Ethylone-Related Deaths: Toxicological Findings

Journal of Analytical Toxicology 2015;39:567 –571 doi:10.1093/jat/bkv053 Advance Access publication May 29, 2015 Technical Note Ethylone-Related Deaths: Toxicological Findings Dayong Lee, Chris W. Chronister, Jennifer Hoyer and Bruce A. Goldberger* Forensic Toxicology Laboratory, Division of Forensic Medicine, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, 4800 SW 35th Drive, Gainesville, FL 32608, USA *Author to whom correspondence should be addressed. Email: bruce-goldberger@ufl.edu Introduction Synthetic cathinones are emerging drugs of abuse with central nervous system-stimulant properties similar to cocaine, 3,4-methylenedioxymethamphetamine (MDMA) and other conventional amphetamines (1, 2). These are b-keto amphetamine derivatives of cathinone, the principal psychoactive constituent in the plant Catha edulis (Khat) (3). Social media began alluding to synthetic cathinones in 2007 (1). In 2010, the American Association of Poison Control Centers (AAPCC) reported 303 calls related to synthetic cathinones; the number sharply increased to 6,137 calls in 2011 and declined to 996 in 2013 (4). Similarly, the National Forensic Laboratory Information System (NFLIS) initially reported 602 synthetic cathinone-positive cases in 2010, which increased to 6,542 in 2011; 7,997 cases had been recorded as of June 2013 (5). The products are surreptitiously sold as ‘bath salts’, ‘plant food’ or ‘research chemicals’ and labeled ‘not for human consumption’ to evade drug control legislation (6). They can be obtained on the internet, in ‘head shops’ or ‘smart shops’, and also from local drug suppliers. The most prevalent drugs found in these synthetic cathinone products have been 3,4-methylenedioxyN-methylcathinone (methylone), 3,4-methylenedioxypyroval erone (MDPV), 4-methyl-N-methylcathinone (mephedrone) and more recently, a-pyrrolidinopentiophenone (a-PVP), 4-methylethcathinone (4-MEC), 2-(methylamino)-1-phenylpen tan-1-one ( pentedrone), and others have additionally been identified (5). However, the composition of synthetic cathinones on the clandestine drug market is continually transforming and new compounds have been manufactured via slight alterations in chemical structure to subvert existing regulations. In 2011, the US Drug Enforcement Administration categorized mephedrone, methylone and MDPV as Schedule I drugs (7). In 2014, 10 other synthetic cathinones were placed into Schedule I (8): 4-MEC, 4-methyl-a-pyrrolidinopropiophenone (4-MePPP), a-PVP, 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butan-1-one (butylone), pentedrone, 1-(1,3-benzodioxol-5-yl)-2-(methyl amino)pentan-1-one ( pentylone), 4-fluoro-N-methylcathinone (4-FMC), 3-fluoro-N-methylcathinone (3-FMC), 1-(naphthalen2-yl)-2-( pyrrolidin-1-yl)pentan-1-one (naphyrone) and a-pyrro lidinobutiophenone (a-PBP). Ethylone [1-(1,3-benzodioxol-5-yl)-2-(ethylamino)propan1-one; 3,4-methylenedioxy-N-ethylcathinone, MDEC; b-ketomethylenedioxyethylamphetamine, bk-MDEA] is a newer, N-ethyl form of methylone (Figure 1). The NFLIS had not received ethylone-positive cases until the second half of 2011. From then to the first half of 2013, 105 ethylone-positive reports were submitted from Federal, state and local laboratories throughout the USA (5). Four of the 35 ‘bath salt’ products purchased from California retail stores and the Internet in August – December 2011 contained 0.8 –155 mg of ethylone (9). An in vitro radioligand binding assay showed that ethylone nonselectively inhibits the monoamine transporters with potency comparable to or lower than that of cocaine (mean IC50, 2.5 – 5.7); the drug also releases serotonin (mean EC50, 9.9 mM) similar to MDMA and other entactogens (10). Ethylone is mainly metabolized via demethylenation of the methylenedioxy ring, followed by O-methylation and subsequent conjugation with glucuronic acids and/or sulfates; the minor pathways include N-deethyl ation and b-ketone reduction (11, 12). While acidic hydrolysis increased the concentrations of the phenolic metabolites (4-hydroxy-3-methoxy- and 3-hydroxy-4-methoxy-N-ethylcathi nones), the parent compound seems to be the primary analyte in human urine (11, 13, 14). In another study, 34,561 random urine samples collected in 2011–2013 were analyzed for 16 synthetic cathinones, and 16 (0.05%) were positive for ethylone; a-PVP was the most prevalent (2.5%), followed by MDPV (1.7%) and pentedrone (1.2%) (14). When 325 hair samples from 2009 to 2010 initially positive for amphetamines and/or MDMA were reanalyzed for seven synthetic cathinones, ethylone was not identified at the limit of detection of 10 pg/mg; mephedrone was found # The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: Synthetic cathinones are an emerging class of designer drugs, frequently with deceptive labels and a multitude of analogs to circumvent drug control regulations. Research regarding the pharmacological effects and toxicity of these amphetamine derivatives is scarce, heightening the risk to the public health and safety. The composition of synthetic cathinone products continually changes and laboratories began to notice ethylone-positive products in late 2011. This report presents nine postmortem cases in whom ethylone was identified. Ethylone was isolated using solid-phase extraction and detected by gas chromatography – mass spectrometry. Seven of the cases had measurable concentrations of ethylone in blood, ranging from 38 to 2,572 ng/mL; ethylone was detected in the blood sample of one case with a concentration below the assay limit of quantification (25 ng/mL), and one case did not have detectable ethylone in blood. Besides ethylone, all but one case were also positive for 11-nor-9-carboxy-D9-tetrahydrocannabinol; seven cases had other drugs quantified in blood, including ethanol, alprazolam, benzoylecgonine, diphenhydramine, morphine and tramadol. In five cases where ethylone was present at blood concentrations >400 ng/mL, no other drugs excluding ethanol, cannabis metabolite and doxylamine (one case) were found. The assay also tested for mephedrone, methylone and three dimethoxyamphetamine analogs; no case was positive for these analytes. The present report documents postmortem blood concentrations of ethylone, a novel synthetic cathinone, along with other concurrently identified substances. The findings provide valuable information for developing analytical assays and evaluating a toxic concentration range of ethylone. Table I Summary of Demographics and Decedent Cause of Death in 11 samples and methylone in 1 sample (15). Recently, a suspected impaired driving case positive for ethylone, a-PVP and methylone was reported (16). Research on synthetic cathinones in biological matrices is limited, especially in postmortem cases. Evaluation of ethylone disposition is even scarcer owing to its more recent appearance on the clandestine drug market. This study reports (...truncated)