According to DAWN,currently,the drug that causes the greatest number of death by overdose,in absolute numbers,is:

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Opiates, including prescription painkillers and heroin, cause the greatest number of deaths by overdose in absolute numbers. In 2018, 46,802 overdose deaths were attributed to opioids in the United States, according to the Centers for Disease Control and Prevention. This is significantly higher than the number of deaths attributed to cocaine, alcohol, antidepressants, or benzodiazepines.

According to DAWN,currently,the Drug That Causes the Greatest Number of Death