):B4914.
• No evidence of an effect on depression among postmenopausal women with breast cancer treated with 3 mg oral melatonin daily for 4 months compared to placebo in a small RCT⁴¹Chen WY, Giobbie-Hurder A et al. A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes. Breast Cancer Research and Treatment. 2014;145(2):381-388.
• No evidence of an effect on depression after cancer resection among people with non-small cell lung cancer treated with 20 mg melatonin nightly for 1 year after surgery compared to placebo in a large RCT⁴²Seely D, Legacy M et al. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): a randomized placebo controlled clinical trial. EClinicalMedicine. 2021 Feb 27;33:100763.

• Dramatically decreased fatigue during radio/chemotherapy among people with solid tumor cancers treated with 20 mg oral melatonin compared to controls in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 8 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁴³Wang YM, Jin B et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemotherapy and Pharmacology. 2012 May;69(5):1213-20.
• Lower fatigue scores and substantially lower frequency of fatigue among people with breast cancer treated with 18 mg per day of oral melatonin from one week before until one month after adjuvant radiotherapy compared to controls (no intervention) in a small RCT⁴⁴Sedighi Pashaki A, Mohammadian K et al. A randomized, controlled, parallel-group, trial on the effects of melatonin on fatigue associated with breast cancer and its adjuvant treatments. Integrative Cancer Therapies. 2021 Jan-Dec;20:1534735420988343.
• Less severe fatigue during hormonal or trastuzumab therapy among people with metastatic breast cancer treated with 5 mg melatonin at bedtime for 2 months compared to baseline in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design⁴⁵Innominato PF, Lim AS et al. The effect of melatonin on sleep and quality of life in patients with advanced breast cancer. Supportive Care in Cancer. 2016 Mar;24(3):1097-105.
• Less asthenia among people with untreatable advanced solid tumors treated with supportive care and 20 mg oral melatonin per day during the dark period of the day compared to supportive care alone in a very large RCT⁴⁶Lissoni P. Is there a role for melatonin in supportive care? Supportive Care in Cancer. 2002 Mar;10(2):110-6.
• Less asthenia during chemotherapy among people with metastatic cancer with chemotherapy-resistant tumor histotypes treated with 20 mg oral melatonin per day during the dark period of the day compared to chemotherapy alone in a mid-sized RCT⁴⁷Lissoni P. Is there a role for melatonin in supportive care? Supportive Care in Cancer. 2002 Mar;10(2):110-6.
• Less asthenia during chemotherapy among people with metastatic solid tumors treated with 20 mg oral melatonin every day compared to chemotherapy alone in a mid-sized RCT⁴⁸Lissoni P, Barni S et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. European Journal of Cancer. 1999;35(12):1688-1692.
• Less asthenia and discomfort or illness (malaise) during chemotherapy among people with metastatic solid tumors (lung, breast, or gastrointestinal) who were in poor clinical condition treated with 20 mg oral melatonin per day in the evening compared to chemotherapy alone in a small RCT⁴⁹Lissoni P, Tancini G et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Supportive Care in Cancer. 1997;5(2):126-129.
• No evidence of an effect on fatigue after cancer resection among people with non-small cell lung cancer treated with 20 mg melatonin nightly for 1 year after surgery compared to placebo in a large RCT⁵⁰Seely D, Legacy M et al. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): a randomized placebo controlled clinical trial. EClinicalMedicine. 2021 Feb 27;33:100763.
• No evidence of an effect on fatigue among people with advanced cancer treated with 20 mg oral melatonin each night for a week in a small RCT⁵¹Lund Rasmussen C, Klee Olsen M et al. Effects of melatonin on physical fatigue and other symptoms in patients with advanced cancer receiving palliative care: a double-blind placebo-controlled crossover trial. Cancer. 2015 Oct 15;121(20):3727-36.

• No evidence of an effect on hot flashes among postmenopausal breast cancer survivors treated with 3 mg oral melatonin daily for 4 months compared to placebo in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁵²Chen WY, Giobbie-Hurder A et al. A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes. Breast Cancer Research and Treatment. 2014;145(2):381-388.

