Access to this full-text is provided by Karger Publishers.
Content available from Medical Cannabis and Cannabinoids
This content is subject to copyright.
Preclinical Science and Clinical Studies – Review Article
Med Cannabis Cannabinoids 2020;3:61–73
Delta-9-Tetrahydrocannabinol and
Cannabidiol Drug-Drug Interactions
Paul T. Kocis
a, b Kent E. Vrana
b
aDepartment of Pharmacy, Penn State Health, Milton S. Hershey Medical Center, Hershey, PA, USA;
bDepartment of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
Received: March 16, 2020
Accepted: April 19, 2020
Published online: July 7, 2020
Paul T. Kocis
Department of Pharmacology
Penn State College of Medicine
500 University Drive, R130, Hershey, PA 17033 (USA)
puk4@psu.edu
© 2020 The Author(s)
Published by S. Karger AG, Basel
karger@karger.com
www.karger.com/mca
DOI: 10.1159/000507998
Keywords
Tetrahydrocannabinol · Cannabidiol · Drug-drug
interactions · Cytochrome P450 · Medical marijuana ·
Cannabis · Metabolism
Abstract
Although prescribing information (PI) is often the initial
source of information when identifying potential drug-drug
interactions, it may only provide a limited number of exem-
plars or only reference a class of medications without provid-
ing any specific medication examples. In the case of medical
cannabis and medicinal cannabinoids, this is further compli-
cated by the fact that the increased therapeutic use of mari-
juana extracts and cannabidiol oil will not have regulatory
agency approved PI. The objective of this study was to pro-
vide a detailed and comprehensive drug-drug interaction
list that is aligned with cannabinoid manufacturer PI. The
cannabinoid drug-drug interaction information is listed in
this article and online supplementary material as a PRECIPI-
TANT (cannabinoid) medication that either INHIBITS/INDUC-
ES the metabolism or competes for the same SUBSTRATE tar-
get (metabolic enzyme) of an OBJECT (OTHER) medication.
In addition to a comprehensive list of drug-drug interac-
tions, we also provide a list of 57 prescription medications
displaying a narrow therapeutic index that are potentially
impacted by concomitant cannabinoid use (whether
through prescription use of cannabinoid medications or
therapeutic/recreational use of cannabis and its extracts).
© 2020 The Author(s)
Published by S. Karger AG, Basel
Introduction
For decades, there has been scientific interest in the
involvement of the endocannabinoid system in the phys-
iological regulation of conditions such as pain, nausea
and vomiting, seizures, and multiple sclerosis [1]. The
Cannabis sativa plant contains more than 100 phytocan-
nabinoids classified into 11 chemical classes [2–4], of
which the psychoactive delta-9-tetrahydrocannabinol
(∆9-THC) and the non-intoxicating cannabidiol (CBD)
are the compounds most widely studied [5, 6]. Cannabis
sativa still remains illegal at the federal level in the USA;
however, as of June 2019, there are 33 States and the Dis-
trict of Columbia that have legalized one or more compo-
nents of C. sativa [7]. In addition, the 2018 Farm Bill ren-
dered CBD oil (hemp-derived extract) legal as long as its
is article is licensed under the Creative Commons Attribution-
NonCommercial-NoDerivatives 4.0 International License (CC BY-
NC-ND) (http://www.karger.com/Services/OpenAccessLicense).
Usage and distribution for commercial purposes as well as any dis-
tribution of modied material requires written permission.
Kocis/Vrana
Med Cannabis Cannabinoids 2020;3:61–73
62
DOI: 10.1159/000507998
formulation is derived from hemp from a licensed grow-
er, produced consistently with Federal and State laws, and
following specific regulations [8]. Indeed, in November
2019, the U.S. Food and Drug Administration (FDA) sent
warning letters to several companies selling CBD-con-
taining products for violating the Federal Food, Drug,
and Cosmetic Act regulations concerning false advertis-
ing [9].
