Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. ACS Omega. 2024 Oct 15;9(43):43875-43883. doi: 10.1021/acsomega.4c06923. 
eCollection 2024 Oct 29.

Gut Bacterial Metabolites from Tryptophan and Phenylalanine Induce Melatonin 
Synthesis and Extend Sleep Duration in Mice.

Lee JH(1), Hwang SJ(2), Ham SL(3), Kim J(3), Bang HJ(2), Park JS(4), Jang HH(5), 
Kim TY(6), Park JW(6), Seo YR(6), Kim BS(6), Kim GS(7), Lee HJ(2), Kim 
CS(1)(2)(3).

Author information:
(1)Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon 
16419, Republic of Korea.
(2)School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
(3)Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 
16419, Republic of Korea.
(4)Preclinical Research Center (PRC), Daegu-Gyeongbuk Medical Innovation 
Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea.
(5)Research Institute of Biological R&D Center, Eco-Prime Co., Changwon 51371, 
Republic of Korea.
(6)Kick the Hurdle Co., Changwon 51139, Republic of Korea.
(7)Research Institute of Life Science and College of Veterinary Medicine, 
Gyeongsang National University, Jinju 52828, Republic of Korea.

The human gut microbiota significantly influences various physiological systems, 
including immune, nervous, and metabolic systems. Recent studies suggest that 
gut microbiota may affect sleep quality with certain bacteria and metabolites 
being linked to sleep patterns. However, the underlying chemical signaling 
pathway remains unclear. In this study, we investigated the effect of four gut 
bacteria-derived metabolites, tryptamine (1), indolokine A5 (2), 
2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE, 3), and 
phenethylamine (PEA, 4), on sleep characteristics in mice and melatonin 
biosynthesis pathways in zebrafish. Their sleep-promoting effects were evaluated 
in a pentobarbital-induced sleep mouse model, revealing significant increases in 
sleep duration and blood melatonin levels, particularly with ITE (3) and PEA 
(4). Further tests in zebrafish embryos showed that ITE (3) and PEA (4) 
increased the expression of genes for melatonin biosynthesis (Aanat1, Aanat2, 
Tph1a, and Hiomt) in a concentration-dependent manner, indicating their 
potential as therapeutic agents for sleep disorders.

© 2024 The Authors. Published by American Chemical Society.

DOI: 10.1021/acsomega.4c06923
PMCID: PMC11525535
PMID: 39493976

Conflict of interest statement: The authors declare no competing financial 
interest.


2. Microb Biotechnol. 2024 Nov;17(11):e70039. doi: 10.1111/1751-7915.70039.

Optimized psilocybin production in tryptophan catabolism-repressed fungi.

Janevska S(1), Weiser S(2)(3), Huang Y(4)(5), Lin J(4), Hoefgen S(4), Jojić 
K(4), Barber AE(6), Schäfer T(7)(8), Fricke J(7)(8), Hoffmeister D(7)(8), 
Regestein L(2), Valiante V(4), Kufs JE(2).

Author information:
(1)(Epi-)Genetic Regulation of Fungal Virulence, Leibniz Institute for Natural 
Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany.
(2)Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection 
Biology-Hans Knöll Institute, Jena, Germany.
(3)Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany.
(4)Biobricks of Microbial Natural Product Syntheses, Leibniz Institute for 
Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, 
Germany.
(5)Paleobiotechnology, Leibniz Institute for Natural Product Research and 
Infection Biology-Hans Knöll Institute, Jena, Germany.
(6)Fungal Informatics, Friedrich Schiller University, Jena, Germany.
(7)Pharmaceutical Microbiology, Friedrich Schiller University, Jena, Germany.
(8)Pharmaceutical Microbiology, Leibniz Institute for Natural Product Research 
and Infection Biology-Hans Knöll Institute, Jena, Germany.

