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Oklahoma's medical cannabis is some of the least restrictive in the US. Previous research suggests that American Indian/Alaska Native (AIAN) have higher rates of cannabis use than other racial or ethnic groups. The goals of this paper are, first, to look at cannabis use among high school students living on the Cherokee Nation Reservation before (2017) and after (2019) medical cannabis because legal in Oklahoma (2018) utilizing the Cherokee Nation Youth Risk Behavior Survey (CNYRBS). Second, to describe the socio-demographic characteristics of youth using cannabis in the Cherokee Nation Reservation. Data were retrieved from the 2017 and 2019 CNYRBS. The data for this study included 1,216 high school students who completed the 2017 and 1,476 who completed the 2019 CNYRBS. After removal of incomplete records, there were 2,602 students whose data was analyzed in this study. Data were weighted to be representative of public-school students attending grades 9–12 within Cherokee Nation Reservation. Despite the legalization of medical cannabis in Oklahoma in 2018, there was no change in cannabis use among youth between 2017 and 2019. There were variations in cannabis use based on demographic factors and other substance uses. AIAN individuals had higher odds of current cannabis use compared to non-Hispanic White students, but there were no differences based on ethnicity. Additionally, the use of cigarettes, e-cigarettes, alcohol, and illegal drugs were associated with increased odds of cannabis use among both current and former users compared to those who had never used it. There was no spike in use among youth at least immediately after the legalization of cannabis in the Cherokee Nation Reservation. There were socio-demographic as well as substance use disparities in the use of cannabis. [ABSTRACT FROM AUTHOR]