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Article ; Online: N, N

Eckernäs, Emma / Macan-Schönleben, Alicia / Andresen-Bergström, Moa / Birgersson, Sofia / Hoffmann, Kurt-Jürgen / Ashton, Michael

Xenobiotica; the fate of foreign compounds in biological systems

2023 Volume 53, Issue 8-9, Page(s) 515–522

Abstract: N, N ...

Abstract	N, N
MeSH term(s)	Humans ; Cytochrome P-450 CYP2D6/metabolism ; N,N-Dimethyltryptamine/metabolism ; Monoamine Oxidase/metabolism ; Cytochromes/metabolism ; Microsomes, Liver/metabolism
Chemical Substances	Cytochrome P-450 CYP2D6 (EC 1.14.14.1) ; N,N-Dimethyltryptamine (WUB601BHAA) ; Monoamine Oxidase (EC 1.4.3.4) ; Cytochromes
Language	English
Publishing date	2023-11-26
Publishing country	England
Document type	Journal Article
ZDB-ID	120287-x
ISSN	1366-5928 ; 0049-8254
ISSN (online)	1366-5928
ISSN	0049-8254
DOI	10.1080/00498254.2023.2278488
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Article ; Online: Plasma N-terminal containing tau fragments (NTA-tau): a biomarker of tau deposition in Alzheimer's Disease.

Lantero-Rodriguez, Juan / Salvadó, Gemma / Snellman, Anniina / Montoliu-Gaya, Laia / Brum, Wagner S / Benedet, Andrea L / Mattsson-Carlgren, Niklas / Tideman, Pontus / Janelidze, Shorena / Palmqvist, Sebastian / Stomrud, Erik / Ashton, Nicholas J / Zetterberg, Henrik / Blennow, Kaj / Hansson, Oskar

Molecular neurodegeneration

2024 Volume 19, Issue 1, Page(s) 19

Abstract: ... ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and ... plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294 ... and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and ...

Abstract	Background: Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer's disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain. Methods: NTA is a novel ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294, and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and disease progression in AD, including tau accumulation, brain atrophy and cognitive decline. Results: We demonstrate that plasma NTA-tau increases across the AD continuum¸ especially during late stages, and displays a moderate-to-strong association with tau-PET (β = 0.54, p < 0.001) in Aβ-positive participants, while weak with Aβ-PET (β = 0.28, p < 0.001). Unlike plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with tau-PET is the most prominent contributor to NTA-tau variance (52.5% of total R Conclusion: Our results indicate that plasma NTA-tau levels increase across the AD continuum, especially during mid-to-late AD stages, and it is closely associated with in vivo tau tangle deposition in AD and its downstream effects. Moreover, this novel biomarker has potential as a cost-effective and easily accessible tool for monitoring disease progression and cognitive decline in clinical settings, and as an outcome measure in clinical trials which also need to assess the downstream effects of successful Aβ removal.
MeSH term(s)	Humans ; Alzheimer Disease ; tau Proteins ; Amyloid beta-Peptides ; Atrophy ; Biomarkers ; Cognitive Dysfunction ; Disease Progression ; Positron-Emission Tomography
Chemical Substances	tau Proteins ; Amyloid beta-Peptides ; Biomarkers
Language	English
Publishing date	2024-02-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-024-00707-x
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Article ; Online: Optimized infusion rates for N,N-dimethyltryptamine to achieve a target psychedelic intensity based on a modeling and simulation framework.

Eckernäs, Emma / Koomen, Jeroen / Timmermann, Christopher / Carhart-Harris, Robin / Röshammar, Daniel / Ashton, Michael

CPT: pharmacometrics & systems pharmacology

2023 Volume 12, Issue 10, Page(s) 1398–1410

Abstract: N,N-dimethyltryptamine (DMT) is a psychedelic compound that is being studied as a therapeutic ...

