How Cannabinoids Interact with the Liver Enzymes That Process Most Medications
A systematic review found that THC and CBD are processed by specific liver enzymes (CYP2C9, CYP3A4, CYP2C19) and generally pose a low risk of clinically significant drug interactions at typical doses.
Quick Facts
What This Study Found
The review identified the specific cytochrome P-450 (CYP-450) enzymes responsible for metabolizing major cannabinoids. THC is primarily metabolized by CYP2C9 and CYP3A4. CBD is metabolized by CYP2C19 and CYP3A4. CBN uses CYP2C9 and CYP3A4. Synthetic cannabinoids JWH-018 and AM2201 use CYP1A2 and CYP2C9.
Clinical pharmacogenetic data confirmed CYP2C9 as important for THC metabolism, and a drug interaction study with ketoconazole (a CYP3A4 inhibitor) confirmed CYP3A4's role for both THC and CBD. However, a study with omeprazole suggested CYP2C19 may play a less significant role in CBD metabolism than in vitro data predicted.
Overall, studies of THC, CBD, and CBN inhibition and induction of major CYP-450 enzymes suggested a low risk of clinically significant drug interactions with most use, though the authors noted that specific human data were lacking. Smoked cannabis appeared to induce CYP1A2, which metabolizes theophylline.
Key Numbers
THC: CYP2C9, CYP3A4. CBD: CYP2C19, CYP3A4. CBN: CYP2C9, CYP3A4. JWH-018: CYP1A2, CYP2C9. AM2201: CYP1A2, CYP2C9. Overall drug interaction risk rated as low for most clinical use.
How They Did This
This was a systematic review of published data on cannabinoid drug metabolism, including in vitro studies of enzyme substrates, inhibitors, and inducers, pharmacogenetic studies, and clinical pharmacokinetic interaction studies. The review covered both natural cannabinoids (THC, CBD, CBN) and synthetic cannabinoids (JWH-018, AM2201).
Why This Research Matters
As cannabis use becomes more common alongside prescription medications, understanding drug interaction potential is essential for patient safety. This review provides the pharmacokinetic foundation for predicting which drug combinations could be problematic.
The Bigger Picture
Drug interactions are a critical safety consideration for any new therapeutic agent. This review establishes the metabolic profile of major cannabinoids, providing a framework that physicians and pharmacists can use to evaluate potential interactions with patients' existing medications.
What This Study Doesn't Tell Us
Most data came from in vitro studies, which may not fully predict in vivo interactions. The low interaction risk assessment was based on limited human data. Cannabinoid doses used in in vitro studies may not reflect clinical concentrations. The review predated the widespread use of high-dose CBD products, which may pose greater interaction risks.
Questions This Raises
- ?Do high-dose CBD products (like Epidiolex) have greater drug interaction potential?
- ?How do genetic variations in CYP enzymes affect individual responses to cannabinoids?
- ?Should patients on certain medications be advised to avoid cannabis?
Trust & Context
- Key Stat:
- THC metabolized by CYP2C9 and CYP3A4; low overall drug interaction risk at typical doses
- Evidence Grade:
- This is a systematic review of pharmacokinetic data. While comprehensive, much of the evidence is from in vitro studies with limited clinical confirmation.
- Study Age:
- Published in 2014. Since then, FDA-approved CBD (Epidiolex) has revealed clinically significant CYP interactions at high doses, particularly with clobazam.
- Original Title:
- Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.
- Published In:
- Drug metabolism reviews, 46(1), 86-95 (2014)
- Authors:
- Stout, Stephen M, Cimino, Nina M
- Database ID:
- RTHC-00870
Evidence Hierarchy
Analyzes all available research on a topic using a structured method.
What do these levels mean? →Frequently Asked Questions
Can cannabis interact with my medications?
At typical recreational or medical doses, the risk of significant interactions appears low for most medications. However, high-dose CBD products and certain drug combinations (particularly with drugs metabolized by CYP2C19 or CYP3A4) may pose higher risks. Consult your pharmacist or physician.
Why does smoked cannabis affect theophylline?
Smoked cannabis appears to induce CYP1A2, the same enzyme that processes theophylline (an asthma drug). This induction accelerates theophylline metabolism, potentially reducing its effectiveness. However, it is unclear whether the cannabinoids or other combustion products cause this effect.
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Cite This Study
https://rethinkthc.com/research/RTHC-00870APA
Stout, Stephen M; Cimino, Nina M. (2014). Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.. Drug metabolism reviews, 46(1), 86-95. https://doi.org/10.3109/03602532.2013.849268
MLA
Stout, Stephen M, et al. "Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.." Drug metabolism reviews, 2014. https://doi.org/10.3109/03602532.2013.849268
RethinkTHC
RethinkTHC Research Database. "Exogenous cannabinoids as substrates, inhibitors, and induce..." RTHC-00870. Retrieved from https://rethinkthc.com/research/stout-2014-exogenous-cannabinoids-as-substrates
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.