Cancer Hates Darkness: The Remarkable Story of Melatonin

Not just a sleeping pill....Targets multiple cancer pathways

Melatonin, N-acetyl-5-methoxytryptamine, is a small lipophilic molecule that is secreted by the pineal gland and its synthesis shows a circadian pattern. Melatonin is mainly produced by the pineal gland in response to darkness. (1) At night, melatonin levels increase, then start to decrease in the early morning and throughout the day. Elevated levels of melatonin at night stimulate target organs to enter into suitable homeostatic metabolic rhythms, which help protect the body from developing different diseases. (2)

Exposing the body to light at night may result in disruption of melatonin production and the circadian rhythm. Peak melatonin levels in the blood vary between individuals and depend on age, with levels decreasing rapidly after age 40. (3)

Melatonin has specific receptors to regulate many physiological functions namely MT1 and MT2; both are members of the seven transmembrane G-protein coupled receptor family. (4) Melatonin receptors are found throughout the body, which explains its multiple biological functions. (1) In addition, mitochondria of all cells produce melatonin in an autocrine fashion under the influence of near-infrared irradiation. (5, 6) Melatonin has numerous biological properties acting both directly and indirectly as a potent antioxidant. (1) Melatonin plays a critical role in normal mitochondrial function, being a strong inducer of oxidative phosphorylation.

Anticancer pathways and mechanisms

Low melatonin levels have been implicated in the etiology of cancer. Several studies have shown reduced levels of melatonin in patients with certain types of cancers, compared with normal, healthy people of the same age. (3) Disruption of nocturnal melatonin secretion in night shift workers has been associated with a modestly increased risk for breast and other cancer types. A meta-analysis of 26 observational studies found significantly increased breast cancer incidence among female airline cabin crew. (7) The International Agency for Research on Cancer reclassified “shiftwork that involves circadian disruption“ from a possible to a probable human carcinogen, in recognition of this relationship. (8)

In experimental models, melatonin has demonstrated a broad spectrum of anticancer activity with multiple underlying mechanisms being proposed (see Figure 1). (2, 9) Melatonin exerts cytotoxic, anti-mitotic, and pro-apoptotic actions in breast cancer cells. The antiproliferative activity of melatonin has been demonstrated in both ER-positive and ER-negative human breast cancer cell lines. In most of these reports, melatonin acted via the MT1 membrane receptor. In addition, melatonin activates cancer cell apoptosis; this may be mediated by PUMA up-regulation. Melatonin increases the expression of pro-apoptotic mediators such as BAX/BAK, Apaf-1, caspases, and p53. (10) Melatonin has been demonstrated to inhibit the proliferation of cancer stem cells and to reduce the expression of Ki67 and matrix metalloproteinase 9. (11) Melatonin can cause cancer cells to switch from anaerobic glycolysis to conventional oxidative phosphorylation via the Krebs cycle. This slows down the proliferative activity of cancer cells, reduces their metastatic potential, and directs the cells to undergo apoptosis. Melatonin stimulates the synthesis of acetyl-CoA from pyruvate by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase. (12) A study demonstrated that melatonin altered Ewing sarcoma metabolic profile by inhibiting the Warburg effect. (13) In prostate cancer cells, melatonin was able to reduce glucose metabolism via the downregulation of glycolysis and the pentose phosphate pathway. (14) The antiestrogenic action of melatonin could also enhance the ability of this hormone to limit the proliferation of hormone-sensitive breast cancer. (9)

Metabolic reprogramming and deregulated cellular energetics are hallmarks of cancer. The aberrant metabolism of cancer cells is thought to be the product of differential oncogene activation and tumor suppressor gene inactivation. MYC is one of the most important oncogenic drivers, its activation being reported in a variety of cancer types and sub-types, among which are the most prevalent and aggressive of all malignancies. (15-17) Melatonin suppresses c-MYC signaling, and because c-MYC is a major transcriptional regulator of the glutamine transporter ASCT2 (SLC1A5), melatonin may indirectly reduce ASCT2-mediated glutamine uptake (see Figure 2). The interplay between c-MYC and ASCT2 represents a critical metabolic node in aggressive tumors such as glioblastoma and triple-negative breast cancer. Reduced glutamine availability has several downstream consequences. These include decreased mTOR signaling, reduced nucleotide synthesis, diminished protein production, and lower glutathione synthesis, which impairs the cell’s antioxidant defenses. At the same time, metabolic stress and apoptosis are increased. Melatonin’s modulation of this axis suggests potential for combination therapies targeting glutamine metabolism. (15-17)

Anti-angiogenesis is one of the major mechanisms by which melatonin exerts its anticancer effects. Melatonin inhibits hypoxia-induced factor 1-α thereby preventing vascular endothelial growth factor (VEGF) expression. Melatonin also inhibits endothelial cell migration, endothelial cell invasion, and endothelial cell tube formation. It also prevents cancer cell migration via alteration of PI3K and MAPK signaling pathways in both receptor-dependent and independent manner. (11) Melatonin has been demonstrated to stimulate T cell and natural killer (NK) production and reduce regulatory T cells (Tregs). (18, 19)

Melatonin may benefit cancer patients who are also receiving chemotherapy, radiotherapy, supportive therapy, or palliative therapy by improving survival and ameliorating the side effects of chemotherapy.

