As US Fentanyl Use Declines, Polysubstance Abuse Including Fentanyl Soars: Millennium Health Signals Report
Fentanyl overdoses increasingly reveal combined use of stimulants including cocaine and methamphetamine, according to the 2025 update.
Fentanyl detection in urine drug tests declined by more than 12% from its peak in 2022, but polysubstance use among individuals using fentanyl continues to evolve, according to the latest Millennium Health Signals Report.1
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Analysis of more than 1.4 million urine drug tests revealed that in 2024, approximately 93% of fentanyl-positive specimens contained additional substances, with a 14% increase in stimulant co-use compared to the previous year.1 Data from the CDC echo the findings, showing that nearly 60% of 2023’s fatal fentanyl overdoses involved stimulants. The trend, referred to by some as the “fourth wave” of the overdose epidemic, adds complexity to already complicated public health responses.2
Polysubstance drug use can occur with or without a persons knowledge. The range of potential exposures found in combination overdose deaths include illegally made fentanyls, psychostimulants, benzodiazepines and prescription opioids in addition to illicit opioids, ie, heroin.2
Heroin detection in the polysubstance abuse population rose nearly 18% nationwide from 2023 to 2024, a disturbing increase and the first significant one in nearly a decade, according to the report. Heroin co-detection surpassed 30% in the latter half of 2024.1
“While fentanyl use is falling, the rise in heroin co-use among those using fentanyl is a trend we are watching closely,” Angela G Huskey, PharmD, CPE, Millennium Health senior vice president and chief clinical officer, said in the Signals Report. “Coupled with the continued increases in stimulant co-use, rapid shifts like this make the illicit drug supply dangerously unpredictable. This would be especially concerning if we were to see a further increase in the use of even more deadly opioids like carfentanil,” she added.1
Cocaine and methamphetamine were detected in the population using fentanyl more frequently in nearly every state during 2024. However, the report also found wide regional variations, with methamphetamine use most prevalent among fentanyl users in the West (more than 78%) and cocaine co-use highest in the Northeast (more than 54%).1
Although it was not included in the analysis for this report, the tranquilizer xylazine is being found increasingly in the illegal drug supply in the US and is particularly deadly when combined with opioids of any type, but especially fentanyl, according to the CDC.3 A study from the CDC’s State Unintentional Drug Overdose Reporting System demonstrated the monthly percentage of deaths involving illegally made fentanyl with xylazine detected increased from 3% in January 2019 to 11% in June 2022 among the 20 states sampled, plus Washington, DC.4
Urine drug testing samples for the 2025 Millennium Signals Report analysis were collected between January 1, 2016 and November 30, 2024 from individuals aged 18 years and older with a documented substance use disorder diagnosis. The specimens come from health care practices in all 50 states and represent nearly 500 000 unique patients, according to the press statement.1
