Melatonin: Facts, Extrapolations and Clinical Trials

**Background:** Melatonin is a natural hormone synthesized in the pineal gland during nighttime, with established roles in regulating circadian rhythms and sleep via its high-affinity G-protein coupled receptors MT1 and MT2. However, since the 1990s, a second wave of research has proposed that melatonin acts as a potent antioxidant and scavenger, leading to claims that it can treat a vast array of diseases including cancers, Alzheimer's, Parkinson's, and COVID-19. This review critically examines the evidence behind these extrapolations, focusing on the gap between preclinical studies using supraphysiological concentrations and clinical outcomes.

**Methods:** The authors conducted a narrative review of the literature, analyzing historical and recent publications on melatonin's mechanisms, clinical trials registered on ClinicalTrials.gov (accessed 23 January 2023), and safety data from poison centers and regulatory agencies. They evaluated 742 clinical studies on melatonin, categorizing them by condition and status, and specifically reviewed four completed cancer trials with published results. The review also scrutinizes claims about melatonin synthesis in bacteria and mitochondria, its proposed nuclear receptor RZRα, and its role as a co-substrate for NQO2.

**Key Results:** The authors found that most clinical trials are based on weak preclinical data. For example, of 65 cancer trials, only four published results: one showed no improvement in appetite or quality of life (NCT00513357), one suggested benefit (NCT00668707), one found no improvement in fatigue (NCT00925899), and one reported no statistically significant reduction in tumor residue (NCT04137627). The review highlights that melatonin doses in trials range from 0.5 to 100 mg, with 100 mg producing plasma Cmax up to 1,252,500 pg/mL (i.v.) or 101,163 pg/mL (oral), far exceeding physiological nighttime levels of 30–70 pg/mL. Safety data are limited: a 2012–2021 US poison center report documented over 250,000 pediatric ingestions, 45,000 symptomatic effects, 3,211 serious outcomes, and 2 deaths. The French ANSES reported 90 adverse events from 2009–2017, including a possible link to infant sudden death syndrome. The review also debunks several mechanisms: the 1994 claim of a nuclear melatonin receptor (RZRα) was retracted in 1997 but continues to be cited; the hypothesis that melatonin is a co-substrate of NQO2 was experimentally disproven; and evidence for bacterial melatonin synthesis is weak, with only six publications and no independent replication for key species like Rhodospirillum rubrum. Mitochondrial melatonin synthesis was supported by one study (Suofo et al.) showing AANAT and ASMT in mouse brain mitochondria, but quantitative data are lacking.

**Clinical Implications:** The authors argue that the vast spectrum of conditions claimed to be treatable by melatonin—from mental disorders to infectious diseases—is a weakness, not a strength, of the literature. They emphasize that high-dose melatonin's safety profile is poorly characterized, especially in children and pregnant women, and that no formal long-term safety trials exist. They recommend restricting high-dose use as a precaution, especially in infants, and call for rigorous preclinical studies that include dose-response curves, appropriate controls (e.g., other indoles), and mechanistic clarity. The review concludes that most clinical trials have yielded negative or modest results, and that the field should refocus on melatonin's established circadian roles rather than unsubstantiated therapeutic claims.