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Now in its second decade, the opioid epidemic has claimed more than 800 000 lives in the US, more than the combined total of all deaths in all US wars and armed conflicts from the Revolutionary War to the present. Starting in approximately 2013, with the introduction of substantial quantities of the inexpensive and highly potent synthetic opioid fentanyl, the opioid epidemic entered a particularly lethal phase, with the death rate increasing more than10-fold. In 2020, the most recent year for which the Centers for Disease Control and Prevention currently reports, the death toll from opioid overdose was the worst ever, at more than 100 000.1 In this issue, Whitley and colleagues2 have reported the possibility of using clinical drug test results from substance use disorder clinics to document time patterns in the frequency of drug detection via urine samples submitted for clinical testing. Spanning 2013 to 2020, their results provide a clear picture of the evolution of synthetic opioids (primarily fentanyl) into their position of dominance in the US illicit drug supply. The rapid increase in death rates associated with this proliferation of fentanyl is largely a consequence of the drug being approximately 50 times more potent than heroin, thus putting the unsuspecting user in great jeopardy of unintentional overdose.3 Fentanyl is also being found in the nonopioid drug supply and being sold with stimulants and even cannabis. This issue is especially concerning for patients whose intent is to use one of these nonopioid agents because they may be opioid naive. As also clearly seen in the data presented by Whitley et al,2 methamphetamine detections have increased in parallel with those observed for synthetic opioids since 2013. The reasons for the emergence of methamphetamine over this period and the concurrent increase in methamphetamine-related deaths are complex and not completely understood. There has traditionally been a subset of opioid users who prefer to simultaneously use a stimulant, typically cocaine, together with an opioid in what has been colloquially referred to as a speedball. This combination was popularized by the belief that the resulting euphoria, or rush, would be intensified, and the posteuphoric central nervous system depression induced by the opioid would be reduced. There is also an unfounded belief that co-use of stimulants will counteract opioid-induced respiratory depression. Most recently, this concept has been applied to the simultaneous use of fentanyl and methamphetamine in a combination known as a goofball. It is likely that there are several reasons for the parallel patterns in the detection of synthetic opioids and methamphetamine reported by Whitley et al2 and other researchers.4 While some cases are the result of intentional simultaneous use of stimulants with opioids, others are due to the inadvertent use of stimulants that have been contaminated or adulterated with opioids in the drug supply. People may also choose to use these drugs in combination to overcome the sedating effect of fentanyl.5 However, it cannot be concluded from urine drug test results that the presence of both a stimulant and an opioid in a urine sample signifies that there was co-use given that sequential use of these drugs would yield similar urine drug screening results. Knowledge of the most current drug use patterns is important for many reasons. First, it allows clinicians to accurately counsel patients regarding the risks of drug use based on the effects of substances known to be currently present in the drug supply. Second, it informs testing and treatment decisions. Third, it forms the basis for public policy decisions, such as a need to increase access to harm-reduction techniques, including naloxone distribution, test dosing, staggered administrations, safe injection sites, or fentanyl testing strips. + Related article