RATIONALE: The opioid crisis in North America has recently seen a fourth wave, which is dominated by drug-related deaths due to the combined use of illicitly manufactured fentanyl [IMF] and stimulants such as cocaine and methamphetamine. OBJECTIVES: A systematic review addressing the question why drug users combine opioids and stimulants and why the combination results in such a high overdose mortality: from specific and dangerous pharmacokinetic or pharmacodynamic interactions or from accidental poisoning? RESULTS: Motives for the combined use include a more intensive high or rush when used at the same time, and some users have the unfounded and dangerous belief that co-use of stimulants will counteract opioid-induced respiratory depression. Overdose deaths due to combined (intravenous) use of opioids and stimulants are not likely to be caused by specific pharmacokinetic or pharmacodynamic interactions between the two drugs and it is unlikely that the main cause of overdose deaths is due to accidental poisoning. CONCLUSION: The unexpectedly high overdose rates in this population could not be attributed to accidental overdosing or pharmacokinetic/pharmacodynamic interactions. The most likely explanation for the high rate of drug-related deaths in opioid-cocaine co-users is careless overdosing with either cocaine, opioid(s) or both, probably facilitated by the high level of preexisting impulsivity in these co-users and a further acute increase in impulsivity following cocaine use. The primary corollary is that cocaine users should avoid IMF use in the same time window. In addition, IMF users should refrain from cocaine use to avoid impulsive IMF overdosing.