Understanding Substance Dependence: What Differentiates Addictive from Non-Addictive Drugs?

Abstract Addiction is a global health challenge, yet the molecular features that distinguish addictive from non-addictive drugs remain incompletely understood at the pathway and circuit levels. Here, we present a systematic computational framework that integrates drug-target binding predictions (provided by FINDSITE comb2.0 ) with brain-region-specific protein expression to compare addictive and non-addictive compounds. We analyzed 457 addictive and 1,774 non-addictive blood-brain barrier permeable drugs and mapped their predicted targets and associated pathways onto proteins expressed across 120 addiction-relevant brain regions. This analysis reveals widespread convergence between the two classes (addictive and non-addictive drugs) on shared molecular pathways, accompanied by distinct patterns of target and pathway engagement. Functional annotation of differentially engaged targets highlights biases toward plasticity-associated components for addictive drugs. In contrast, non-addictive drugs interact with both plasticity-associated proteins and proteins within the same molecular complex that have addiction suppression, regulatory, and homeostatic functions. Notably, both target classes co-localize within the same addiction-relevant circuits and form an integrated protein-protein interaction network. Together, these results define a differential engagement landscape that links chemical interactions to pathway-level utilization in the brain, revealing molecular features associated with differences in addiction propensity. Significance Statement Addiction is a global health crisis, yet the molecular features that distinguish addictive from non-addictive drugs remain poorly defined. By systematically comparing drug–target and pathway engagement across shared addiction-relevant brain circuits, this study identifies distinct signatures in which addictive compounds preferentially engage plasticity- and stress-associated targets, while non-addictive compounds engage these as well as addiction suppression, regulatory, transport, and metabolic pathways. These results provide a circuit- and pathway-level framework for interpreting addiction liability and guiding the design of safer therapeutics.