The rapid and ongoing emergence of novel psychoactive substances poses a serious public health and safety threat. We investigated how clinical and forensic toxicology laboratories can best address novel psychoactive substances proliferation. We performed a comprehensive literature review of 913 articles to identify knowledge gaps in the pharmacodynamics, pharmacokinetics, epidemiology, chemistry, toxicity, and detection of synthetic cannabinoids. Synthetic cannabinoids provided users an alternative to achieve cannabis' effects and avoid detection in routine drug tests, making synthetic cannabinoids intake attractive to individuals subject to drug testing including athletes, police, commercial drivers, and military personnel. We analyzed 20,017 randomly collected urine specimens from US service members stationed around the world for synthetic cannabinoids and piperazines with a biochip array technology immunoassay. We identified 1432 synthetic cannabinoids and 840 piperazines presumptive-positive specimens. After confirmation of presumptive-positive and randomly selected presumptive-negative specimens by liquid chromatography tandem mass spectrometry (LC-MS/MS) or LC-high-resolution MS (LC-HRMS), we obtained a 1.4% synthetic cannabinoids positivity rate. In addition, 0.4% specimens confirmed for designer piperazines, the majority positive (N=72) for 1-(3-chlorophenyl)piperazine (mCPP) and trazodone, an antidepressant metabolizing to mCPP and prescribed to treat insomnia and/or post-traumatic stress disorder. We also optimized immunoassay performance for four synthetic cannabinoids and three designer piperazines urine drug screening methods. Our AB-FUBINACA metabolic stability and metabolite profile studies with human liver microsomes and human hepatocytes incubation and LC-HRMS identified AB-FUBINACA as a low-clearance drug (extraction ratio =0.34) with a window of detection in urine of a few days. Of 11 metabolites identified in human hepatocytes, AB-FUBINACA carboxylic acid was the most dominant metabolite generated by amide hydrolysis. Metabolites also were verified in authentic urine specimens. We present here best approaches for novel psychoactive substances identification in urine for clinical and forensic drug testing programs, and analytical methods for determining metabolic stability and profiles with human liver microsomes, human hepatocytes, and HRMS. Identifying specific synthetic cannabinoid intake is critical for tying the drug to adverse events and educating the public on the drugs' danger.