Cannabidiol (CBD): Drug Interactions and Liver Safety

Introduction

Cannabidiol (CBD) is a non-intoxicating phytocannabinoid increasingly used in medical and consumer products. In clinical and regulatory contexts, particular attention has been given to potential drug interactions and liver-related safety concerns associated with CBD.

Scientific evidence indicates that cannabidiol is primarily metabolized in the liver and may influence the activity of cytochrome P450 enzymes, which are involved in the metabolism of many commonly prescribed medications. In addition, dose-dependent elevations of liver enzymes have been observed in certain clinical settings.

This overview summarizes current regulatory assessments and peer-reviewed findings regarding CBD-related drug interactions and liver safety.

​

Pharmacokinetics of Cannabidiol

Cannabidiol is absorbed and metabolized mainly in the liver following oral or sublingual administration. Its metabolism involves hepatic enzymes responsible for drug biotransformation.

As a result, cannabidiol may alter the metabolic clearance of other substances processed by the same enzymatic pathways, potentially leading to clinically relevant drug interactions.

​

Cytochrome P450 Enzymes and CBD

CYP3A4 and CYP2C19 Inhibition

Experimental and clinical studies have shown that cannabidiol can inhibit cytochrome P450 enzymes, particularly CYP3A4 and CYP2C19.

These enzymes are involved in the metabolism of a wide range of pharmaceuticals, including antiepileptics, anticoagulants, and certain psychotropic drugs. Inhibition of these enzymes may increase plasma concentrations of co-administered medications.

​

Comparison With Other CYP Inhibitors

The inhibitory effect of cannabidiol on cytochrome P450 enzymes has been compared to that of known dietary inhibitors such as grapefruit juice.

While the magnitude of interaction may vary depending on dosage and formulation, regulatory agencies emphasize the importance of monitoring potential interactions in individuals using CBD alongside prescription medicines.

​

Clinically Documented Drug Interactions

Antiepileptic Drugs

Clinical studies have documented interactions between cannabidiol and certain antiepileptic medications,

most notably clobazam.

Co-administration has been associated with increased serum levels of active metabolites,

which may require clinical monitoring and dose adjustments.

​

Anticoagulants and Cardiovascular Medications

Due to its effect on hepatic enzymes, cannabidiol may influence the metabolism of anticoagulants and other cardiovascular drugs.

Regulatory guidance recommends caution when CBD is used concurrently with medications that have a narrow therapeutic index.

​

Antidepressants and Psychotropic Drugs

Some antidepressants and psychotropic medications are metabolized via cytochrome P450 pathways affected by cannabidiol.

Although clinical data remain limited, potential interactions have been identified in pharmacokinetic studies, warranting further investigation.

​

Liver Enzyme Elevation Associated With CBD

ALT and AST Findings

Elevations in liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported in clinical trials involving high doses of pharmaceutical-grade cannabidiol.

These findings were generally dose-dependent and reversible following dose reduction or discontinuation.

​

Dose-Dependent Effects

Available evidence suggests that liver-related effects of cannabidiol are more likely to occur at higher dosages, particularly in combination with other hepatically metabolized drugs.

Lower doses used in consumer products have been less consistently associated with clinically significant liver enzyme changes.

Populations at Increased Risk

Patients With Pre-existing Liver Disease

Individuals with impaired liver function may be at increased risk of adverse effects when using cannabidiol.

Clinical guidelines recommend careful monitoring of liver enzymes in these populations.

​

Older Adults and Polypharmacy

Older adults frequently use multiple medications, increasing the likelihood of drug–drug interactions.

The addition of cannabidiol in such contexts may further complicate pharmacokinetic interactions.

​

Regulatory and Medical Guidance

International regulatory agencies, including the World Health Organization (WHO) and the U.S. Food and Drug Administration (FDA), have highlighted the importance of evaluating potential drug interactions and liver safety when cannabidiol is used in clinical or consumer settings.

Ongoing pharmacovigilance and further research are recommended.

​

Conclusion

Current scientific and regulatory evidence indicates that cannabidiol may interact with commonly prescribed medications and affect liver enzyme activity under certain conditions.

While many effects appear to be dose-dependent, careful consideration of drug interactions and liver safety remains essential in both clinical research and real-world use.

​

References

1. World Health Organization (WHO). Cannabidiol (CBD): Critical Review Report. Expert Committee on Drug Dependence.
   https://www.who.int/publications/i/item/WHO-MVP-EMP-2018.2

2. U.S. Food and Drug Administration (FDA). What You Need to Know About Products Containing Cannabis or Cannabis-derived Compounds, Including CBD.
   https://www.fda.gov/consumers/consumer-updates/what-you-need-know-about-products-containing-cannabis-or-cannabis-derived-compounds-including-cbd

3. U.S. Food and Drug Administration (FDA). Cannabidiol (CBD) Drug Interactions.
   https://www.fda.gov/drugs/medical-cannabis/cannabidiol-cbd

4. Zendulka O, et al. Cannabinoids and Cytochrome P450 Interactions. Current Drug Metabolism. 2016.
   https://pubmed.ncbi.nlm.nih.gov/26651971/

5. Gaston TE, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017.
   https://pubmed.ncbi.nlm.nih.gov/28782097/

6. Chesney E, et al. Adverse effects of cannabidiol: a systematic review and meta-analysis. Neuropsychopharmacology. 2020.
   https://pubmed.ncbi.nlm.nih.gov/32231303/

7. Huestis M. Cannabidiol adverse effects and toxicity. Current Neuropharmacology. 2019.
   https://pubmed.ncbi.nlm.nih.gov/31577351/

8. European Medicines Agency (EMA). Epidyolex – Assessment Report.
   https://www.ema.europa.eu/en/medicines/human/EPAR/epidyolex