Metabolism and clearance | Enzyme or efflux transporter inhibition or induction | Half-life (hours) | Pharmacokinetic interactions | ||
CBD (pharmaceutical and standardized extract)*[1,2] | |||||
Hepatic and gut metabolism via CYP2C19 (minor), CYP3A4 (major), glucuronidation (UGT1A7, UGT1A9, and UGT2B7) to active metabolite (7-OH-CBD) and inactive metabolite (7-COOH-CBD) Metabolites cleared in feces (primarily) and urine (minor) | Inhibits: CYP2C19 (moderate), CYP1A2 (weak), CYP2C9 (weak), CYP3A4 (weak), P-gp/ABCB1, BSEP/ABCB11 | 56 to 61 | Potential for CBD to affect other medications | ||
CBD can increase serum concentrations, clinical effects, and toxicity of substrates of CYP2C19, CYP2C9, CYP1A2, CYP3A4, and P-gp (examples): | |||||
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Potential for CBD to be affected by other medications | |||||
Serum concentrations, clinical effects, and toxicity of CBD can increase if coadministered with CYP3A4 inhibitors (examples):¶ | |||||
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Serum concentrations and clinical effects of CBD can decrease if coadministered with CYP3A4 and/or CYP2C19 inducers (examples):¶ | |||||
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Cannabis (pharmaceutical THC and CBD)Δ[3] | |||||
Hepatic metabolism via CYP2C9 (major), 2C19 (minor), 2D6 (minor), and 3A4 (major), glucuronidation (UGT1A7, UGT1A9, and UGT2B7) to active metabolites (11-OH-THC, 7-OH-CBD) and oxidation to inactive metabolite (11-nor-9-COOH-THC, 7-COOH-CBD) Metabolites are cleared in feces (primarily) and urine (minor) | Preliminary in vitro data provided in the manufacturer's labeling suggest the possibility of metabolic inhibitory or induction effects, but clinical relevance is largely unconfirmed.◊ In a pharmacokinetic study, THC extract alone did not alter CYP metabolism[2]. | 24 to 36 (or longer) | Potential for cannabis to affect other medications | ||
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Potential for cannabis to be affected by other medications | |||||
Serum concentrations, clinical effects, and toxicity of cannabis can increase if coadministered with CYP3A4 and/or 2C9 inhibitors (examples):¶ | |||||
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Serum concentrations and clinical effects of cannabis can decrease if coadministered with strong CYP3A4 inducers (examples):¶ | |||||
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NOTE: Examples of drug interactions are for illustrative purposes; many other interactions can occur. Specific interactions may warrant dose adjustment or avoidance of some combinations. Additive or antagonistic interactions (eg, additive sedation with opioids, alcohol, sedatives) are not addressed in this table. To determine a full set of potential interactions for a specific patient's medication list, use the drug interactions program included within UpToDate.
CYP, UGT, and P-gp classifications are based on US Food and Drug Administration guidance[4,5]. Other sources may use a different classification system, resulting in some agents being classified differently.11-nor-9-COOH-THC: 11-nor-9-carboxytetrahydrocannabinol; 11-OH-THC: 11-hydroxytetrahydrocannabinol; 7-COOH-CBD: 7-carboxy-cannabidiol; 7-OH-CBD: 7-hydroxycannabidiol; BSEP: bile salt export pump; CBD: cannabidiol; CYP: cytochrome P450; INR: international normalized ratio; P-gp: P-glycoprotein drug efflux pump; THC: tetrahydrocannabinol; UGT: uridine 5'-diphospho-glucuronosyltransferase.
* CBD data are derived mainly from labeling for an orally administered pharmaceutical antiseizure drug[1] and results of a pharmacokinetic study of an orally administered CBD extract containing a trace amount of THC[2]. Other nonpharmaceutical CBD products (eg, herbal oils, gummies, etc) can vary widely in potency and are administered by other routes, which can variably alter metabolic effects and potential for interactions.
¶ Lists of strong and moderate CYP3A inhibitors and inducers are available as a separate table in UpToDate.
Δ Cannabis data are derived mainly from labeling for standardized THC-CBD (Sativex)[3] administered as an oromucosal spray and a pharmacokinetic study of cannabis extracts[2]. Other cannabis preparations and herbal products have different constituent potencies and are administered by other routes (inhaled, ingested, etc), which can variably alter metabolic effects and potential for interactions.
◊ According to the THC-CBD (Sativex) product monograph[3] (Canada), in vitro data suggest cannabis components may inhibit CYP3A4 and UGT glucuronidation and/or induce CYP1A2, 2B6, and 3A4. The labeling advises a regimen review if administered with sensitive (eg, narrow therapeutic margin) substrates. These potential interactions have not yet been confirmed by adequate pharmacokinetic or clinical data.Data from: UpToDate Lexidrug. More information available at https://online.lexi.com/.
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