Opioid Overdose Crisis Compounded by Polysubstance Use

New strategies can reduce the risks from using more than one drug

Opioid Overdose Crisis Compounded by Polysubstance Use
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Polysubstance use—when more than one drug is used or misused over a defined period of time1—can occur from either the intentional use of opioids with other drugs or by accident, such as if street drugs are contaminated with synthetic opioids.2 In the first half of 2018, nearly 63% of opioid overdose deaths in the United States also involved cocaine, methamphetamine, or benzodiazepines, signaling the need to address polysubstance use as part of a comprehensive response to the opioid epidemic.3 Fentanyl, a highly potent synthetic opioid, has been identified as a driver of overdose deaths involving other opioids, benzodiazepines, alcohol, methamphetamine, and cocaine.4

Two classes of drugs are frequently co-used with opioids: depressants and stimulants. Although there are medical uses for some drugs in these classes, they also all have high potential for misuse.5 Mixing opioids—which are depressants—with other depressants or stimulants, either intentionally or unknowingly, has contributed to the rising number of opioid overdose deaths, which have more than doubled since 2010.6 Efforts to reduce opioid overdose deaths should incorporate strategies to prevent, mitigate, and treat the use of multiple substances. 


Depressants act on the central nervous system to induce relaxation, reduce anxiety, and increase drowsiness.7 Opioid use concurrent with the use of another sedating drug compounds the respiratory depressant effect of each drug, creating a higher risk for overdose and fatal overdose than when either drug is used alone.8


Benzodiazepines are prescribed for medical use as sedatives but are commonly misused for nonmedical purposes and in combination with prescription and illicit opioids.9 In 2018, just over 9,000 U.S. deaths involved both opioids and benzodiazepines, more than twice the number of 2008 deaths due to such co-use.10  Moreover, in 2018, nearly half (47.2%) of benzodiazepine overdose deaths involved synthetic opioids (e.g., fentanyl).11 Fatal overdoses involving both prescription opioids and benzodiazepines nearly tripled from 2004 to 2011.12


In 2017, 15% of opioid overdose deaths involved alcohol.13 From 2012 to 2014, more than 2 million people who misused prescription opioids were also binge drinkers of alcohol (defined as more than five drinks for a man or more than four drinks for a woman within a two-hour period); compared with nondrinkers, binge drinkers were associated with being twice as likely to misuse prescription opioids.14 Evidence indicates that about 23% of people with an opioid use disorder have a concurrent alcohol use disorder.15


Stimulants increase arousal and activity in the brain.16 In 2017, opioids were involved in more than half of stimulant-involved overdose deaths—about 15,000 total.17 The co-use of stimulants with synthetic opioids such as fentanyl either intentionally or through drug contamination has increased the number of stimulant-involved overdose deaths.18 The opposing impacts of increased arousal from stimulants and sedation from opioids on the body can make the outcomes of co-use less predictable and raise the risk of overdose.19


About 12% of opioid overdose deaths from January to June 2018 involved methamphetamine, an illicit drug.20 In 2017, opioids were involved in 50% of methamphetamine-involved deaths, and recent data suggests synthetic opioids are driving increases in methamphetamine-involved deaths.21 One study found that 65% of those seeking opioid treatment had reported a history of methamphetamine use, with more than three-quarters of them indicating that they had used methamphetamines and opioids mostly at the same time or on the same day.22


Of the nearly 15,000 cocaine overdose deaths in 2018, nearly 11,000 also involved opioids; this number accounts for about 23% of the total opioid overdose deaths that year.23 In fact, since 2010 the number of deaths caused by a combination of opioids and cocaine has increased more than fivefold.24 People who primarily use cocaine but sometimes co-use opioids are at high risk for overdose because of the increasing presence and potency of fentanyl in the drug supply and a lower tolerance for opioids than someone who regularly uses them.25

What should be done?

