Worldwide, there are plants known as psychoactive plants that naturally contain psychedelic active components. They have a high concentration of neuroprotective substances that can interact with the nervous system to produce psychedelic effects. Despite these plants' hazardous potential, recreational use of them is on the rise because of their psychoactive properties. Early neuroscience studies relied heavily on psychoactive plants and plant natural products (NPs), and both recreational and hazardous NPs have contributed significantly to the understanding of almost all neurotransmitter systems. Worldwide, there are many plants that contain psychoactive properties, and people have been using them for ages. Psychoactive plant compounds may significantly alter how people perceive the world.
1. Benef Microbes. 2024 Oct 4:1-15. doi: 10.1163/18762891-bja00039. Online ahead of print. Effects of complex probiotics on intestinal function and its regulatory mechanism in patients with constipation. Zhang X(1), Jia Y(1), Li X(1), Wang X(1), Li L(2), Zhang P(2), Dong X(2), Ze X(3), An Y(4), Li J(1). Author information: (1)State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Food Science, 74561Zhejiang Academy of Agricultural Sciences, 298 Desheng Middle Road, Hangzhou 310021, China P.R. (2)The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou 310015, China P.R. (3)BYHEALTH Institute of Nutrition & Health, 3-3 Techway Golden Valley, Science City, Whampoa District, Guangzhou 510663, China P.R. (4)Department of Gastroenterology, The First Hospital of Shanxi University of Chinese Medicine, 75-1 Jinzi Road, Taiyuan 030024, China P.R. Chronic constipation is a multi-symptomatic, multifactorial, and heterogeneous gastrointestinal disorder. Current pharmacological treatments for chronic constipation are limited and might negatively impact the patients' quality of life. Although probiotics have been shown to improve constipation symptoms, their specific regulatory mechanisms remain unclear. This study sought to explore how probiotic complexes may affect chronic constipation by improving patients' defecation habits. Furthermore, microbial profiles and non-targeted metabolites were assessed to explore the metabolic pathways involved in the improvement of constipation by probiotics. Patients with chronic constipation were treated using a single-blind, randomised, placebo-controlled trial design. The experimental group was administered Lactobacillus powder prepared from 15 probiotic products, and maltodextrin was used as a placebo. Samples were collected twice daily for 4 weeks, and faecal samples were analysed using 16S rRNA sequencing and untargeted metabolic histology. Probiotic treatment changed the makeup of the gut microbiota, enhanced the quantity of Bifidobacterium and Lactobacillus, and markedly reduced clinical symptoms. The 16S rRNA analysis revealed that the abundance of Bifidobacterium and Prevotella increased while that of Thickettsia declined. Moreover, there was a decrease in the abundance of Faecalibacterium and Roseburia. Non-targeted metabolomics analysis identified several differential metabolites, including succinic acid, fumaric acid, cholesterol, xanthurenic acid, 3-alpha,7-alpha-trihydroxy-5beta-cholestan-26-oic, and N-methyltryptamine. KEGG analysis showed that these metabolites were mainly associated with metabolic pathways such as primary bile acid biosynthesis, tryptophan metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, cholesterol metabolism, and propanoate metabolism. In this study, gut microbiome and non-targeted metabolome analyses were performed on collected faecal samples to compare characteristic microorganisms and differential metabolites to provide new insights and references for probiotic intervention in constipation. Trial registered at chictr.org.cn under number: ChiCTR2200056274. DOI: 10.1163/18762891-bja00039 PMID: 39389577 2. Ecotoxicol Environ Saf. 2024 Sep 15;283:116969. doi: 10.1016/j.ecoenv.2024.116969. Epub 2024 Aug 30. Pathophysiological impacts of 5-MeO-MiPT on zebrafish (Danio rerio) via the Gα(q/11)-PLC(β) signaling pathway. Zhao S(1), Liu M(1), Chen J(2), Meng L(3), Wang Y(4). Author information: (1)Zhejiang Police College, Zhejiang Key Laboratory of Drug Prevention and Control Technology, Hangzhou 310053, PR China. (2)College of Environment, Zhejiang University of Technology, Hangzhou 310014, PR China. (3)Department of Forensic Science, Fujian Police College, Fuzhou 350007, PR China. Electronic address: mengliang@fjpsc.edu.cn. (4)Inovia Materials (HangZhou) Co. Ltd, Hangzhou, Zhejiang 310053, PR China. Electronic address: wangyanjiao@zju.edu.cn. Novel Psychoactive Substances (NPS) derived from tryptamines has been detected in aquatic environments, leading to environmental toxicology concerns. However, the specific toxicological mechanism, underlying these NPS, remains unclear. In our previous work, we used 5-Methoxy-N-isopropyl-N-methyltryptamine (5-MeO-MiPT) as the representative drug for NPS, and found that, 5-MeO-MiPT led to obvious behavioral inhibition and oxidative stress responses in zebrafishes model. In this study, Zebrafish were injected with varying concentrations of 5-MeO-MiPT for 30 days. RNA-seq, qPCR, metabolomics, and histopathological analyses were conducted to assess gene expression and tissue integrity. This study confirms that 5-MeO-MiPT substantially influences the transcription and expression of 13 selected genes, including ucp1, pet100, grik3, and grik4, mediated by the Gαq/11-PLCβ signaling pathway. We elucidate the molecular mechanism that 5-MeO-MiPT can inhibit DAG-Ca2+/Pkc/Erk, Pkc/Pla2/PLCs and Ca2+/Camk Ⅱ/NMDA, while enhance Ca2+/Creb. Those secondary signaling pathways may be the mechanisms mediating 5-MeO-MiPT inhibiting normal behavior in zebrafish. These findings offer novel insights into the toxicological effects and addiction mechanisms of 5-MeO-MiPT. Moreover, it presents promising avenues for investigating other tryptamine-based NPS and offers a new direction for diagnosing and treating liver-brain pathway-related diseases. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.ecoenv.2024.116969 PMID: 39216220 [Indexed for MEDLINE] Conflict of interest statement: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 3. EBioMedicine. 2024 Jun;104:105150. doi: 10.1016/j.ebiom.2024.105150. Epub 2024 May 9. Gut microbial metabolism is linked to variations in circulating non-high density lipoprotein cholesterol. Zhou S(1), Liu L(2), Ye B(2), Xu Y(2), You Y(1), Zhu S(1), Ju J(1), Yang J(1), Li W(1), Xia M(3), Liu Y(4). Author information: (1)Guangdong Provincial Key Laboratory of Food, Nutrition and Health, PR China; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, PR China. (2)Guangdong Provincial Key Laboratory of Food, Nutrition and Health, PR China; Department of Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, PR China. (3)Guangdong Provincial Key Laboratory of Food, Nutrition and Health, PR China; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, PR China. Electronic address: xiamin@mail.sysu.edu.cn. (4)Guangdong Provincial Key Laboratory of Food, Nutrition and Health, PR China; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, PR China. Electronic address: liuyan215@mail.sysu.edu.cn. BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-c) was a strong risk factor for incident cardiovascular diseases and proved to be a better target of lipid-lowering therapies. Recently, gut microbiota has been implicated in the regulation of host metabolism. However, its causal role in the variation of non-HDL-c remains unclear. METHODS: Microbial species and metabolic capacities were assessed with fecal metagenomics, and their associations with non-HDL-c were evaluated by Spearman correlation, followed by LASSO and linear regression adjusted for established cardiovascular risk factors. Moreover, integrative analysis with plasma metabolomics were performed to determine the key molecules linking microbial metabolism and variation of non-HDL-c. Furthermore, bi-directional mendelian randomization analysis was performed to determine the potential causal associations of selected species and metabolites with non-HDL-c. FINDINGS: Decreased Eubacterium rectale but increased Clostridium sp CAG_299 were causally linked to a higher level of non-HDL-c. A total of 16 microbial capacities were found to be independently associated with non-HDL-c after correcting for age, sex, demographics, lifestyles and comorbidities, with the strongest association observed for tricarboxylic acid (TCA) cycle. Furthermore, decreased 3-indolepropionic acid and N-methyltryptamine, resulting from suppressed capacities for microbial reductive TCA cycle, functioned as major microbial effectors to the elevation of circulating non-HDL-c. INTERPRETATION: Overall, our findings provided insight into the causal effects of gut microbes on non-HDL-c and uncovered a novel link between non-HDL-c and microbial metabolism, highlighting the possibility of regulating non-HDL-c by microbiota-modifying interventions. FUNDING: A full list of funding bodies can be found in the Sources of funding section. Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.ebiom.2024.105150 PMCID: PMC11090025 PMID: 38728837 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests The authors have no conflicts of interest to report. 