Abstract	N,N-dimethyltryptamine (DMT) is a psychedelic compound that is being studied as a therapeutic option in various psychiatric disorders. Due to its short half-life, continuous infusion of DMT has been proposed to extend the psychedelic experience and potential therapeutic effects. The primary aim of this work was to design an infusion protocol for DMT based on a desired level of psychedelic intensity using population pharmacokinetic/pharmacodynamic modeling. As a secondary aim, the impact of choosing a continuous variable or a bounded integer pharmacokinetic/pharmacodynamic model to inform such an infusion protocol was investigated. A previously published continuous variable model and two newly developed bounded integer models were used to assess optimal doses for achieving a target response. Simulations were performed to identify an optimal combination of a bolus dose and an infusion rate. Based on the simulations, optimal doses to achieve intensity ratings between 7 and 9 (possible range = 0-10) were a bolus dose of 16 mg DMT fumarate followed by an infusion rate of 1.4 mg/min based on the continuous variable model and 14 mg with 1.2 mg/min for the two bounded integer models. However, the proportion within target was low (<53%) for all models, indicating that individual dose adjustments would be necessary. Furthermore, some differences between the models were observed. The bounded integer models generally predicted lower proportions within a target of 7-9 with higher proportions exceeding target compared with the continuous variable model. However, results varied depending on target response with the major differences observed at the boundaries of the scale.
MeSH term(s)	Humans ; Hallucinogens/pharmacology ; Hallucinogens/therapeutic use ; N,N-Dimethyltryptamine/pharmacology ; N,N-Dimethyltryptamine/therapeutic use ; Infusions, Intravenous ; Computer Simulation
Chemical Substances	Hallucinogens ; N,N-Dimethyltryptamine (WUB601BHAA)
Language	English
Publishing date	2023-09-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13037
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Article ; Online: N,N-dimethyltryptamine affects electroencephalography response in a concentration-dependent manner-A pharmacokinetic/pharmacodynamic analysis.

Eckernäs, Emma / Timmermann, Christopher / Carhart-Harris, Robin / Röshammar, Daniel / Ashton, Michael

CPT: pharmacometrics & systems pharmacology

2023 Volume 12, Issue 4, Page(s) 474–486

Abstract: N,N-dimethyltryptamine (DMT) is a psychedelic substance and is being used as a research tool ...

Abstract	N,N-dimethyltryptamine (DMT) is a psychedelic substance and is being used as a research tool in investigations of the neurobiology behind the human consciousness using different brain imaging techniques. The effects of psychedelics have commonly been studied using electroencephalography (EEG) and have been shown to produce suppression of alpha power and increase in signal diversity. However, the relationship between DMT exposure and its EEG effects has never been quantified. In this work, a population pharmacokinetic/pharmacodynamic analysis was performed investigating the relationship between DMT plasma concentrations and its EEG effects. Data were obtained from a clinical study where DMT was administered by intravenous bolus dose to 13 healthy subjects. The effects on alpha power, beta power, and Lempel-Ziv complexity were evaluated. DMT was shown to fully suppress alpha power. Beta power was only partially suppressed, whereas an increase in Lempel-Ziv complexity was observed. The relationship between plasma concentrations and effects were described using effect compartment models with sigmoidal maximum inhibitory response or maximum stimulatory response models. Values of the concentration needed to reach half of the maximum response (EC
MeSH term(s)	Humans ; N,N-Dimethyltryptamine/pharmacology ; Electroencephalography/methods
Chemical Substances	N,N-Dimethyltryptamine (WUB601BHAA)
Language	English
Publishing date	2023-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12933
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Article ; Online: Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias.