• Dramatically decreased neurotoxicity during radio/chemotherapy among people with solid tumor cancers treated with 20 mg oral melatonin compared to controls in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 8 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁵³Wang YM, Jin B et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemotherapy and Pharmacology. 2012 May;69(5):1213-20.

• Less incidence of stomatitis during chemotherapy among people with metastatic cancer with chemotherapy-resistant tumor histotypes treated with 20 mg oral melatonin per day during the dark period of the day compared to chemotherapy alone in a mid-sized RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁵⁴Lissoni P. Is there a role for melatonin in supportive care? Supportive Care in Cancer. 2002 Mar;10(2):110-6.
• Less incidence of stomatitis during chemotherapy among people with metastatic solid tumors treated with 20 mg oral melatonin every day compared to chemotherapy alone in a mid-sized RCT⁵⁵Lissoni P, Barni S et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. European Journal of Cancer. 1999;35(12):1688-1692.
• Less severe oral mucositis during radiotherapy among people with head and neck cancer treated with 20 mg melatonin compared to controls in an RCT⁵⁶Elsabagh HH, Moussa E, Mahmoud SA, Elsaka RO, Abdelrahman H. Efficacy of melatonin in prevention of radiation-induced oral mucositis: a randomized clinical trial. Oral Diseases. 2020 Apr;26(3):566-572.
• Delayed onset of of grade 3 oral mucositis, resulting in fewer interrupted treatments of chemoradiation (5 days/week of radiation plus chemotherapy 3 or 6 cycles), among people with head and neck cancer treated with 20 mg melatonin gargle before each irradiation, and 20 mg melatonin capsules taken nightly during 7 weeks of concurrent chemoradiation compared to placebos in a small RCT⁵⁷Onseng K, Johns NP et al. Beneficial effects of adjuvant melatonin in minimizing oral mucositis complications in head and neck cancer patients receiving concurrent chemoradiation. Journal of Alternative and Complementary Medicine. 2017 Dec;23(12):957-963.
• Less incidence of stomatitis during chemotherapy among people with metastatic solid tumors (lung, breast, or gastrointestinal) who were in poor clinical condition treated with 20 mg oral melatonin per day in the evening compared to chemotherapy alone in a small RCT⁵⁸Lissoni P, Tancini G et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Supportive Care in Cancer. 1997;5(2):126-129.

• Less pain among people with head and neck cancer undergoing radiotherapy with 20 mg melatonin compared to controls in an RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁵⁹Elsabagh HH, Moussa E, Mahmoud SA, Elsaka RO, Abdelrahman H. Efficacy of melatonin in prevention of radiation-induced oral mucositis: a randomized clinical trial. Oral Diseases. 2020 Apr;26(3):566-572.
• Lower pain scores and less use of synthetic opioids (fentanyl and tramadol) during elective prostatectomy among men with prostate cancer treated with 6 mg melatonin the night before and 1 h before surgery compared to placebo in a small RCT⁶⁰Borazan H, Tuncer S, Yalcin N, Erol A, Otelcioglu S. Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial. Journal of Anesthesia. 2010 Apr;24(2):155-60.
• No evidence of an effect on pain after cancer resection among people with non-small cell lung cancer treated with 20 mg melatonin nightly for 1 year after surgery compared to placebo in a large RCT⁶¹Seely D, Legacy M et al. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): a randomized placebo controlled clinical trial. EClinicalMedicine. 2021 Feb 27;33:100763.