4. J Pharm Biomed Anal. 2024 Apr 15;241:115987. doi: 10.1016/j.jpba.2024.115987. Epub 2024 Jan 20. Biotransformation of 5-methoxy-N-isopropyl-N-methyltryptamine by zebrafish and human liver microsome with high-resolution mass spectrometry. Sen Zhao(1), Wang Y(2), Zhong C(3), Chen J(3), Meng L(4). Author information: (1)Zhejiang Police College, Key Laboratory of Drug Prevention and Control Technology of Zhejiang Province, Hangzhou 310053, PR China; College of Environment, Zhejiang University of Technology, Hangzhou 310014, PR China. (2)Binjiang Institute of Zhejiang University, Hangzhou 310053, PR China. (3)College of Environment, Zhejiang University of Technology, Hangzhou 310014, PR China. (4)Department of Forensic Science, Fujian Police College, Fuzhou 350007, PR China. Electronic address: mengliang@fjpsc.edu.cn. To explore the metabolites of 5-Methoxy-N-isopropyl-N-methyltryptamine (5-MeO-MiPT) and unveil its toxicological effects, we examined its metabolic profiles using zebrafish and human liver microsome models. Employing ultra-high-performance liquid chromatography Q Exactive hybrid quadrupole-Orbitrap high-resolution mass spectrometry (UPLC-QE-HRMS), we analyzed samples from intoxicated zebrafish and human liver microsomes. In the zebrafish model, we identified a total of six metabolites. Primary phase I metabolic pathways involved N-Demethylation and Indole-hydroxylation reactions, while phase II metabolism included Glucoside conjugation directly, Glucoside conjugation after Indole-hydroxylation, and Sulfonation following Indole-hydroxylation. In the human liver microsome model, nine metabolites were generated. Major phase I metabolic pathways encompassed N-Demethylation, 5-O-Demethylation, and N-Depropylation, N-Oxidation, Indole-hydroxylation, N-Demethylation combined with Indole-hydroxylation, and 5-O-Methylation-carboxylation. Phase II metabolism involved Glucoside conjugation after Indole-hydroxylation, as well as Glucoside conjugation after 5-O-Demethylation. Proposed phase I metabolites, such as 5-MeO-MiPT-N-Demethylation (5-MeO-NiPT) and 5-MeO-MiPT-Indole-hydroxylation, alongside the phase II metabolite OH&Glucoside conjugation-5-MeO-MiPT, were identified as effective markers for screening 5-MeO-MiPT intake. This study systematically delineates the phase I and II metabolites of 5-MeO-MiPT, confirming their pathways through in vivo and in vitro extrapolation. Additionally, inclusion of the parent drug itself and OH&Glucoside conjugation-5-MeO-MiPT could serve as valuable confirmation tools. Copyright © 2024 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jpba.2024.115987 PMID: 38280235 [Indexed for MEDLINE] Conflict of interest statement: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 5. Sci Rep. 2023 Jan 6;13(1):280. doi: 10.1038/s41598-023-27538-y. Indolethylamine N-methyltransferase (INMT) is not essential for endogenous tryptamine-dependent methylation activity in rats. Glynos NG(#)(1)(2), Carter L(#)(1), Lee SJ(3)(4), Kim Y(5), Kennedy RT(5), Mashour GA(2)(6)(7), Wang MM(1)(3)(4)(7), Borjigin J(8)(9)(10)(11). Author information: (1)Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. (2)Michigan Psychedelic Center, University of Michigan, Ann Arbor, MI, USA. (3)Department of Neurology, University of Michigan, Ann Arbor, MI, USA. (4)Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA. (5)Department of Chemistry, University of Michigan, Ann Arbor, MI, USA. (6)Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA. (7)Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA. (8)Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. borjigin@umich.edu. (9)Michigan Psychedelic Center, University of Michigan, Ann Arbor, MI, USA. borjigin@umich.edu. (10)Department of Neurology, University of Michigan, Ann Arbor, MI, USA. borjigin@umich.edu. (11)Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA. borjigin@umich.edu. (#)Contributed equally Indolethylamine N-methyltransferase (INMT) is a transmethylation enzyme that utilizes the methyl donor S-adenosyl-L-methionine to transfer methyl groups to amino groups of small molecule acceptor compounds. INMT is best known for its role in the biosynthesis of N,N-Dimethyltryptamine (DMT), a psychedelic compound found in mammalian brain and other tissues. In mammals, biosynthesis of DMT is thought to occur via the double methylation of tryptamine, where INMT first catalyzes the biosynthesis of N-methyltryptamine (NMT) and then DMT. However, it is unknown whether INMT is necessary for the biosynthesis of endogenous DMT. To test this, we generated a novel INMT-knockout rat model and studied tryptamine methylation using radiometric enzyme assays, thin-layer chromatography, and ultra-high-performance liquid chromatography tandem mass spectrometry. We also studied tryptamine methylation in recombinant rat, rabbit, and human INMT. We report that brain and lung tissues from both wild type and INMT-knockout rats show equal levels of tryptamine-dependent activity, but that the enzymatic products are neither NMT nor DMT. In addition, rat INMT was not sufficient for NMT or DMT biosynthesis. These results suggest an alternative enzymatic pathway for DMT biosynthesis in rats. This work motivates the investigation of novel pathways for endogenous DMT biosynthesis in mammals. © 2023. The Author(s). DOI: 10.1038/s41598-023-27538-y PMCID: PMC9822953 PMID: 36609666 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests.