Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Br J Clin Pharmacol. 2024 Oct 29. doi: 10.1111/bcp.16320. Online ahead of
print.

Feasibility of dried blood spot collection for caffeine pharmacokinetic studies 
in microgravity: Insights from parabolic flight campaigns.

Derobertmasure A(1)(2), Toh LS(3), Verstuyft C(4), Lukic S(5), De Sousa Carvalho 
C(5), Couronné R(1), Beauvalet M(1), Chhun S(5), Boutouyrie P(1)(2).

Author information:
(1)INSERM PARCC UMRS 970, Université Paris-Cité, Paris, France.
(2)Assistance Publique Des Hôpitaux De Paris, Hôpital Européen Georges Pompidou, 
Clinical Pharmacology Unit and DMU CARTE, Paris, France.
(3)School of Pharmacy, Faculty of Science, University of Nottingham, University 
Park, Nottingham, UK.
(4)Molecular Genetics, Pharmacogenetics, and Hormonology Unit of Bicêtre, 
Paris-Saclay University Hospitals, Assistance Publique-Hôpitaux de Paris, 
Bicêtre Hospital, Paris, France.
(5)Laboratory of Immunology and DMU BIOPHYGEN, Georges Pompidou European 
Hospital and Necker-enfants malades Hospital, AP-HP; Université Paris-Cité, INEM 
U1151, Paris, France.

AIMS: Therapeutic drug monitoring for astronauts faces limitations in 
conventional blood sampling and sample management onboard the international 
space station. Here, we explore the feasibility of dried blood spot (DBS) 
collection during parabolic flights (PF) to overcome these constraints.
METHODS: We assessed the feasibility of blood deposition on blotting paper for 
preanalytical aspects in a PF using synthetic blood. Subsequently, DBS sampling 
validation was carried out in another PF campaign. Twenty volunteers 
participated in a pharmacokinetic study on caffeine and its metabolite, 
paraxanthine, conducted during parabolic flights. After >18 h caffeine washout, 
coffee (115 mg), tea (30 mg) or dark chocolate (11 mg) were ingested by the 
participants. DBS samples were collected at baseline, during weightlessness and 
post-flight. Caffeine and paraxanthine were analysed using liquid 
chromatography-tandem mass spectrometry (LC-MS/MS). Genotyping for cytochrome 
P450-1A2 (CYP1A2) was performed and a metabolic ratio by area under the curve 
for caffeine and paraxanthine (AUCPAX/AUCCAF) for CYP1A2 was determined. A user 
experience survey was also conducted.
RESULTS: Full in-flight pharmacokinetic study was feasible in seventeen 
volunteers with three unable to perform the sampling due to motion sickness. 
Nineteen participants (twelve males and seven females) completed pharmacokinetic 
profiles, with repeated pharmacokinetic studies for six participants. CYP1A2 
genotyping resulted in eight ultrarapid, eleven intermediate, and one poor 
metabolizer. Among the women, four were on oestrogen contraceptives, a known 
inhibitor of CYP1A2, and were considered as poor metabolizers. Expected 
differences in kinetic profiles, consistent with consumption habits, the 
ingested dose and the genotypic/phenotypic information, were observed. The mean 
caffeine AUC for coffee, tea and chocolate were 9419 ng.h.mL-1 (95% confidence 
interval [CI]: 6222-12 616, n = 10), 6917 ng.h.mL-1 (95% CI: 2729-11 105), 
n = 7) and 3039 ng.h.mL-1 (95% CI: 1614-4142, n = 12), respectively. The mean 
paraxanthine AUC were 10 566 ng.h.mL-1 (95% CI: 6242-14 890, n = 10), 
4011 ng.h.mL-1 (95% CI: 2305-5716, n = 7) and 3638 ng.h.mL-1 (95% CI: 
1589-40 859, n = 12), respectively. The mean metabolic ratio in 
oestrogen-treated women was 0.53 (95% CI: 0.35-0.71) compared to 1.19 (95% CI: 
0.99-1.33) in others. The mean metabolic ratio was 1.02 (95% CI: 0.81-1.23, 
n = 15) on the ground and 1.10 (95% CI: 0.70-1.41, n = 13) during the parabolic 
flights, with no significant difference observed between the two conditions. 
Overall participants were satisfied with the usability of the method.
CONCLUSIONS: DBS collection was safe, stable, feasible and well accepted in 
weightlessness. This method would offer valuable insights into human metabolism 
adaptation during long-term spaceflight, addressing space pharmacology 
challenges.

