Perspectives of cannabis-based medicines in a view of pharmacokinetic studies of Δ9-THC and CBD in humans

The pharmacokinetic (PK) profiling of major plant cannabinoids (phytocannabinoids, PCs), i.e., Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), is an important contribution to the search for novel therapeutic applications, optimal drug formulations and time of dosing in specific disease conditions. Final products of medicinal cannabis with dominant content of Δ9-THC or CBD or equal composition of both PCs are available in multiple formulations, and can also be administered via different routes, including inhalation (smoking/vaporization), oral consumption, or topical application. Clinical studies on healthy volunteers and patients demonstrate how dosage, route of administration, co-administered compounds, and formulation types influence PK parameters, such as C_max, T_max, and AUC values. This comprehensive review explores the PK and clinical applications of Δ9-THC and CBD with emphasis on the metabolism of both compounds, and therapeutic and side effects reported in preclinical and clinical trials performed in the past 5 years. In patients, both PCs demonstrate efficacy for conditions such as epilepsy, chronic pain, and anxiety. However, Δ9-THC and CBD undergo extensive hepatic metabolism primarily via cytochrome P450 enzymes, producing both active and inactive metabolites, with interindividual variability influenced by genetics, sex, and drug interactions. Moreover, various drug formulations, including oral, inhaled, transdermal, and oromucosal, affect the PK profile and therapeutic efficacy of each compound, although novel delivery systems (e.g., nanoformulations, inhaled powders) show promise in enhancing bioavailability. This review highlights the need for individualized dosing strategies, considering patient-specific factors, and underscores the necessity for further research into formulation development and long-term safety.