["The Milbank Quarterly, EarlyView. ", "\n\n\n\nPolicy Points\n\nThe liberalization of medical and recreational cannabis policies may increase cannabis initiation across age groups, with increased prevalence of cannabis use among young adults and adults and weaker effects among youth. Evidence also suggests increases in cannabis‐related health care utilization among adults.\nAlcohol use may decrease following medical legalization (suggesting use of cannabis in place of alcohol), but it may increase among young adults following recreational legalization (suggesting co‐consumption).\nEvidence suggests a potential decrease in tobacco use across age groups and cannabis policy changes, and most studies found no change or a decrease in opioid‐related outcomes, although evidence was less consistent for opioid‐related mortality specifically.\n\n\n\nContext\nSubstantial changes in cannabis policies are occurring globally; however, the impacts of these reforms on cannabis use, as well as downstream effects on other substance use, remain unclear.\n\n\nMethods\nWe conducted a systematic review to identify studies examining the impact of a cannabis policy change on substance use. We searched Embase, Medline, PsycINFO, the Web of Science Core Collection, and the Criminal Justice Database, as well as gray literature sources including the Social Science Research Network. The included studies employed a quasi‐experimental approach and were assessed for risk of bias using a modified version of ROBINS‐I to facilitate the assessment of these designs. The findings were synthesized using a descriptive, analytical approach.\n\n\nFindings\nThe included reports (N = 176) were published between 1993 and 2024, with approximately two‐thirds published after 2019. Most were peer‐reviewed publications (n = 148) applying a difference‐in‐differences (n = 129) or interrupted time series (n = 42) approach to data from the United States (n = 141). Medical and recreational cannabis legalization may increase cannabis initiation across age groups, with increased prevalence of cannabis use among young adults and adults and inconsistent evidence among youth. The impacts on alcohol use were differential by policy and age group, with potential decreases following medical legalization and potential increases following recreational legalization among young adults. Evidence from a limited number of studies suggested potential decreases in tobacco use among all age groups. Most studies found no change or a decrease in opioid‐related outcomes, although evidence was less consistent for opioid‐related mortality. We found few studies examining cannabis decriminalization, with no clear evidence of changes in cannabis or other substance use.\n\n\nConclusions\nOverall, these findings suggest that medical and recreational legalization increase cannabis use, with weaker effects among youth. In addition, potential substitution effects were identified for other substances (e.g., alcohol, tobacco, opioids), excepting complementary alcohol use among young adults following recreational cannabis legalization.\n\n"]