Melatonin in Musculoskeletal and Spine-Related Conditions: A Systematic Review of Preclinical and Clinical Evidence

Background and Objectives: Experimental studies suggest that melatonin can influence antioxidant, inflammatory, mitochondrial, and chronobiological pathways relevant to musculoskeletal degeneration, repair, and selected spine-related conditions, but clinical translation remains uncertain. This systematic review evaluated primary in vitro, animal, and human evidence concerning exogenous parent melatonin in these conditions. Materials and Methods: PubMed/MEDLINE and Europe PMC were searched from inception to 6 August 2026; ClinicalTrials.gov was mapped separately. Eligible reports were peer-reviewed comparative primary investigations. One reviewer performed screening, extraction, and a screen-level methodological limitation assessment, followed by a complete consistency pass; no automation tools were used. Complete articles were consulted where accessible, but access status was not logged prospectively and the exact number accessed cannot be reconstructed reliably. Because quantitative pooling was not appropriate, evidence was synthesized by stream and clinical domain according to PRISMA 2020 and SWiM. The review was not registered, and no standalone protocol was prepared. Results: The searches yielded 3201 records and 1646 unique records after deduplication. Of 437 reports taken forward for retrieval and report-level assessment using available information, 208 were included (23 in vitro, 142 animal, and 43 human reports). Preclinical studies generally reported osteogenic, chondroprotective, antioxidant, anti-inflammatory, mitochondrial, and tissue-repair effects, but findings were not uniformly favorable: high-dose fracture-remodeling impairment and MT2-dependent heterotopic ossification were reported. Human evidence was limited, heterogeneous, and showed frequent screen-level methodological limitations. Formulations, routes, and exposures were non-equivalent. Conclusions: Melatonin is biologically plausible but clinically unproven in the reviewed conditions. No formulation, dose, or route can presently be recommended for disease modification, neurological recovery, or tissue regeneration.