Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Polydrug overdose mortality caused by synthetic opioids and stimulants: current sex- and age-specific trajectories in United States national data for 2018–2024

Neuropsychopharmacology (2025)Cite this article

Subjects

Abstract

Recent years have shown increases in overdose (OD) mortality caused by polydrug exposure to synthetic opioids such as fentanyl and stimulants such as methamphetamine or cocaine. The goal of this study is to understand the recent trajectory in this polydrug OD mortality, especially as associated with decedents’ sex and age. We carried out a cross-sectional analysis of national data for persons aged 15–74, from CDC WONDER for 2018–2024 (data for 2024 are considered provisional at the time of analysis). The outcome measure was OD mortality/100,000 population; annual data for 2018–2024 were analyzed with joinpoint regression, and the most recent years (2023–2024) were analyzed with ANOVA and multiple linear regression. Males had greater polydrug OD mortality caused by synthetic opioids and stimulants compared to females, across 2018–2024. Sex-specific joinpoint regressions detected increases in these polydrug OD after 2018, then decreases from 2023 in males, and from 2022 in females. For these polydrug OD, the mean annual percent change (APC) in 2024 versus 2023 was −36% and −31% in males and females, respectively. For synthetic opioids without stimulants, OD trends in 2024 versus 2023 were similar to those for polydrug OD (−42% and −39% APC in males and females, respectively). However, OD for stimulants without synthetic opioids showed relatively smaller changes (−3% and −2% APC in males and females, respectively). Stratification into 10-year age groups for polydrug OD revealed that mortality peaked at age 35–44 and then declined at older ages. Recent decreases in polydrug OD mortality were observed across age groups, with joinpoints detected in 2022 or 2023. These findings indicate that after increases from 2018 onward, polydrug OD mortality caused by synthetic opioids and stimulants exhibited substantial decreases in both males and females in the most recent data for 2024, across a broad age range. Because relatively smaller changes were observed in OD mortality caused by stimulants without synthetic opioids in this time period, the decreases in polydrug OD mortality are more likely to be caused by changes in exposure, prevention or intervention strategies focused on opioids rather than on stimulants. While this polydrug OD mortality has decreased in 2024, it remains at concerning levels.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Yearly mortality (2018-2024) for overdoses caused by polydrug synthetic opioids and stimulants, synthetic opioids without stimulants, and stimulants without synthetic opioids.
Fig. 2: Overdose rates in the most recent years (2023 and 2024).
Fig. 3: Polydrug OD mortality across sex and age group.

Similar content being viewed by others

Data availability

Overdose data analyzed herein are publicly available from the United States Centers for Disease Control and Prevention CDC WONDER platform (https://wonder.cdc.gov/mcd-icd10-provisional.html). Naloxone dispensing rates from the CDC are publicly available from https://www.cdc.gov/overdose-prevention/data-research/facts-stats/naloxone-dispensing-rate-maps.html. Sociodemographic data are publicly available from the American Community Survey for 2023, from the United States Census Bureau (https://data.census.gov/).

References

  1. Han B, Einstein EB, Jones CM, Cotto J, Compton WM, Volkow ND. Racial and Ethnic Disparities in Drug Overdose Deaths in the US During the COVID-19 Pandemic. JAMA Netw Open. 2022;5:e2232314 https://doi.org/10.1001/jamanetworkopen.2022.32314.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Brown KG, Chen CY, Dong D, Lake KJ, Butelman ER. Has the United States Reached a Plateau in Overdoses Caused by Synthetic Opioids After the Onset of the COVID-19 Pandemic? Examination of Centers for Disease Control and Prevention Data to November 2021. Front Psychiatry. 2022; https://www.frontiersin.org/articles/10.3389/fpsyt.2022.947603/full.

