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Precursors are indispensable for manufacturing synthetic opioids, methamphetamines, and semi-refined drugs like heroin and cocaine, yet the impact of their regulation on illicit drug markets remains underexplored. The last significant review, focused solely on North American methamphetamine and published 15 years ago, has left a knowledge gap now partially filled by newer studies that hint at the broader effects on other drugs but with inconsistent findings. This paper presents a systematic review, spanning 12 databases, to scrutinize the influence of precursor control on the supply and usage of illegal drugs, adhering to The Cochrane Collaboration's standards. Despite certain evidence limitations, our analysis indicates that regulating precursors could significantly curtail drug availability and alleviate related issues, potentially offering a cost-effective solution against the surge of synthetic opioids like fentanyl, which are increasingly problematic in North America and Europe. With the opioid crisis causing significant fatalities, effective precursor management might be key to reducing these tragic outcomes.