Cannabinoid-containing products can be inhaled by
smoking cigarettes, pipes, water pipes, and emptied cigars
and also inhaled (minus the smoke) when vaporized,
dabbed, and nebulized. Orally, cannabinoids can be ad-
ministered by a capsule, oil, solution, or tincture. Addi-
tionally, cannabinoids can be mixed in food (i.e., edibles)
and eaten as brownies, cookies, and candy or mixed or
infused in a drink or brewed into a tea. Cannabinoids can
also be administered sublingually and through the oral
mucosa route with a lollipop, lozenge, or spray. Topically,
cannabinoids can be applied as a gel, cream, ointment,
patch, or inserted as a suppository [10, 11]. Of the 169,036
survey participants in the 2016–2017 “National Survey of
Marijuana Use Among U.S. Adults With Medical Condi-
tions,” 77.5% of adult survey participants reported smok-
ing as the primary route of administration [7]. During a
2017–2018 online CBD survey, the most common meth-
od of CBD administration was sublingual, followed by
vaping, oral ingestion of capsules and liquids, smoking,
edibles, and topical administration [4].
From 1995 to 2014, the average percentage composi-
tion of ∆9-THC in U.S. Drug Enforcement Agency (DEA)
seized recreational marijuana specimens had increased
from ∼4 to ∼12% [12]. There are also published reports
of adding adulterants, such as tobacco, to cannabis so as
to enhance the cannabimimetic effects of ∆9-THC [13].
Reports on CBD manufacturers (that are not being sys-
tematically regulated) suggest that labeled CBD formula-
tions frequently do not accurately reflect the stated con-
centration or actual composition [4]. A report of online
retail purchases of CBD suggested that 43% of products
were under-labeled and that 26% were over-labeled when
analyzed for their actual CBD concentration. Indeed, sig-
nificant amounts of ∆9-THC were detected in 21% of
these CBD oils when it was presumed to have low or un-
detectable THC levels [14]. In the USA, the concentration
of ∆9-THC in hemp-derived CBD cannot exceed 0.3%
[8].
As ∆9-THC and CBD over-the-counter (OTC) prod-
ucts and prescription medications are becoming increas-
ingly available from a pharmacy, dispensary, Internet, lo-
cal retail store, or by illicit means (Fig. 1), there is an in-
creased likelihood of an unintended drug-drug interaction
when coadministered with another herbal, OTC, or pre-
scription medication. It is important to take this into con-
sideration whether the cannabinoid-containing products
are used to relieve acute symptoms, in the treatment of a
routine medical condition, or during recreational use
[15]. The concern for potential drug-drug interactions is
of increasing concern and the subject of several recent
reviews [16–21].
Although prescribing information (PI) is often the ini-
tial source of information, it may only provide a limited
number of exemplars or only reference a class of medica-
Medical cannabis
(raw extract)
(x:y Δ9-THC/CBD)
Cannabinoids
Nabiximols (Rx)
(purified)
(1:1 Δ9-THC/CBD)
- Sativex®
CBD Cannabidiol (CBD)
(non-prescription)
Δ9-THC
Cannabidiol (Rx)
- Epidiolex®
Dronabinol (Rx)
- Marinol®
- Syndros®
Nabilone (Rx)
- Cesament®
Fig. 1. Δ⁹-THC and CBD cannabinoid (prescription, OTC, and medical cannabis) formulations.
THC and CBD Drug-Drug Interactions
63
Med Cannabis Cannabinoids 2020;3:61–73
DOI: 10.1159/000507998
tions without providing any specific medication exam-
ples. In the case of medical cannabis and medicinal can-
nabinoids, this is further complicated by the fact that the
increased therapeutic use of marijuana extracts and CBD
oil may not have regulatory agency approved PI. In either
event, this still prompts the healthcare provider to con-
duct further research in order to identify potential drug-
drug interactions. The objective of this work was to de-
velop a detailed, comprehensive, and updateable drug-
drug interaction list that is aligned with the cannabinoid
manufacturer PI and further supplemented with the FDA
“Drug Development and Drug Interactions: Table of Sub-
strates, Inhibitors and Inducers” online document [22]
and the DrugBank database [23].
