Raising awareness of new psychoactive substances: chemical analysis and in vitro toxicity screening of 'legal high' packages containing synthetic cathinones
Raising awareness of new psychoactive substances: chemical analysis and in vitro toxicity screening of 'legal high' packages containing synthetic cathinones
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DOI：
10.1007/s00204-014-1278-7
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发表时间：
2015-05-01
影响因子：
6.1
通讯作者：
de Pinho, Paula Guedes
中科院分区：
文献类型：
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作者：
Araujo, Ana Margarida;Valente, Maria Joao;de Pinho, Paula Guedes
近年来，以新型麻醉药品或精神药品为代表的新型精神活性物质（NPS）迅速出现，其纯品或制剂不受国际公约管制，但可能对公共健康构成与这些公约所列物质相当的威胁，全球消遣性毒品现状发生了巨大变化。这些新的精神活性物质，也被称为“合法兴奋剂”或“智能药物”，通常通过互联网或“智能商店”作为受控物质的合法替代品出售，被称为“浴盐”和“植物饲料”，经常受到特别是年轻人的追捧。尽管新精神活性物质被认为是安全的，但绝大多数尚未经过测试，并且已经报告了几起死亡病例，即合成卡西酮，其病理模式与安非他明相当。此外，新的精神活性物质在全球范围内以前所未有的速度出现和分布，给实时分析程序的开发和风险评估带来了技术困难。在这项研究中，通过气相色谱-质谱法和核磁共振波谱法对 27 种作为“植物饲养剂”商业化的产品进行了化学表征。还首次评估了各种合成卡西酮的体外肝毒性作用，即甲基酮、戊二酮、4-甲基乙卡西酮 (4-MEC) 和 3,4-亚甲二氧基吡咯戊酮 (MDPV)。还测试了主要含有卡西酮衍生物的两种商业混合物（“Bloom”和“Blow”），并使用 3,4-亚甲基二氧基甲基苯丙胺（MDMA）作为参考药物。该研究鉴定出 19 种化合物，表明合成卡西酮是这些产品中存在的主要活性化合物。在匹配或不同的“智能商店”中以相同商品名称销售的产品在质量和数量上存在差异。在原代培养大鼠肝细胞中进行的毒性研究中，pentedrone 和 MDPV 被证明是最有效的单独药物，EC50 值分别为 0.664 和 0.742 mM，其次是 MDMA (EC50 = 0.754 mM)。 4-MEC 和甲基酮是效力最弱的物质，EC50 值显着较高（分别为 1.29 和 1.18 mM；与 MDMA 相比，p < 0.05）。 “Bloom”和“Blow”表现出与 MDMA 相似的肝毒性作用（EC50 分别为 0.788 和 0.870 mM），这些混合物中存在的卡西酮对总体毒理学作用有额外贡献。我们的研究结果表明，“合法高”产品中存在多种精神活性化合物，具有明显的肝毒性作用。这些数据有助于提高人们对“合法高”包装的真实成分的认识，并揭示 NPS 带来的健康风险。
The world's status quo on recreational drugs has dramatically changed in recent years due to the rapid emergence of new psychoactive substances (NPS), represented by new narcotic or psychotropic drugs, in pure form or in preparation, which are not controlled by international conventions, but that may pose a public health threat comparable with that posed by substances listed in these conventions. These NPS, also known as 'legal highs' or 'smart drugs', are typically sold via Internet or 'smartshops' as legal alternatives to controlled substances, being announced as 'bath salts' and 'plant feeders' and is often sought after for consumption especially among young people. Although NPS have the biased reputation of being safe, the vast majority has hitherto not been tested and several fatal cases have been reported, namely for synthetic cathinones, with pathological patterns comparable with amphetamines. Additionally, the unprecedented speed of appearance and distribution of the NPS worldwide brings technical difficulties in the development of analytical procedures and risk assessment in real time. In this study, 27 products commercialized as 'plant feeders' were chemically characterized by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. It was also evaluated, for the first time, the in vitro hepatotoxic effects of individual synthetic cathinones, namely methylone, pentedrone, 4-methylethcathinone (4-MEC) and 3,4-methylenedioxypyrovalerone (MDPV). Two commercial mixtures ('Bloom' and 'Blow') containing mainly cathinone derivatives were also tested, and 3,4-methylenedioxymethamphetamine (MDMA) was used as the reference drug. The study allowed the identification of 19 compounds, showing that synthetic cathinones are the main active compounds present in these products. Qualitative and quantitative variability was found in products sold with the same trade name in matching or different 'smartshops'. In the toxicity studies performed in primary cultured rat hepatocytes, pentedrone and MDPV proved to be the most potent individual agents, with EC50 values of 0.664 and 0.742 mM, respectively, followed by MDMA (EC50 = 0.754 mM). 4-MEC and methylone were the least potent substances, with EC50 values significantly higher (1.29 and 1.18 mM, respectively; p < 0.05 vs. MDMA). 'Bloom' and 'Blow' showed hepatotoxic effects similar to MDMA (EC50 = 0.788 and 0.870 mM, respectively), with cathinones present in these mixtures contributing additively to the overall toxicological effect. Our results show a miscellany of psychoactive compounds present in 'legal high' products with evident hepatotoxic effects. These data contribute to increase the awareness on the real composition of 'legal high' packages and unveil the health risks posed by NPS.