The high therapeutic potential of psilocybin, a prodrug of the psychotropic 
psilocin, holds great promise for the treatment of mental disorders such as 
therapy-refractory depression, alcohol use disorder and anorexia nervosa. 
Psilocybin has been designated a 'Breakthrough Therapy' by the US Food and Drug 
Administration, and therefore a sustainable production process must be 
established to meet future market demands. Here, we present the development of 
an in vivo psilocybin production chassis based on repression of l-tryptophan 
catabolism. We demonstrate the proof of principle in Saccharomyces cerevisiae 
expressing the psilocybin biosynthetic genes. Deletion of the two 
aminotransferase genes ARO8/9 and the indoleamine 2,3-dioxygenase gene BNA2 
yielded a fivefold increase of psilocybin titre. We transferred this knowledge 
to the filamentous fungus Aspergillus nidulans and identified functional ARO8/9 
orthologs involved in fungal l-tryptophan catabolism by genome mining and 
cross-complementation. The double deletion mutant of A. nidulans resulted in a 
10-fold increased psilocybin production. Process optimization based on 
respiratory activity measurements led to a final psilocybin titre of 267 mg/L in 
batch cultures with a space-time-yield of 3.7 mg/L/h. These results demonstrate 
the suitability of our engineered A. nidulans to serve as a production strain 
for psilocybin and other tryptamine-derived pharmaceuticals.

© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons 
Ltd.

DOI: 10.1111/1751-7915.70039
PMCID: PMC11530996
PMID: 39487767 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


3. Benef Microbes. 2024 Oct 29:1-13. doi: 10.1163/18762891-bja00046. Online ahead
 of print.

Oral supplementation of heat-killed Enterococcus faecalis strain EC-12 relieves 
gastrointestinal discomfort and alters the gut microecology in academically 
stressed students.

Li J(1), Terajima T(1), Liu H(1), Miyata S(1), Kambe J(1), Makioka-Itaya Y(2), 
Inoue R(3), Yamamoto Y(1), Nagaoka K(1).

Author information:
(1)Laboratory of Veterinary Physiology, Cooperative Department of Veterinary 
Medicine, 13125Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, 
Fuchu-shi, Tokyo 183-8509, Japan.
(2)Life Science Division, Combi Corporation, Saitama, Japan.
(3)Laboratory of Animal Science, Department of Applied Biological Sciences, 
Setsunan University, Osaka, Japan.

Stress significantly affects gastrointestinal and mental health, and the gut 
microbiota plays a pivotal role in this process. Enterococcus faecalis strain 
EC-12 (EC-12) is a lactic acid bacterium that has several health benefits. To 
investigate the impact of oral supplementation with heat-killed EC-12 on the 
discomfort caused by stress, a randomised, double-blind, placebo-controlled 
trial was conducted with students under academic stress taking EC-12 (n = 14) or 
a placebo (n = 13) daily for one week. Improvement in the students' symptoms was 
assessed using the visual analogue scale. Faecal microbiota was characterised by 
next-generation sequencing of 16S rRNA genes, and faecal metabolites and 
short-chain fatty acids were analysed using a GC-MS metabolomics approach. 
Significant improvements in abdominal pain and rumbling of the stomach were 
found in the EC-12 group compared to the placebo group, but no changes were 
observed in mental symptoms or salivary cortisol levels. The relative abundance 
of E. faecalis significantly increased in the EC-12 group after the trial; 
however, the composition and diversity of the gut microbiota did not change 
significantly. Functional analysis of the gut microbiota suggested that EC-12 
intake alters specific metabolic pathways. Although the levels of faecal 
short-chain fatty acids did not change between the groups before and after the 
trial, EC-12 intake altered the composition of faecal metabolites, with a 
significant increase in tryptamine levels. The ratio of students with improved 
symptoms to those with increased tryptamine levels was calculated based on the 
number of students with elevated faecal tryptamine levels who showed symptomatic 
improvements. The ratio of improved rumbling stomach was higher than that of 
other types of digestive discomfort. These results suggest that oral 
supplementation with EC-12 has a potentially beneficial effect on stress-induced 
gastrointestinal discomfort, which may occur through alterations in gut 
microbiota composition and metabolism. This study was registered at the 
University Hospital Medical Information Network Center (UMIN) under the UMIN ID: 
UMIN000048184.

DOI: 10.1163/18762891-bja00046
PMID: 39481416


4. Chem Biodivers. 2024 Oct 28:e202401699. doi: 10.1002/cbdv.202401699. Online 
ahead of print.

Tryptamine-Derived Schiff Bases: Potent Antimicrobial Agents and Evaluation of 
Cytotoxicity, ADME and DNA Binding Properties.

Marjanović JS(1), Petrović N(2), Kosanić M(2), Košarić J(3), Mirić A(3), 
Milivojević N(3), Kostić MD(3), Divac VM(4).

