Although there is little dispute about the impact of the US opioid epidemic on recent mortality, there is less consensus about whether trends reflect increasing despair among American adults. The issue is complicated by the absence of established scales or definitions of despair as well as a paucity of studies examining changes in psychological health, especially well-being, since the 1990s. We contribute evidence using two cross-sectional waves of the Midlife in the United States (MIDUS) study to assess changes in measures of psychological distress and well-being. These measures capture negative emotions such as sadness, hopelessness, and worthlessness, and positive emotions such as happiness, fulfillment, and life satisfaction. Most of the measures reveal increasing distress and decreasing well-being across the age span for those of low relative socioeconomic position, in contrast to little decline or modest improvement for persons of high relative position.