Polysubstance Overdose

At a glance

  • Polysubstance drug use occurs with exposure to more than one drug, with or without the person's knowledge.
  • Polysubstance overdose deaths have increased. These include deaths involving stimulants, opioids, xylazine, and counterfeit pills.
Woman with her head on the corner of a bed.

Polysubstance overdose deaths have increased

Polysubstance drug use occurs with exposure to more than one drug, with or without the person's knowledge. This growing issue also means that an opioid-involved overdose often occurs in combination with exposure to other opioids and/or other non-opioid substances.1 Some examples of polysubstance exposures found in combination in overdose deaths include illegally made fentanyls (IMFs) and psychostimulants like cocaine and methamphetamine, and IMFs combined with benzodiazepines and prescription opioids or illicit opioids like heroin.2

Polysubstance Use (Using more than one drug)‎

-Exposure to more than one drug, with or without the person's knowledge


-Opioid-involved overdoses often occur in combination with exposure to other opioids and/or other non-opioid substances

From 2010-2016, there were significant increases in overdose deaths involving synthetic opioids that also involved prescription opioids, heroin, and other illegal or prescription drugs. Among synthetic opioid–involved overdose deaths in 2016, almost 80% involved another drug or alcohol, such as: another opioid, heroin, cocaine, prescription opioids, benzodiazepines, alcohol, psychostimulants, and antidepressants.2 In 2020, approximately 40% of deaths involving IMFs also involved stimulants.3

Polysubstance overdose deaths involving stimulants and opioids

Data indicate that the involvement of opioids in stimulant-involved deaths has increased. Nearly three-quarters (72.7%) of cocaine-involved overdose deaths also involved an opioid in 2017.4 Data have also indicated that synthetic opioids, in particular, appear to be driving increases in cocaine-involved overdose deaths.2 Approximately one-third of psychostimulant-involved deaths also involved synthetic opioids in 2019.5

Polysubstance overdose deaths involving illicit opioids and xylazine

A tranquilizer not approved for use in humans called xylazine is increasingly being found in the US illegal drug supply and linked to overdose deaths.6 Xylazine is especially dangerous when combined with opioids like fentanyl.

The presence of xylazine in drugs tested in labs increased in every region of the United States from 2020-2021, with the largest increase in the South.7 Studies from specific areas found similar increases. One study from 10 US cities showed xylazine was involved in less than 1% of drug overdose deaths in 2015 and in nearly 7% in 2020.8 In samples from eight syringe services programs in Maryland tested between 2021 and 2022, xylazine was found in almost 80% of drug samples that contained opioids.9 In Philadelphia, Pennsylvania, xylazine was found in 31% of overdose deaths involving heroin and/or fentanyl in 2019.10 In a recent study from CDC's State Unintentional Drug Overdose Reporting System (SUDORS), among 20 states and Washington D.C., the monthly percentage of deaths involving illegally made fentanyl (IMF) with xylazine detected increased from 3% in January 2019 to 11% in June 2022.11

Polysubstance overdose involving counterfeit pills

Unintentional polysubstance use occurs when a person takes drugs that have been mixed or cut with other substances, like fentanyl, without their knowledge. This can happen when drugs are mixed together, like when counterfeit pills contain more than one substance. Counterfeit pills, often containing dangerous substances like illegally made fentanyl (IMF) or other illegal drugs, are increasingly involved in overdose deaths. Younger people who have misused prescription drugs in the past are more likely to be affected.12

  • The percentage of overdose deaths with counterfeit pill evidence more than doubled from July–September 2019 (2.0%) to October–December 2021 (4.7%)
  • People who died from overdose involving counterfeit pills more often were younger, Hispanic, and had prescription drug misuse history12

What can people do to curtail or reduce the risk of overdose involving counterfeit pills:

  • Only take pills that are prescribed
  • Be aware that pills bought illegally might contain highly potent illegal drugs
  • Use fentanyl test strips (FTS), small strips of paper that can detect the presence of fentanyl in all different kinds of drugs (cocaine, methamphetamine, heroin, etc.) and drug forms (pills, powder, and injectables)
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Content Source:
National Center for Injury Prevention and Control
  1. CDC WONDER
  2. Jones CM, Einstein EB, Compton WM. Changes in Synthetic Opioid Involvement in Drug Overdose Deaths in the United States, 2010-2016. JAMA. 2018;319(17):1819-1821.
  3. O'Donnell J, Tanz LJ, Gladden RM, Davis NL, Bitting J. Trends in and Characteristics of Drug Overdose Deaths Involving Illicitly Manufactured Fentanyls — United States, 2019–2020. MMWR Morb Mortal Wkly Rep 2021;70:1740-1746. DOI: http://dx.doi.org/10.15585/mmwr.mm7050e3external icon.
  4. Kariisa M, Scholl L, Wilson N, Seth P, Hoots B. Drug Overdose Deaths involving Cocaine and Psychostimulants with Abuse Potential – United States, 2003-2017. Morb Mortal Wkly Rep. ePub. 3 May 2019.
  5. Kariisa M, Seth P, Scholl L, Wilson N, Davis N. Drug Overdose Deaths Involving Cocaine and Psychostimulants with Abuse Potential among Racial and Ethnic Groups – United States, 2004-2019. Drug and Alcohol Dependence. 2021; 227. https://doi.org/10.1016/j.drugalcdep.2021.109001
  6. Kariisa M, Patel P, Smith H, Bitting J. Notes from the field: xylazine detection and involvement in drug overdose deaths—United States, 2019. Morbidity and Mortality Weekly Report. 2021;70(37):1300.
  7. Drug Enforcement Administration. The growing threat of xylazine and its mixture with illicit drugs. 2022. https://www.dea.gov/sites/default/files/2022-12/The%20Growing%20Threat%20of%20Xylazine%20and%20its%20Mixture%20with%20Illicit%20Drugs.pdf
  8. Friedman J, Montero F, Bourgois P, et al. Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis. Drug and alcohol dependence. 2022;233:109380.
  9. Russell E, Sisco E, Thomson A, et al. Rapid Analysis of Drugs: A Pilot Surveillance System To Detect Changes in the Illicit Drug Supply To Guide Timely Harm Reduction Responses – Eight Syringe Services Programs, Maryland, November 2021-August 2022. MMWR Morb Mortal Wkly Rep. 2023;72(17):458-462. Published 2023 Apr 28. doi:10.15585/mmwr.mm7217a2
  10. J. Johnson, L. Pizzicato, C. Johnson, K. Viner. Increasing presence of xylazine in heroin and/or fentanyl deaths, Philadelphia, Pennsylvania, 2010-2019Inj. Prev. (2021), 10.1136/injuryprev-2020-043968 [pii]
  11. Kariisa M, O'Donnell J, Kumar S, Mattson CL, Goldberger BA. Illicitly Manufactured Fentanyl–Involved Overdose Deaths with Detected Xylazine — United States, January 2019–June 2022. MMWR Morb Mortal Wkly Rep 2023;72:721–727. DOI: http://dx.doi.org/10.15585/mmwr.mm7226a4
  12. O'Donnell J, Tanz LJ, Miller KD, et al. Drug Overdose Deaths with Evidence of Counterfeit Pill Use — United States, July 2019–December 2021. MMWR Morb Mortal Wkly Rep 2023;72:949–956. DOI: http://dx.doi.org/10.15585/mmwr.mm7235a3.