In this work, two methods combining a short C18 column with trap/elute LC setup hyphenated to vDMS and mass spectrometric detection in SIM mode were developed for the simultaneous quantification of cocaine, tramadol, THC, CBD and their metabolites. A one minute LC-vDMS-SIM/MS method facilities screening of 13 drugs of abuse and quantification 12 (i.e., cocaine, tramadol, and their metabolites and 5 cannabinoids). A second 4 minute LC-vDMS-SIM/MS method was developed for subsequent accurate quantification of THC and CBD, where detected. An advantage of the prototype vDMS system is that a small fraction of the LC organic solvent is transferred into the vDMS cell through the interface and works as a modifier in a cluster/declustering mechanism without the use of additional hardware. This characteristic enables optimisation of vDMS performance via LC mobile phase conditions. In this case the use of 20% acetonitrile as a modifier enables complete baseline separation of isomeric cocaine and tramadol metabolites facilitating a five-fold reduction in the analysis time compared to the LC-MRM/MS method. In addition, vDMS can be used to remove potential interferences for improved quantification and selectivity. In the case of cannabinoids, the isomeric THC and CBD were separated in the LC dimension using a small gradient (77-95% CH3CN) in SIM mode.