Epidemiological, pharmacological and toxicological investigation of new psychoactive substances

Abstract

New Psychoactive Substances (NPS) are synthesised to produce similar effects to controlled drugs of misuse, with an alteration in chemical structure to circumvent drugs of misuse legislation. One of the most prevalent NPS groups are synthetic cannabinoid receptor agonists (SCRAs). This research was performed to investigate the epidemiology and mechanisms of NPS toxicity. Analysis of enquiry data from the UK National Poisons Information Service (NPIS) demonstrated that SCRAs were the NPS group most commonly reported in episodes of toxicity. There were increases in reported episodes of NPS toxicity over the last decade, with reductions associated with legal controls for specific NPS, e.g. mephedrone (2010). There has been a recent decline in episodes predating the introduction of the UK Psychoactive Substances Act (2016), which has since continued. Reports of toxicity resembling serotonin syndrome in SCRA users could be due to structural similarities between indole SCRAs (e.g. JWH-018) and serotonin. This was investigated using ex-vivo rat brain slices. The inhibitory effect on serotonin reuptake observed with fluoxetine was not demonstrated with JWH-018 or CP 55,940 (nonindole SCRA). Effects of chronic exposure to SCRA were investigated in a human neuronal stem cell model, examining effects on cell viability and gene (RNAseq) and protein expression (western blotting). The SCRAs studied had different toxicity profiles and were more toxic to immature than mature cells, while the cathinone stimulant mephedrone was toxic to mature cells. Chronic low dose exposure to the SCRAs MDMB-CHMICA and 5F-ADB induced changes in gene and protein expression related to protein synthesis, perturbation of mitochondrial function and increased cellular stress. Toxicity caused by NPS in the UK has recently declined and legislation may have contributed to this. Neurotoxicity, gene and protein expression results suggest that chronic SCRA use could lead to adverse neurological effects.