Effect fingerprinting of new psychoactive substances (NPS): What can we learn from in vitro data?

Abstract

The use of new psychoactive substances (NPS) is increasing and currently >600 NPS have been reported. However, limited information on neuropharmacological and toxicological effects of NPS is available, hampering risk characterization. We reviewed the literature on the in vitro neuronal modes of action to obtain effect fingerprints of different classes of illicit drugs and NPS. The most frequently reported NPS were selected for review: cathinones (MDPV, α-PVP, mephedrone, 4-MEC, pentedrone, methylone), cannabinoids (JWH-018), (hallucinogenic) phenethylamines (4-fluoroamphetamine, benzofurans (5-APB, 6-APB), 2C-B, NBOMes (25B-NBOMe, 25C-NBOMe, 25I-NBOMe)), arylcyclohexylamines (methoxetamine) and piperazine derivatives (mCPP, TFMPP, BZP). Our effect fingerprints highlight the main modes of action for the different NPS studied, including inhibition and/or reversal of monoamine reuptake transporters (cathinones and non-hallucinogenic phenethylamines), activation of 5-HTreceptors (hallucinogenic phenethylamines and piperazines), activation of cannabinoid receptors (cannabinoids) and inhibition of NDMA receptors (arylcyclohexylamines). Importantly, we identified additional targets by relating reported effect concentrations to the estimated human brain concentrations during recreational use. These additional targets include dopamine receptors, α- and β-adrenergic receptors, GABAreceptors and acetylcholine receptors, which may all contribute to the observed clinical symptoms following exposure. Additional data is needed as the number of NPS continues to increase. Also, the effect fingerprints we have obtained are still incomplete and suffer from a large variation in the reported effects and effect sizes. Dedicated in vitro screening batteries will aid in complementing specific effect fingerprints of NPS. These fingerprints can be implemented in the risk assessments of NPS that are necessary for eventual control measures to reduce Public Health risks.

Piperazine designer drugs elicit toxicity in the alternative in vivo model Caenorhabditis elegans

“…Besides, neurotransmitters, such as dopamine, regulate nematode body size affecting muscle function as they affect the activity of motor neurons (Nagashima, Oami, Kutsuna, Ishiura, & Suo, 2016). Considering that piperazine designer drugs could act at noradrenergic, dopaminergic and serotonergic synapses (Hondebrink, Zwartsen, & Westerink, 2018), it is possible that the reduction of body area is connected to dopaminergic effects. Notably, in vivo BZP stimulates the release of dopamine by reversing transporter flux, inhibits dopamine reuptake, blocks dopamine transporters and acts as an agonist at postsynaptic dopamine receptors (Katz et al, 2016).…”

Symposia, case conference, and medical update: Abstracts & summaries

“…9 The combination of the dopaminergic activity, and the absence of cannabidiol, may facilitate "unopposed" activity at CB1 and could explain why synthetic cannabinoids are significantly more potent than delta-9 THC, a partial CB1 agonist. 10 As synthetic cannabinoids do not appear on traditional urine drug tests, a high clinical suspicion is required as intoxication can mimic primary psychiatric illness, such as mania and schizophrenia-spectrum psychosis. 3 Unfortunately, chronic synthetic cannabinoid users can develop sensitization to some of its adverse effects, such as agitation and psychosis.…”

Should NPS be included in workplace drug testing?

“…4 Secondly, among the large variety of NPS, some are proven to have "desirable" pharmacological effects, while others are more likely to disappear because of their unpleasant side-effects. [5][6][7] Third, pharmacokinetic studies progressively provide information about the various NPS metabolic pathways and the target analytes to look for, in different biological matrices. Lastly, and most importantly, recent technological developments may make screening analysis for NPS more affordable and effective.…”