© 2024 The Author(s). British Journal of Clinical Pharmacology published by John 
Wiley & Sons Ltd on behalf of British Pharmacological Society.

DOI: 10.1111/bcp.16320
PMID: 39473131


2. J Toxicol Sci. 2024;49(10):447-457. doi: 10.2131/jts.49.447.

Simultaneous analysis of caffeine and paraxanthine provides potentially useful 
indexes in the treatment of acute caffeine intoxication.

Yamazaki Y(1)(2), Kaizaki-Mitsumoto A(1)(2), Sato M(3), Inoue Y(3), Miyamoto 
K(4), Suzuki K(4), Hayashi M(4)(5), Dohi K(4), Numazawa S(1)(2).

Author information:
(1)Department of Toxicology, Showa University Graduate School of Pharmacy.
(2)Showa University Pharmacological Research Center.
(3)Department of Hospital Pharmaceutics, Showa University Graduate School of 
Pharmacy.
(4)Department of Emergency, Critical Care and Disaster Medicine, Showa 
University Graduate School of Medicine.
(5)Department of Emergency, Critical Care and Disaster Medicine, Showa 
University Fujigaoka Hospital.

Caffeine (CFF) is efficiently absorbed after ingestion, and approximately 80% of 
ingested CFF is metabolized to paraxanthine (PXT). Although PXT has 
approximately twice the adenosine receptor antagonist activity of CFF, there are 
few reports measuring the metabolite concentrations during CFF intoxication. 
Furthermore, no studies have examined the efficacy of hemodialysis (HD) on PXT 
or the indicators that contribute to treatment strategies for patients with 
acute CFF intoxication. This study analyzed the association between CFF and PXT 
blood levels, the blood biochemical data, and the vital signs of 27 cases with 
information on CFF intake and elapsed time data. It was found that HD was not as 
effective as CFF against PXT in CFF intoxication; however, HD was effective in 
cases with relatively high PXT concentrations (>10 μg/mL). Simultaneous analysis 
of CFF and PXT would make it possible to estimate the time elapsed from CFF 
intake and the risk of hyperCKemia, which may develop in cases left untreated 
for a prolonged period after ingestion. Therefore, the measurement of PXT, in 
addition to CFF, is expected to provide useful information for understanding the 
pathogenesis of CFF intoxication and the development of treatment strategies of 
acute CFF intoxication.

DOI: 10.2131/jts.49.447
PMID: 39358234 [Indexed for MEDLINE]


3. Nutr Rev. 2024 Sep 27:nuae133. doi: 10.1093/nutrit/nuae133. Online ahead of 
print.

Exhaustive Search of Dietary Intake Biomarkers as Objective Tools for 
Personalized Nutrimetabolomics and Precision Nutrition Implementation.

de la O V(1)(2), Fernández-Cruz E(1)(2), Valdés A(3), Cifuentes A(3), Walton 
J(4), Martínez JA(1)(5)(6).

Author information:
(1)Nutrition Precision and Cardiometabolic Health Program of IMDEA-Food 
Institute (Madrid Institute for Advances Studies), 28040, Madrid, Spain.
(2)Faculty of Health Sciences, International University of La Rioja, 26006, 
Logroño, Spain.
(3)Foodomics Lab, Institute of Food Science Research, Spanish National Research 
Council, 28049, Madrid, Spain.
(4)Department of Biological Sciences, Munster Technological University, Cork, 
Republic of Ireland.
(5)Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la 
Nutrición, Instituto de Salud Carlos III, 28049, Madrid, Spain.
(6)Department of Medicine and Endocrinology, Campus of Soria, University of 
Valladolid, Valladolid, Spain.