Prescription Δ⁹-THC and CBD Cannabinoid
Medications
Dronabinol (Marinol® and Syndros®)
Dronabinol, a synthetic form of ∆9-THC, is available
as either an oral capsule (Marinol®) or an oral solution
(Syndros®). As per the FDA approved manufacturer la-
beling, both of these dronabinol medications are FDA ap-
proved for “the treatment of adults with anorexia associ-
ated with weight loss in AIDS and for the treatment of
adults with nausea and vomiting associated with cancer
chemotherapy who have failed to respond adequately to
conventional antiemetic treatments” [24, 25].
Nabilone (Cesamet®)
Nabilone (Cesamet®) is a synthetic, but structurally
distinct, derivative of ∆9-THC that is available as an oral
capsule and has an FDA approved indication for “the
treatment of nausea and vomiting associated with cancer
chemotherapy in patients who have failed to respond ad-
equately to conventional antiemetic treatments” [26]. It
is important to note that the “failed to respond adequate-
ly to conventional antiemetic treatments” restriction is
required for nabilone, as well as for dronabinol, because
of the psychotomimetic reactions not normally observed
with other antiemetic agents.
CBD (Epidiolex®)
CBD (Epidiolex®) is a 98% pure plant-derived oral
CBD solution [27], with an FDA approved indication:
“For the treatment of seizures associated with Lennox-
Gastaut syndrome or Dravet syndrome in pediatric pa-
tients 2 years of age and older” [28].
Nabiximols 1:1 ∆9-THC and CBD (Sativex®)
Sativex®, also known by its United States Adopted
Name (USAN), nabiximols, is available as a 1:1 (∆9-THC
and CBD) plant-derived oral mucosal spray formulation
[29, 30]. Nabiximols is indicated as treatment in more
than 25 countries, other than the USA, for “symptom im-
provement in adult patients with moderate to severe spas-
ticity due to multiple sclerosis who have not responded
adequately to other anti-spasticity medication and who
demonstrate clinically significant improvement in spas-
ticity-related symptoms during an initial trial of therapy”
[29]. In the USA, nabiximols is an investigational drug for
polyneuropathy, HIV-associated neuropathy, advanced
cancer pain, and palliative care [31].
While the restricted use of prescription cannabinoids
presents a potential concern for drug-drug interactions,
another major concern arises from the increased use of
cannabis and cannabis extracts as therapeutic agents (e.g.,
medical marijuana and CBD oils). In addition, the in-
creased use of recreational cannabis presents a significant
concern for healthcare providers in knowing when to be
concerned about unintended drug-drug interactions.
These concerns arise because these cannabinoid-contain-
ing products can interfere with the metabolism of a large
number of other medications, especially those that are
required to be maintained in a narrow concentration
range in order to obtain clinical benefit without untoward
side effects. These medications are said to have a Narrow
Therapeutic Index (NTI).
Cannabinoid Metabolism
Most xenobiotic medications are metabolized by a
phase I hepatic cytochrome P450 enzyme (oxidative/
functionalization reaction) and then by a phase II conju-
gation reaction catalyzed by a hepatic UDP-glucurono-
syltransferase (UGT) enzyme [19, 32]. Combined, these
cytochrome P450 and UGT enzymes metabolize more
than 90% of medications that are dependent on hepatic
metabolism [32]. The metabolism of the cannabinoids is
primarily by the CYP3A4, CYP2C9, and CYP2C19 en-
zymes and the UGT enzymes, UGT1A9 and UGT2B7 [22,
33].
