Liquid chromatography and electrospray mass spectrometry was evaluated for screening of more than 70 central nervous system-stimulating drugs in human plasma. Protein precipitation was utilized as a simple sample preparation procedure, and the subsequent screening procedure involved two injections in a liquid chromatography-mass spectrometry system for each sample; a first screening without source induced dissociation to maximize sensitivity where potential positive identifications were based on retention time and molecular ion masses, and secondly a source induced dissociation confirmation based on retention time, molecular ions, and one or two fragment ions for each target generated by a 25V fragmentation energy. The majority of central nerve system stimulating drugs were possible to identify within the actual therapeutic ranges. Experiences with 175 real samples supported this and strongly indicated that information reported by patients on their consumption of central nerve system stimulating drugs is highly unreliable. Thus, protein precipitation and liquid chromatography-mass spectrometry may be a valuable tool for broad drug screening in human plasma in the future.