  3. Ciccarone D. Bending the overdose curve — still not enough. N Engl J Med. 2024;391:1052–3. https://doi.org/10.1056/nejme2406359.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Amaducci A, Aldy K, Campleman SL, Li S, Meyn A, Abston S, et al. Naloxone Use in Novel Potent Opioid and Fentanyl Overdoses in Emergency Department Patients. JAMA Netw Open. 2023;6:e2331264 https://doi.org/10.1001/jamanetworkopen.2023.31264.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Shastry S, Lin J, Aldy K, Brent J, Wax P, Krotulski A, et al. Heroin or fentanyl: Prevalence of confirmed fentanyl in ED patients with suspected heroin overdose. J Am Coll Emerg Physicians Open. 2024;5:e13235 https://doi.org/10.1002/emp2.13235.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Butelman ER, Huang Y, Epstein DH, Shaham Y, Goldstein RZ, Volkow ND, et al. Overdose mortality rates for opioids and stimulant drugs are substantially higher in men than in women: state-level analysis. Neuropsychopharmacology. 2023. https://doi.org/10.1038/s41386-023-01601-8.

  7. Ciccarone D. The rise of illicit fentanyls, stimulants and the fourth wave of the opioid overdose crisis. Curr Opin Psychiatry. 2021;34:344–50. https://doi.org/10.1097/yco.0000000000000717.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tanz LJ, Dinwiddie AT, Mattson CL, O’Donnell J, Davis NL. Drug Overdose Deaths Among Persons Aged 10-19 Years - United States, July 2019-December 2021. MMWR Morb Mortal Wkly Rep. 2022;71:1576–82. https://doi.org/10.15585/mmwr.mm7150a2.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wilson N, Kariisa M, Seth P, Smith H 4th, Davis NL. Drug and Opioid-Involved Overdose Deaths - United States, 2017-2018. MMWR Morb Mortal Wkly Rep. 2020;69:290–7. https://doi.org/10.15585/mmwr.mm6911a4.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Shastry S, Shulman J, Aldy K, Brent J, Wax P, Manini AF, et al. Psychostimulant drug co-ingestion in non-fatal opioid overdose. Drug Alcohol Depend Rep. 2024;10:100223 https://doi.org/10.1016/j.dadr.2024.100223.

    Article  PubMed  PubMed Central  Google Scholar 

  11. CDC. The Fentalog Study: A Subset of Nonfatal Suspected Opioid-Involved Overdoses with Toxicology Testing. In: Overdose Prevention. 2024. https://www.cdc.gov/overdose-prevention/data-research/facts-stats/fentalog-study-dashboard.html.

  12. Liu S, Scholl L, Hoots B, Seth P. Nonfatal drug and polydrug overdoses treated in emergency departments - 29 states, 2018-2019. MMWR Morb Mortal Wkly Rep. 2020;69:1149–55. https://doi.org/10.15585/mmwr.mm6934a1.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Cotten JF. Goofball polypharmacy. J Pharm Exp Ther. 2024;388:241–3. https://doi.org/10.1124/jpet.123.001930.

    Article  CAS  Google Scholar 

  14. Ondocsin J, Holm N, Mars SG, Ciccarone D. The motives and methods of methamphetamine and “heroin” co-use in West Virginia. Harm Reduct J. 2023;20:88. https://doi.org/10.1186/s12954-023-00816-8.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Volkow ND, Califf RM, Sokolowska M, Tabak LA, Compton WM. Testing for Fentanyl - Urgent Need for Practice-Relevant and Public Health Research. N Engl J Med. 2023. https://doi.org/10.1056/NEJMp2302857.

    Article  PubMed  Google Scholar 

  16. Palamar JJ, Fitzgerald N, Carr TH, Cottler LB, Ciccarone D. National and regional trends in fentanyl seizures in the United States, 2017–2023. Int J Drug Policy. 2024;104417. https://doi.org/10.1016/j.drugpo.2024.104417.

  17. Karandinos G, Unick J, Ciccarone D Mortality risk among individuals who smoke opioids compared with those who inject: A propensity score-matched cohort analysis of United States national treatment data. Addiction. 2025. https://doi.org/10.1111/add.16740.

  18. Glidden E, Gladden RM, Dion C, Spyres MB, Seth P, Aldy K, et al. Suspected counterfeit M-30 oxycodone pill exposures and acute withdrawals reported from a single hospital - Toxicology Investigators Consortium Core Registry, U.s. census Bureau Western Region, 2017-2022. MMWR Morb Mortal Wkly Rep. 2024;73:642–7. https://doi.org/10.15585/mmwr.mm7329a2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Allen C, Arredondo C, Dunham R, Fishman M, Lev L, Mace S, et al. Guidance for Handling the Increasing Prevalence of Drugs Adulterated or Laced With Fentanyl. PS. 2023;74:1059–62. https://doi.org/10.1176/appi.ps.202100660.

