This research explores alternative in vitro metabolomic approaches to assist in the identification of appropriate metabolites for NPS monitoring in forensic toxicological screening and confirmation. NPS refers to a category of newly modified or synthesized drugs designed to mimic CNS pharmacological effects associated with more classical illicit substances. Using simple or complex changes to core structures, synthesis of NPS can result in a variety of physiological effects as well as yielding a wide array of metabolic products. Human liver microsome (HLM) studies are one of the most common in vitro assays performed to predict phase I metabolism of drugs. However, these may not encompass the full panel of metabolites that may be generated in human subjects. To better understand and develop metabolomic data for NPS, other methods must be explored. This study takes a multidimensional approach on the phase I metabolism for two synthetic cannabinoids, JWH-018 and 5F-APINAC. Utilizing traditional HLM, electrochemical oxidation (ECO), and in silico tool: MetaSite, phase I metabolism was assessed. Previous published data has shown metabolomic spectra of the older generation NPS JWH-018 via HLM. However, there is little to no information regarding the in vitro metabolism profiles of 5F-APINAC via HLM, much less ECO and in silico methods. Also, the efficacy between the various in vitro methods featured in this study have yet to be investigated. Therefore, the resultant metabolomic data produced from the various in vitro methods were comparatively assessed. The metabolic assays conducted in this study, allowed for the screening and confirmation of parent JWH-018 and 5F-APINAC as well as their metabolites. A total of 10 metabolites were produced for JWH-018. The in vitro assays performed on 5F-APINAC yielded a total of 15 metabolites. Metabolites were categorized based on mono-, di-, trihydroxylation, among dealkylation among other phase I biotransformations commonly seen in