Determination of psychoactive drugs in the context of clinical and forensic toxicology, down to the low ng/mL range from only 250 μL of blood plasma or serum, is described in this work. A comprehensively automated “multi method” based on solid-phase extraction (SPE) coupled online to LC–MS/MS is used to determine 65 compounds, including benzodiazepines, various sedatives, antidepressants, antipsychotics, methadone, and their relevant metabolites. The method has been fully validated for 52 of those compounds following the guidelines of the Society of Toxicological and Forensic Chemistry (GTFCh). Semi-quantitative or qualitative determination of some less relevant drugs and metabolites is also included in this work.