OBJECTIVE: To conduct an exhaustive scoping search of existing literature, 
incorporating diverse bibliographic sources to elucidate the relationships 
between metabolite biomarkers in human fluids and dietary intake.
BACKGROUND: The search for biomarkers linked to specific dietary food intake 
holds immense significance for precision health and nutrition research. Using 
objective methods to track food consumption through metabolites offers a more 
accurate way to provide dietary advice and prescriptions on healthy dietary 
patterns by healthcare professionals. An extensive investigation was conducted 
on biomarkers associated with the consumption of several food groups and 
consumption patterns. Evidence is integrated from observational studies, 
systematic reviews, and meta-analyses to achieve precision nutrition and 
metabolism personalization.
METHODS: Tailored search strategies were applied across databases and gray 
literature, yielding 158 primary research articles that met strict inclusion 
criteria. The collected data underwent rigorous analysis using STATA and Python 
tools. Biomarker-food associations were categorized into 5 groups: cereals and 
grains, dairy products, protein-rich foods, plant-based foods, and a 
miscellaneous group. Specific cutoff points (≥3 or ≥4 bibliographic appearances) 
were established to identify reliable biomarkers indicative of dietary 
consumption.
RESULTS: Key metabolites in plasma, serum, and urine revealed intake from 
different food groups. For cereals and grains, 3-(3,5-dihydroxyphenyl) propanoic 
acid glucuronide and 3,5-dihydroxybenzoic acid were significant. Omega-3 fatty 
acids and specific amino acids showcased dairy and protein foods consumption. 
Nuts and seafood were linked to hypaphorine and trimethylamine N-oxide. The 
miscellaneous group featured compounds like theobromine, 7-methylxanthine, 
caffeine, quinic acid, paraxanthine, and theophylline associated with coffee 
intake.
CONCLUSIONS: Data collected from this research demonstrate potential for 
incorporating precision nutrition into clinical settings and nutritional advice 
based on accurate estimation of food intake. By customizing dietary 
recommendations based on individualized metabolic profiles, this approach could 
significantly improve personalized food consumption health prescriptions and 
support integrating multiple nutritional data.This article is part of a 
Nutrition Reviews special collection on Precision Nutrition.

© The Author(s) 2024. Published by Oxford University Press on behalf of the 
International Life Sciences Institute. All rights reserved. For permissions, 
please e-mail: journals.permissions@oup.com.

DOI: 10.1093/nutrit/nuae133
PMID: 39331531


4. Front Nutr. 2024 Aug 26;11:1458442. doi: 10.3389/fnut.2024.1458442.
eCollection  2024.

Genetic liability to human serum metabolites is causally linked to telomere 
length: insights from genome-wide Mendelian randomization and metabolic pathways 
analysis.

Liu J(1), Pan R(2).

Author information:
(1)Department of Psychiatry, Longyou People's Hospital Affiliated with Sir Run 
Run Shaw Hospital, Zhejiang University School of Medicine, Quzhou, China.
(2)Department of Urology, The Quzhou Affiliated Hospital of Wenzhou Medical 
University, Quzhou People's Hospital, Quzhou, China.

BACKGROUND: Telomere has been recognized as a biomarker of accelerating aging, 
and telomere length (TL) shortening is closely related to diverse chronic 
illnesses. Human serum metabolites have demonstrated close correlations with TL 
maintenance or shortening in observational studies. Nevertheless, little is 
known about the underlying pathological mechanisms, and Mendelian randomization 
(MR) analysis of serum metabolites may provide a more comprehensive 
understanding of the potential biological process.
METHODS: We employed a two-sample MR analysis method to assess the causal links 
between 486 serum metabolites and TL. We applied the inverse-variance weighted 
(IVW) approach as our primary analysis, and to assure the stability and 
robustness of our results, additional analysis methods including the weighted 
median, MR-Egger, and weighted mode were conducted. MR-Egger intercept test was 
utilized to detect the pleiotropy. Cochran's Q test was implemented to quantify 
the extent of heterogeneity. Furthermore, the pathway analysis was conducted to 
identify potential metabolic pathways.
RESULTS: We identified 11 known blood metabolites associated with TL. Among 
these metabolites, four were lipid (taurocholate, dodecanedioate, 
5,8-tetradecadienoate, and 15-methylpalmitate), one amino acid (levulinate 
(4-oxovaleate)), one carbohydrate (lactate), one nucleotide (pseudouridine), one 
energy (phosphate), and three xenobiotics (2-hydroxyacetaminophen sulfate, 
paraxanthine, and ergothioneine). The known protective metabolites included 
levulinate (4-oxovaleate), dodecanedioate, 5,8-tetradecadienoate, lactate, 
phosphate, paraxanthine, and ergothioneine. Multiple metabolic pathways have 
been identified as being implicated in the maintenance of telomere length.
CONCLUSION: Our MR analysis provided suggestive evidence supporting the causal 
relationships between 11 identified blood metabolites and TL, necessitating 
further exploration to clarify the mechanisms by which these serum metabolites 
and metabolic pathways may affect the progression of telomeres.

