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

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; mass spectrometry; mechanism of action; new psychoactive substances (NPS); toxicodynamic.

Figure 1

PRISMA flow diagram of the present review. From: Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS medicine, 2009, 6(7): e1000097 [8].

Figure 2

Modified from Guzman et al. Cannabinoids: Potential anticancer agents. Nat Rev Cancer. Mechanism activated by the receptor of human cannabinoids 1 (CB1R), ranging from binding to G-protein-coupled receptors (Gi/o) with inhibition of the adenylyl cyclase (AdeC), and therefore of the cyclicAMP (cAMP) and of the protein kinase A (PKA). Inhibition of voltage-sensitive Ca²⁺ channels (VSCC); release of Ca²⁺ from intracellular stores; activation of the phosphatidylinositol 3-kinase (PI3K)–AKT pathway; activation of mitogen-activated protein kinase cascades as extracellular-signal-regulated kinase (ERK), JUN amino-terminal kinase (JNK), and p38 and ceramide generation through FAN–sphingomyelinase (factor associated with neutral sphingomyelinase activation–SMase).

Figure 3

Selectivity of stimulants with the ratio between dopamine (DAT) and serotonin (SERT) transporters. Slightly modified from Luethi et al. [7].