In this application, a 3-step load-wash-elute SPE protocol, eliminating conditioning and equilibration, was successfully employed to extract 22 synthetic cannabinoids and metabolites from whole blood samples. Superior analyte recoveries (90–110%), minimum %RSDs (3–7%) and modest matrix effects (ME) were achieved across the entire panel of compounds. At the same time, parallel extractions were conducted with other reversed phase (RP) SPE devices using recommended 5 step SPE protocols. Lower recoveries (as low as 46%), higher %RSDs (as high as 41%) and higher matrix effects were obtained. For the cannabinoid JWH-203, all other SPE devices showed severe matrix effects with approximately 80% ion suppression, while Oasis PRiME HLB yielded minimum matrix effects of 11%. This was demonstrated to be directly related to phospholipid removal by Oasis PRiME HLB. Oasis PRiME HLB represents a successful next generation reversed SPE product that produces cleaner extracts with simpler protocols and faster processing time.