Cannabidiol (CBD) is the main non-intoxicating component in the Cannabis sativa L. plant and has recently attracted interest as a therapeutic for the treatment of a number of diseases and conditions due to observed beneficial effects in many preclinical disease models, including epilepsy, cardiovascular disease, inflammation, and cancer (Pacher, Kogan, & Mechoulam, 2020). Like other drugs, CBD has intrinsic pharmacologic effects and thus has the potential for adverse drug events (ADEs) along with the potential for pharmacokinetic and pharmacodynamic drug–drug interactions (DDIs). Given CBD use among patients with complex conditions and treatment regimens, as well as its expanded consumer use, awareness of potential safety issues with CBD is needed. Prescribing information for federally approved products containing CBD were reviewed. Common ADEs include transaminase elevations, sedation, sleep disturbances, infection, and anemia. Given CBD effects on common biological targets implicated in drug metabolism (e.g., CYP3A4/2C19) and excretion (e.g., P-glycoprotein), the potential for DDIs with commonly used medication is high. General clinical recommendations of reducing substrate doses, monitoring for ADEs, and finding alternative therapy should be considered, especially in medically complex patients. CBD is implicated as both a victim and perpetrator of DDIs and has its own ADE profile. These effects should be considered in the risk-benefit assessment of CBD therapy and patients and consumers made aware of potential safety issues with CBD use. *Article adapted from Potential Adverse Drug Events and Drug–Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use (Brown & Winterstein, 2019), licensed by a Creative Commons Attribution license (CC BY 4.0).

1. with Medical and Consumer
Cannabidiol (CBD) Use
Like other medications, CBD has a complex pharmacokinetic and pharmacodynamic
profile and therefore has the potential to interact with other medications and medical
conditions.
C A N N A B I D I O L
( C B D )
Potential Drug-Drug Interactions
1
P H A R M A C O D Y N A M I C
I N T E R A C T I O N S
CBD can potentially alter the
sensitivity or responsiveness of
tissues to another drug by having
the same (agonistic) or a blocking
(antagonistic) effect.
T Y P E S O F C B D
P H A R M A C O K I N E T I C
I N T E R A C T I O N S
CBD may alter the absorption,
distribution, protein binding,
metabolism, or elimination of
another drug, changing the amount
and persistence of available drug at
receptor sites.
Drug-Drug Interactions
2,3,4
clinical practice and cannabinoid drug development.1,2,3
Drug-drug interactions remain a critical issue in
2,4
C B D M E T A B O L I C E N Z Y M E
Substrates, Inhibitors, & Inducers
Adverse pharmacokinetic drug interactions
may occur when drugs that are
of the same metabolizing enzymes are co-
administered, potentially altering the expected
rate of metabolism of one or both compounds.
substrates, inducers and/or inhibitors
3
CYP2C19
CYP3A4
CBD is
metabolized
primarily by
the enzymes
2
a family of isozymes
that catalyze the
biotransformation of
many endo/exogenous
compounds, including
xenobiotics, drugs,
and fatty acids.
Cytochrome
P450 (CYP450)
3,6
CY3PA4 enzyme
The clinical
consequences of
may include altered
drug disposition
altered efficacy,
and/or toxicity.3
drug-drug
interactions (DDIs)
I N H I B I T O R S
An inhibitor is a drug that
impairs the ability of drug-
metabolizing enzymes (eg.,
CYP3A4) to metabolize other
coadministered substrates
by competing for the same
enzyme receptor site.
The more potent inhibitor
will predominate, resulting
in decreased metabolism of
the competing drug. Co-
administration of CBD with
enzyme inhibitors may
increase CBD bioavailability
and increased serum levels.
S U B S T R A T E S
A substrate is a drug that requires
metabolism to a more hydrophilic
compound for ultimate
elimination.
I N D U C E R S
Inducers are drugs that increase
metabolic activity by increasing
the synthesis of the CYP enzymes
involved.
Because inducers increase CYP450
enzyme activity, co-administration
with CBD may decrease CBD
bioavailability and may decrease
its effectiveness.
