A central question in the study of health politics and policy is the degree to which the state can shape American medicine. This long-standing debate began amid early battles over health insurance and continues through the contemporary opioid epidemic. Unlike recent and post–Affordable Care Act claims emphasizing the federal government's strong ability to intervene in healthcare marketplaces, this article supports claims of medicine's autonomy from political intervention, drawing on an extensive analysis of recurrent, halting, and largely unsuccessful efforts to regulate popular psychopharmaceutical drugs from the 1940s through the 1980s. I first develop an account of a “pocket of weakness,” the post-marketing pharmaceutical regulatory process, in an otherwise strong institution, the Food and Drug Administration (FDA). I then demonstrate how this regulatory structure, interacting with policymakers’ incentives, caused constrained responses, inaction, and drift. Amid concerns about misuse, overuse, abuse, side effects, and addiction, regulators and legislators found it difficult to restrict access to or disincentivize the prescription and consumption of problematic therapeutics, in spite of their varied and repeated regulatory efforts. This elaboration of a pocket of weakness has important theoretical implications for historical institutionalist scholarship that principally focuses on state strength. This account also has substantive implications for scholarship on health politics and policy, mental health treatment, and the political causes of medicalization, and can help explain the opioid epidemic's emergence, potential trajectory, and circumscribed solution set.