α-Pyrrolidinohexanophenone (α-PHP) vs. α-pyrrolidinoisohexanophenone (α-PiHP): A toxicological investigation about plasma concentrations and behavior in forensic routine cases.

New psychoactive substances (NPS), like pyrrolidinophenones, are still very present on the illegal drug market. The presented study reports on two members of this substance group, α-pyrrolidinohexanophenone (α-PHP) and α-pyrrolidinoisohexanophenone (α-PiHP), which occurred in forensic routine cases in the last 6 years. α-PHP could be detected predominantly by a validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) method in 33 authentic human plasma samples and α-PiHP in 8. α-PHP concentrations ranged from ca. 0.75 to 128 µg/L (mean: 23.2, median: 16.3) and α-PiHP concentrations from 7.33 to 118 µg/L (mean: 44.7, median: 33.7, quantified via α-PHP). Individuals were predominantly male and middle aged. As different studies have shown, some pyrrolidinophenones are able to cause aggressive behavior. Therefore, we set out to investigate the relation of α-PHP and α-PiHP plasma concentrations and the behavior of the consumers, reported by police and medical experts. Part of the subjects showed aggressive behavior, including agitation and restlessness. Lethargic and unremarkable behavior might be explained by co-consumption of other drugs, such as opiates/opioids, benzodiazepines, pregabalin or alcohol as well as by drug tolerance and subacute effects of stimulants. Multi-drug use could be detected in all cases; also stimulating substances and multiple different pyrrolidinophenones were determined. Nevertheless, users of α-PHP and α-PiHP showed a tendency to act aggressively, possibly triggered by a high selectivity for dopamine transporter inhibition. In accordance, committed offenses were often violent crimes. This might be considered in terms of toxicological assessment of criminal responsibility and driving ability.

Alpha-Pyrrolidinopentiothiophenone (α-PVT): A forensic case study including plasma concentrations.

Alpha-Pyrrolidinopentiothiophenone (α-PVT) belongs to the drug class of pyrrolidinophenones, a subgroup of synthetic cathinones, which are among the most prevalent new psychoactive substances. The study describes a series of 44 authentic forensic cases with analytical confirmed intake of α-PVT. Plasma concentrations, determined by a validated LC-MS/MS method, ranged from ca. 0.9 to 306 µg/L (median 35.6; mean 66.6 µg/L). Comprehensive toxicological analysis proved excessive co-consumption in almost all cases, including other pyrovalerones and classic stimulants as well as central depressant drugs such as opiates/opioids, benzodiazepines, pregabalin and/or ethanol. Subjects were aged between 26 and 54 years (median 35 years, mean 36 years) and appeared to be mainly experienced intravenous drug consumers. A high incidence of aberrant behavior in terms of aggressive, combative behavior and psychotic changes could be observed, as also reflected in accused offences, which frequently presented violent crimes. In consideration of several confounding factors, the study suggests a relationship between frequency of such impairment and plasma concentrations of α-PVT, but individual cases without signs of behavioral changes and high plasma concentrations also occurred, which might be explained by developed tolerance and/or individual vulnerably for the psychotic effects of pyrovalerones.

New Psychoactive Substances: Chemistry, Pharmacology, Metabolism, and Detectability of Amphetamine Derivatives With Modified Ring Systems.

In recent years, new amphetamine derivatives with modified ring systems were sold and consumed as new drugs of abuse. They belong together with other new drugs of abuse classes to the so-called new psychoactive substances (NPS). The chemistry, pharmacology, toxicology, metabolism, and toxicokinetics are shortly discussed of camfetamine, 3 methylphenyl-amphetamines (2-MA, 3-MA, and 4-MA), 2-methiopropamine (2-MPA), and 5-(2-aminopropyl)benzofuran (5-APB), 6-(2-aminopropyl)benzofuran (6-APB, so-called "benzofury") and their N-methyl derivatives 5-MAPB and 6-MAPB. Only a rough assessment of the pharmacology and toxicology NPS can be performed in most cases using published data of analogs, trip reports, and described clinical cases. Accordingly, they all act more or less as central nervous stimulants mainly by increasing the concentration of the neurotransmitters noradrenaline, dopamine, and serotonin (5-HT) by inducing their release and reuptake inhibition. Thus, the acute toxicity is associated with the sympathomimetic effects, such as mydriasis, hyperthermia, hypertension, tachycardia, insomnia, and anxiety. With the exception of 5- and 6-APB, these NPS were extensively metabolized by N-demethylation and/or aromatic hydroxylation catalyzed by various cytochrome P450 isoenzymes followed by partial glucuronidation and/or sulfation. For urinalysis, the unchanged drugs and/or the nor-metabolites are the main targets.