It Not Just Opioid Overdose Epidemic, but a PolySubstance Use Epidemic Causing Overdoses

Man sitting by a river sad about the stigma of addiction

While we are waiting for the COVID crisis to stabilize and vaccinations begin, we notice a resurgence in the opioid overdose and opioid use crisis. The US Centers for Disease Control and Prevention’s (CDC’s) National Center for Health Statistics estimated that 19, 416 individuals died of a drug overdose in the first three months of 2020.

The CDC said that last year during the same three months, only 16 682 people died from a drug overdose. The CDC also estimates that 75, 500 overdose deaths occurred in the 12 months between March 2019 and March 2020, an increase of approximately 10%.

Rather than the over-hyped progress in the drug and opioid overdose epidemic, the United States is actually on track to reach a new record for overdose fatalities. The individual States are reporting increases ranging from 25% to 50% from March 2019 to March 2020 in O.D.s.

Again, according to the CDC, opioids are the chief drivers of drug overdose fatalities. However, their data show that the majority of post mortem reports of opioid overdose deaths show other drugs of abuse, other misused medications, alcohol, and marijuana.

Two classes of drugs are are frequently co-used with opioids: depressants and stimulants. Mixing opioids with other depressants or stimulants, either intentionally or unknowingly, has been recognized by experts as a significant cause of opioid overdose deaths.

Benzodiazepine, alcohol, other sedatives, and hypnotics mixed with opioids have contributed to overdoses more than doubling since 2010. Speedball, cocaine plus heroin, which became popular in the late ‘870s with Saturday Night Live users and overdoses, is making a comeback today with the co-use of methamphetamine and opioids or cocaine and opioids and even ketamine and cocaine.

What Can We Learn About Opioid Overdose From Adolescent Use and Trends?

From 1999 to 2016, opioid-related deaths reported for young adults aged 13 to 25 years tripled. Opioid overdose deaths in adult populations often involve benzodiazepines and, more recently, psychostimulants.

Little is known about polysubstance involvement in opioid overdose deaths among youth. But, between 1999 and 2018, opioid-only and polysubstance-involved overdose deaths among youth increased by 384% and 760%, respectively.

Man who survived an Opioid OverdoseIn 2018, polysubstance- involved opioid overdose deaths became more prevalent than those involving only opioids. A new study was just reported in JAMA Pediatrics that is the first study characterizing polysubstance involvement in opioid overdose deaths among youth [1].

After analyzing the fatalities data, they said that in 2018, polysubstance- involved opioid overdose deaths became more prevalent than deaths involving opioids alone. The first time experts concluded that a preponderance of polysubstance, not opioid alone, was occurring.

Of the polysubstance- involved in opioid overdose deaths, stimulants were most commonly affected. Most of the overdoses arise in young people who are not drug-naïve but mixing drugs.

These adolescent data are consistent with surveys of the general adult populations showing stimulant-involved opioid overdose deaths increasing over the past decade. Cocaine is now the substance most commonly co-involved in opioid overdose deaths.

How Does Opioid Overdose Occur in Regular Users?

Polysubstance use [2] is defined by the use of more than one drug during the same period. It is often intentional but can occur because of the adulteration of the illicit or illegal drugs consumed.

Unintentional polysubstance use may be much more common than previously thought as illicit drugs are mixed and adulterated with expired medications, filler, or contaminated street drugs. In the first half of 2018, nearly 63% of adult opioid overdose deaths in the United States also involved cocaine, methamphetamine, or benzodiazepines.

This is much more co-occurring use than experts had thought. Most experts had considered the cause of death and overdose to be opioid intoxication, but drug interactions appear more likely for many overdoses.

This was the first sign that we had over-simplified the crisis and was much more than an opioid use problem. About 12% of opioid overdose deaths from January to June 2018 involved methamphetamine.

In 2017, opioids were involved in 50% of methamphetamine-involved deaths. 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.

Since 2010, the number of deaths caused by a combination of opioids and cocaine has increased more than fivefold. 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.

Recent data suggests synthetic opioids are driving increases in methamphetamine-involved deaths. 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 simultaneously or on the same day [3].

Overdoses occur most often when the user is at home and with others present. Both inexperienced and experienced users overdose and die. Experienced drug users overdose and do not know why.

It is generally attributable to drug-drug interactions and polydrug use [4]. An ambulance was called for 38% of cases, and 26% were admitted to a hospital emergency department.

Police were seldom involved, and there were no complaints about police involvement at the overdose time. Participants commonly had a history of overdose, and most were on prescription medications for physical and mental health problems.