• No evidence of an effect on quality of life after cancer resection among people with non-small cell lung cancer treated with 20 mg melatonin nightly for 1 year after surgery compared to placebo in a large RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁶²Seely D, Legacy M et al. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): a randomized placebo controlled clinical trial. EClinicalMedicine. 2021 Feb 27;33:100763.
• Better health-related quality of life scores for social well-being among people with advanced non-small cell lung cancer treated with 10 mg or 20 mg of melatonin compared to placebo in a mid-sized RCT⁶³Sookprasert A, Johns NP et al. Melatonin in patients with cancer receiving chemotherapy: a randomized, double-blind, placebo-controlled trial. Anticancer Research. 2014 Dec;34(12):7327-37.
• Better quality of life during trastuzumab or hormone therapy among people with metastatic breast cancer treated with 5 mg melatonin at bedtime for 2 months compared to baseline in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design⁶⁴Innominato PF, Lim AS et al. The effect of melatonin on sleep and quality of life in patients with advanced breast cancer. Supportive Care in Cancer. 2016 Mar;24(3):1097-105.

Without regard to treatment phase: preliminary evidence of better sleep quality among people with cancer treated with melatonin

• Better subjective sleep quality among postmenopausal women with breast cancer treated with 3 mg oral melatonin daily for 4 months compared to placebo in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁶⁵Chen WY, Giobbie-Hurder A et al. A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes. Breast Cancer Research and Treatment. 2014;145(2):381-388.

With surgery: insufficient (conflicting) evidence of better sleep quality after surgery among people treated with melatonin

• No evidence of an effect on sleep after cancer resection among people with non-small cell lung cancer treated with 20 mg melatonin nightly for 1 year after surgery compared to placebo in a large RCT⁶⁶Seely D, Legacy M et al. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): a randomized placebo controlled clinical trial. EClinicalMedicine. 2021 Feb 27;33:100763.
• Better sleep efficiency and less waking after sleep onset for 2 weeks after breast cancer surgery among people treated with 6 mg melatonin approximately 60 minutes before bedtime 3 nights before surgery until at least 1 week after surgery compared to placebo in a small RCT⁶⁷Madsen MT, Hansen MV et al. Effect of melatonin on sleep in the perioperative period after breast cancer surgery: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Sleep Medicine. 2016 Feb;12(2):225-33.
• Better sleep efficiency and total sleep period but not subjective sleep quality during 3 months after surgery among people with breast cancer treated with 6 mg oral melatonin compared to placebo in a small RCT⁶⁸Hansen MV. Chronobiology, cognitive function and depressive symptoms in surgical patients. Danish Medical Journal. 2014 Sep;61(9):B4914.
• Better sleep quality among men with prostate cancer undergoing elective prostatectomy treated with 6 mg melatonin the night before and 1 h before surgery compared to placebo in a small RCT;⁶⁹Borazan H, Tuncer S, Yalcin N, Erol A, Otelcioglu S. Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial. Journal of Anesthesia. 2010 Apr;24(2):155-60. our note: melatonin may impact the effects of anesthesia, so discuss any planned use before surgery with your surgery team; see Safety and precautions ›
  

During cancer treatment: preliminary evidence of better sleep quality during cancer treatment among people treated with melatonin

• Better sleep quality during a first cycle of adjuvanttreatment applied after initial treatment for cancer, especially to suppress secondary tumor formation chemotherapy after lumpectomy or mastectomy among people with breast cancer treated with 20 mg of oral melatonin daily approximately 1 hour before bedtime for 10 days beginning 3 days before their first chemotherapy session compared to placebo in a small RCT⁷⁰Palmer ACS, Zortea M 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 Apr 17;15(4):e0231379.
• Better objective sleep quality, sleep fragmentation and quantity, and subjective sleep during hormonal or trastuzumab therapy among people with metastatic breast cancer treated with 5 mg melatonin at bedtime for 2 months compared to baseline in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design⁷¹Innominato PF, Lim AS et al. The effect of melatonin on sleep and quality of life in patients with advanced breast cancer. Supportive Care in Cancer. 2016 Mar;24(3):1097-105.

• Moderately less grade 1/2 (mild/moderate) acute radiation dermatitis after breast-conserving surgery for stage 0-2 breast cancer among people treated with a melatonin emulsion twice daily during radiation treatment and 2 weeks following the end of radiotherapy compared to placebo in an RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁷²Ben-David MA, Elkayam R, Gelernter I, Pfeffer RM. Melatonin for prevention of breast radiation dermatitis: a phase ii, prospective, double-blind randomized trial. Israeli Medical Association Journal. 2016 Mar-Apr;18(3-4):188-92.