Alcolea, Daniel / Delaby, Constance / Muñoz, Laia / Torres, Soraya / Estellés, Teresa / Zhu, Nuole / Barroeta, Isabel / Carmona-Iragui, María / Illán-Gala, Ignacio / Santos-Santos, Miguel Ángel / Altuna, Miren / Sala, Isabel / Sánchez-Saudinós, Mª Belén / Videla, Laura / Valldeneu, Sílvia / Subirana, Andrea / Pegueroles, Jordi / Hirtz, Christophe / Vialaret, Jérôme /

Lehmann, Sylvain / Karikari, Thomas K / Ashton, Nicholas J / Blennow, Kaj / Zetterberg, Henrik / Belbin, Olivia / Blesa, Rafael / Clarimón, Jordi / Fortea, Juan / Lleó, Alberto

Journal of neurology, neurosurgery, and psychiatry

2021 Volume 92, Issue 11, Page(s) 1206–1214

Abstract: Objectives: All categories included in the AT(N) classification can now be measured in plasma ... the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD ... participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied ...

Abstract	Objectives: All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD) through an easy and minimally invasive approach. Methods: We measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination. Results: The plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A-T- participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1-42/Aβ1-40 (Rho=-0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001). Conclusions: Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Alzheimer Disease/blood ; Alzheimer Disease/diagnosis ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Cognitive Dysfunction/blood ; Cognitive Dysfunction/diagnosis ; Female ; Frontotemporal Dementia/blood ; Frontotemporal Dementia/diagnosis ; Humans ; Lewy Body Disease/blood ; Lewy Body Disease/diagnosis ; Male ; Middle Aged ; Neurofilament Proteins/blood ; Phosphorylation ; tau Proteins/blood
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; Neurofilament Proteins ; neurofilament protein L ; tau Proteins
Language	English
Publishing date	2021-06-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3087-9
ISSN	1468-330X ; 0022-3050
ISSN (online)	1468-330X
ISSN	0022-3050
DOI	10.1136/jnnp-2021-326603
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Article ; Online: Plasma and CSF concentrations of N-terminal tau fragments associate with in vivo neurofibrillary tangle burden.

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 19, Issue 12, Page(s) 5343–5354

Abstract: ... greatly needed.: Methods: We measured cerebrospinal fluid (CSF) and plasma concentrations of N-terminal ... in clinical settings and trials.: Highlights: An assay for detecting N-terminal tau fragments (NTA-tau ...

Abstract	Introduction: Fluid biomarkers capable of specifically tracking tau tangle pathology in vivo are greatly needed. Methods: We measured cerebrospinal fluid (CSF) and plasma concentrations of N-terminal tau fragments (NTA-tau), using a novel immunoassay (NTA) in the TRIAD cohort, consisting of 272 individuals assessed with amyloid beta (Aβ) positron emission tomography (PET), tau PET, magnetic resonance imaging (MRI) and cognitive assessments. Results: CSF and plasma NTA-tau concentrations were specifically increased in cognitively impaired Aβ-positive groups. CSF and plasma NTA-tau concentrations displayed stronger correlations with tau PET than with Aβ PET and MRI, both in global uptake and at the voxel level. Regression models demonstrated that both CSF and plasma NTA-tau are preferentially associated with tau pathology. Moreover, plasma NTA-tau was associated with longitudinal tau PET accumulation across the aging and Alzheimer's disease (AD) spectrum. Discussion: NTA-tau is a biomarker closely associated with in vivo tau deposition in the AD continuum and has potential as a tau tangle biomarker in clinical settings and trials. Highlights: An assay for detecting N-terminal tau fragments (NTA-tau) in plasma and CSF was evaluated. NTA-tau is more closely associated with tau PET than amyloid PET or neurodegeneration. NTA-tau can successfully track in vivo tau deposition across the AD continuum. Plasma NTA-tau increased over time only in cognitively impaired amyloid-β positive individuals.
MeSH term(s)	Humans ; Neurofibrillary Tangles/pathology ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Alzheimer Disease/diagnosis ; Positron-Emission Tomography/methods ; Biomarkers/cerebrospinal fluid ; Cognitive Dysfunction/diagnosis
Chemical Substances	Amyloid beta-Peptides ; tau Proteins ; Biomarkers
Language	English
Publishing date	2023-05-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13119
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Article ; Online: Population pharmacokinetic/pharmacodynamic modeling of the psychedelic experience induced by N,N-dimethyltryptamine - Implications for dose considerations.

