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Population pharmacokinetic/pharmacodynamic modeling of the psychedelic experience induced by N,N‐dimethyltryptamine – Implications for dose considerations

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

Clinical and Translational Science September 11, 2022 DOI: 10.1111/cts.13410 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Population pharmacokinetic and pharmacodynamic analysis Peer reviewed
Sample size 13
Population Healthy subjects
Intervention N
Dose 1, 4, 7, 14, and 20 mg (simulated doses)
Topics 5-MeO-DMT DMT
Keywords Pharmacology Nonmem Pharmacokinetics Pharmacodynamics Population Active metabolite
Citations 22
Key points DMT clearance is 26 L/min, and the concentration at the effect site producing half-maximal psychedelic intensity is 95 nM.

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 ( E max ) 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.

Comparable studies

Other experimental studies on DMT, most cited first.

Study Year Design Participants
Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Human cerebral organoids 2017 Experimental study
Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment Volunteers 2019 Within-subjects experimental study n = 11
Metabolism and disposition of N,N‐dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca Healthy male volunteers 2012 Observational pharmacokinetic study n = 10
Unmasking of a neonatal somatovesical reflex in adult cats by the serotonin autoreceptor agonist 5-methoxy-N,N-dimethyltryptamine. Adult cats 1990 Experimental study n = 10
Studies on the Mechanism of Action of Monoamine Oxidase: Metabolism of N,N-Dimethyltryptamine and N,N-Dimethyltryptamine-N-Oxide 1962 Experimental study

Citations in the library

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5-MeO-DMT DMT