With the epidemiological transition, causes of death shifted from communicable to non-communicable diseases (NCDs) and life expectancy increased, as these NCD deaths occurred later in life. However, in the United States, over the past years, life expectancy has been stagnating or decreasing despite decreasing NCD mortality rates. Analyses of the most important underlying causes of death with increasing premature mortality reveal that psychoactive substance use played a crucial role for these increases. Furthermore, it can be shown, that a high proportion of the increased premature mortality and decreased life expectancies happened in lower socio-economic strata. Substance use policies should thus focus on lowering the gap between substance-attributable mortality in higher versus lower socioeconomic strata.