Copyright © 2024 Liu and Pan.

DOI: 10.3389/fnut.2024.1458442
PMCID: PMC11381963
PMID: 39253325

Conflict of interest statement: The authors declare that the research was 
conducted in the absence of any commercial or financial relationships that could 
be construed as a potential conflict of interest.


5. Sci Rep. 2024 Aug 23;14(1):19644. doi: 10.1038/s41598-024-70370-1.

Causal relationship between immune cells and epilepsy mediated by metabolites 
analyzed through Mendelian randomization.

Chen J(1), Yu H(2), Liu H(3), Yu H(4), Liang S(5), Wu Q(6), Zhang X(7), Zeng 
R(1), Diao L(8)(9).

Author information:
(1)Guangxi University of Chinese Medicine, Nanning, 530200, China.
(2)Guangxi Technological College of Machinery and Electricity, Nanning, 530007, 
China.
(3)Guangxi Zhuang Autonomous Region Brain Hospital, Liuzhou, 545005, China.
(4)Harbin Medical University, Harbin, 150086, China.
(5)Nanning Traditional Chinese Medicine Hospital, Nanning, 530000, China.
(6)Xin Yang Central Hospital, Xinyang, 464000, China.
(7)Department of Neurology, Guangxi Zhuang Autonomous Region Brain Hospital, 
Liuzhou, 545005, China.
(8)Department of Neurology, Guangxi Zhuang Autonomous Region Brain Hospital, 
Liuzhou, 545005, China. Diaolimei0810@163.com.
(9)Department of Neurology, The First Affiliated Hospital of Guangxi University 
of Chinese Medicine, Nanning, 530023, China. Diaolimei0810@163.com.

Our study investigated the causal relationship between immune cells, 
metabolites, and epilepsy using two-sample Mendelian Randomization (MR) and 
mediation MR analysis of 731 immune cell traits and 1400 metabolites. Our core 
methodology centered on inverse-variance weighted MR, supplemented by other 
methods. This approach was crucial in clarifying the potential intermediary 
functions of metabolites in the genetic links between traits of immune cells and 
epilepsy. We found a causal relationship between immune cells and epilepsy. 
Specifically, the genetically predicted levels of CD64 on CD14-CD16- are 
positively correlated with the risk of epilepsy (p < 0.001, OR = 1.0826, 95% CI 
1.0361-1.1312). Similarly, metabolites also exhibit a causal relationship with 
both immune cells (OR = 1.0438, 95% CI 1.0087-1.0801, p = 0.0140) and epilepsy 
(p = 0.0334, OR = 1.0897, 95% CI 1.0068-1.1795), and sensitivity analysis was 
conducted to further validate these relationships. Importantly, our intermediate 
MR results suggest that the metabolite Paraxanthine to linoleate (18:2n6) ratio 
may mediate the causal relationship between immune cell CD64 on CD14-CD16- and 
epilepsy, with a mediation effect of 5.05%. The results suggest the importance 
of specific immune cell levels and metabolites in understanding epilepsy's 
pathogenesis, which is significant for its prevention and treatment.

© 2024. The Author(s).

DOI: 10.1038/s41598-024-70370-1
PMCID: PMC11343848
PMID: 39179617 [Indexed for MEDLINE]

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