Phytocannabinoid-drug interactions: pharmacokinetic and pharmacodynamic mechanisms, clinical relevance and toxicological considerations.

Abstract

The therapeutic use of phytocannabinoids has expanded considerably over the past decade because of their potential application across a wide range of clinical conditions. However, their concomitant use with conventional medications raises important concerns regarding drug interactions and patient safety. This narrative review provides a critical overview of current evidence on the pharmacokinetic (PK), pharmacodynamic, and toxicological interactions of major phytocannabinoids, with particular emphasis on cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), while also discussing emerging evidence related to minor phytocannabinoids and the potential contribution of terpenes. Phytocannabinoids modulate the activity of drug-metabolizing enzymes, particularly cytochrome P450 isoenzymes, and may affect selected drug transporters, thereby altering the systemic exposure and clinical effects of co-administered medications. Conversely, conventional medications that inhibit or induce cannabinoid-metabolizing enzymes may modify phytocannabinoid exposure, efficacy, and tolerability. Documented or potentially clinically relevant interactions have been reported for antiseizure medications, anticoagulants, antidepressants, opioids, alcohol, and other central nervous system depressants. However, the strength of the supporting evidence varies considerably, ranging from in vitro predictions and case reports to controlled PK and clinical studies. The magnitude and clinical relevance of these interactions are influenced by multiple factors, including cannabinoids formulation, dose, route of administration, treatment duration, pharmacogenetic variability, patient-specific characteristics, and polypharmacy. Particular attention should be given to vulnerable populations, such as pregnant women, children, older adults, and patients with hepatic impairment, in whom altered PK and increased susceptibility to adverse effects may further complicate treatment. Although substantial progress has been made in understanding cannabinoid pharmacology, important knowledge gaps remain regarding the clinical significance of many predicted interactions, the interaction profiles of minor phytocannabinoids, full-spectrum preparations, and terpenes and the long-term safety of cannabinoid-based therapies. Careful differentiation between mechanistically plausible and clinically demonstrated interactions, together with consideration of cannabinoid composition, dose, route of administration, patient vulnerability, and concomitant medications, can support safer and more individualized clinical management while guiding future research priorities.