Approaches to evaluate the pharmacology of new psychoactive substances

Resumo

In the last decade, the rapid emergence of a group of compounds known as novel psychoactive substances (NPS) has become a worrying problem due to their ambiguous legal status, their easy availability, their extensive consumption and their severe adverse effects. NPS are compounds designed to mimic existing established recreational drugs. The most commonly clinically encountered NPS are stimulants (such as mephedrone) and cannabinoids (such as “spice”) and our knowledge of their pharmaco-toxicological profile is very limited. The evaluation of hundreds of substances in a short time period is a challenge for public health and drug policies globally. This thesis aims to contribute to the pharmacological evaluation of NPS by developing a targeted metabolomics approach (on neurotransmitters and steroids) applied to brain tissue as well as in plasma and urine as a tool to predict the pharmacological profile of NPS, circumventing limitations of the current evaluation approach. We focused on specific NPS (i.e. cathinones, synthetic cannabinoids) to demonstrate the proof of principle of the methodological approach developed. By using chromatographic techniques coupled to tandem mass spectrometry, the quantification of endogenous and exogenous compounds, presumably altered after drug intake, was achieved in different biological matrices. We studied more in depth the metabolic clearance of mephedrone in humans focusing on its pharmacokinetics and pharmacogenetics aspects regulating its disposition as well as the interactions with its pharmacodynamics in a set of multi-dose randomized double-blind clinical trials. The pharmacological predictions for novel drugs was accomplished by quantifying the neuro-metabolomic fingerprint alterations of NPS compared to those observed after the intake of classical drugs of abuse. In brief, this work has contributed to describe the human disposition of mephedrone and it also highlight the potential of using targeted metabolomics as a tool to predict the pharmacological profile of NPS.