Prevalence of Illicit Drug Detection in 5 US Cities Among Out-of-Treatment People Who Inject Drugs.

Importance: In the US, the overdose crisis continues to be driven by fentanyl, xylazine, and stimulant-involved polysubstance use among people who inject drugs, especially those who are not engaged in medical care. Objective: To estimate the overall prevalence of illicit drugs detected among people who inject drugs in 5 US cities by city and sociodemographic characteristics and assess trends in drug detection over a 2-year period. Design, Setting, and Participants: This cross-sectional study included data from individuals enrolled in HIV Prevention Trials Network (HPTN) 094, a randomized clinical trial to evaluate an integrated mobile unit engaging adults aged 18 years or older who inject drugs in HIV services between June 2021 and September 2023 in New York City; Houston, Texas; Los Angeles, California; Philadelphia, Pennsylvania; and Washington, DC. All analyses were completed between August 2021 and August 2025. Main Outcomes and Measures: Baseline prevalence of toxicologic detection was assessed using liquid chromatography-high-resolution mass spectrometry. Differences in toxicologic detection by sociodemographic characteristics (age, race and ethnicity, housing status, and incarceration history), study site, and illicit drug type over time were analyzed using generalized linear models. Results: Across 444 participants, 303 (68.2%) were male, 267 (60.1%) were aged 30 to 49 years, 203 of 440 (46.1%) were unhoused, and 91 of 442 (20.6%) had a recent incarceration history. In all, 414 participants (93.2%) tested positive for fentanyl, 328 (73.9%) for cocaine, 299 (67.3%) for amphetamine-type stimulants, and 234 (52.7%) for xylazine. Nearly all participants (421 [94.8%]) tested positive for polysubstance drugs (fentanyl or opioids with stimulants, benzodiazepines, cocaine, and/or xylazine). Fentanyl detection was high across all sites; xylazine was most common in New York City (68 of 94 [72.3%]), Philadelphia (111 of 112 [99.1%]), and Washington, DC (31 of 41 [75.6%]). Every 6 months, xylazine detection increased in New York City by 10.3% (95% CI, 4.0%-16.5%; P = .001), and its prevalence stayed high in Philadelphia. Amphetamine-type stimulant detection increased in Washington, DC, by 15.0% (95% CI, 2.9%-27.1%) every 6 months over the enrollment period (P = .02). Across all sites, cocaine prevalence was higher among unhoused than housed participants (difference, 11.4%; 95% CI, 3.6%-19.2%; P = .004), and stimulant detection was elevated among those recently incarcerated vs not (difference, 9.9%; 95% CI, 1.4%-18.5%; P = .02). Conclusions and Relevance: This cross-sectional study found widespread fentanyl and polysubstance detection, with rising xylazine and stimulant detection that varied by sociodemographic and structural vulnerabilities and may be due to adulteration within the unregulated drug supply. These findings highlight urgent public health needs for real-time drug supply surveillance, targeted harm-reduction services, and integrated treatment approaches to reduce overdose risk and address social and structural vulnerabilities.