Author information:
(1)University of Kragujevac Faculty of Science and Mathematics, Chemistry, 
Radoja Domanovica 12, Kragujevac, SERBIA.
(2)University of Kragujevac Faculty of Science and Mathematics, Biology and 
Ecology, Radoja Domanovica 12, Kragujevac, SERBIA.
(3)University of Kragujevac Institute for Information Technologies, Science, 
Jovana Cvijica bb, Kragujevac, SERBIA.
(4)University of Kragujevac, Faculty of Science, Department of Chemistry, Radoja 
Domanovica 12, 34000, Kragujevac, SERBIA.

Inspired by the fact that the introduction of indole pharmacophore in organic 
scaffolds could enable interesting pharmacological properties, the series of 
novel tryptamine-derived Schiff bases was synthetized. Tryptamine was used as a 
source of indole pattern, as well as an example of biogenic amines which 
chemical transformations lead to the compounds with prominent biological 
activities. The obtained results for antimicrobial activity against a range of 
bacterial and fungal strains and cytotoxic activities have revealed that Schiff 
base TSB4 combining the tryptamine and p-nitro aryl patterns in the structure 
showed better antifungal activity at low concentrations than standard drug 
Fluconazole, while compound TSB6 with molecular scaffold composed from 
tryptamine and quinoline moieties showed certain cytotoxic effect on HCT-116 
cell line with a strongly expressed selectivity about healthy fibroblast cells, 
MRC-5. For these two selected compounds, additional ADME analysis and DNA 
interactions were performed. to obtain better insight into their 
pharmacokinetics and determination of binding mode for DNA molecules. As results 
suggested, strong binding of examined compounds to CT-DNA was observed, while 
the ADME screening showed that selected compounds possess suitable 
physicochemical properties for oral bioavailability and druglikeness.

© 2024 Wiley‐VCH GmbH.

DOI: 10.1002/cbdv.202401699
PMID: 39467206


5. Neurotherapeutics. 2024 Oct 26:e00470. doi: 10.1016/j.neurot.2024.e00470.
Online  ahead of print.

Gut microbial metabolism in Alzheimer's disease and related dementias.

Kang JW(1), Vemuganti V(2), Kuehn JF(2), Ulland TK(3), Rey FE(2), Bendlin BB(4).

Author information:
(1)Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School 
of Medicine and Public Health, Madison, WI, USA.
(2)Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, 
USA.
(3)Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School 
of Medicine and Public Health, Madison, WI, USA; Department of Pathology and 
Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA.
(4)Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School 
of Medicine and Public Health, Madison, WI, USA; Wisconsin Alzheimer's 
Institute, School of Medicine and Public Health, University of 
Wisconsin-Madison, Madison, WI, USA. Electronic address: bbb@medicine.wisc.edu.

Multiple studies over the last decade have established that Alzheimer's disease 
and related dementias (ADRD) are associated with changes in the gut microbiome. 
These alterations in organismal composition result in changes in the abundances 
of functions encoded by the microbial community, including metabolic 
capabilities, which likely impact host disease mechanisms. Gut microbes access 
dietary components and other molecules made by the host and produce metabolites 
that can enter circulation and cross the blood-brain barrier (BBB). In recent 
years, several microbial metabolites have been associated with or have been 
shown to influence host pathways relevant to ADRD pathology. These include short 
chain fatty acids, secondary bile acids, tryptophan derivatives (such as 
kynurenine, serotonin, tryptamine, and indoles), and 
trimethylamine/trimethylamine N-oxide. Notably, some of these metabolites cross 
the BBB and can have various effects on the brain, including modulating the 
release of neurotransmitters and neuronal function, inducing oxidative stress 
and inflammation, and impacting synaptic function. Microbial metabolites can 
also impact the central nervous system through immune, enteroendocrine, and 
enteric nervous system pathways, these perturbations in turn impact the gut 
barrier function and peripheral immune responses, as well as the BBB integrity, 
neuronal homeostasis and neurogenesis, and glial cell maturation and activation. 
This review examines the evidence supporting the notion that ADRD is influenced 
by gut microbiota and its metabolites. The potential therapeutic advantages of 
microbial metabolites for preventing and treating ADRD are also discussed, 
highlighting their potential role in developing new treatments.

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.neurot.2024.e00470
PMID: 39462700

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.