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Adding to the complexity of this resurgent methamphetamine threat is the reality that the increases in methamphetamine availability and harms are occurring in the midst of and intertwined with the ongoing opioid overdose crisis. Opioid involvement in psychostimulant\u2010involved overdose deaths increased from 34.5% of overdose deaths in 2010 to 53.5% in 2019\u2014an increase of more than 50%. This latest evolution of the nation's overdose epidemic poses novel challenges for prevention, treatment, and harm reduction. This narrative review synthesizes what is known about changing patterns of methamphetamine use with and without opioids in the United States, other characteristics associated with methamphetamine use, the contributions of the changing illicit drug supply to use patterns and overdose risk, motivations for couse of methamphetamine and opioids, and awareness of exposure to opioids via the illicit methamphetamine supply. 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