Cytochrome P450 Enzymes
Based on the regulatory agency approved PI, CBD,
nabiximols, nabilone, and dronabinol are primarily
metabolized by 6, 6, 4, and 2 different cytochrome P450
enzymes, respectively. As noted in Table1, the 3 major
Kocis/Vrana
Med Cannabis Cannabinoids 2020;3:61–73
64
DOI: 10.1159/000507998
cytochrome P450 enzymes for the cannabinoids are
CYP3A4, CYP2C9, and CYP2C19 and account for be-
tween 20 and 70% of the total cytochrome P450 activity
in the liver. Therefore, the ability of the cannabinoids
to impact the activity of these enzymes can have dra-
matic effects on other medications. Note that while oth-
er enzymes are capable of metabolizing the compounds
(see Table 1), we primarily focus our attention here
on these 3 major enzymes (CYP3A4, CYP2C9, and
CYP2C19).
UGT Enzymes
The UGT enzymes serve to catalyze phase II reactions
in which the cannabinoids are conjugated to a sugar to
render them more readily excreted. There has been little
reported on the UGT-dependent conjugation of the can-
nabinoids with the exception of CBD (Epidiolex®). In
this case, CBD is metabolized by UGT1A9 and UGT2B7
enzymes in the liver and UGT1A7 that is expressed in the
gastrointestinal tract [28]. These enzymes comprise only
about 13% of the total UGT activity and so their inhibi-
tion or induction may be less impactful globally. There
are no references to metabolism by UGT in the other can-
nabinoid PI; however, it could be assumed that at least
nabiximols (Sativex®) would involve UGT metabolism
since it also contains CBD. Moreover, given their shared
structures, it is likely that the other cannabinoids are sim-
ilarly metabolized.
Cytochrome P450 Enzyme INHIBITORS and
INDUCERS
A PRECIPITANT medication can INHIBIT the me-
tabolism of an OBJECT medication by the cytochrome
P450 enzyme and/or the UGT enzyme, resulting in an
increase (↑) in the OBJECT medication’s drug effect and/
or an increase in adverse events. Conversely, the PRE-
CIPITANT medication can INDUCE the metabolism of
an OBJECT medication resulting in a decrease (↓) in that
medication’s effect. In general, this INDUCTION hap-
pens when the mRNA for a metabolic enzyme is increased
by the PRECIPITATING medication.
Cytochrome P450 Enzyme SUBSTRATES with a NTI
Cannabinoid-containing products, along with con-
comitantly prescribed OTC, herbal, or prescription med-
ications, can all compete as the SUBSTRATE for the
same metabolic enzyme, thus resulting in an increase in
their relative drug concentrations (effectively function-
ing as INHIBITORS). Although two or more medica-
tions may compete as SUBSTRATES for the same en-
zyme, this may not prove to be clinically significant if
there is a wide range of safe therapeutic concentrations
and a favorable toxicology profile. Therefore, in order to
minimize false alerts and alert fatigue and to provide a
manageable and clinically significant list, the SUB-
STRATES that have an NTI are emphasized here. Table2
presents a unified list of NTI medications that will be
subject to potential cannabinoid drug-drug interactions
of one kind or another. For the most part, they are iden-
tified based on CYP2C9, CYP3A4, and CYP2C19. A
more complete list of potential drug-drug interactions is
provided in the online supplementary material (along
with detailed specifics of the enzymes involved). It is also
important to note that the cannabinoid (as PRECIPI-
TANT) may affect the metabolism of an OBJECT medi-
cation; therefore, Table2 provides a list of important NTI
medications to be closely monitored when coadminis-
tered with cannabinoids, either therapeutically or recre-
ationally.