Note cautions about the effects of melatonin on anesthesia in Safety and precautions ›

Anxiety

Good evidence of less anxiety while preparing for surgery among adults treated with melatonin, comparable to results with benzodiazepines

Good evidence of less anxiety after surgery among people treated with melatonin

• Modest improvements in anxiety among adults preparing for surgery treated with melatonin compared to placebo in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 7 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects of high quality, and comparable effects as midazolam in an analysis of 2 further RCTs⁷³Hansen MV, Halladin NL, Rosenberg J, Gögenur I, Møller AM. Melatonin for pre- and postoperative anxiety in adults. Cochrane Database of Systematic Reviews. 2015 Apr 9;2015(4):CD009861.
• Modest improvements in anxiety before surgery among adults treated with melatonin compared to placebo in a meta-analysis of 18 RCTs of moderate quality⁷⁴Madsen BK, Zetner D, Møller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database of Systematic Reviews. 2020 Dec 8;12(12):CD009861.
• Comparable levels of anxiety before surgery among adults treated with melatonin or benzodiazepines in a meta-analysis of 7 RCTs of moderate quality⁷⁵Madsen BK, Zetner D, Møller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database of Systematic Reviews. 2020 Dec 8;12(12):CD009861.
• Slightly less anxiety immediately after surgery among adults treated with melatonin compared to placebo in a meta-analysis of 7 RCTs of low quality⁷⁶Madsen BK, Zetner D, Møller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database of Systematic Reviews. 2020 Dec 8;12(12):CD009861.
• Less delayed anxiety after surgery among adults treated with melatonin compared to placebo in a meta analysis of 2 RCTs of low quality⁷⁷Madsen BK, Zetner D, Møller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database of Systematic Reviews. 2020 Dec 8;12(12):CD009861.
• Comparable levels of anxiety after surgery among adults treated with melatonin or benzodiazepines in a meta-analysis of 3 RCTs of low quality⁷⁸Madsen BK, Zetner D, Møller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database of Systematic Reviews. 2020 Dec 8;12(12):CD009861.
• Small improvements in anxiety 6 hours after surgery, but not at 90 minutes after surgery among adults treated with melatonin compared to placebo in a meta-analysis of 7 RCTs of moderate quality, and comparable to effects from treatment with midazolam in an analysis of 2 further RCTs⁷⁹Hansen MV, Halladin NL, Rosenberg J, Gögenur I, Møller AM. Melatonin for pre- and postoperative anxiety in adults. Cochrane Database of Systematic Reviews. 2015 Apr 9;2015(4):CD009861.
• Lower anxiety scores among people preparing for surgery treated with melatonin compared to placebo in a systematic review of 24 controlled trialsa study design in which people are assigned to either an experimental group or a control group to compare the outcomes from different treatment; assignment is not random, and so this is not as strong a study design as a randomized controlled trial, but still stronger than an uncontrolled trial⁸⁰Andersen LP, Werner MU, Rosenberg J, Gögenur I. A systematic review of peri-operative melatonin. Anaesthesia. 2014 Oct;69(10):1163-71.

Depression: no evidence of an effect on depression scores among people with depression treated with melatonin in a combined analysis of studies

• No change in depression scores among people with depression treated with melatonin compared to placebo in a meta-analysis of 4 controlled trials⁸¹Hansen MV, Danielsen AK, Hageman I, Rosenberg J, Gögenur I. The therapeutic or prophylactic effect of exogenous melatonin against depression and depressive symptoms: a systematic review and meta-analysis. European Neuropsychopharmacology. 2014 Nov;24(11):1719-28.