It is critical that state policies addressing the rise in polysubstance use and its link to increased risk of overdose span across prevention, harm reduction, and treatment strategies. To effectively accomplish this, states should:

  • Enact policies that increase provider use of prescription drug monitoring programs (PDMPs) to reduce the co-prescription of opioids and benzodiazepines.26 PDMPs, state-based electronic databases that contain information on controlled substance prescriptions, allow prescribers and pharmacists to monitor patients’ prescription drug use and can promote safer prescribing practices that help prevent overdoses. High rates of benzodiazepine prescribing are correlated with the drug’s involvement in opioid overdose deaths.27
  • Expand naloxone distribution to reach people who use stimulants.28 Naloxone reverses the respiratory depression effects of opioids to safeguard against a fatal overdose and remains effective when people use opioids in combination with other drugs.29 Considering that opioids are frequently implicated in cocaine and methamphetamine overdose deaths, people who primarily use stimulants are recognized as an at-risk population for opioid overdose.30 Laws that allow for increased community distribution of naloxone can help safeguard against polysubstance use overdoses.31
  • Amend drug paraphernalia laws to allow possession of fentanyl test strips. Fentanyl test strips can detect the presence of fentanyl in a person’s drug supply when dipped into a solution of a small amount of the drug in water. People who use drugs have indicated that if a test strip found fentanyl in their supply, they would take measures to prevent an overdose, such as injecting at a slower pace or using less of the drug at a time.32 Fentanyl test strips are mainly used by people who inject opioids but can also be helpful for those who use stimulants and fear fentanyl contamination by preventing unintentional co-use that could lead to a fatal overdose.33 Amending drug paraphernalia laws to allow the possession of drug-checking devices, including fentanyl test strips, would permit agencies and organizations to distribute test strips to people who use drugs and help to prevent fentanyl-related overdose deaths.34
  • Prohibit the discharge of patients from publicly funded opioid use disorder (OUD) treatment programs for their continued substance use.35 Treatment programs often discharge patients from treatment involuntarily because of their continued illicit drug use (a practice commonly called administrative discharge).36 This practice poses a particular risk for patients being treated for OUD with methadone or buprenorphine who are at high risk for overdose if discharged without medication.37 Although co-use of other drugs, such as stimulants, with medications for OUD can interfere with treatment, it remains safer for patients to continue medication treatment because of their high risk for overdose from using illicit opioids.38 People with OUD who use benzodiazepines are particularly at higher risk for overdose when not on medication treatment.39 Federal guidelines recommend avoiding administrative discharge and instead suggest that treatment programs re-evaluate a patient’s needed level of care if the current treatment plan proves ineffective.40


As the increase in opioid use evolves into an increase in polysubstance use, understanding how different substances interact may inform strategies that help prevent overdose. Though some individuals knowingly combine or co-use opioids with stimulants or other depressants, an additional and growing concern is the adulteration of other drug supplies with fentanyl. Strengthening policy efforts across the continuum of prevention, harm reduction, and treatment to address the risks of polysubstance use can slow the rates of drug overdose deaths in the United States.


