A review of nine years of NPS synthesis research projects supported by EUROSTARS

Since 2008, Chiron has been continuously running toxicology and new psychoactive substance (NPS) reference standard-focused synthesis research projects. This work has been carried out in collaboration with the German rapid test provider nal-von-minden and a variety of Nordic institutions: St. Olavs Hospital, The Norwegian Public Health Institute (now Oslo University Hospital), and, more recently, with Linköping University, Sweden. A considerable knowledge-base on systematic NPS drug trend analysis, synthesis of emerging and prophetic NPS reference standards and NPS metabolite reference standards has been accumulated through the EUROSTARS-funded projects QUANTUM SPICE (2013–2016), PSYCHOMICS (2016–2019), and the current NPS REFORM (2019–2022). The aim of this presentation is to provide an overview of what has been learnt and how the NPS market is expected to develop in future. The outcomes of the current and previous EUROSTARS projects will be presented and the future expected developments in the field will be discussed. The synthesis approach developed and applied in these projects is denoted “P4”, a Predictive Parallel Production Platform. It uses our knowledge-base to predict which new NPS compounds will arrive on the illicit or grey market and to produce as many analogues and isomers as possible of those chemicals by applying key intermediates and parallel synthesis and analytical instrumental characterisation. It also considers the most likely analogues to appear on the market based on precursor availability and price. An extensive portfolio of NPS reference materials (including NPS metabolites) has been made available to forensic chemists and clinical and forensic toxicologists across the scientific community. This community is operating within the context of a rapidly evolving, and often transient, illicit drugs market. To date, the EUROSTARs-funded projects have produced approximately 600 new native NPS compounds and NPS metabolites, in addition to approximately 50 labelled internal standards, characterised by GC-MS, LC-MS, NMR and other methodologies. The current project, NPS-REFORM, supplies emerging, often highly potent synthetic opioid reference materials (e.g., nitazenes and other emerging chemical classes); new, emerging and prophetic classes of synthetic cannabinoids appearing on the illicit market; as well as cathinones and other NPS compounds entering the marketplace. Not only do the EUROSTARs projects provide reference materials to the forensic and clinical scientific communities, they support a wide range of in vitro metabolism studies, which have identified and synthesised suitable metabolites and biomarkers to support the detection of NPS in biological fluids, an overview of which is provided. The NPS-focused EUROSTARs projects have greatly increased the breadth and availability of the NPS and NPS reference standards that are a fundamental cornerstone of drug detection in analytical laboratories. A fourth EUROSTARS project is in planning, again in collaboration with Linköping University and with the focus on various new synthetic variations of THC and other phytocannabinoids, and on the new synthetic cannabinoids emerging in response to recent legislative changes in the People's Republic of China and beyond.