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

Gomes D.; Eufrázio W.; Ribeiro M.; Ribeiro de Novais Júnior L.; Rigo F.; de Aguiar Amaral P.; Campanale A.; Inserra A.; Mariano de Bitencourt R. · Frontiers in toxicology · 2026

**Background & Methods** This is a narrative review synthesizing current evidence on pharmacokinetic, pharmacodynamic, and toxicological interactions between phytocannabinoids (particularly CBD and THC) and conventional medications. The review critically evaluates interaction mechanisms, clinical relevance, and safety considerations across diverse drug classes and patient populations. **Key Findings** • Phytocannabinoids modulate cytochrome P450 isoenzymes and drug transporters, significantly altering systemic exposure and clinical efficacy of co-administered medications; conversely, drugs that inhibit or induce cannabinoid-metabolizing enzymes may modify phytocannabinoid exposure and tolerability. • Clinically relevant interactions have been documented or identified for antiseizure medications, anticoagulants, antidepressants, opioids, alcohol, and central nervous system depressants, though evidence strength varies considerably from in vitro predictions and case reports to controlled pharmacokinetic and clinical studies. • Interaction magnitude and clinical significance are influenced by multiple factors including cannabinoid formulation, dose, route of administration, treatment duration, pharmacogenetic variability, patient characteristics, and polypharmacy status, with particular concerns in vulnerable populations (pregnant women, children, older adults, hepatic impairment). **Dosage & Administration** Not reported. The review does not specify standardized doses or routes for individual phytocannabinoids, noting instead that formulation, dose, route of administration, and treatment duration significantly influence interaction profiles. **Safety & Adverse Effects** The review does not detail specific adverse effects but emphasizes that altered pharmacokinetics in vulnerable populations may increase susceptibility to adverse effects. Critical safety gaps exist regarding long-term cannabinoid therapy safety and the interaction profiles of minor phytocannabinoids, full-spectrum preparations, and terpenes. **Evidence Quality** This narrative review exhibits moderate to significant limitations. Evidence supporting documented interactions ranges from weak (in vitro predictions, case reports) to moderate/strong (controlled pharmacokinetic and clinical studies), with considerable heterogeneity in study design and quality. The authors acknowledge substantial knowledge gaps regarding clinical significance of predicted interactions, minor phytocannabinoid profiles, and long-term safety. The review emphasizes the critical need to differentiate between mechanistically plausible interactions and clinically demonstrated effects, highlighting the necessity for future controlled research to establish definitive interaction profiles across diverse patient populations and cannabinoid formulations.

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