Pain: modest evidence of less pain from surgery not specific to cancer among people treated with melatonin

• Slightly less pain after surgery among people undergoing surgery treated with melatonin compared to placebo in a systematic review of controlled trials⁸²Andersen LP, Werner MU, Rosenberg J, Gögenur I. A systematic review of peri-operative melatonin. Anaesthesia. 2014 Oct;69(10):1163-71.
• Lower pain severity, longer duration before needing analgesia after surgery, less need for analgesics after surgery, and quicker resumption of activity after elective cesarean section among people receiving 5 or 10 mg melatonin before surgery compared placebo in addition to spinal anesthesia, and greater benefit with the higher dose of melatonin for some effects, in a mid-sized RCT⁸³Kiabi FH, Emadi SA, Jamkhaneh AE, Aezzi G, Ahmadi NS. Effects of preoperative melatonin on postoperative pain following cesarean section: a randomized clinical trial. Annals of Medical Surgery (London). 2021 May 12;66:102345.
• Lower mean pain scores and total morphine consumption, less supplemental analgesic, and less nausea and vomiting for 24 hours after surgery among adults treated with vitamin C 1 hour before surgery compared to placebo in a mid-sized RCT⁸⁴Laflı Tunay D, Türkeün Ilgınel M et al. Comparison of the effects of preoperative melatonin or vitamin C administration on postoperative analgesia. Bosnian Journal of Basic Medical Sciences. 2020;20(1):117-124.

Sleep disruption

Modest evidence of better markers of sleep among children and adolescents but no evidence of an effect among adults with chronic insomnia but without other health conditions treated with melatonin

Modest evidence of shorter sleep onset latency among adults with chronic insomnia and other health conditions (comorbidities) treated with melatonin

• Shorter sleep onset latency and longer total sleep time among children and adolescents but no evidence of an effect among adults with chronic insomnia but without other health conditions (comorbidities) treated with melatonin compared to placebo in a meta-analysis of 24 RCTs⁸⁵Choi K, Lee YJ, Park S, Je NK, Suh HS. Efficacy of melatonin for chronic insomnia: systematic reviews and meta-analyses. Sleep Medicine Reviews. 2022 Dec;66:101692.
• Shorter sleep onset latency among adults with chronic insomnia and other health conditions (comorbidities) treated with melatonin compared to placebo in a meta-analysis of 4 RCTs⁸⁶Choi K, Lee YJ, Park S, Je NK, Suh HS. Efficacy of melatonin for chronic insomnia: systematic reviews and meta-analyses. Sleep Medicine Reviews. 2022 Dec;66:101692.
• Less time to fall asleep (shorter sleep latency) with melatonin in 7 of 31 meta-analyses not specific to cancer in an umbrella review⁸⁷Posadzki PP, Bajpai R et al. Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action. BMC Medicine. 2018 Feb 5;16(1):18.
• Better sleep quality but no difference in the duration of night sleep or on anxiety or pain during intensive care (ICU) and treatment with analgesics and/or sedatives among people further treated with an intervention of 10 mg oral melatonin for up to 7 consecutive nights compared to placebo in a mid-sized RCT⁸⁸Gandolfi JV, Di Bernardo APA et al. The effects of melatonin supplementation on sleep quality and assessment of the serum melatonin in ICU patients: a randomized controlled trial. Critical Care Medicine. 2020 Dec;48(12):e1286-e1293.

