ArticleEuropean journal of drug metabolism and pharmacokinetics2025
Pharmacokinetic/Pharmacodynamic Modeling of the Acute Heart Rate Effects of Delta-9 Tetrahydrocannabinol and Its Major Metabolites After Intravenous Injection in Healthy Volunteers.
Article in European journal of drug metabolism and pharmacokinetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
BACKGROUND AND
objectivesCannabis consumption is increasing in both the recreational and medical settings. Tetrahydrocannabinol (THC) is known to produce cardiovascular effects, but the specific roles of THC and its metabolites THC-OH and THC-COOH in cannabinoid-induced cardiovascular effects remain unclear. We hypothesized that THC and THC-OH mediate a cannabinoid-induced increase in heart rate in either an additive or synergistic fashion.
methodsThe present study uses prospectively obtained data to evaluate the effect of THC and its metabolites on heart rate in healthy volunteers through non-linear mixed-effect pharmacokinetic/pharmacodynamic (PK/PD) modeling.
resultsThe PK/PD models reveal that THC, THC-OH and a combination of THC and THC-OH, but not THC-COOH, are responsible for THC-induced tachycardia. The EC50 of the THC Emax model was 0.53 µM, 25-fold the EC50 for the THC-OH Emax model. The General Empiric Dynamic Model indicates that THC and THC-OH act synergistically to increase heart rate. Neither sex nor CYP2C9 polymorphism contributes to THC-induced tachycardia.
conclusionTHC-OH but not THC-COOH contributes to the heart rate effect of THC and THC-OH may be acting in a synergistic manner with THC. This contributes to understanding the cardiovascular effects of THC and cannabis-induced cardiovascular events. Future research including further hemodynamic data will allow a detailed systems pharmacology or response surface model approach.
trial registrationwww.isrctn.com ; registration number ISRCTN53019164.
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