    Article  Google Scholar 

  20. Friedman J, Ciccarone D. The public health risks of counterfeit pills. Lancet Public Health. 2025;10:e58–e62. https://doi.org/10.1016/S2468-2667(24)00273-1.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Skolnick P. Treatment of overdose in the synthetic opioid era. Pharmacol Ther. 2021;108019. https://doi.org/10.1016/j.pharmthera.2021.108019.

  22. Baldo BA. Opioid-induced respiratory depression: clinical aspects and pathophysiology of the respiratory network effects. Am J Physiol Lung Cell Mol Physiol. 2025;328:L267–L289. https://doi.org/10.1152/ajplung.00314.2024.

    Article  PubMed  CAS  Google Scholar 

  23. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science. 1987;237:1219–23. https://doi.org/10.1126/science.2820058.

    Article  PubMed  CAS  Google Scholar 

  24. Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci. 1995;15:4102–8. https://doi.org/10.1523/jneurosci.15-05-04102.1995.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Richards JR, Laurin EG. Methamphetamine toxicity. StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. Available: https://www.ncbi.nlm.nih.gov/books/NBK430895/.

  26. Heard K, Palmer R, Zahniser NR. Mechanisms of acute cocaine toxicity. Open Pharm J. 2008;2:70–78. https://doi.org/10.2174/1874143600802010070.

    Article  CAS  Google Scholar 

  27. FDA approves first over-the-counter naloxone nasal spray. In: U.S. Food and Drug Administration. FDA; 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-over-counter-naloxone-nasal-spray.

  28. Bennett AS, Freeman R, Des Jarlais DC, Aronson ID. Reasons people who use opioids do not accept or carry no-cost naloxone: Qualitative interview study. JMIR Form Res. 2020;4:e22411. https://doi.org/10.2196/22411.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wakeman SE, Larochelle MR, Ameli O, Chaisson CE, McPheeters JT, Crown WH, et al. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder. JAMA Netw Open. 2020;3:e1920622. https://doi.org/10.1001/jamanetworkopen.2019.20622.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Shastry S, Carpenter J, Krotulski A, Brent J, Wax P, Aldy K, et al. Disparities in treatment and referral after an opioid overdose among emergency department patients. JAMA Netw Open. 2025;8:e2518569. https://doi.org/10.1001/jamanetworkopen.2025.18569.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hooker SA, Starkey C, Bart G, Rossom RC, Kane S, Olson AW. Predicting buprenorphine adherence among patients with opioid use disorder in primary care settings. BMC Prim Care. 2024;25:361. https://doi.org/10.1186/s12875-024-02609-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Wakeman SE, McGovern S, Kehoe L, Kane MT, Powell EA, Casey SK, et al. Predictors of engagement and retention in care at a low-threshold substance use disorder bridge clinic. J Subst Abus Treat. 2022;141:108848. https://doi.org/10.1016/j.jsat.2022.108848.

    Article  CAS  Google Scholar 

  33. D’Onofrio G, O’Connor PG, Pantalon MV, Chawarski MC, Busch SH, Owens PH, et al. Emergency Department-Initiated Buprenorphine/Naloxone Treatment for Opioid Dependence: A Randomized Clinical Trial. JAMA. 2015;313:1636–44. https://doi.org/10.1001/jama.2015.3474.

    Article  PubMed  PubMed Central  Google Scholar 

  34. National Institute on Drug Abuse. Reduced drug use is a meaningful treatment outcome for people with stimulant use disorders. In: National Institute on Drug Abuse. 2024. https://nida.nih.gov/news-events/news-releases/2024/01/reduced-drug-use-is-a-meaningful-treatment-outcome-for-people-with-stimulant-use-disorders.

  35. Hiranita T, Ho NP, France CP. Ventilatory effects of fentanyl, heroin, and d -methamphetamine, alone and in mixtures, in male rats breathing normal air. J Pharmacol Exp Ther. 2023. https://doi.org/10.1124/jpet.123.001653.

