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J Pharm Sci. 2018 Feb;107(2):745-755. doi: 10.1016/j.xphs.2017.09.009. Epub 2017 Sep 20.

Relating Observed Psychoactive Effects to the Plasma Concentrations of Delta-9-Tetrahydrocannabinol and Its Active Metabolite: An Effect-Compartment Modeling Approach.

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Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242.
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242; Positron Emission Tomography Imaging Center, Department of Radiology, University of Iowa, Iowa City, Iowa 52242. Electronic address:


The medical use of marijuana is increasing, yet little is known about the exposure-response relationship for its psychoactive effects. It is well known that the plasma concentrations of the principal psychoactive component of marijuana, Δ9-tetrahydrocannabinol (THC), do not directly correlate to the observed psychoactive effects. The purpose of this research was to use an effect-compartment modeling approach to predict and relate the concentrations of the psychoactive components (THC and its active metabolite) in the "hypothetical" effect-site compartment to the observed psychoactive effects. A "hypothetical" effect-compartment model was developed using literature data to characterize the observed delay in peak "highness" ratings compared with plasma concentrations of the psychoactive agents following intravenous administration of THC. A direct relationship was established between the reported psychoactive effects ("highness" or intoxication) and the predicted effect-site concentrations of THC. The differences between estimated equilibration half-lives for THC and THC-OH in the effect-compartment model indicated the differential equilibration of parent drug and the active metabolite between plasma and the effect-site. These models contribute to the understanding of the pharmacokinetic-pharmacodynamic relationships associated with marijuana use and are important steps in the prediction of pharmacodynamic effects related to the psychoactive components in marijuana.


clinical pharmacokinetics; metabolism; metabolite kinetics; pharmacokinetic/pharmacodynamic models; pharmacokinetics; pharmacokinetics/pharmacodynamics; population pharmacokinetics

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