An analysis by Zinnia Health identified the deadliest drugs in the U.S. with opioids responsible for over 644,000 fatalities since 1999 and psychostimulants holding the largest increase in overdose death rate at 5,848%. In analyzing overdose data from the National Institute of Drug Abuse (NIDA), they discovered the total fatalities caused by various drugs and the percentage increase in deaths over 20 years.

“These increasing overdose death rates are made all the more tragic by the fact that only a small fraction of people struggling with addiction ever receive any formal treatment, said Dr. David Hu at Zinnia Health. “This is a growing problem, but our response in the U.S. has been largely static. People suffering from substance use disorders should seek help as soon as possible because effective treatments that can help prevent overdose death and other negative outcomes do exist.” 

Drugs With the Highest Overdose Rates  

Opioids stand out as the biggest killer, causing over 644,000 deaths, a figure comparable to the entire population of Vermont. Opioids include synthetic options like fentanyl, legally prescribed pain relievers including oxycodone and hydrocodone, and illegal substances like Heroin. According to the World Health Organization (WHO), fewer than 10% of individuals with opioid addiction receive the necessary treatment.

Stimulants have the second-highest number of overdose deaths surpassing 306,000 since 1999. In 2016, stimulants had the highest year-over-year surge in overdose deaths, with an increase of 42%, going from 12,122 deaths in 2015 to 17,258 in 2016. This figure is 36,000 fewer than in 2021, where a total of 53,495 people were killed by an overdose of stimulants.

Cocaine ranked as the third most dangerous drug with a count of approximately 185,000 overdose deaths since 1999, of which 13.2% occurred in 2021 alone (24,486 deaths). During this time, there has been a 541% increase in deaths associated with its use. Depending on the duration of dependence, cocaine can lead to various adverse effects, including seizures, kidney problems, and strokes.

Since 1999, heroin has also been responsible for around 152,000 deaths, benzodiazepines account for 143,000 deaths, psychostimulants for 135,000 deaths, and antidepressants are associated with 88,000 deaths.

Drugs With the Highest Increase In Overdose

Psychostimulants have seen the most significant increase in overdose deaths over the period the study measured. In 1999, there were 527 overdose deaths recorded compared to a catastrophic 32,537 in 2021— a staggering 5,848% increase. In 2021, there were 14,101 more overdose deaths for males compared to females. Psychostimulants, over the past 20 years, have seen five times the increase in overdose deaths compared to the next highest drug. 

Stimulants have seen the second-highest increase in overdose deaths at 1,153%. The highest number of fatalities recorded due to stimulants since 1999 occurred in 2021 at 53,495.

Benzodiazepines had the third-highest increase in overdose deaths at 1,001% since 1999. 420 deaths were registered for women in 1999 with 715 for men compared to 5,056 for women and 7,443 for men in 2021. The use of benzodiazepines, like Xanax or Valium, poses inherent dangers, particularly when combined with alcohol or other substances, which can increase the risk to a potentially fatal level.

Cocaine saw an overdose death increase of 541% over the past twenty years with Heroin following closely at 368% and antidepressants at 235%.


Zinnia Health’s Methodology: “By using the NIDA’s most recent Number of National Drug Overdose Deaths report, we can see what drug has caused the largest number of fatalities per year. By intricately looking at the increase rates between each year, we could work out the total average increase rate since 1999 to determine which has the highest levels of growth. This increase in users also allowed us to determine the worst year for each drug, depending on the highest growth in users.”


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Arturo Dominguez

Arturo is an anti-racist political nerd. He is an upcoming author, journalist, advocate for social justice, and a married father of three. He is a top writer on Medium and a regular contributor to several news media outlets. He writes educational and informative material about systemic racism, white supremacy, and racial injustice.

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