  36. Burke O, Ely SF, Gill JR. Cardiovascular disease in acute cocaine compared to acute fentanyl intoxication deaths. Am J Forensic Med Pathol. 2024. https://doi.org/10.1097/paf.0000000000000994.

  37. Zuin M, Mohanty S, Aggarwal R, Bertini M, Bikdeli B, Hamade N, et al. Trends in sudden cardiac death among adults aged 25 to 44 years in the United States: An analysis of 2 large US databases. J Am Heart Assoc. 2025;14:e035722. https://doi.org/10.1161/JAHA.124.035722.

    Article  PubMed  Google Scholar 

  38. Mann J, Samieegohar M, Chaturbedi A, Zirkle J, Han X, Ahmadi SF, et al. Development of a Translational Model to Assess the Impact of Opioid Overdose and Naloxone Dosing on Respiratory Depression and Cardiac Arrest. Clin Pharm Ther. 2022;112:1020–32. https://doi.org/10.1002/cpt.2696.

    Article  CAS  Google Scholar 

  39. Reddy PKV, Ng TMH, Oh EE, Moady G, Elkayam U. Clinical characteristics and management of methamphetamine-associated cardiomyopathy: State-of-the-art review. J Am Heart Assoc. 2020;9:e016704. https://doi.org/10.1161/JAHA.120.016704.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Kevil CG, Goeders NE, Woolard MD, Bhuiyan MS, Dominic P, Kolluru GK, et al. Methamphetamine Use and Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2019;39:1739–46. https://doi.org/10.1161/ATVBAHA.119.312461.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Post LA, Ciccarone D, Unick GJ, D’Onofrio G, Kwon S, Lundberg AL, et al. Decline in US drug overdose deaths by region, substance, and demographics. JAMA Netw Open. 2025;8:e2514997. https://doi.org/10.1001/jamanetworkopen.2025.14997.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kiang MV, Humphreys K. Recent drug overdose mortality decline compared with pre-COVID-19 trend. JAMA Netw Open. 2025;8:e2458090. https://doi.org/10.1001/jamanetworkopen.2024.58090.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Spencer MR, Garnett M, Miniño A. Drug overdose deaths in the United States, 2002-2022. National Center for Health Statistics (U.S.); 2023. https://doi.org/10.15620/cdc:135849.

  44. Berger JC, Severe AD, Jalloh MS, Manini AF. Naloxone dosing and hospitalization for nitazene overdose: A scoping review. J Med Toxicol. 2025. https://doi.org/10.1007/s13181-025-01059-8.

  45. Joinpoint Regression Program. 2025. Available: https://surveillance.cancer.gov/joinpoint.

  46. Ingram DD, Malec DJ, Makuc DM, Kruszon-Moran D, Gindi RM, Albert M, et al. National Center for Health Statistics guidelines for analysis of trends. Vital Health Stat 2. 2018; 1–71. https://www.ncbi.nlm.nih.gov/pubmed/29775435.

  47. Kim H-J, Chen H-S, Byrne J, Wheeler B, Feuer EJ. Twenty years since Joinpoint 1.0: Two major enhancements, their justification, and impact. Stat Med. 2022;41:3102–30. https://doi.org/10.1002/sim.9407.

    Article  PubMed  Google Scholar 

  48. Social Determinants of Health. 2025. https://odphp.health.gov/healthypeople/priority-areas/social-determinants-health.

  49. CDC. Naloxone dispensing rate maps. In: Overdose Prevention. 2024. https://www.cdc.gov/overdose-prevention/data-research/facts-stats/naloxone-dispensing-rate-maps.html.

  50. U.S. Census Bureau. Explore Census Data. 2025. https://data.census.gov/advanced.

  51. Hedegaard H, Miniño AM, Warner M. Co-involvement of opioids in drug overdose deaths involving cocaine and psychostimulants. In: NCHS Data Brief, no 406. Hyattsville, MD: National Center for Health Statistics. 2021. https://doi.org/10.15620/cdc:103966.

  52. Oles WC, Liu M, Wakeman SE, Larochelle MR. Geographic trends in opioid and polysubstance overdose deaths in the US, 2014–2023. J Gen Intern Med. 2025. https://doi.org/10.1007/s11606-025-09589-1.

