Identifying the challenges of emerging novel psychoactive substances

Novel psychoactive substances (NPS) are compounds similar to common drugs of abuse with slight modifications to their chemical structure. These modifications can be dangerous and sometimes fatal due the lack of knowledge and/or studies of their adverse effects. NPS are sometimes marketed as “legal highs” or “research chemicals” in order to mimic effects of illicit drugs while simultaneously bypassing legislation. Although there are many drugs that are classified as NPS, novel synthetic opioids and synthetic cannabinoids are the focus of this research. Since little is known about these novel psychoactive substances difficulties may arise when analyzing toxicological samples suspected to contain NPS. To address the emergence of novel psychoactive substances, it is necessary to properly identify issues that could hinder analyses by assessing prevalence, examining instability, determining pharmacology, and identifying potential metabolites. The goals of this study were to 1) develop and validate a method to quantify novel synthetic opioids (NSO), buprenorphine, and heroin markers in oral fluid and apply the method to the analysis of oral fluid collected from detainees; 2) using the acquisition method from the oral fluid method, validate a blood method for the NSO and perform a long term stability study; 3) develop and validate a method to detect a NSO (U-47700) and its metabolites in plasma using a small sample volume (100 µL) and cross validate in rat plasma for a pharmacokinetic study in rats; and 4) identify metabolites for two prominent synthetic cannabinoids in vitro verify metabolism with analysis of authentic urine samples. A method was validated for the quantification of morphine, 6-acetylmorphine, buprenorphine, U-47700, U-49900, U-50488, AH-7921, MT-45, W-18, and W-15 in oral fluid and was deemed acceptable according to Scientific Working Group for Forensic Toxicology (SWGTOX) guidelines. This method was applied to analysis of oral fluid collected from detainees (n=20) in Texas detention centers participating in a drug recognition evaluatoion (DRE) certification program. Although NSO were not detected, valuable data were collected that reinforced oral fluid as viable matrix when compared to presumptive urine results and impairment observations. A blood method was validated for seven NSO and then applied to assess the stability of these analytes over a 36-week study at four temperature conditions (-20°C,4°C, 25°C , and 35°C). The results showed minimal effect on stability at the elevated temperature during the first two weeks, indicating that these analytes would be stable in the event of improper transport/handling within this timeframe. A method was validated for the quantification of U-47700, N-desmethyl-U-47700, and N,N-didesmethyl-U-47700 in human and rat plasma. This method was applied to a pharmacokinetic study where rats were injected with 0 (saline), 0.3, 1.0 or 3.0 mg/kg U-47700. Blood samples were collected at 15, 30, 60, 120, 240, 480 min after injection for quantification of U-47700 and its metabolites. Pharmacodynamic effects were also assessed at the same time points. It was determined that doses of U-47700 had a positive correlation with the behaviors observed which further demonstrates the analgesic effects of this novel synthetic opioid. Finally, a metabolic study utilizing human liver microsomes was conducted to investigate 5F-MDMB-PICA and 5F-MDMB-PINACA in vitro metabolism. In vitro metabolites were verified in vivo by analyzing authentic case specimens. Additionally, the potency and efficacy of 5F-MDMB-PICA and 5F-MDMB-PINACA were identified by examining activity at the CB1 receptor. The EC50 at the CB1 receptor for 5F-MDMB-PICA and 5F-MDMB-PINACA were found to be comparable to each other and JWH-018. There were 22 metabolites identified for 5F-MDMB-PICA and 21 metabolites identified for 5F-MDMB-PINACA. These studies have sought to identify toxicological issues that could arise when detecting a new NPS while providing the necessary data to the forensic toxicology community to further understand the activity and prevalence of such compounds. The challenges that arise when faced with a newly emerged NPS may be detrimental for forensic analysis and thorough characterization of new compounds is necessary for proper identification and detection.