The endogenous and
exogenous cannabinoids
can behave as substrates,
inhibitors, and/or inducers.
1,2,4,7
2
3
3
3
2,6,7
Metabolic Drug-Drug Interactions Between
Cannabidiol and Enzyme Substrates,
Inhibitors, or Inducers
Table adapted from Brown & Winterstein, 2019, p 5.
CYP3A4
substrates
Immunosuppressants,
chemotherapeutics, antidepressants,
antipsychotics, opioids,
benzodiazepines, z-hypnotics, statins,
calcium channel blockers, others
Increased risk of side effects related to
substrate. Avoid co-administration, reduce
substrate dose, monitor for adverse effects and
toxicity. Avoid prescribing cascade with new
treatment for side effects.
ENZYME
ISOFORM
MEDICATION EXAMPLES EFFECT/RECOMMENDATION
CYP3A4
inhibitors
Strong: Protease inhibitors,
ketoconazole, loperamide, nefazodone
Moderate: Amiodarone, verapamil,
cimetidine, aprepitant, imatinib
Increased CBD bioavailability, possible increase
in risk of adverse effects. Reduce CBD dose.
CYP3A4
inducers
Strong: Enzalutamide, phenytoin
Moderate: Carbamazepine,
topiramate, phenobarbital, rifampicin,
efavirenz, pioglitazone
Decreased CBD bioavailability, possible decrease
in CBD effectiveness. Increase CBD dose.
CYP2C19
substrates
Antidepressants, antiepileptics, proton
pump inhibitors, clopidogrel,
propranolol, carisoprodol,
cyclophosphamide, warfarin
Increased risk of side effects related to
substrate. Avoid co-administration, reduce
substrate dose, monitor for adverse effects and
toxicity. Avoid prescribing cascade with new
treatment for side effects.
CYP2C19
inhibitors
Strong: Fluvoxamine, fluoxetine
Other: Proton pump inhibitors,
cimetidine, ketoconazole, clopidogrel,
fluconazole, efavirenz
Increased CBD bioavailability, possible increase
in risk of adverse effects. Reduce CBD dose.
CYP2C19
inducers
Rifampin, carbamazepine,
phenobarbital, phenytoin, St. John’s
Wort
Decreased CBD bioavailability, possible decrease
in CBD effectiveness. Increase CBD dose.
CYP2C8/9
substrates
Rosiglitazone, burprenorphine,
montelukast, celecoxib, sulfonylureas,
losartan, naproxen, phenobarbital,
phenytoin, rosuvastatin, valsartan,
warfarin
Increased risk of side effects related to
substrate. Avoid co-administration, reduce
substrate dose, monitor for adverse effects and
toxicity. Avoid prescribing cascade with new
treatment for side effects.
1
CBD inhibits uridine 5’-diphospho-glucuronosyltransferase
(UGT) enzymes, which catalyze glucuronidation of
xenobiotics in a primary pathway of phase II
metabolism. In addition to UGT, CBD may also inhibit
certain membrane transporter proteins.
1
Drug-Drug Interactions Between Cannabidiol
and Secondary Metabolism or
Membrane Transporter Proteins
UGT1A9
Regorafenib,
acetaminophen,
canagliflozin,
sorafenib, irinotecan,
propofol,
mycophenolate,
valproic acid,
haloperidol,
ibuprofen,
dabigatran,
dapagliflozin, others
Hydromorphone,
losartan,
ibuprofen,
naproxen,
ezetimibe,
lovastatin,
simvastatin,
carbamazepine,
valproate, others
Paclitaxel,
digoxin, statins,
telmisartan,
glyburide,
ketoconazole,
rosiglitazone,
celecoxib
UGT2B7 BCRP BSEP
Effect/Recommendation
Glyburide,
imatinib,
methotrexate,
mitoxantrone,
nitrofurantoin,
prazosin,
statins,
dipyridamole
Increased risk of side effects related to substrate.
Monitor co-administration closely, reduce substrate dose,
monitor for adverse effects and toxicity.