Clinical studies

In addition to case studies, (20, 21) the clinical benefit of melatonin in patients with cancer is supported by the highest level of evidence, namely meta-analyses of RCTs. (22, 23) A classic systematic review of randomized trials (10 RCTs, mostly solid tumors) found that adding melatonin (typically 20 mg nightly) to chemotherapy or supportive care reduced 1‑year mortality (relative risk roughly halved) and improved tumor remission rates, with consistent effects across cancer types and doses.(22) Seely et al systematically reviewed the effects of melatonin in conjunction with chemotherapy, radiotherapy, supportive care, and palliative care on 1-year survival, complete response, partial response, stable disease, and chemotherapy-associated toxicities. (23) This analysis included 21 randomized studies, all of which studied solid tumors. The pooled relative risk (RR) for 1-year mortality was 0.63 (95% CI = 0.53-0.74; P < 0.001). Improved effects were found for complete response, partial response, and stable disease. In trials combining melatonin with chemotherapy, adjuvant melatonin decreased 1-year mortality (RR = 0.60; 95% CI = 0.54-0.67).

A triple‑blind RCT in breast cancer patients undergoing adjuvant radiotherapy (20 mg daily) showed significant reductions in fatigue, anxiety, and depression scores in the melatonin group versus placebo, suggesting a clinically meaningful improvement in radiotherapy‑related symptom burden. (24) A 2024 review of 46 clinical trials of melatonin in oncology (11 with published results) reported that the most consistent positive signals were in improved quality of life and reduced treatment‑related fatigue and sleep disruption, particularly when used adjunctively with chemotherapy or radiotherapy.(25)

Types of cancers that melatonin may be beneficial for

Melatonin may be active in several cancers including cancers of the breast, ovary, pancreas, liver, kidney, mouth, stomach, colon/rectum, brain, lung, prostate, head and neck, and various leukemias and sarcomas. (2, 9)

Dosing and cautions

Despite the expanding literature, there is currently no universally accepted “optimal” anticancer dose of melatonin. Most clinical studies have used doses substantially higher than those commonly prescribed for insomnia. The pioneering work of Paolo Lissoni and colleagues employed melatonin at a dose of 20 mg nightly in patients with advanced malignancies and reported improvements in treatment tolerance, quality of life, and, in some studies, survival outcomes when combined with standard cancer therapies. (26-28) Consequently, 20 mg at bedtime remains the best-studied dose in oncology. However, many integrative oncology practitioners now use doses ranging from 20 to 40 mg nightly, based on the hypothesis that higher concentrations may be required to achieve some of the metabolic and signaling effects observed in laboratory studies.(29, 30) While some clinicians have explored doses exceeding 50–100 mg daily, robust clinical evidence demonstrating superior anticancer efficacy at these higher doses remains lacking.

Although melatonin has an excellent safety profile, initiating therapy at the target dose may lead to transient side effects such as morning drowsiness, vivid dreams, dizziness, or headache. For this reason, a gradual titration strategy is generally recommended. Many clinicians begin with 5–10 mg at bedtime and increase the dose every one to two weeks as tolerated until a target range of 20–40 mg nightly is reached. This approach improves tolerability while allowing patients to identify the lowest effective dose that balances potential therapeutic benefit with minimal adverse effects. Most side effects diminish after several days of continued use.

Melatonin is probably the safest medical compound available, with a LD50 of infinity (it is impossible to kill an animal with industrial doses of melatonin). The only side effects reported are early morning drowsiness and “bad dreams” (when the dose is increased too rapidly). (1)

While it has been claimed and widely disseminated in social media that melatonin is associated with cardiac failure (abstract presented at AHA Scientific Session 2025) this study is profoundly flawed and indeed, melatonin is cardioprotective. (31-36)

Figure 1. Multiple anticancer pathways affected by melatonin. (2)

Figure 2. Melatonin and the glutamine axis

Figure 3. Summary of role of melatonin in cancer

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Important: The discussion of repurposed medications in this article is intended to review the scientific literature and does not constitute a recommendation for self-treatment. Decisions regarding the use of off-label therapies should be made in consultation with a qualified healthcare professional familiar with the patient’s medical history and current treatment plan. Please see the full Medical Disclaimer (Caution to Patients) on the introductory page to Marik’s Cancer & Metabolic Healing Playbook.

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