Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence

This systematic review assesses off-label and repurposed uses of disulfiram (DIS) beyond alcohol dependence, synthesizing clinical trials, case reports, and preclinical studies (2015-2025) per PRISMA 2020 guidelines. Database and registry searches yielded 229 studies: 44 clinical trials (mainly cancer, infectious diseases) and 185 articles. Cancer-led indications, followed by infectious, inflammatory, cognitive, and metabolic diseases. Off-label use is under-documented; trials often failed due to recruitment issues, poor responses, adverse events, or funding. They yielded data on high-dose regimens and safety, stressing risk-benefit assessments. Preclinical promise faces clinical hurdles such as poor bioavailability, formulation limits, and high-dose toxicity. Key barriers: (1) low oral bioavailability and rapid hepatic metabolism, (2) unscaled delivery systems, (3) adverse events needing evaluation. DIS holds life cycle potential via multifaceted mechanisms; success demands optimized delivery, rigorous trials, and scalable formulations.