Gas chromatography–mass spectrometry (GC-MS) and Liquid chromatography–mass spectrometry (LC-MS) are widely used to identify and measure drugs and endogenous compounds of interest in the samples for psychiatric research. Our group has developed new assays for psychotropic drugs and their metabolites with very high specificity and sensitivity. We have utilized these methods in quantitative measurements for hundreds plasma, urine, brain tissues, saliva and cerebrospinal fluid samples each year. In recent years, we have quantitatively assayed THC, nor-carboxy-THC, amphetamine, GABA, gabapentin, lofexidine, quinolinic acid in plasma, and tetrahydrocannabivarin, tetrahydrocannabivarin carboxylic acid in urine samples by GC-MS. We also have used LC-MS to measure oxycodone, cocaine and its metabolites, nicotine, cotinine in plasma, cannabidiol in urine, and anandamide and 2-Arachidonoylglycerol in brain tissues. In addition, we have carried out dose analysis of THC and cocaine by LC-MS procedures.