Pharmacokinetics and pharmacodynamics of the psychedelic compound DMT
Abstract
N,N-dimethyltryptamine (DMT) is a psychedelic compound that is being
investigated as a treatment option in depression. It is also being used as a
research tool in research aiming to investigate the neurobiology of the human
consciousness using brain imaging techniques. However, despite the
increasing research on DMT, much remains to be known about its
pharmacokinetic and pharmacodynamic properties. Increasing this
understanding is essential in assuring safe and efficacious use of DMT in the
future.
The aim of this thesis was to investigate the pharmacokinetics and
pharmacodynamics of DMT as well as to use the newly gained knowledge to
design new dose regimens. A liquid chromatography tandem mass
spectrometry method was developed and validated to enable quantification of
DMT and two of its metabolites in biological samples. Nonlinear mixed effects
modeling was used to describe the pharmacokinetics and pharmacodynamics
of DMT using data obtained from two clinical studies. The models were used
to provide dose recommendations for administering DMT as a continuous
intravenous infusion. A more individualized dose regimen, based on observed
psychedelic intensity ratings, was also developed. The metabolism of DMT in
vitro was assessed using human liver microsomes as well as recombinant
cytochrome P450 enzymes. These experiments showed that DMT is a substrate
for CYP2D6 and that this likely leads to formation of hydroxylated
metabolites.
Overall, this thesis provides new knowledge on the pharmacokinetics and
pharmacodynamics of DMT. It also presents novel dosing strategies and
demonstrates how pharmacokinetic and pharmacodynamic modeling and
simulation can be used to further optimize DMT dosing in future clinical
studies.
Parts of work
I. Eckernäs E, Bendrioua A, Cancellerini C, Timmermann C, Carhart-Harris R, Hoffmann K-J, Ashton M. 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. Journal of Pharmaceutical and Biomedical Analysis, 2022;212:114642
https://doi.org/10.1016/j.jpba.2022.114642 II. Eckernäs E, Timmermann C, Carhart-Harris R, Röshammar D, Ashton M. Population pharmacokinetic/pharmacodynamic modeling of the subjective psychedelic experience induced by
N,N-dimethyltryptamine – implications for dose considerations. Clinical and Translational Science,
2022;15(12):2928-2937
https://doi.org/10.1111/cts.13410 III. Eckernäs E, Timmermann C, Carhart-Harris R, Röshammar D, Ashton M. N,N-dimethyltryptamine affects electroencephalography response in a concentration dependent manner – a pharmacokinetic/pharmacodynamic analysis. CPT:Pharmacometrics and Systems Pharmacology,
2023;12(4):474-486.
https://doi.org/10.1002/psp4.12933 IV. Eckernäs E, Macan-Schönleben A, Andresen-Bergström M, Birgersson S, Hoffmann K-J, Ashton M. N,N-dimethyltryptamine forms oxygenated metabolites via CYP2D6 - an in vitro investigation. Submitted V. Eckernäs E, Koomen J, Timmermann C, Carhart-Harris R, Röshammar D, Ashton M. Optimized infusion rates for N,N-dimethyltryptamine to achieve a target psychedelic intensity based on a modeling and simulation framework. CPT:Pharmacometrics and Systems Pharmacology, 2023;12(10):1398-1410
https://doi.org/10.1002/psp4.13037 VI. Eckernäs E, Luan L, Timmermann C, Carhart-Harris R, Röshammar D, Ashton M. Using
pharmacokinetic/pharmacodynamic modeling and simulation to design individually tailored infusion rates for an extended DMT experience. In manuscript
Degree
Doctor of Philosophy (Pharmaceutical science)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Institute of Neuroscience and Physiology. Department of Pharmacology
Disputation
Onsdagen den 13 december 2023, kl. 9.00, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg
https://gu-se.zoom.us/j/65858326184?pwd=SlhqZlhvUU5rcm1SZVMzckE5bUhYZz09
Date of defence
2023-12-13
emma.eckernas@gu.se
Date
2023-11-15Author
Eckernäs, Emma
Keywords
N,N-dimethyltryptamine
psychedelic
nonlinear mixed effects modeling
pharmacokinetics
pharmacodynamics
Publication type
Doctoral thesis
ISBN
978-91-8069-445-2 (PRINT)
978-91-8069-446-9 (PDF)
Language
eng