  1. J.P. Connor et al., “Polysubstance Use: Diagnostic Challenges, Patterns of Use and Health,” Current Opinion in Psychiatry 27, no. 4 (2014): 269-75, https://www.ncbi.nlm.nih.gov/pubmed/24852056.
  2. Centers for Disease Control and Prevention, “What Is Fentanyl?,” last modified March 19, 2020, https://www.cdc.gov/drugoverdose/opioids/fentanyl.html; M.S. Ellis, Z.A. Kasper, and T.J. Cicero, “Twin Epidemics: The Surging Rise of Methamphetamine Use in Chronic Opioid Users,” Drug and Alcohol Dependence 193 (2018): 14-20, http://www.sciencedirect.com/science/article/pii/S0376871618306872.
  3. R.M. Gladden et al., “Changes in Opioid-Involved Overdose Deaths by Opioid Type and Presence of Benzodiazepines, Cocaine, and Methamphetamine—25 States, July-December 2017 to January-June 2018,” Morbidity and Mortality Weekly Report 68, no. 34 (2019): 73744, https://pubmed.ncbi.nlm.nih.gov/31465320.
  4. Centers for Disease Control and Prevention, “What Is Fentanyl?”; C.M. Jones, E.B. Einstein, and W.M. Compton, “Changes in Synthetic Opioid Involvement in Drug Overdose Deaths in the United States, 2010-2016,” JAMA 319, no. 17 (2018): 1819-21, https://www.ncbi.nlm.nih.gov/pubmed/29715347.
  5. T. Favrod-Coune and B. Broers, “The Health Effect of Psychostimulants: A Literature Review,” Pharmaceuticals 3, no. 7 (2010): 2333-61, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036656/; U.S. Drug Enforcement Administration, “Depressants,” accessed August 24, 2020, https://www.dea.gov/taxonomy/term/316; U.S. Drug Enforcement Administration, “Stimulants,” accessed August 24, 2020, https://www.dea.gov/taxonomy/term/346.
  6. National Institute on Drug Abuse, “Overdose Death Rates,” last modified March 10, 2020, https://www.drugabuse.gov/drug-topics/trends-statistics/overdose-death-rates.
  7. U.S. Drug Enforcement Administration, “Depressants.”
  8. J.D. Jones, S. Mogali, and S.D. Comer, “Polydrug Abuse: A Review of Opioid and Benzodiazepine Combination Use,” Drug and Alcohol Dependence 125, no. 1-2 (2012): 8-18, https://www.ncbi.nlm.nih.gov/pubmed/22857878.
  9. J.A. Gudin et al., “Risks, Management, and Monitoring of Combination Opioid, Benzodiazepines, and/or Alcohol Use,” Postgraduate Medical Journal 125, no. 4 (2013): 115-30, https://www.ncbi.nlm.nih.gov/pubmed/23933900.
  10. Centers for Disease Control and Prevention, Multiple Cause of Death 1999-2018, accessed August 24, 2020, http://wonder.cdc.gov/mcd-icd10.html.
  11. National Institute on Drug Abuse, “Overdose Death Rates”; Centers for Disease Control and Prevention, Multiple Cause of Death 19992018.
  12. C.M. Jones and J.K. McAninch, “Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines,” American Journal of Preventive Medicine 49, no. 4 (2015): 493-50, https://pubmed.ncbi.nlm.nih.gov/26143953/.
  13. M.E. Tori, M.R. Larochelle, and T.S. Naimi, “Alcohol or Benzodiazepine Co-Involvement With Opioid Overdose Deaths in the United States, 1999-2017,” JAMA Network Open 3, no. 4 (2020): e202361, https://www.ncbi.nlm.nih.gov/pubmed/32271389.
  14. M.B. Esser et al., “Binge Drinking and Prescription Opioid Misuse in the U.S., 2012-2014,” American Journal of Preventive Medicine 57, no. 2 (2019): 197-208, https://www.ncbi.nlm.nih.gov/pubmed/31200998.
  15. Y.I. Hser et al., “Chronic Pain Among Patients With Opioid Use Disorder: Results From Electronic Health Records Data,” Journal of Substance Abuse Treatment 77 (2017): 26-30, https://www.ncbi.nlm.nih.gov/pubmed/28476267.
  16. U.S. Drug Enforcement Administration, “Stimulants.”
  17. M. Kariisa et al., “Drug Overdose Deaths Involving Cocaine and Psychostimulants With Abuse Potential—United States, 2003-2017,” Morbidity and Mortality Weekly Report 68, no. 17 (2019): 388-95, https://pubmed.ncbi.nlm.nih.gov/31048676.
  18. Ibid.
  19. A. Al-Tayyib et al., “Heroin and Methamphetamine Injection: An Emerging Drug Use Pattern,” Substance Use & Misuse 52, no. 8 (2017): 1051-58, https://pubmed.ncbi.nlm.nih.gov/28323507/.
  20. Gladden et al., “Changes in Opioid-Involved Overdose Deaths.”
  21. National Institute on Drug Abuse, “What Is the Scope of Methamphetamine Misuse in the United States?,” last modified October 2019, https://www.drugabuse.gov/publications/research-reports/methamphetamine/what-scope-methamphetamine-misuse-in-united-states; Kariisa et al., “Drug Overdose Deaths Involving Cocaine and Psychostimulants.”