  53. Volkow N, Dye LR. Groundbreaking research from NIDA addressing the challenges of the opioid epidemic. J Med Toxicol. 2025;21:69–77. https://doi.org/10.1007/s13181-024-01041-w.

    Article  PubMed  Google Scholar 

  54. Levengood TW, Shaw LC, Zang X, Schackman BR, Walley AY, Urquhart C, et al. A geospatial analysis of naloxone distribution patterns in the Massachusetts overdose education and naloxone distribution program (MA OEND). Drug Alcohol Depend. 2025;274:112783. https://doi.org/10.1016/j.drugalcdep.2025.112783.

    Article  PubMed  CAS  Google Scholar 

  55. Drug Enforcement Administration: 2025 National Drug Threat Assessment. 2025. Available: https://www.dea.gov/sites/default/files/2025-07/2025NationalDrugThreatAssessment.pdf.

  56. Naloxone Distribution Project. In: California Department of Health Care Services. 2025. Available: https://www.dhcs.ca.gov/individuals/Pages/Naloxone_Distribution_Project.aspx.

  57. OASAS announces the availability of lifesaving resources to address the state’s opioid crisis. In: Office of Addiction Services and Supports. 2025. https://oasas.ny.gov/news/oasas-announces-availability-lifesaving-resources-address-states-opioid-crisis.

  58. Gelberg KH, El-Bassel N, Babineau DC, Vickers-Smith RA, Fanucchi LC, Childerhose JE, et al. Association of fentanyl test strip results and change in drug use behaviors: A multi-state, community-based observational study. Int J Drug Policy. 2025;143:104867. https://doi.org/10.1016/j.drugpo.2025.104867.

    Article  PubMed  Google Scholar 

  59. Park JN, Tardif J, Thompson E, Rosen JG, Lira JAS, Green TC. A survey of North American drug checking services operating in 2022. Int J Drug Policy. 2023;121:104206. https://doi.org/10.1016/j.drugpo.2023.104206.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Maghsoudi N, Tanguay J, Scarfone K, Rammohan I, Ziegler C, Werb D, et al. Drug checking services for people who use drugs: a systematic review. Addiction. 2022;117:532–44. https://doi.org/10.1111/add.15734.

    Article  PubMed  Google Scholar 

  61. Samuels EA, Rosen AD, Abusaa S, Dekker AM, Schriger DL, Shoptaw SJ, et al. Increasing emergency department patient navigation and buprenorphine use: A model for low-barrier treatment. Health Aff. 2025;44:1138–47. https://doi.org/10.1377/hlthaff.2025.00333.

    Article  Google Scholar 

  62. Dekker AM, Schriger DL, Herring AA, Samuels EA. Emergency clinician buprenorphine initiation, subsequent prescriptions, and continuous prescriptions. JAMA. 2025. https://doi.org/10.1001/jama.2024.27976.

  63. Hughes T, Nasser N, Mitra A. Overview of best practices for buprenorphine initiation in the emergency department. Int J Emerg Med. 2024;17:23. https://doi.org/10.1186/s12245-024-00593-6.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Jones CM, Shoff C, Blanco C, Losby JL, Ling SM, Compton WM. Overdose, Behavioral Health Services, and Medications for Opioid Use Disorder After a Nonfatal Overdose. JAMA Intern Med. 2024. https://doi.org/10.1001/jamainternmed.2024.1733.

