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In 2009, the U.S. Department of Justice issued a memo stating that it would not prosecute users and sellers who complied with the state laws allowing for medical use of marijuana. There are growing concerns about legalization of marijuana use and its related public health effects. We performed an interrupted time series analysis to evaluate these effects.We collected a representative sample of hospital discharge data from the Healthcare Cost and Utilization Project, from January 1993 to December 2014. We divided the data in to 3 groups: the prelegalization period (1993–2008), the legalization period (2009), and the postlegalization period (2010–2014). The disease variables were International Classification of Disease-Ninth Revision-Clinical Modification 304.30 cannabinoid dependency unspecified (CDU), 536.2 persistent vomiting, and an aggregate of CDU and persistent vomiting. We performed interrupted time series and Poisson-Gamma regression analysis to calculate each year’s incidence rate of unspecified and persistent vomiting and CDU per 100,000 hospital discharges. CDU, persistent vomiting, and aggregate of CDU and persistent vomiting were modeled separately to estimate average incidence rate ratio and 95% confidence interval for each study phase.We observed an increasing trend of CDU or an aggregate of CDU and persistent vomiting during the prelegalization period. The legalization of marijuana significantly increased the incidence rate during the legalization period (by 17.9%) and the yearly average increase in rate by 6% after policy implementation, compared to the prelegalization period. The increase in rate of persistent vomiting after policy implementation increased significantly (by about 8%), although there were no significant trends in increase prior to or during marijuana legalization in 2009.In an interrupted time series analysis of before, during, and after medical marijuana legalization, we estimated levels and rate changes in CDU and persistent vomiting. We found persistent increases in rates of CDU and persistent vomiting during and after legalization of marijuana.