Scoping review of associations between cytochrome P450 3A4/5 single nucleotide polymorphisms and risk factors for fentanyl overdose.

INTRODUCTION

Fentanyl overdose is a public health crisis in the United States, as fentanyl was implicated in nearly 70% of drug overdose deaths in 2023. To provide insight into genetic factors that may influence risk of fentanyl overdose, we conducted a scoping review of associations between cytochrome P450 3A4 (CYP3A4) and 3A5 (CYP3A5) genetic variants and relevant phenotypes.

AREAS COVERED: We searched databases through August 2025 for peer-reviewed studies of human subjects or postmortem samples, and integrated evidence from 64 genetic association studies that analyzed single nucleotide polymorphisms in CYP3A4 or CYP3A5. We considered a diverse range of phenotypes relevant to fentanyl overdose, including opioid overdose, fentanyl pharmacokinetics and pharmacodynamics, opioid use (disorder), and pharmacotherapy response.

EXPERT OPINION AND COMMENTARY: Evidence from 64 studies suggested that the no-function CYP3A5 * 3 (rs776746) allele contributes to increased fentanyl overdose risk, with strongest support coming from studies of fentanyl pharmacokinetics in clinical settings. There was less robust evidence for the role of CYP3A4 variants (e.g. rs2242480). Future research should prioritize prospective genotyping of at-risk populations, development of models that integrate pharmacogenetics with psychiatric genetics, and large-scale harmonization of relevant datasets.