Madrid-Gambin Francisco, Gomez-Gomez Alex, Busquets-Garcia Arnau, Haro Noemí, Marco Santiago, Mason Natasha L, Reckweg Johannes T, Mallaroni Pablo, Kloft Lilian, van Oorsouw Kim, Toennes Stefan W, de la Torre Rafael, Ramaekers Johannes G, Pozo Oscar J
Applied Metabolomics Research Group, IMIM-Institut Hospital del Mar d'Investigacions Mèdiques, 08003 Barcelona, Spain; Signal and Information Processing for Sensing Systems, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
Applied Metabolomics Research Group, IMIM-Institut Hospital del Mar d'Investigacions Mèdiques, 08003 Barcelona, Spain.
Biomed Pharmacother. 2022 May;149:112845. doi: 10.1016/j.biopha.2022.112845. Epub 2022 Mar 24.
There has been a renewed interest in the potential use of psychedelics for the treatment of psychiatric conditions. Nevertheless, little is known about the mechanism of action and molecular pathways influenced by ayahuasca use in humans. Therefore, for the first time, our study aims to investigate the human metabolomics signature after consumption of a psychedelic, ayahuasca, and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids. Plasma samples of 23 individuals were collected both before and after ayahuasca consumption. Samples were analysed through targeted metabolomics and further integrated with subjective ratings of the ayahuasca experience (i.e., using the 5-Dimension Altered States of Consciousness Rating Scale [ASC]), and plasma ayahuasca-alkaloids using integrated network analysis. Metabolic pathways enrichment analysis using diffusion algorithms for specific KEGG modules was performed on the metabolic output. Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Integrated network results indicated that most of the LNAAs were inversely associated with 9 out of the 11 subscales of the ASC, except for tryptophan which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with the ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis. In conclusion, a crosstalk between the circulating LNAAs and the subjective effects is suggested, which is independent of the alkaloid concentrations and provides insights into the specific metabolic fingerprint and mechanism of action underlying ayahuasca experiences.
人们对使用迷幻剂治疗精神疾病的潜在用途重新产生了兴趣。然而，对于在人类中使用死藤水所影响的作用机制和分子途径知之甚少。因此，我们的研究首次旨在调查服用迷幻剂死藤水后的人体代谢组学特征，及其与迷幻剂诱导的主观效应和死藤水生物碱血浆浓度之间的联系。在服用死藤水前后收集了23名个体的血浆样本。通过靶向代谢组学对样本进行分析，并使用综合网络分析将其与死藤水体验的主观评分（即使用五维意识改变状态评定量表[ASC]）以及血浆死藤水生物碱进一步整合。对代谢输出结果使用针对特定KEGG模块的扩散算法进行代谢途径富集分析。与基线相比，服用死藤水增加了N-酰基乙醇胺内源性大麻素，降低了2-酰基甘油内源性大麻素，并改变了几种大中性氨基酸（LNAAs）。综合网络结果表明，除了色氨酸呈正相关外，大多数LNAAs与ASC的11个分量表中的9个呈负相关。几种内源性大麻素和己糖神经酰胺与死藤水生物碱直接相关。富集分析证实了参与神经传递的几种途径（如血清素和多巴胺合成）的失调。总之，提示循环LNAAs与主观效应之间存在相互作用，这与生物碱浓度无关，并为死藤水体验背后的特定代谢指纹和作用机制提供了见解。
