Analysis of Synthetic Cathinones Commonly Found in Bath Salts in Human Performance and Postmortem Toxicology: Method Development, Drug Distribution and Interpretation of Results

Montgomery County Coroner's Office (MCCO)/Miami Valley Regional Crime Laboratory (MVRCL), Dayton, Ohio.
Journal of analytical toxicology (Impact Factor: 2.86). 01/2013; 37(3). DOI: 10.1093/jat/bks136
Source: PubMed


To date, the Toxicology Section of the Montgomery County Coroner's Office/Miami Valley Regional Crime Laboratory has identified six synthetic cathinones, commonly found in bath salt products, in 43 cases. Thirty-two cases will be reviewed here, including all of the postmortem cases, all of the human performance cases that had blood specimens submitted, and one urine-only human performance case. The following compounds have been confirmed: 3,4-methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), pyrovalerone, pentylone, alpha-pyrrolidinopentiophenone (alpha-PVP) and methedrone. The method also screens for mephedrone, butylone and 3-fluoromethcathinone. Case demographics show 42 white males and females ranging in age from 19 to 53 years. The remaining case was that of a 34-year-old Hispanic male. The 43 cases represent 17 driving under the influence, two domestic violence, four suicides, 12 overdoses, six accidents, one drug-facilitated assault and one homicide. Data will be presented on the distribution of some of these cathinones in various matrices. After review, blood concentration does not appear to predict outcome regarding fatalities or impairment. The highest MDPV concentration occurred in a suicide by hanging and the highest methylone concentration was in a driver. The confirmation method is a liquid-liquid extraction with detection by liquid chromatography triple quadrupole mass spectrometry using electrospray ionization in multiple reaction monitoring mode.

