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.