The UC San Diego observational analysis of CDC WONDER data, encompassing every U.S. overdose death from 1999-2024 (a near-complete national sample rather than RCT), documents the first decline across all four epidemic waves. Fentanyl-involved fatalities drove the 24.4% national drop to 23.7 per 100,000, yet the study reveals persistent fourth-wave polysubstance patterns and emerging fifth-wave threats from stimulants alone. This observational design, while robust in scale, lacks the causal controls of randomized trials and carries no reported conflicts. Beyond the MedicalXpress summary, regional policy unevenness explains disparities: states with expanded naloxone distribution and fentanyl test strips saw sharper fentanyl declines, while areas slow to adopt stimulant-specific interventions (e.g., contingency management) face rising methamphetamine and cocaine deaths now at 23.8% of total fatalities. Racial patterns—Black Americans at 1.5x national average despite 29.3% improvement, AIAN at 50.8 per 100,000—mirror longstanding inequities in access to medications for opioid use disorder. Xylazine co-involvement signals supply-chain shifts missed in headline coverage. Synthesizing with Ciccarone's 2023 Addiction review on heroin-to-fentanyl transitions and a 2024 JAMA Network Open analysis of stimulant mortality, the data indicate that single-substance focus in drug policy has plateaued; integrated harm reduction addressing cardiovascular harms from stimulants is now essential.