All of the following statements are true regarding pharmacokinetics of cannabinoids: SELECT THREE

A. Inhalation of cannabinoids produces a slower onset compared to ingestion which has a faster onset: Inhalation results in rapid absorption through the alveoli with effects occurring within minutes. Oral ingestion has delayed onset due to first-pass hepatic metabolism and slower gastrointestinal absorption. The onset pattern described here is reversed from pharmacokinetics. B. There is a high interindividual pharmacokinetic variability in both inhalation and oral ingestion: Cannabinoid absorption and metabolism vary widely due to differences in body fat composition, liver enzyme activity, route of administration, and formulation. Oral products show especially high variability because of inconsistent absorption and first-pass metabolism. This contributes to unpredictable plasma concentrations and effects. C. Cannabinoids are metabolized extensively by the liver: THC and other cannabinoids undergo extensive hepatic metabolism primarily via cytochrome P450 enzymes, especially CYP2C9, CYP2C19, and CYP3A4. This metabolism produces active and inactive metabolites that influence duration and intensity of effects. Liver function significantly impacts cannabinoid pharmacokinetics. D. Cannabinoids are highly protein bound: Cannabinoids are lipophilic compounds that bind extensively to plasma proteins and distribute widely into adipose tissue. High protein binding affects drug–drug interactions and prolongs elimination. This property contributes to prolonged detection and variable clinical effects.