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Drug checking interventions such as fentanyl test strips and Fourier Transform Infrared Spectroscopy are essential for harm reduction, yet they also highlight a central policy failure: they place the burden of safety on people who use drugs (PWUD) and frontline programs after drugs have already entered an unregulated market. We argue for a more pragmatic upstream public health response, authorizing pilots of a safer, regulated drug supply (\u201csafer supply\u201d), broadly defined as legal and regulated access to psychoactive substances or close pharmaceutical alternatives intended to reduce reliance on the unregulated drug market. International experience, particularly models in Switzerland, Canada, and the United Kingdom, demonstrates feasibility and suggests potential benefits, including improved health and social stability, reduced reliance on unregulated supply, and reduced acute care utilization in some settings. For the United States context, we propose a portfolio approach: near-term, healthcare-based pilots leveraging existing controlled-substance infrastructure (eg, opioid treatment programs, clinics, pharmacies, and tech-enabled dispensing) while preserving space for community-governed models with legal protections and longer-horizon, state-regulated pathways. We address predictable concerns (secondary sharing, youth initiation, community impact, mixed population-level findings) and outline guardrails and evaluation strategies that are PWUD-led, nonpunitive, and methodologically rigorous. We conclude with concrete policy actions to authorize pilots, establish legal protections, fund independent evaluation, and scale models that demonstrably reduce harm while integrating with harm reduction and treatment services.<\/jats:p>","DOI":"10.1177\/29767342261462675","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:04:30Z","timestamp":1784005470000},"page":"995-1005","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Upstream Overdose Prevention: Why the US Should Pilot a Safer, Regulated Drug Supply"],"prefix":"10.1177","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-3012","authenticated-orcid":false,"given":"Tessa L.","family":"Rife-Pennington","sequence":"first","affiliation":[{"name":"Pharmacy Service, San Francisco VA Health Care System, CA, USA"},{"name":"Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, CA, USA"},{"name":"Department of Pharmacy Practice, Thomas J. 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