Highly Protein-Bound Medications
The prescription cannabinoid medications (dronabi-
nol, nabilone, CBD, and nabiximols) are highly protein
bound. That is, they are present in the circulation in tight
Table 1. Hepatically expressed cytochrome P450 enzymes
Enzyme Hepatic
expression
range,
% of total
Dronabinol Nabilone CBD Nabiximols
CYP3A4 14.5–37.0 √ √ √ √
CYP2C8
∼
7.5 √ √ √
CYP2E1 5.5–16.5 √
CYP2C9 4.5–29.0 √ √ √ √
CYP1A2 4.4–16.3 √ √
CYP2A6 3.5–14.0
CYP2B6 1.7–5.3 √ √
CYP2D6 1.3–4.3
CYP2C19 0.9–3.8 √ √
CYP2J2 <1.0 √ √ √
CYP1A1 <1.0
CYP1B1 0.0
CYP3A5
∼
1.0
The 3 primary cytochrome P450 enzymes (CYP3A4, CYP2C9,
and CYP2C19) involved in cannabinoid metabolism are highlight-
ed in bold. CBD, cannabidiol.
THC and CBD Drug-Drug Interactions
65
Med Cannabis Cannabinoids 2020;3:61–73
DOI: 10.1159/000507998
Table 2. List of Narrow Therapeutic Index (NTI) medications to be closely monitored when coadministered with
cannabinoids, either therapeutically or recreationally
Narrow Therapeutic Index (NTI) medication Enzyme/metabolism
acenocoumarol (VKA) CYP1A2, CYP2C9, CYP2C19, CYP3A4
alfentanil CYP3A, CYP3A4
aminophylline CYP1A2, CYP3A4
amiodarone CYP1A2, CYP2C8, CYP2C19, CYP3A4
amitriptyline CYP1A2, CYP2B6, CYP2C19, CYP3A4
amphotericin B Protein binding
argatroban CYP3A4
busulfan CYP3A4
carbamazepine CYP1A2, CYP3A4, UGT2B7
clindamycin CYP3A4
clomipramine CYP1A2, CYP2B6, CYP2C19, CYP3A4, UGT2B7
clonidine CYP1A2, CYP3A4
clorindione (VKA) CYP3A4
cyclobenzaprine CYP1A2, CYP3A4
cyclosporine CYP3A4
dabigatran etexilate UGT1A9, UGT2B7
desipramine CYP1A2, CYP2B6
dicoumarol (VKA) CYP2C9
digitoxin CYP3A4
dihydroergotamine CYP3A4
diphenadione (VKA) CYP3A4
dofetilide CYP3A4
dosulepin CYP2B6
doxepin CYP1A2, CYP2C9, CYP2C19, CYP3A4
ergotamine CYP3A4
esketamine CYP2B6, CYP3A4
ethinyl estradiol (oral contraceptives) UGT1A9, UGT2B7
ethosuximide CYP2E1, CYP3A4
ethyl biscoumacetate (VKA) CYP3A4
everolimus CYP3A, CYP3A4
fentanyl CYP3A4
fluindione (VKA) CYP2C9, CYP3A4
fosphenytoin CYP2C8, CYP2C9, CYP2C19, CYP3A4
imipramine CYP1A2, CYP2B6, CYP2C19, CYP3A4
levothyroxine CYP3A4
lofepramine CYP2B6
melitracen CYP2B6
meperidine CYP2B6, CYP3A4
mephenytoin CYP1A2, CYP2C19
mycophenolic acid UGT1A9, UGT2B7
nortriptyline CYP1A2, CYP2B6, CYP3A4
paclitaxel CYP2C8, CYP3A4
phenobarbital CYP2C19
phenprocoumon (VKA) CYP2C8, CYP2C9, CYP3A4
phenytoin CYP2C8, CYP2C9, CYP2C19
pimozide CYP1A2, CYP3A, CYP3A4
propofol UGT1A9
quinidine CYP2C9, CYP2E1, CYP3A4
sirolimus CYP3A, CYP3A4
tacrolimus CYP3A, CYP3A4
temsirolimus CYP3A4
theophylline CYP1A2, CYP3A4
thiopental CYP2C19
tianeptine CYP3A4
trimipramine CYP2B6
valproic acid CYP2C9, UGT1A9, UGT2B7
warfarin (VKA) CYP1A2, CYP2C9, CYP2C19, CYP3A4
VKA, vitamin K antagonist.