• Lower levels of melatonin among women with breast cancer compared to controls without breast cancer in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 9 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods trials⁸⁹Veiga ECA, Simões R et al. Repercussions of melatonin on the risk of breast cancer: a systematic review and meta-analysis. Revista da Associação Médica Brasileira (1992). 2019 Jun 3;65(5):699-705.
• Weak or very weak trendsan apparent change due to a therapy, close to but not achieving full statistical significance (this is the CancerChoices definition; other researchers and studies may define this differently toward higher risk of breast cancer among people with lower levels of a melatonin metabolite, but only among postmenopausal women, estrogen receptor positive breast cancer, or overnight urine samples; no evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on risk of breast cancer among women as a whole with the highest levels of the metabolite compared to other people in a meta-analysis of 6 observational studies⁹⁰Xu J, Huang L, Sun GP. Urinary 6-sulfatoxymelatonin level and breast cancer risk: systematic review and meta-analysis. Scientific Reports. 2017 Jul 13;7(1):5353.
• Modestly lower risk of breast cancer with higher urinary levels of melatonin in meta-analyses of 5⁹¹Basler M, Jetter A et al. Urinary excretion of melatonin and association with breast cancer: meta-analysis and review of the literature. Breast Care (Basel). 2014 Jul;9(3):182-7. and 16⁹²Yang WS, Deng Q, Fan WY, Wang WY, Wang X. Light exposure at night, sleep duration, melatonin, and breast cancer: a dose-response analysis of observational studies. European Journal of Cancer Prevention. 2014 Jul;23(4):269-76. observational studies and a separate large observational study⁹³Wang XS, Tipper S et al. First-morning urinary melatonin and breast cancer risk in the Guernsey Study. American Journal of Epidemiology. 2014 Mar 1;179(5):584-93.

• Lower risk of recurrence (better disease-free survivalthe time during and after successful treatment of a disease during which there are no signs and symptoms of the disease that was treated; this is the same as recurrence-free survival) at 5 years after cancer resection among people with stage 3/4 non-small cell lung cancer treated with 20 mg melatonin nightly for 1 year after surgery compared to placebo, but no evidence of an effect 2 years after surgery or among people with stage 1/2 cancer, in a large RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁹⁴Seely D, Legacy M et al. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): a randomized placebo controlled clinical trial. EClinicalMedicine. 2021 Feb 27;33:100763.

• Lower risk of recurrence (better disease-free survivalthe time during and after successful treatment of a disease during which there are no signs and symptoms of the disease that was treated; this is the same as recurrence-free survival) after surgical treatment for regional node recurrence with a median follow up of 31 months among people with melanoma treated with 20 mg oral melatonin per day in the evening until disease progression compared to no treatment in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁹⁵Lissoni P, Brivio O et al. Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma. Journal of Pineal Research. 1996 Nov;21(4):239-42.
• Less redness (erythema) from ultraviolet radiation with application of topical 12.5% melatonin cream before exposure, with no decrease in cognitive performance, compared to placebo or no treatment in a review of clinical studies and small RCTs⁹⁶Scheuer C. Melatonin for prevention of erythema and oxidative stress in response to ultraviolet radiation. Danish Medicine Journal. 2017 Jun;64(6):B5358.

• Lower serum levels of melatonin among women with ovarian cancer compared to healthy controls in a mid-sized observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁹⁷Zhao M, Wan J et al. The reduction in circulating melatonin level may contribute to the pathogenesis of ovarian cancer: a retrospective study. Journal of Cancer. 2016 Apr 27;7(7):831-6.
• A weak trendan apparent change due to a therapy, close to but not achieving full statistical significance (this is the CancerChoices definition; other researchers and studies may define this differently toward higher risk of ovarian cancer with lower urinary melatonin levels in an observational study in which most women were premenopausal, but no link in another study in which nearly all the women were postmenopausal⁹⁸Poole EM, Schernhammer E, Mills L, Hankinson SE, Tworoger SS. Urinary melatonin and risk of ovarian cancer. Cancer Causes and Control. 2015 Oct;26(10):1501-6.

• Substantially higher risk for advanced prostate cancer among elderly men with lower first morning-void urinary melatonin levels among men with prostate cancer in a mid-sized observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study⁹⁹Sigurdardottir LG, Markt SC et al. Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men. Eur Urol. 2015 Feb;67(2):191-4.
• Lower risk of prostate cancer or advanced stage prostate cancer with higher urinary melatonin levels in a mid-sized observational study¹⁰⁰Tai SY, Huang SP, Bao BY, Wu MT. Urinary melatonin-sulfate/cortisol ratio and the presence of prostate cancer: a case-control study. Scientific Reports. 2016 Jul 8;6:29606.