From occurrence to prioritization: a neurotoxicity-informed assessment of psychoactive substances in the Yangtze River basin

Psychopharmaceuticals and illicit drugs (PIDs) are designed to modulate neural pathways, yet their ecological risks are frequently underestimated by traditional assessments that rely on apical endpoints (e.g., mortality) rather than specific modes of action 1. This study addresses this critical disconnect by applying a neurotoxicity-informed prioritization framework across the Yangtze River Basin. We integrated basin-scale field monitoring (67 sites), in silico molecular docking, and a multi-criteria Toxicological Priority Index (ToxPi) to re-evaluate the hazards of 16 PIDs. Despite the widespread occurrence of nicotine and amphetamine-type stimulants, characterized by detection frequencies over 80% and elevated concentrations in the upper-middle reaches, conventional Risk Quotients (RQs) suggested negligible ecological risks for most compounds. However, this “safety” was contradicted by molecular docking, which revealed strong binding affinities (down to −8.1 kcal/mol) to key neuronal targets (e.g., GABA-A, NMDA, DAT), suggesting significant potential for sub-lethal behavioral disruption not captured by RQs. By synthesizing these mechanistic insights into the ToxPi framework, the prioritization hierarchy was fundamentally altered. Methadone (MTD) emerged as a top-priority contaminant due to its overlooked sediment persistence (high hydrophobicity) and hazard score, while highly prevalent stimulants were elevated in priority based on their neuroactive potency. This study demonstrates that incorporating mechanistic neurotoxicity is essential for accurate risk ranking, offering a scalable, evidence-based strategy to identify “hidden” neuroactive hazards in large river systems.