  22. Ellis, Kasper, and Cicero, “Twin Epidemics.”
  23. Centers for Disease Control and Prevention, Multiple Cause of Death 1999-2018; Kariisa et al., “Drug Overdose Deaths Involving Cocaine and Psychostimulants.”
  24. National Institute on Drug Abuse, “Overdose Death Rates”; Kariisa et al., “Drug Overdose Deaths Involving Cocaine and Psychostimulants”; C. McCall Jones, G.T. Baldwin, and W.M. Compton, “Recent Increases in Cocaine-Related Overdose Deaths and the Role of Opioids,” American Journal of Public Health 107, no. 3 (2017): 430-32; Centers for Disease Control and Prevention, Multiple Cause of Death 1999-2018.
  25. McCall Jones, Baldwin, and Compton, “Recent Increases in Cocaine-Related Overdose Deaths”; M.L. Nolan et al., “Increased Presence of Fentanyl in Cocaine-Involved Fatal Overdoses: Implications for Prevention,” Journal of Urban Health 96, no. 1 (2019): 49-54, https://www.ncbi.nlm.nih.gov/pubmed/30635841.
  26. L.J. Paulozzi, K.A. Mack, and J.M. Hockenberry, “Vital Signs: Variation Among States in Prescribing of Opioid Pain Relievers and Benzodiazepines—United States, 2012,” Morbidity and Mortality Weekly Report 63, no. 26 (2014): 563; https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6326a2.htm.
  27. Tori, Larochelle, and Naimi, “Alcohol or Benzodiazepine Co-Involvement With Opioid Overdose Deaths.”
  28. U.S. Department of Health and Human Services, “Naloxone: The Opioid Reversal Drug That Saves Lives” (2018), https://www.hhs.gov/opioids/sites/default/files/2018-12/naloxone-coprescribing-guidance.pdf. .
  29. Substance Abuse and Mental Health Services Administration, “Naloxone,” last modified August 19, 2020, accessed August 24, 2020, https://www.samhsa.gov/medication-assisted-treatment/treatment/naloxone.
  30. U.S. Department of Health and Human Services, “Naloxone: The Opioid Reversal Drug That Saves Lives.”
  31. K.E. Schneider et al., “Patterns of Polysubstance Use and Overdose Among People Who Inject Drugs in Baltimore, Maryland: A Latent Class Analysis,” Drug and Alcohol Dependence 201 (2019): 71-77, https://www.sciencedirect.com/science/article/abs/pii/S0376871619301711.
  32. N.C. Peiper et al., “Fentanyl Test Strips as an Opioid Overdose Prevention Strategy: Findings From a Syringe Services Program in the Southeastern United States,” International Journal of Drug Policy 63 (2019): 122-28, https://www.ncbi.nlm.nih.gov/pubmed/30292493; S. Sherman et al., “FORECAST Study Summary Report” (Johns Hopkins Bloomberg School of Public Health, 2018).
  33. National Harm Reduction Coalition, “Fentanyl Test Strip Pilot: San Francisco 2017-2018,” last modified September 8, 2020, accessed September 15, 2020, 2018, https://harmreduction.org/issue-area/overdose-prevention-issue-area/fentanyl-test-strip-pilot/.
  34. C.S. Davis, D.H. Carr, and E.A. Samuels, “Paraphernalia Laws, Criminalizing Possession and Distribution of Items Used to Consume Illicit Drugs, and Injection-Related Harm,” American Journal of Public Health 109, no. 11 (2019): 1564-67, https://www.ncbi.nlm.nih.gov/pubmed/31536408.
  35. W.L. White et al., “It’s Time to Stop Kicking People Out of Addiction Treatment,” Counselor 6, no. 2 (2005): 12, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338434/.
  36. Ibid.
  37. National Academies of Sciences, Engineering, and Medicine, “Medications for Opioid Use Disorder Save Lives” (2019), https://doi.org/10.17226/25310.
  38. Ibid.
  39. U.S. Food and Drug Administration, “FDA Drug Safety Communication: FDA Urges Caution About Withholding Opioid Addiction Medications From Patients Taking Benzodiazepines or CNS Depressants: Careful Medication Management Can Reduce Risks,” Sept. 26, 2017, https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-urges-caution-about-withholdingopioid-addiction-medications.
  40. U.S. Department of health and Human Services, “Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs, a Treatment Improvement Protocol: TIP 43” (2005), https://www.asam.org/docs/advocacy/samhsa_tip43_matforopioidaddiction.pdf?sfvrsn=0.

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