Fentanyl-related harm reduction and structural determinants of overdose in the United States: An umbrella review with AMSTAR-2 Appraisal

Background: Illicitly manufactured fentanyl has reshaped the U.S. overdose crisis, driving unprecedented mortality and intensifying demand for harm reduction and policy responses. Although numerous systematic and scoping reviews have examined naloxone distribution, fentanyl test strips (FTS), supervised consumption services, and structural determinants of overdose, the review-level evidence remains fragmented and methodologically heterogeneous. This umbrella review synthesizes existing reviews and appraises their methodological quality using AMSTAR-2.
Methods: A systematic PubMed search identified systematic and scoping reviews published between 2020 and 2025 examining U.S.-focused fentanyl-related harm reduction strategies, behavioral health policy, and structural determinants of overdose. Study selection followed PRISMA 2020 guidance. Methodological quality was assessed using AMSTAR-2. Findings were synthesized narratively and interpreted according to methodological confidence.
Results: Seven reviews met inclusion criteria (three systematic, four scoping). Interventions included naloxone distribution, fentanyl test strips, supervised consumption services, law enforcement drug seizure practices, and equity-focused harm reduction strategies. Naloxone expansion was consistently associated with reduced overdose mortality and improved bystander response. FTS demonstrated high acceptability and self-reported behavioral modification. Structural marginalization including poverty, housing instability, and criminal legal involvement was strongly associated with overdose vulnerability. However, five of seven reviews (71.4%) were rated critically low confidence under AMSTAR-2, primarily due to absence of protocol registration and lack of formal risk-of-bias assessment.
Conclusions: Fentanyl-related harm reduction strategies show consistent directional promise, but the review-level evidence base remains methodologically fragile. Strengthening systematic synthesis and equity-focused evaluation is essential to inform durable overdose prevention policy.