The assumption that melatonin is universally safe at any dose has collided with clinical reality in a way that could reshape how we approach this popular supplement. A rigorously designed trial testing melatonin's neuroprotective potential in multiple sclerosis patients had to be terminated early when participants developed dangerous liver enzyme elevations.
The MELATOMS-1 trial administered 300 mg daily of melatonin—roughly 100 times the typical sleep dose—to patients with primary progressive multiple sclerosis already receiving ocrelizumab, a disease-modifying therapy. This combination triggered hypertransaminasemia, a condition where liver enzymes surge to potentially harmful levels, forcing researchers to halt the study prematurely. The investigators are now analyzing whether drug-drug interactions between high-dose melatonin and ocrelizumab created this hepatotoxic effect, or if the massive melatonin dose alone overwhelmed hepatic processing capacity.
This finding represents a critical inflection point for melatonin research and clinical practice. While melatonin shows genuine promise for neurodegeneration based on robust preclinical data, the leap to therapeutic megadoses appears fraught with unforeseen risks. The liver toxicity signals that melatonin's safety profile, well-established at physiological doses, deteriorates dramatically at pharmacological concentrations. This challenges the widespread assumption that 'natural' compounds remain benign regardless of dose. For practitioners considering high-dose melatonin protocols—whether for neurodegeneration, cancer, or other conditions—this trial provides essential evidence that hepatic monitoring becomes imperative above conventional supplementation ranges. The research also underscores how drug combinations can create unexpected toxicity patterns even with individually well-tolerated therapies.