Polydrug use was the most common finding for those reporting an accidental overdose. Benzodiazepines (e.g., Xanax or Valium) were implicated in just over half of the overdoses.

Most of those reporting a recent overdose also report a history of previous overdoses. Most of those reporting a previous overdose continue to use substances in ways they are aware contribute to overdose risk.

Cars, Driving, Driving Accidents and Fatalities

In fatal driving accidents, fentanyl and carfentanil have been recently implicated. The top three observations in common among the fentanyl and carfentanil death cases were the driver was found unresponsive behind the wheel, the vehicle left the travel lane or roadway, and the driver was involved in a crash [5].

First Responders and Ambulance at Hospital helping an Opioid OverdoseThe increase in fentanyl use not only poses a risk for overdose and death but is also a significant concern for traffic safety. In 2017, carfentanil was the second most frequently detected drug, after ethanol, in driving under the influence cases.

Of all blood cases in which drug testing was performed (n = 145), carfentanil was detected in 38%, followed by alprazolam (29%), fentanyl (27%), delta-9-tetrahydrocannabinol (24%), and morphine (23%). In toxicology cases, carfentanil was rarely identified alone (only four points) and was most commonly identified with other opioids (73% of cases), benzodiazepines (43%), and stimulants (29%) [6].

Concluding Remarks

This recent rise in opioid overdose deaths has occurred from the pain medication misuse and overprescribing to present-day synthetics with fentanyl supplanting heroin as the principal opioid on the street. It is also the primary cause of opioid overdose death.

Most experts say that the current epidemic has had three waves.

  • The first wave involved prescription opioids (natural and semisynthetic opioids and methadone). It began in 1999 or earlier, following increased opioids in the 1990s.
  • A second wave began in 2010, featuring rapid increases in overdose death that involved heroin.
  • The third wave of significant fatalities in 2013 was fueled by synthetic opioids (especially illicitly manufactured fentanyl).

Currently, deaths are being reported due to opioids plus benzodiazepines or methamphetamine or cocaine or alcohol or marijuana or all the above. As the increase in opioid use has evolved, it is crucial to recognize the tremendous polysubstance use changes.

Barriers to drug use have decreased, and many current users are current users of multiple types of drugs and CNS medications. They commonly co-use opioids -fentanyl with cocaine or methamphetamine or other depressants- in marijuana and alcohol. Opioid reversal with naloxone is still the treatment for overdoses, but it reverses opioid and not necessarily polysubstance overdoses and consequences.


1. Lim JK, Earlywine JJ, Bagley SM, Marshall BDL, Hadland SE. Polysubstance Involvement in Opioid Overdose Deaths in Adolescents and Young Adults, 1999-2018. JAMA Pediatr. Published online November 23, 2020. doi:10.1001/jamapediatrics.2020.5035



4. Najman JM, McIlwraith F, Kemp R, Smirnov A. When Knowledge and Experience Do Not Help: A Study of Nonfatal Drug Overdoses. J Addict Med. 2017 Jul/Aug;11(4):280-285. doi: 10.1097/ADM.0000000000000305. PMID: 28368905.

5. Rohrig TP, Nash E, Osawa KA, Shan X, Scarneo C, Youso KB, Miller R, Tiscione NB. Fentanyl and Driving Impairment. J Anal Toxicol. 2020 Aug 14:bkaa105. doi: 10.1093/jat/bkaa105. Epub ahead of print. PMID: 32797151.

6. Tiscione NB, Alford I. Carfentanil in Impaired Driving Cases and the Importance of Drug Seizure Data. J Anal Toxicol. 2018 Sep 1;42(7):476-484. doi: 10.1093/jat/bky026. PMID: 29659874.

About the Author:

Mark GoldMark S. Gold, M.D., Professor, Washington University School of Medicine – Department of Psychiatry, served as Professor, the Donald Dizney Eminent Scholar, Distinguished Professor and Chair of Psychiatry from 1990-2014. He was the first Faculty from the College of Medicine to be selected as a University-wide Distinguished Alumni Professor and served as the 17th University of Florida’s Distinguished Alumni Professor.

Dr. Gold is also a Distinguished Fellow, American Society of Addiction Medicine; Distinguished Life Fellow, the American Psychiatric Association; Distinguished Fellow, American College of Clinical Pharmacology; Clinical Professor of Psychiatry, Tulane University School of Medicine; Professor( Adjunct), Washington University in St Louis, School of Medicine, Department of Psychiatry; National Council, Washington University in St Louis, Institute for Public Health

Learn more about Mark S. Gold, MD

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Published on December 21, 2020. Published on
Reviewed by Jacquelyn Ekern, MS, LPC on December 21, 2020

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