Recent research has suggested that increases in mortality among middle-aged US Whites are being driven by suicides and poisonings from alcohol and drug use. Increases in these 'despair' deaths have been argued to reflect a cohort-based epidemic of pain and distress among middle-aged US Whites. We examine trends in all-cause and cause-specific mortality rates among younger and middle-aged US White men and women between 1980 and 2014, using official US mortality data. We estimate trends in cause-specific mortality from suicides, alcohol-related deaths, drug-related deaths, 'metabolic diseases' (i.e. deaths from heart diseases, diabetes, obesity and/or hypertension), and residual deaths from extrinsic causes (i.e. causes external to the body). We examine variation in mortality trends by gender, age and cause of death, and decompose trends into period- and cohort-based variation. Trends in middle-aged US White mortality vary considerably by cause and gender. The relative contribution to overall mortality rates from drug-related deaths has increased dramatically since the early 1990s, but the contributions from suicide and alcohol-related deaths have remained stable. Rising mortality from drug-related deaths exhibit strong period-based patterns. Declines in deaths from metabolic diseases have slowed for middle-aged White men and have stalled for middle-aged White women, and exhibit strong cohort-based patterns. We find little empirical support for the pain- and distress-based explanations for rising mortality in the US White population. Instead, recent mortality increases among younger and middle-aged US White men and women have likely been shaped by the US opiate epidemic and an expanding obesogenic environment.