Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications, Arianna Giorgetti et al., 2021

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

Arianna Giorgetti, Jennifer P. Pascali, Paolo Fais, Guido Pelletti, Andrea Gabbin, Giorgia Franchetti, Giovanni Cecchetto  and Guido Viel

Life, 2021, 11, 440, 1-17.

doi : 10.3390/life11050440


Abstract :

Novel psychoactive substances (NPS) represent a severe health risk for drug users. Even though the phenomenon has been growing since the early 2000s, the mechanisms of action of NPS at the receptors and beyond them are still scarcely understood. The aim of the present study was to provide a systematic review of the updated knowledge regarding the molecular mechanisms underlying the toxicity of synthetic opioids, cannabinoids, cathinones, and stimulants. The study was conducted on the PubMed database. Study eligibility criteria included relevance to the topic, English language, and time of publication (2010–2020). A combined Mesh and free-text protocols search was performed. Study selection was performed on the title/abstract and, in doubtful cases, on the full texts of papers. Of the 580 records identified through PubMed searching and reference checking, 307 were excluded by title/abstract and 78 additional papers were excluded after full-text reading, leaving a total of 155 included papers. Molecular mechanisms of synthetic opioids, synthetic cannabinoids, stimulants, psychedelics, and hallucinogens were reviewed and mostly involved both a receptor-mediated and non-receptor mediated cellular modulation with multiple neurotransmitters interactions. The molecular mechanisms underlying the action of NPS are more complex than expected, with a wide range of overlap among activated receptors and neurotransmitter systems. The peculiar action profile of single compounds does not necessarily reflect that of the structural class to which they belong, accounting for possible unexpected toxic reactions.

Keywords : forensic toxicology; new psychoactive substances (NPS); mass spectrometry; toxicodynamic; mechanism of action


1. Introduction

Novel Psychoactive Substances (NPS) are an inhomogeneous group of substances which are typically sold as “legal” alternatives to the classical scheduled drugs of abuse, such as heroin, cocaine, cannabinoides synthamphetamines, benzodiazepines etc. [1]. The term “novel” derives from the fact that, contrarily to classical drugs of abuse, NPS were not covered by the International Drug Control Conventions of 1961–1971 [1,2]. Nowadays, the term could be considered somehow misleading, since many of the compounds have been later included in the list of scheduled substances at a national or international level [2]. Nonetheless, the “legality” of these compounds still represents one of the main attractions for consumers [2]. One of the characteristics of the NPS phenomenon resides in the ease of producing novel compounds by minimal twisting or modifications of the chemical structures, producing a nonscheduled molecule and circumventing existing legislations. Some authors have underlined that the huge efforts of national/international organizations, striving to include a molecule within the list of prohibited substances, are the main trigger for the innovation and production of novel compounds (the so-called “cat and mouse model”) [2,3], which have rated more than 50 novel compounds per year since early 2000. Thus, even if many of these substances are now controlled, several are still nonscheduled, undetected, and unidentified. These substances are not even consumed or produced, but certainly will be in the next future. To date, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has monitored 790 new psychoactive substances [1,4,5]. The main drives for consuming NPS are also the reported “safety” and “natural origin” by the supplier, both concepts that have led to an extraordinary growth in popularity of NPS since 2007, especially among younger users browsing the Internet [5–7]. Although they are claimed as “safe” or sold “not for human consumption,” these substances pose severe health risks, the prevention of which cannot disregard from an in-depth understanding of their
pharmacokinetic and pharmacodynamic properties.

The aim of the present review is to provide an overview of the molecular mechanisms of action of the main classes of novel psychoactive substances (synthetic opioids, synthetic cannabinoids, and synthetic cathinones and stimulants) to better understand the health risks and the effects arising from their consumption, according to the PICOS process:

P—population/problem: Novel psychoactive substances, synthetic opioids, synthetic cannabinoids, synthetic cathinones, and stimulants;

I—intervention: In vivo or in vitro studies;

C—comparison, control: Previous knowledge;

O—outcome of interest: Description of the molecular mechanisms of action of novel psychoactive substances;

S—study design: PubMed review.