Highlights
- Fentanyl detection was nearly universal (93.2%) among out-of-treatment people who inject drugs (PWID) across five major US cities.
- Polysubstance use is the norm, with 94.8% of participants testing positive for fentanyl or opioids in combination with stimulants, benzodiazepines, or xylazine.
- Xylazine prevalence is extremely high in Philadelphia (99.1%) and rapidly increasing in New York City and Washington, DC.
- Unstable housing and recent incarceration are significantly associated with higher rates of cocaine and stimulant detection.
The Shifting Landscape of the American Overdose Crisis
The United States is currently navigating the most lethal phase of the overdose epidemic, often characterized as the fourth wave. This era is defined not just by the dominance of synthetic opioids like fentanyl, but by the rapid diversification and adulteration of the illicit drug supply. Clinicians and public health officials are increasingly confronted with polysubstance use patterns that complicate emergency response, withdrawal management, and long-term treatment engagement. Particularly vulnerable are those individuals who inject drugs (PWID) but remain outside the traditional medical and substance use disorder (SUD) treatment systems.
Understanding the real-time composition of the drug supply is critical for developing effective harm-reduction strategies. However, traditional surveillance often relies on post-mortem toxicology or seizure data, which may lag behind current street-level trends. The HPTN 094 study provides a crucial snapshot of the toxicological profile of active, out-of-treatment PWID across diverse geographic regions in the US.
Study Design and Methodology
The findings stem from a cross-sectional analysis of baseline data from the HIV Prevention Trials Network (HPTN) 094 study, a randomized clinical trial evaluating the efficacy of integrated mobile health units. The study enrolled 444 adults (aged 18 or older) who reported injecting drugs within the past 30 days and were not currently engaged in formal SUD treatment.
Data collection took place between June 2021 and September 2023 across five cities: New York City, Houston, Los Angeles, Philadelphia, and Washington, DC. Participants underwent comprehensive sociodemographic assessments, including housing status and recent incarceration history. The primary outcome was the toxicologic detection of illicit drugs using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), a highly sensitive method capable of identifying a wide array of substances and their metabolites.
Key Findings: A Crisis of Polysubstance Adulteration
The results of the analysis paint a sobering picture of the current drug environment. Across the total cohort, fentanyl was detected in 93.2% of participants, confirming its position as the foundational element of the illicit opioid market in all five cities. However, the presence of co-occurring substances was the most striking finding.
The Prevalence of Polysubstance Use
Approximately 94.8% of participants tested positive for polysubstance combinations. This includes the co-detection of fentanyl or other opioids with stimulants (cocaine or amphetamine-type stimulants), benzodiazepines, or the veterinary tranquilizer xylazine. The clinical implication of this is profound: the traditional model of treating a single-substance addiction is increasingly obsolete, as the majority of patients are inadvertently or intentionally consuming complex chemical cocktails.
Geographic Hotspots and the Xylazine Surge
While fentanyl was ubiquitous, the prevalence of other substances varied significantly by region. Xylazine, often referred to as tranq, was nearly universal in Philadelphia, detected in 99.1% of participants. The study also documented a significant upward trend in other East Coast cities. In New York City, xylazine detection increased by 10.3% every six months during the study period. Washington, DC, also showed high prevalence (75.6%). In contrast, Houston and Los Angeles reported significantly lower xylazine detection, though experts warn that these markets may soon follow the East Coast trend.
Stimulant Trends and Sociodemographic Vulnerabilities
The detection of stimulants—specifically cocaine and amphetamine-type stimulants (ATS)—remained high. Cocaine was detected in 73.9% of the total sample, while ATS were found in 67.3%. Interestingly, ATS detection in Washington, DC, saw a significant increase of 15.0% every six months. The study also highlighted how social determinants of health influence drug exposure. Cocaine prevalence was 11.4% higher among unhoused participants compared to those with stable housing. Furthermore, individuals with a history of recent incarceration were nearly 10% more likely to test positive for stimulants, suggesting that the transition from correctional facilities back to the community is a period of heightened risk for stimulant-involved drug use.
Clinical Implications and Expert Commentary
The high prevalence of xylazine and stimulants alongside fentanyl necessitates a shift in clinical management. Xylazine, a non-opioid alpha-2 adrenergic agonist, does not respond to naloxone. While naloxone remains the gold standard for reversing the opioid component of an overdose, clinicians must be prepared to provide enhanced respiratory support and manage severe necrotic skin ulcerations associated with chronic xylazine exposure.
The prevalence of stimulants also complicates the treatment of opioid use disorder (OUD). Patients using both fentanyl and stimulants may experience more severe withdrawal symptoms and may have lower retention rates in traditional methadone or buprenorphine programs. Integrated care models—such as the mobile units evaluated in HPTN 094—that address OUD, stimulant use, and primary medical needs (like wound care and HIV prevention) are essential.
Furthermore, the data suggests that much of this polysubstance use may be driven by the unregulated supply rather than individual preference. When the market is saturated with adulterants, PWID lose the ability to manage their own dosage and risk, making real-time drug checking services and public health alerts a vital component of modern harm reduction.
Conclusion
The HPTN 094 study underscores that the overdose crisis in the US has evolved into a complex polysubstance epidemic. With fentanyl now the baseline and xylazine and stimulants rapidly becoming standard additives, the risk of fatal overdose and associated morbidity is higher than ever. Addressing this crisis requires more than just expanding access to medications for OUD; it demands a comprehensive public health response that integrates real-time toxicological surveillance, addresses social vulnerabilities like housing and incarceration, and provides low-barrier, multi-disciplinary care to those most at risk.
Funding and Trial Registration
This research was supported by the HIV Prevention Trials Network (HPTN) and funded by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). The HPTN 094 study is registered at ClinicalTrials.gov (NCT04805125).
References
- El-Bassel N, Shoptaw S, Skalland T, et al. Prevalence of Illicit Drug Detection in 5 US Cities Among Out-of-Treatment People Who Inject Drugs. JAMA Netw Open. 2026;9(2):e2555882. doi:10.1001/jamanetworkopen.2025.55882
- Friedman J, Shover CL. The 4th wave: surging deaths involving stimulants and fentanyl in the United States. Addiction. 2023;118(11):2102-2111.
- Gupta R, Holtgrave DR, Ashburn MA. Xylazine — Medical and Public Health Imperatives. N Engl J Med. 2023;388(24):2209-2212.