Eckernäs, Emma / Timmermann, Christopher / Carhart-Harris, Robin / Röshammar, Daniel / Ashton, Michael

Clinical and translational science

2022 Volume 15, Issue 12, Page(s) 2928–2937

Abstract: N,N-dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential ...

Abstract	N,N-dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential as a therapeutic option in several psychiatric disorders. The number of clinical investigations with DMT is increasing. However, very little is known about the pharmacokinetic properties of DMT as well as any relationship between its exposure and effects. This study aimed to characterize population pharmacokinetics of DMT as well as the relationship between DMT plasma concentrations and its psychedelic effects as measured through subjective intensity ratings. Data were obtained from 13 healthy subjects after intravenous administration of DMT. The data were analyzed using nonlinear mixed-effects modeling in NONMEM. DMT plasma concentrations were described by a two-compartment model with first-order elimination leading to formation of the major metabolite indole 3-acetic acid. The relationship between plasma concentrations and psychedelic intensity was described by an effect site compartment model with a sigmoid maximum effect (E
MeSH term(s)	Humans ; N,N-Dimethyltryptamine/pharmacology ; Hallucinogens/pharmacokinetics ; Hallucinogens/therapeutic use ; Infusions, Intravenous
Chemical Substances	N,N-Dimethyltryptamine (WUB601BHAA) ; Hallucinogens
Language	English
Publishing date	2022-09-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.13410
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Article ; Online: Plasma pTau-217 and N-terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid-β positive individuals.

Woo, Marcel S / Tissot, Cécile / Lantero-Rodriguez, Juan / Snellman, Anniina / Therriault, Joseph / Rahmouni, Nesrine / Macedo, Arthur C / Servaes, Stijn / Wang, Yi-Ting / Arias, Jaime Fernandez / Hosseini, Seyyed Ali / Chamoun, Mira / Lussier, Firoza Z / Benedet, Andrea L / Ashton, Nicholas J / Karikari, Thomas K / Triana-Baltzer, Gallen / Kolb, Hartmuth C / Stevenson, Jenna /

Mayer, Christina / Kobayashi, Eliane / Massarweh, Gassan / Friese, Manuel A / Pascoal, Tharick A / Gauthier, Serge / Zetterberg, Henrik / Blennow, Kaj / Rosa-Neto, Pedro

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 20, Issue 2, Page(s) 1166–1174

Abstract: Introduction: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aβ) positive participants using plasma biomarkers.: Methods: In this cross-sectional study we assessed 234 participants across the AD continuum who were ... ...

Abstract	Introduction: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aβ) positive participants using plasma biomarkers. Methods: In this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [ Results: Highest associations with tau positivity in Aβ+ individuals were found for plasma pTau-217 (AUC [CI Discussion: The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice. Highlights: We found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity. We found that in Aβ+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity. Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification.
MeSH term(s)	Humans ; Alzheimer Disease ; tau Proteins ; Cross-Sectional Studies ; Amyloid beta-Peptides ; Biomarkers ; Positron-Emission Tomography
Chemical Substances	tau Proteins ; Amyloid beta-Peptides ; Biomarkers
Language	English
Publishing date	2023-11-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13528
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Article ; Online: Development and application of a highly sensitive LC-MS/MS method for simultaneous quantification of N,N-dimethyltryptamine and two of its metabolites in human plasma.

Eckernäs, Emma / Bendrioua, Adam / Cancellerini, Chiara / Timmermann, Christopher / Carhart-Harris, Robin / Hoffmann, Kurt-Jürgen / Ashton, Michael

Journal of pharmaceutical and biomedical analysis

2022 Volume 212, Page(s) 114642

Abstract: A highly sensitive LC-MS/MS method for the quantification of N,N-dimethyltryptamine (DMT) and ... its metabolites indole-3-acetic acid and DMT N-oxide in human plasma has been developed and validated ... and dilution integrity. The validated linear range was 0.25-200 nM for DMT and 15-250 nM for DMT N ...

