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

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


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.

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

MeSH terms

  • Administration, Intravenous / methods
  • Adolescent
  • Adult
  • Cannabis / adverse effects
  • Dronabinol / adverse effects
  • Dronabinol / analogs & derivatives*
  • Dronabinol / blood
  • Dronabinol / metabolism
  • Female
  • Half-Life
  • Humans
  • Male
  • Marijuana Smoking / adverse effects
  • Marijuana Smoking / blood
  • Marijuana Smoking / metabolism
  • Middle Aged
  • Plasma / metabolism*
  • Psychotropic Drugs / adverse effects*
  • Psychotropic Drugs / blood*
  • Psychotropic Drugs / metabolism
  • Young Adult


  • Psychotropic Drugs
  • delta-8-tetrahydrocannabinol
  • Dronabinol