Analyses of LSD analogs in illegal products: The identification of 1cP-AL-LAD, 1cP-MIPLA and 1V-LSD

Abstract

Recently, many lysergic acid diethylamide (LSD) analogs have appeared as designer drugs globally. These compounds are mainly distributed as sheet products. In a previous study [1] , we identified seven LSD analogs in paper sheet products distributed in Japan. In this study, we identified three more newly distributed LSD analogs from paper sheet products. Three paper sheet products were obtained from August 2021 to March 2022 in Japan. Each sheet was cut into 2 mm squares and extracted with methanol in 15 min under sonication. The extracts were concentrated to dryness and redissolved in acetonitrile for GC-MS, LC-MS, and HR-MS analyses. For the NMR measurement, each cut sheets were sonicated in 1.0 mL of methanol at room temperature for 5 minutes. The extraction procedure was repeated 3 times. The extracts were combined and concentrated to dryness in a vacuum. The residue was dissolved in methanol-d4 and was subjected to NMR measurement (JEOL JMN-ECA800 or ECZ800 spectrometer). Identification of the compounds was performed using 1H-NMR, 13C-NMR, HMQC, HMBC, H-H COSY, and NOESY. As a result of the analysis by the NMR, the compounds in the three products were identified as 4-(cyclopropanecarbonyl)-N,N-diethyl-7-(prop-2-en-1-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1cP-AL-LAD), 4-(cyclopropanecarbonyl)-N-methyl-N-isopropyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo-[4,3-fg]quinoline-9-carboxamide (1cP-MIPLA), N,N-diethyl-7-methyl-4-pentanoyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1V-LSD). On the sheets containing 1cP-MIPLA and 1V-LSD, the NMR and the LC-PDA-MS data showed the presence of minor compounds. They were estimated to be iso-1cP-MIPLA and iso-1V-LSD, C9 epimerized 1cP-MIPLA and 1V-LSD. In 1cP-MIPLA, minor signals of the rotational isomer were also confirmed from the NMR data. It has been reported that the N1-acylated LSD analogs were deacylated during the GC-MS analysis using methanol as a solvent. In this study, it was observed that 1V-LSD, extracted from the sheet, was also deacylated to LSD under the same conditions. On the other hand, in 1cP-AL-LAD and 1cP-MIPLA (which were also acylated at the N1 position), the deacylation was not observed by the GC-MS analysis. Based on the structure of LSD, 1cP-AL-LAD is converted at the positions at N1 and N6, and 1cP-MIPLA is at the positions at N1 and N18. This is the first report that the LSD analogs, which were converted at multiple positions, have been detected in illegal products in Japan. In this study, these compounds in methanol solutions were not deacylated during the GC-MS analysis and further examination is necessary because N1-acylated LSD analogs, such as ALD-52, 1P-LSD, 1cP-LSD, and 1B-LSD, have been reported to be deacylated to LSD under the same conditions. Halberstadt et al., [2] reported that high levels of LSD were detected in the plasma of rats after a subcutaneous administration of ALD-52 and 1P-LSD. Therefore, 1V-LSD might be deacylated in vivo and might function as a prodrug of LSD. The products containing these prodrug-type compounds might cause health damage like LSD. The metabolic pathway and biological activities of 1cP-AL-LAD and 1cP-MIPLA have not been reported. Although the deacylation of these compounds were not observed during the GC-MS analysis, the possibility of the deacylation in vivo and the conversion into AL-LAD or MIPLA, should be further investigated. In addition, there are concerns about the distribution of sheet drug products containing new LSD analogs in the future. Therefore, the continuous monitoring of newly detected compounds in the illeagal products is important.