Abstract	A highly sensitive LC-MS/MS method for the quantification of N,N-dimethyltryptamine (DMT) and its metabolites indole-3-acetic acid and DMT N-oxide in human plasma has been developed and validated. Chromatography was performed using a diphenyl column with gradient elution (0.1% formic acid in methanol/water). The mass spectrometer was operated in multiple reaction monitoring mode. A methanolic solution containing internal standards 2-methylindole 3-acetic acid and deuterated DMT, was added to plasma samples, followed by protein precipitation with acetonitrile. The samples were centrifuged and supernatants transferred to new tubes and evaporated to dryness before reconstitution in aqueous mobile phase. The method was validated with regards to accuracy, precision, sensitivity, selectivity, recovery, matrix effects, stability, carry-over and dilution integrity. The validated linear range was 0.25-200 nM for DMT and 15-250 nM for DMT N-oxide. For the endogenous compound indole-3-acetic acid a different approach was taken due to its significant presence in blank samples. The change in signal response from a blank sample was used when constructing the calibration curve with linearity demonstrated between elevations of 500-5000 nM above the blank. Applicability of the described method was demonstrated through analysis of plasma samples from healthy volunteers having received intravenous injections of DMT. The presented method for rapid and sensitive quantification of DMT and its metabolites in human plasma can be applied to future studies aiming to characterize DMT disposition and its relationship to immediate psychedelic or long-term antidepressive effects.
MeSH term(s)	Calibration ; Chromatography, Liquid/methods ; Humans ; N,N-Dimethyltryptamine ; Reproducibility of Results ; Tandem Mass Spectrometry/methods
Chemical Substances	N,N-Dimethyltryptamine (WUB601BHAA)
Language	English
Publishing date	2022-02-03
Publishing country	England
Document type	Journal Article
ZDB-ID	604917-5
ISSN	1873-264X ; 0731-7085
ISSN (online)	1873-264X
ISSN	0731-7085
DOI	10.1016/j.jpba.2022.114642
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Article ; Online: Population pharmacokinetic/pharmacodynamic modeling of the psychedelic experience induced by N,N‐dimethyltryptamine – Implications for dose considerations

Emma Eckernäs / Christopher Timmermann / Robin Carhart‐Harris / Daniel Röshammar / Michael Ashton

Clinical and Translational Science, Vol 15, Iss 12, Pp 2928-

2022 Volume 2937

Abstract: Abstract N,N‐dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential ...

Abstract	Abstract N,N‐dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential as a therapeutic option in several psychiatric disorders. The number of clinical investigations with DMT is increasing. However, very little is known about the pharmacokinetic properties of DMT as well as any relationship between its exposure and effects. This study aimed to characterize population pharmacokinetics of DMT as well as the relationship between DMT plasma concentrations and its psychedelic effects as measured through subjective intensity ratings. Data were obtained from 13 healthy subjects after intravenous administration of DMT. The data were analyzed using nonlinear mixed‐effects modeling in NONMEM. DMT plasma concentrations were described by a two‐compartment model with first‐order elimination leading to formation of the major metabolite indole 3‐acetic acid. The relationship between plasma concentrations and psychedelic intensity was described by an effect site compartment model with a sigmoid maximum effect (Emax) response. DMT clearance was estimated at 26 L/min, a high value indicating elimination of DMT to be independent of blood flow. Higher concentrations of DMT were associated with a more intense experience with the concentration of DMT at the effect site required to produce half of the maximum response estimated at 95 nM. The maximum achievable intensity rating was 10 and the simulated median maximum rating was zero, 2, 4, 8, and 9 after doses of 1, 4, 7, 14, and 20 mg, respectively. The model can be useful in predicting suitable doses for clinical investigations of DMT based on the desired intensity of the subjective experience.
Keywords	Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
Subject code	610
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
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