The U.S. is in the throes of what researchers have deemed a “fourth wave” of the opioid crisis, a phase characterized by overdose deaths caused by the combination of stimulants and the powerful synthetic opioid fentanyl.

Overdose deaths in the U.S. surpassed 100,000 for the first time in 2021, fueled by the rise of synthetic opioids, which accounted for 75% of those deaths. Once propelled by prescription opioids and then heroin, the decadeslong crisis was overwhelmed by synthetic opioids in the mid-2010s.

Now it has taken on a new challenge: so-called polysubstance overdoses, which include more than one drug.

The proportion of overdoses involving fentanyl and a stimulant — most commonly cocaine and methamphetamine — increased more than fiftyfold from 2010 to 2021, a study published Thursday in the journal Addiction found.