  65. Larochelle MR, Bernson D, Land T, Stopka TJ, Wang N, Xuan Z, et al. Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study. Ann Intern Med. 2018;169:137–45. https://doi.org/10.7326/m17-3107.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Marley GT, Annis IE, Egan KL, Delamater P, Carpenter DM. Naloxone Availability and Cost After Transition to an Over-the-Counter Product. JAMA Health Forum. 2024;5:e241920 https://doi.org/10.1001/jamahealthforum.2024.1920.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Håkansson A, Alanko Blomé M, Isendahl P, Landgren M, Malmqvist U, Troberg K. Distribution of intranasal naloxone to potential opioid overdose bystanders in Sweden: effects on overdose mortality in a full region-wide study. BMJ Open. 2024;14:e074152. https://doi.org/10.1136/bmjopen-2023-074152.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Walley AY, Xuan Z, Hackman HH, Quinn E, Doe-Simkins M, Sorensen-Alawad A, et al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ. 2013;346:f174. https://doi.org/10.1136/bmj.f174.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Moustaqim-Barrette A, Papamihali K, Williams S, Ferguson M, Moe J, Purssell R, et al. Adverse events related to bystander naloxone administration in cases of suspected opioid overdose in British Columbia: An observational study. PLoS One. 2021;16:e0259126. https://doi.org/10.1371/journal.pone.0259126.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Butelman ER, Chen CY, Brown KG, Kreek MJ. Escalation of drug use in persons dually diagnosed with opioid and cocaine dependence: Gender comparison and dimensional predictors. Drug Alcohol Depend. 2019;205:107657. https://doi.org/10.1016/j.drugalcdep.2019.107657.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Boitor M, Ballard A, Emed J, Le May S, Gélinas C. Risk factors for severe opioid-induced respiratory depression in hospitalized adults: A case-control study. Can J Pain. 2020;4:103–10. https://doi.org/10.1080/24740527.2020.1714431.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Duell N, Steinberg L, Icenogle G, Chein J, Chaudhary N, Di Giunta L, et al. Age patterns in risk taking across the world. J Youth Adolesc. 2018;47:1052–72. https://doi.org/10.1007/s10964-017-0752-y.

    Article  PubMed  Google Scholar 

  73. Romer D. Adolescent risk taking, impulsivity, and brain development: implications for prevention. Dev Psychobiol. 2010;52:263–76. https://doi.org/10.1002/dev.20442.

    Article  PubMed  PubMed Central  Google Scholar 

  74. McLellan AT, Volkow ND. Goals for opioid use disorder medications - protection, remission, and recovery. N Engl J Med. 2025. https://doi.org/10.1056/NEJMp2505377.

  75. Kariisa M, Davis NL, Kumar S, Seth P, Mattson CL, Chowdhury F, et al. Vital signs: Drug overdose deaths, by selected sociodemographic and social determinants of health characteristics - 25 states and the District of Columbia, 2019-2020. MMWR Morb Mortal Wkly Rep. 2022;71:940–7. https://doi.org/10.15585/mmwr.mm7129e2.

    Article  PubMed  PubMed Central  Google Scholar 

  76. What are fentanyl and nitazenes? Explaining the rise and risks of potent synthetic opioids. 2025. https://adf.org.au/insights/fentanyl-and-nitazenes/.

  77. Health Canada. Multi-drug combinations in national apparent opioid and stimulant toxicity deaths. 2024. https://www.canada.ca/en/health-canada/services/opioids/data-surveillance-research/multi-drug-combinations-national-opioid-stimulant-toxicity-deaths.html.

  78. Roberts A-O, Richards GC. Is England facing an opioid epidemic? Br J Pain. 2023;17:320–4. https://doi.org/10.1177/20494637231160684.

    Article  PubMed  PubMed Central  Google Scholar 

  79. European Drug Report 2025: Trends and Developments. 2025. https://www.euda.europa.eu/publications/european-drug-report/2025_en.

  80. Jones CM, Compton WM, Han B, Baldwin G, Volkow ND. Methadone-Involved Overdose Deaths in the US Before and After Federal Policy Changes Expanding Take-Home Methadone Doses From Opioid Treatment Programs. JAMA Psychiatry. 2022. https://doi.org/10.1001/jamapsychiatry.2022.1776.

  81. Zimmerman JL. Cocaine intoxication. Crit Care Clin. 2012;28:517–26. https://doi.org/10.1016/j.ccc.2012.07.003.

    Article  PubMed  Google Scholar 

  82. Curran L, Nah G, Marcus GM, Tseng Z, Crawford MH, Parikh NI. Clinical Correlates and Outcomes of Methamphetamine-Associated Cardiovascular Diseases in Hospitalized Patients in California. J Am Heart Assoc. 2022;11:e023663. https://doi.org/10.1161/JAHA.121.023663.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Spencer MR, Ahmad S. Timeliness of Death Certificate Data for Mortality Surveillance and Provisional Estimates. In: National Vital Statistics System. 2016. https://www.cdc.gov/nchs/data/vsrr/report001.pdf.