UGT = uridine 5′-diphospho-glucoronosyltransferase; BCRP = breast cancer resistance protein; BSEP = bile salt
export pump. Table adapted from Brown & Winterstein, 2019, p 7.
1
CLINICAL IMPLICATIONS
Expect that interactions involving cannabinoids will vary widely in
their clinical significance due to the considerable variability in
products, doses, routes of administration, populations using
cannabinoids, genetics, and other factors.7
Current recommended cannabinioid initiation and
maintenance: START LOW, GO SLOW, STAY LOW.8
Medical CBD users under clinical supervision should be screened for
potential DDIs and adverse drug events between CBD, other
pharmacotherapies, and patients' underlying conditions.1
Be aware of the potential for DDIs with CBD and strategically
prescribe and manage patients on multidrug regimens while
considering patient desires for complementary or alternative
therapies.1
Limited data exist on significant drug interactions caused by CBD.
Thus, evidence-based clinical guidelines on interactions of drugs with
CBD and other cannabinoids are still lacking.1
WORKS CITED
1. Brown, J. D., & Winterstein, A. G. (2019). Potential adverse drug events and drug-drug interactions with medical and consumer cannabidiol
(CBD) use. Journal of Clinical Medicine, 8(7), 989. https://doi.org/10.3390/jcm8070989
2. Zendulka, O., Dovrtělová, G., Nosková, K., Turjap, M., Šulcová, A., Hanuš, L., & Juřica, J. (2016). Cannabinoids and Cytochrome P450
Interactions. Current Drug Metabolism, 17(3), 206–226. https://doi.org/10.2174/1389200217666151210142051
3. Zhou S. F. (2008). Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Current Drug Metabolism, 9(4), 310–
322. https://doi.org/10.2174/138920008784220664 | OPEN ACCESS
4. Lynch, S. S. (2019). Drug Interactions. Merck Manual: Professional Version [Webpage]. Retrieved from
https://www.merckmanuals.com/professional/clinical-pharmacology/factors-affecting-response-to-drugs/drug-interactions (February 2, 2021)
| OPEN ACCESS
5. US FDA (2020). Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Drug Interactions and Labeling
[Website]. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table3-2
6. FDA (2018). EPIDIOLEX: Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf
7. Stout, S. M., & Cimino, N. 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
8. MacCallum, C. A., & Russo, E. B. (2018). Practical considerations in medical cannabis administration and dosing. European Journal of
Internal Medicine, 49, 12–19. https://doi.org/10.1016/j.ejim.2018.01.004
W W W . C A N N A S C I O P E N . C O M
IMAGE CREDITS
Title photo CBD Oil by CBD Infos on Unsplash
Types of CBD DDI hexagons: 1QPS enzyme by Boghog2, Public domain, via Wikimedia Commons; Balls in the Sky by Raphaël Biscaldi on
Unsplash; Colorful Drug Mix by Myriam Zilles on Unsplash
Pharmacodynamic interactions: Photo by David Clarke on Unsplash; pharmacokinetic interactions: photo by Alvaro Pinot on Unsplash
CYP3A4 Enzyme by Minutemen 20:03, Public Domain, Wikimedia Commons
Substrates hexagon: Photo by Andrea Leopardi on Unsplash; Inhibitors hexagon: Colorful Drug Mix by Myriam Zilles on Unsplash; Inducers
hexagon: Dancing Roof by Ricardo Gomez Angel on Unsplash
Metabolic Drug-Drug Interactions Between Cannabidiol and Enzyme Substrates, Inhibitors, or Inducers: Undulating Negative Space by
Tobias van Schneider on Unsplash
Drug-Drug Interactions Between CBD and Secondary Metabolism or Membrane Transporter Proteins: The Palm by Nick Fewings on Unsplash
Stethoscope photo by Hush Naidoo on Unsplash
Green Rope Meshwork by Clint Adair on Unsplash
Works Cited: 6bd7 by Astrogan, Creative Commons Attribution-Share Alike 4.0 International license
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