a–c Statistically unsupervised analysis of TMT-LC/MS proteomics comprising all samples. All 28 of our TMT-LC/MS samples were first subjected to a statistically unbiased analysis that did not consider a priori hypotheses or the quasi-independent nature of each of our treatment conditions. This yielded a clustering solution (a) that identified differential expression of 41 specific proteomic targets that differed from vehicle controls (b). These proteins were correspondingly mapped to their Reactome pathways of origin (c). Note, the ordering of groups for presentation purposes are assigned based on the results of statistically unsupervised clustering. d–i Reactome pathway analysis split by narcotic and neuropsychiatric-related treatment. Analysis of the Reactome pathways split by our individual treatments revealed novel enrichment patterns for each narcotic compound and enviromimetic treatment conditions. As described in-text, WIN 55,212-2, IL17a, and cortisol exhibited the most distinct Reactome pathway patterning, indicating a greater degree of divergence in pathway alterations. Contrary to this, our nicotine, ethanol, and endomorphin treatment groups tended to exhibit a closer degree of convergence. Specifically, these groups tended to exhibit greater enrichment for neurodevelopment-related Reactome pathways including factors mapped to “nervous system development”, “ROBO receptor signaling”, and/or “axon guidance”. However, each of these groups still maintained unique patterns of Reactome pathway enrichment, which perhaps indicates a common role in their ability to alter neurodevelopmental factors albeit via divergent intermediaries. For all panels, each donor sample was treated with all experimental compounds (4 iPSC donors x 7 groups = 28 total samples for analysis).