Kocis/Vrana
Med Cannabis Cannabinoids 2020;3:61–73
66
DOI: 10.1159/000507998
association with plasma proteins (see Table3). The per-
centage used to identify highly protein-bound medica-
tions was interpreted from a report by Scheife that states
“differences appear to be of slight clinical importance”
when protein binding is “less than 80–85%” [34]. There-
fore, when defining highly protein bound in this article,
≥85% protein binding was chosen.
Cannabinoids can displace and hence increase the free
fraction of OTHER highly protein-bound medications,
especially those that have an NTI and, thus, may require
dose adjustments (see Table3). Conversely, other highly
protein-bound medications may have an effect on can-
nabinoid protein binding and availability. The ∆9-THC–
derived medication dronabinol (Marinol® and Syn-
dros®) is 97% protein bound [24, 25]. The FDA approved
PI for the nabilone (Cesamet®) states “highly bound” but
without providing a specific percentage, nor does the
DrugBank drug monograph provide a specific percentage
of protein binding [26, 30]. As for CBD (Epidiolex®), it is
>94% protein bound as per the FDA PI [28]. The com-
bined 1:1 ∆9-THC and CBD-based medication, nabixi-
mols (Sativex®), is >97% protein bound (∆9-THC) but
the Summary of Product Characteristics (SmPC) does
not provide a specific percentage of protein binding for
the CBD component [29, 30].
Tobacco Smoke
Tobacco smoke contains polycyclic aromatic hydro-
carbons that can INDUCE the metabolism of certain
medications by the CYP1A1, CYP1A2, and CYP2E1 en-
zymes [35]. More specifically, smoking produces an in-
ter-individual variability in CYP1A2 activity when me-
tabolizing select medications (e.g., aminophylline, amio-
darone, clozapine, and warfarin) [36, 37]. Table4 presents
a list of medications where tobacco smoke can INDUCE
the metabolism of CYP1A2 SUBSTRATES, with an NTI,
that also interact with cannabinoids. In this case, the
healthcare provider will want to question the use of to-
bacco products, as well as reference the cannabinoid
drug-drug interaction list (see Table2).
Source of Drug-Drug Interaction Information
PI
The U.S. FDA PI information was the initial source
of drug-drug interaction information for dronabinol
(Marinol® and Syndros®), nabilone (Cesamet®), and
CBD (Epidiolex®) [24–26]. The SmPC was the initial
source of drug-drug interaction information for the
combined ∆9-THC and CBD product nabiximols (Sa-
tivex®) [29].
FDA.gov Drug Interaction Table
Tables within the FDA “Drug Development and Drug
Interactions: Table of Substrates, Inhibitors and Induc-
ers” online document [22] were recently revised on De-
cember 3rd, 2019. As per the FDA website, these tables
Table 3. Narrow Therapeutic Index (NTI) and cannabinoid med-
ications with protein binding ≥85%
NTI medications Protein binding ≥85%
amphotericin B >90
cannabidiola, b >94
cyclosporine 90
dronabinola, b 97
levothyroxine >99
nabilonea, b Highlyc
nabiximolsa, b >94
phenytoin 90
quinidine 88
tacrolimus >99
valproic acid 85
warfarin (VKA) 99
VKA, vitamin K antagonist; PI, prescribing information. aNot
considered an NTI. bCannabinoid medication. c As defined by
nabilone (Cesamet®) PI.
Table 4. Smoking INDUCES the metabolism of NTI medications
that serve as a CYP1A2 enzyme SUBSTRATE
acenocoumarol (VKA)
aminophylline
amiodarone
amitriptyline
carbamazepine
clomipramine
clonidine
cyclobenzaprine
desipramine
doxepin
imipramine
mephenytoin
nortriptyline
pimozide
theophylline
warfarin (VKA)
VKA, vitamin K antagonist; NTI, Narrow Therapeutic Index.
