Antidepressant doses used in conventional rodent models of depression often exceed those used in clinical practice by 1.5 to 25 times, potentially engaging mechanisms irrelevant to human therapeutic effects. A review of forced swim test studies found median doses of 10 mg/kg across antidepressants, while the more recently developed affective bias test showed doses closer to clinical levels. In a separate analysis of 232 ketamine and 202 fluoxetine rodent studies, median doses were also 10 mg/kg, exceeding animal equivalent doses by 1.6–6.5 times. This mismatch may explain why positive preclinical results often fail to translate into clinical efficacy.
A growing number of novel psychoactive substances (NPS) are entering circulation, yet their pharmacological profiles and risks are often unknown. To aid prediction of properties for uncharacterized analogues, a chemical inventory of 690 distinct NPS with defined structures was compiled from governmental and analytical reports, supplemented by 155 established psychoactive drugs of abuse (EPDA). Classification by molecular features, subjective effects, and pharmacological mechanisms identified over forty chemical groupings, seven effect categories, and six mechanisms. Co-occurrence of NPS and EPDA within classes was common, highlighting potential for chemical read-across and derivation of structural alerts.