The consumption of legal and illegal drugs follows an organic trend comparable to the current trend in food consumption. The investigation of such drugs is therefore of interest to characterize the active ingredients of plants and drug preparations. A new method of nonaqueous capillary electrophoresis coupled to mass spectrometry (NACE-MS) as a powerful tool for the separation of complex alkaloid mixtures in difficult matrices is presented in this study for the analysis of samples of Sceletium tortuosum and drug products called Kanna made thereof. The method was found to be suitable for the investigation of the alkaloid composition and relative quantification of the ingredients. It proved of value to separate a large number of isobaric compounds, most probably including diastereomers, double-bond isomers, and further structurally closely related compounds. A comparison of plant samples from different vendors, self-fermented samples, and products ready for consumption was made. The high separation power obtained allowed a better description of the chemotypic differences of plant samples as well as Kanna preparations compared to other methods presented in the literature so far. Thus, the use of the NACE-MS enables a new perspective on the alkaloid profile of Sceletium species.