  84. Johnson SC, Cunningham M, Dippenaar IN, Sharara F, Wool EE, Agesa KM, et al. Public health utility of cause of death data: applying empirical algorithms to improve data quality. BMC Med Inf Decis Mak. 2021;21:175. https://doi.org/10.1186/s12911-021-01501-1.

    Article  Google Scholar 

  85. Boslett AJ, Denham A, Hill EL. Using contributing causes of death improves prediction of opioid involvement in unclassified drug overdoses in US death records: Methods for predicting fatal opioid overdoses. Addiction. 2020;115:1308–17. https://doi.org/10.1111/add.14943.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Love JS, Levine M, Aldy K, Brent J, Krotulski AJ, Logan BK, et al. Opioid overdoses involving xylazine in emergency department patients: a multicenter study. Clin Toxicol. 2023;61:173–80. https://doi.org/10.1080/15563650.2022.2159427.

    Article  CAS  Google Scholar 

  87. Friedman JR. Assessing an ICD-10 code approach for estimating xylazine-involved overdose deaths in the United States. Drug Alcohol Depend. 2025;274:112781. https://doi.org/10.1016/j.drugalcdep.2025.112781.

    Article  PubMed  CAS  Google Scholar 

  88. Hughes A, Spungen H, Culbreth R, Aldy K, Krotulski A, Hendrickson RG, et al. Benzodiazepine co-exposure among patients presenting to the emergency department with a confirmed opioid overdose. Acad Emerg Med. 2025. https://doi.org/10.1111/acem.70104.

  89. Woodcock EA, Lundahl LH, Stoltman JJ, Greenwald MK. Progression to regular heroin use: examination of patterns, predictors, and consequences. Addict Behav. 2015;45:287–93. https://doi.org/10.1016/j.addbeh.2015.02.014.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Rodriguez-Cintas L, Daigre C, Grau-Lopez L, Barral C, Perez-Pazos J, Voltes N, et al. Impulsivity and addiction severity in cocaine and opioid dependent patients. Addict Behav. 2016;58:104–9. https://doi.org/10.1016/j.addbeh.2016.02.029.

    Article  PubMed  Google Scholar 

  91. Lim TY, Dong H, Stringfellow E, Hasgul Z, Park J, Glos L, et al. Temporal and spatial trends of fentanyl co-occurrence in the illicit drug supply in the United States: a serial cross-sectional analysis. Lancet Reg Health Am. 2024;39:100898. https://doi.org/10.1016/j.lana.2024.100898.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The authors gratefully acknowledge funding from NIDA-NIH DA5U01DA053625 (ERB), 2R01DA048009 (AM), 1R01DA060914 (RZG), 5R01DA049547 (NAK, RZG). The funder had no role in the design, drafting or editing of the project.

Author information

Authors and Affiliations

  1. Neuropsychoimaging of Addictions and Related Conditions, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Eduardo R. Butelman, Yuefeng Huang, Rita Z. Goldstein & Nelly Alia-Klein

  2. Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Siri Shastry & Alex F. Manini

Authors
  1. Eduardo R. Butelman
    View author publications

    Search author on:PubMed Google Scholar

  2. Yuefeng Huang
    View author publications

    Search author on:PubMed Google Scholar

  3. Siri Shastry
    View author publications

    Search author on:PubMed Google Scholar

  4. Alex F. Manini
    View author publications

    Search author on:PubMed Google Scholar

  5. Rita Z. Goldstein
    View author publications

    Search author on:PubMed Google Scholar

  6. Nelly Alia-Klein
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Concept and Design: ERB Data acquisition: publicly available de-identified data from CDC WONDER Analysis: ERB Interpretation and writing: All authors.

Corresponding author

Correspondence to Eduardo R. Butelman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Butelman, E.R., Huang, Y., Shastry, S. et al. Polydrug overdose mortality caused by synthetic opioids and stimulants: current sex- and age-specific trajectories in United States national data for 2018–2024. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02284-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41386-025-02284-z

Search

Advanced search

Quick links