This Week’s Focus: 'Fentanyl-Plus'

This week, we decided to turn our focus to the content of Dan Ciccarone's, NDEWS SAG Chair, Donovan Memorial Fund Lecture on "fentanyl-plus." This Memorial Lecture is linked in this briefing for your convenience. This phenomenon, occurring late in the opioid crisis, involves “intentional combination use” like fentanyl with stimulants such as cocaine/methamphetamine; “unintentional use” stemming from adulteration of fentanyl with xylazine or benzos, and “unpredictably mixed substances” that were intended to be used as pharmaceutical drugs.

For this week, we analyzed EMS encounters for nonfatal overdoses (as we usually do) that involved fentanyl+cocaine or fentanyl+methamphetamine. We like to review nonfatal overdoses because they are an indicator of the effort we need to make with our harm reduction and prevention programs. Here the data show an increase in overdoses for northeastern states only.

Our Reddit analyses focused on fentanyl with benzodiazepine use. Several additional papers were included on use of both fentanyl and other drugs but two things are noteworthy: they focus on fatal consequences and the data they report are older. Our mission is continue to search for emerging trends of substances and as always, we rely on you for your support and guidance.

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Out of 31,147 EMS encounters for nonfatal "fentanyl-plus" (fentanyl+cocaine or fentanyl+methamphetamine)-related overdoses from January 1, 2024 to November 30, 2025,16,226 (52.1%) occurred in Western states, 3,751 (12.1%) in Midwestern states, 9,037 (29.0%) in Southern states and 2,133 (6.8%) in Northeastern states.

To view the entire Special Report from the weekly briefing, click here.

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Why are we reporting on this? The combination of Xanax (alprazolam) and fentanyl has high levels of discussion online. Discussants report fatal overdoses among peers, express fear about contaminated pill supplies, and describe using Xanax as a comfort medication during fentanyl withdrawal attempts.

What is Xanax + Fentanyl? Xanax (alprazolam) is a prescription benzodiazepine used to treat anxiety and panic disorders, while fentanyl is a potent synthetic opioid. The combination occurs through two primary routes: deliberate co-administration by Reddit users seeking enhanced sedation and euphoria, and unintentional exposure via counterfeit pressed Xanax bars contaminated with fentanyl. Bars pressed to resemble Xanax are widely available through in-person sellers as well as online markets, with commenters frequently reporting these pills contain either fentanyl or novel research chemical benzodiazepines rather than pharmaceutical alprazolam.

Public Health Impacts: Reddit discussants report significant concerns about fatal overdose risk from combining these central nervous system depressants. Multiple Reddit users describe deaths among friends and acquaintances attributed to fentanyl-adulterated Xanax or intentional co-use of both substances. Commenters express fear about respiratory depression, with some describing experiences of dangerously shallow breathing. Reddit users frequently discuss employing fentanyl test strips to screen pressed pills, though they acknowledge this does not guarantee safety. Multiple commenters describe extended blackout periods, memory loss, and impaired decision-making from combining these substances, sometimes leading to additional risky drug use while intoxicated.

How is it Being Discussed? Reddit commenters express significant anxiety about the prevalence of fentanyl in counterfeit Xanax pills. Discussants describe testing Xanax pills with fentanyl strips and finding positive results. Some discussants intentionally combine Xanax with fentanyl, describing the combination as producing enhanced sedation and euphoria. There is active discussion about Xanax and other benzodiazepines as comfort medications during fentanyl detoxification. Multiple posts describe attempts to transition from fentanyl.

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A recently published special article in the Journal of Medical Toxicology by NDEWS SAG Chair Dan Ciccarone overviews his keynote address from the 2025 ACMT Ward and Ryan Donovan Memorial Fund lecture. Ciccarone discussed polysubstance use in the "fentanyl-plus" era. Read the special article here.

A recently published study in Neuropsychopharmacology by Butelman et al. examined polydrug overdose mortality involving synthetic opioids (primarily fentanyl) and stimulants. The study utilized CDC WONDER data and joinpoint regression to determine that males consistently had double the overdose rates compared to females. The annual percent change for polydrug overdose dropped by 36% in males and 31% in females from 2023 to 2024. However, despite recent reductions, polydrug overdose rates remain higher than single-drug categories. Read the full study here.

A recently published study in Drug and Alcohol Dependence by Ray et al. examined overdose deaths in rural counties located in northern Minnesota. Data from 967 overdose deaths from 2022 to 2024 were analyzed and found that fentanyl was found in 55.2% of the cases, while 57.2% of stimulant-related deaths also involved co-use of opioids. A poly drug pattern of fentanyl + cocaine was found among Black/African American, while a poly drug pattern of fentanyl + methamphetamine was found among American Indian/Alaska Native and White deaths. Read the study here.

A recently published study in Pediatrics by Miller et al. analyzed youth overdose deaths from 2018-2022 as the illicit drug supply has become increasingly contaminated with fentanyl and other synthetics. The study noted that overdoses involving synthetic opioid and cocaine increased by 125%, and synthetic opioids and other stimulants rose 443%. Synthetic opioid plus benzodiazepines also spiked 146%, with the steepest year-to-year rise occurring between 2019 and 2020. The authors noted that the findings underscore the need for harm-reduction strategies targeting polysubstance risk. Read the full study here.

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The NDEWS Weekly Briefing curates emerging data and findings from across the Early Warning Network, which includes three core components: our Scientific Advisory Group (SAG), comprised of national experts and federal partners; our Sentinel Site Directors (SSDs), who lead local surveillance in key geographic regions; and our Community-Based Health Experts, who provide on-the-ground insights from populations most impacted by drug trends. Together, these contributors generate timely, multidisciplinary and impactful information, ranging from peer-reviewed research findings to local surveillance data. These contributions inform public health and research communities.

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If you miss or want to learn more about NDEWS Original Content, you can find our archived content on the NDEWS website:

     • NDEWS Hotspot Alerts using substance-related EMS data
     • NDEWS Rapid Street Reporting (RSR) survey data reports
     • NDEWS Web Monitoring Team Reddit Alerts
     • NDEWS Sentinel Site Reports
     • Previous issues of the NDEWS Weekly Briefings

The Weekly Briefing is a newsletter published each week by the National Drug Early Warning System (NDEWS) Coordinating Center, which is funded by the National Institute on Drug Abuse (U01DA051126) to the University of Florida (MPI: Cottler (contact), Co-Is: Goldberger, Nixon, Striley), NYU Langone Health (MPI: Palamar), and Florida Atlantic University (Co-I: Barenholtz). Any item may be reproduced provided the source is acknowledged.