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    • "All these cathinones are characterized by a pyrrolidine ring structure, making them different structurally and possibly also pharmacologically from other synthetic cathinones (Marusich et al., 2014; Simmler et al., 2013). Among the pyrovalerone cathinones, MDPV is currently the most widely detected and used, both in the EU (European Monitoring Center for Drugs and Drug Addiction, 2014b; Helander et al., 2014; Zuba and Byrska, 2013) and US (Leffler et al., 2014; Marinetti and Antonides, 2013; Spiller et al., 2011). In fact, MDPV has become the most frequently detected and used of all cathinones ( " bath salts " ) in some EU countries (Helander et al., 2014; Zuba and Byrska, 2013) and the US (Leffler et al., 2014). "
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    ABSTRACT: The pharmacology of novel psychoactive substances is mostly unknown. We evaluated the transporter and receptor interaction profiles of a series of para-(4)-substituted amphetamines and pyrovalerone cathinones. We tested the potency of these compounds to inhibit the norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporters (NET, DAT, and SERT, respectively) using human embryonic kidney 293 cells that express the respective human transporters. We also tested the substance-induced efflux of NE, DA, and 5-HT from monoamine-loaded cells, binding affinities to monoamine receptors, and 5-HT2B receptor activation. Para-(4)-substituted amphetamines, including 4-methylmethcathinone (mephedrone), 4-ethylmethcathinone, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcatinone (flephedrone), and 4-bromomethcathinone, were relatively more serotonergic (lower DAT:SERT ratio) compared with their analogs amphetamine, methamphetamine, and methcathinone. The 4-methyl, 4-ethyl, and 4-bromo groups resulted in enhanced serotonergic properties compared with the 4-fluoro group. The para-substituted amphetamines released NE and DA. 4-Fluoramphetamine, 4-flouromethamphetamine, 4-methylmethcathinone, and 4-ethylmethcathinone also released 5-HT similarly to 3,4-methylenedioxymethamphetamine. The pyrovalerone cathinones 3,4-methylenedioxypyrovalerone, pyrovalerone, α-pyrrolidinovalerophenone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, and 3,4-methylenedioxy-α-pyrrolidinobutiophenone potently inhibited the NET and DAT but not the SERT. Naphyrone was the only pyrovalerone that also inhibited the SERT. The pyrovalerone cathinones did not release monoamines. Most of the para-substituted amphetamines exhibited affinity for the 5-HT2A receptor but no relevant activation of the 5-HT2B receptor. All of the cathinones exhibited reduced trace amine-associated receptor 1 binding compared with the non-β-keto-amphetamines. In conclusion, para-substituted amphetamines exhibited enhanced direct and indirect serotonergic agonist properties and are likely associated with more MDMA-like effects. The pharmacological profile of the pyrovalerone cathinones predicts pronounced stimulant effects and high abuse liability.
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    • "Chemical analyses of numerous bath salts products have identified that the main active ingredients are usually analogues of the amphetaminelike stimulant cathinone (National Drug Intelligence Center, 2011). The presence of synthetic cathinone analogues was confirmed by toxicology screening and post mortem analysis of patients who had presented with bath salts intoxication (Coppola & Mondola, 2012; Marinetti & Antonides, 2013). Synthetic cathinone analogues first started to appear in Japan, Australia, and several European countries as early as 2006 and in the United States in 2009 (Camilleri et al., 2010; Bronstein et al., 2011; Gunderson et al., 2013; Zawilska & Wojcieszak, 2013). "
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    ABSTRACT: Several novel synthetic amphetamines have been marketed worldwide as "bath salts." The use of bath salts is associated with severe medical consequences resulting in a US federal ban over the last 3 years on the more common substances found in this group. Bath salts intoxication has a relatively nonspecific presentation, and urine toxicology confirmation in emergency departments (EDs) is impractical because the turnaround time is several days. Emergency clinicians must therefore rely heavily on patients' self-reports to verify the diagnosis. We performed an online survey of emergency clinicians to determine their degree of exposure to bath salts-intoxicated patients, the clinically relevant features of such patients, and the typical emergency management. We invited 124 physicians and physician assistants in 7 Cleveland Clinic EDs to participate in an online survey. From a total of 43 of the 124 respondents, 77% did not specifically ask patients about bath salts use. Sixty percent had encountered a bath salts-intoxicated individual. Most respondents reported that the majority of patients were male, were between 19 and 29 years old, and used other drugs in addition to bath salts. Agitation, aggression/violence, and hallucinations were reported to be the most common presentations, and intravenous/intramuscular tranquilization was reported as the most often used management. Most patients were discharged home from the ED. Despite the lack of toxicology screening in EDs, about two thirds of the surveyed emergency clinicians encountered bath salts-intoxicated individuals. Our study demonstrates the need for increased screening of bath salts intoxication in EDs, especially in agitated patients.
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    • "Accordingly, both drugs are readily selfadministered and facilitate intracranial self-stimulation in rat models (Aarde et al, 2013a; Bonano et al, 2014; Hadlock et al, 2011; Watterson et al, 2014). As noted above, a number of second-generation analogs of mephedrone and MDPV have recently appeared in the recreational drug marketplace (Leffler et al, 2014; Marinetti and Antonides, 2013). We and others have shown that newly emerging analogs of MDPV, like a-pyrrolidinovalerophenone (a-PVP), are potent blockers at DAT and NET (Kolanos et al, 2013; Marusich et al, 2014). "
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    ABSTRACT: The nonmedical use of synthetic cathinones is increasing on a global scale. 4-Methyl-N-methylcathinone (mephedrone) is a popular synthetic cathinone that is now illegal in the United States and other countries. Since the legislative ban on mephedrone, a number of 'second generation' analogs have appeared in the street drug marketplace, including 4-methyl-N-ethylcathinone (4-MEC) and 4-methyl-α-pyrrolidinopropiophenone (4-MePPP). Here we characterized the interactions of 4-MEC and 4-MePPP with transporters for 5-HT (SERT) and dopamine (DAT) using molecular, cellular and whole animal methods. In vitro transporter assays revealed that 4-MEC displays unusual 'hybrid' activity as a SERT substrate (i.e., 5-HT releaser) and DAT blocker, whereas 4-MePPP is a blocker at both transporters but more potent at DAT. In vivo microdialysis experiments in rat brain demonstrated that 4-MEC (1-3 mg/kg, i.v.) produced large increases in extracellular 5-HT, small increases in dopamine, and minimal motor stimulation. By contrast, 4-MePPP (1-3 mg/kg, i.v.) produced selective increases in dopamine and robust motor stimulation. Consistent with its activity as a SERT substrate, 4-MEC evoked inward current in SERT-expressing Xenopus oocytes, while 4-MePPP was inactive in this regard. To examine drug-transporter interactions at the molecular level, we modeled the fit of 4-MEC and 4-MePPP into the binding pockets for DAT and SERT. Subtle distinctions in ligand-transporter binding were found that account for the differential effects of 4-MEC and 4-MePPP at SERT. Collectively, our results provide key information about the pharmacology of newly-emerging mephedrone analogs, and give clues to structural requirements that govern drug selectivity at DAT versus SERT.Neuropsychopharmacology accepted article preview online, 15 December 2014. doi:10.1038/npp.2014.325.
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