A method, using 0.5 mL of urine, was developed for the simultaneous determination of ecgonine methyl ester, benzoylecgonine, morphine, codeine, 6-acetylmorphine, amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and d-lysergic acid diethylamide (LSD). The analysis was performed by liquid chromatography with tandem mass spectrometry, after solid-phase extraction in the presence of their deuterated analogues. Reversed-phase separation on an Atlantis dC18 column was achieved in 12.5 min, under gradient conditions. The method was fully validated, including linearity (1-2000 microg/L for ecgonine methyl ester, benzoylecgonine, 6-acetylmorphine, methamphetamine, MDMA, and EDDP; 2-2000 microg/L for morphine, codeine, MDA, and methadone; 2-1000 microg/L for amphetamine, and 0.2-100 microg/L for LSD; r(2)>0.99); recovery (>65%), within-day and between-day precision, and accuracy (CV and MRE<15%); limit of detection (0.1 microg/L for LSD, 0.5 microg/L for ecgonine methyl ester, benzoylecgonine, methamphetamine, MDMA, 6-monoacetylmorphine, and EDDP, and 1 microg/L for amphetamine, MDA, morphine, and methadone); quantitation (lowest level of the calibration curve); relative ion intensities, freeze-and-thaw stability, and matrix effect. The procedure showed to be sensitive and specific, and was applied to real cases and quality control samples from a quality control program.