Drug abuse is a worldwide problem. Although commonly abused drugs can be identified during routine urine drug testing, less commonly abused drugs may escape detection. These less commonly abused drugs not only include some designer drugs such as synthetic cannabinoid but also include abuse of psychedelic magic mushroom (active ingredients: psilocybin and psilocin), peyote cactus (active ingredient: mescaline), and khat plants (active ingredient: cathinone). Moreover, solvent and glue abuse is gaining popularity among teenagers and young adults which may even cause fatality. Amphetamine/methamphetamine immunoassay has a low cross-reactivity with psilocin. Cathinone, if present in the urine, can be detected by amphetamine/methamphetamine immunoassay due to cross-reactivity of cathinone with assay antibody. Currently there is one commercially available immunoassay which is capable of detecting synthetic cathinone known as bath salts as well as mescaline. However, gas chromatography combined with mass spectrometry as well as liquid chromatography combined with tandem mass spectrometry (LC/MS/MS)-based method is available for confirmation of the active ingredients present in magic mushroom, peyote cactus, and khat plant. Such chromatography-based methods also offer more sensitivity and specificity compared to an immunoassay.