Global Patterns of Fatalities With Toxicological Detection of Novel Psychoactive Substances: A Systematic Review and Meta-analysis

Novel psychoactive substances (NPS) have rapidly diversified the global drug market, creating escalating challenges for forensic toxicology and mortality surveillance. While regional reports have described fatal NPS involvement, the global prevalence and temporal trends of NPS detection in fatalities are insufficiently quantified. A search following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines was performed in PubMed, Embase, Scopus, and Web of Science (January 2008-May 2025), supplemented by screening a repository of 96 primary studies, to find studies with toxicologically confirmed detection of NPS in fatalities. We included autopsy or surveillance datasets with analytical confirmation by gas chromatography-mass spectrometry, liquid chromatography-tandem mass spectrometry (LC-MS/MS), high-resolution mass spectrometry, or nuclear magnetic resonance spectroscopy. The primary outcome was the proportion of NPS-positive cases among all forensic cases undergoing comprehensive toxicological analysis. Random-effects meta-analysis estimated pooled proportions and subgroup trends. Heterogeneity, I², meta-regression by year, region, and analytical method, and publication bias by Egger's test were assessed. Of 621 records screened (525 from databases and 96 from supplementary repository), 125 studies met the inclusion criteria and 86 contributed to quantitative synthesis. The pooled global proportion of fatalities with NPS detection was 7.8% (95% CI: 6.2%-9.8%), with a marked increase from 2.5% (2008-2014) to 9.3% (2015-2025). Synthetic opioids predominated (3.4%), followed by cathinones (2.1%) and cannabinoids (1.6%). North America showed the highest pooled proportion (9.4%), followed by Europe (6.9%). Meta-regression showed that later study year (β = 0.12, p = 0.004) and LC-MS/MS use (β = 0.17, p = 0.019) independently predicted higher detection proportions. Publication bias was not significant (p = 0.27). The detection of NPS in fatalities has increased globally, driven by potent synthetic opioids and enhanced analytical detection. Enhanced forensic capacity, standardization of toxicological panels, and real-time surveillance need to be developed to mitigate the emerging global risks.