Hazard characterization of new psychoactive substances: Legal highs – A problem in disguise?

New psychoactive substances (NPS) are a fast-growing group of drugs that yearly cause many intoxications and incidental deaths. However, knowledge on their neuropharmacological mechanisms is scarce. In this thesis, neurotransmission and NPS are introduced and the literature on neuropharmacological mechanisms of NPS is reviewed, highlighting the current data gaps. This thesis fills several of these gaps by investigating the toxicological risks of ~20 NPS and illicit drugs. Most drugs potently inhibit the dopamine and norepinephrine transporters. Inhibition of the serotonin transporter and neuronal activity is observed at higher concentrations. Subsequently, the obtained data is related to concentrations relevant for human exposure, linked to clinical symptoms, and used to identify specific chemical structures responsible for changes in potency. Furthermore, this thesis shows that besides neurons, cardiomyocytes are also affected by illicit drugs and NPS at concentrations relevant for human exposure. Additionally, this thesis highlights the impact of interindividual differences. This thesis shows that two mutations in the dopamine transporter result in a decrease of (therapeutic) effect of psychoactive substances and a specific clinical course. Also, several recommendations are made to increase the predictability of in vitro experiments by mimicking human exposure as best as possible. It has been demonstrated that prolonged exposure, recovery following exposure and hyperthermia are important conditions to account for in the hazard characterization of NPS. Lastly, all findings are summarized, and the present shortcomings and future opportunities are discussed.