THC and CBD Drug-Drug Interactions
67
Med Cannabis Cannabinoids 2020;3:61–73
DOI: 10.1159/000507998
provide drug-drug interaction examples and were not in-
tended to be a complete list. See the online supplemen-
tary material for a list of FDA defined terms and defini-
tions (e.g., Moderate INHIBITOR and Strong INHIBI-
TOR) that are included in the FDA “Drug Development
and Drug Interactions: Table of Substrates, Inhibitors
and Inducers” online document [22].
DrugBank.ca Database
DrugBank (v5.1.4, released on July 2nd, 2019) is a
comprehensive drug database sourced from the FDA and
Health Canada drug labeling information and from the
primary literature of FDA approved, experimental or in-
vestigational drugs [23]. The DrugBank database project
is supported by the Canadian Institutes of Health Re-
search (CIHR), Alberta Innovates - Health Solutions, and
The Metabolomics Innovation Centre (TMIC).
Regulatory Agency Approved PI
Dronabinol (Marinol® and Syndros®)
As described in the Marinol® and Syndros® PI,
dronabinol is primarily metabolized by the CYP2C9 and
CYP3A4 enzymes (see Table5) [24, 25]. Other than de-
scribing the increased (↑) elimination half-life of pento-
barbital by 4 h for both the Marinol® and Syndros® PI,
there are no other medications specifically identified
whose metabolism is affected by dronabinol [24, 25].
With the dronabinol PI stating that the enzyme and inhi-
bition potential of dronabinol is not fully understood, it
can be assumed that there are potential drug-drug inter-
actions with the CYP2C9 and CYP3A4 SUBSTRATES.
In the present context (see Table 2), the CYP2C9 and
CYP3A4 SUBSTRATES are limited to those medications
that have an NTI and are likely to be affected by ∆9-THC
legal or illicit use. A comprehensive list of these drug-
drug interactions is provided in the online supplemen-
tary material.
Disulfiram-Like Interaction: Dronabinol (Syndros®)
In addition to the synergistic effect of alcohol (e.g.,
drowsiness and sedation) with a cannabinoid, the
dronabinol (Syndros®) formulation contains 50% (w/w)
dehydrated alcohol that can precipitate a disulfiram-like
reaction (e.g., abdominal cramps, nausea, vomiting,
headaches, and flushing) with medications (e.g., disulfi-
ram [Antabuse®] and metronidazole) that inhibit alde-
hyde dehydrogenase when administered at the same time
or within a certain period of time of one another [25].
Nabilone (Cesamet®)
Nabilone is a synthetic, but structurally distinct deriv-
ative of ∆9-THC, and the route and rate of metabolism of
its metabolites are similar to those observed with other
cannabinoids, including ∆9-THC (dronabinol) [30]. The
nabilone PI states that nabilone has a WEAK INHIBI-
TORY effect on CYP2E1 and CYP3A4 and has a MOD-
ERATE INHIBITORY effect on CYP2C8 and CYP2C9
[26] (see Table5). In the “Drug Interaction” section of the
nabilone (Cesamet®) PI, there are generalized case re-
ports of central nervous system and cardiovascular ad-
verse events that were only associated with marijuana
smoking and not specific to nabilone; therefore, these
case reports were not included in this article [26].
CBD (Epidiolex®)
As described in the CBD (Epidiolex®) PI, CBD can ei-
ther INHIBIT or INDUCE the metabolism of OTHER
medications serving as a CYP1A2 SUBSTRATE (e.g., the-
ophylline and caffeine) and CYP2B6 SUBSTRATE (e.g.,
bupropion and efavirenz), resulting in an increase (↑) or
decrease (↓) in the OTHER medication’s effect (see Ta-
ble5). Moreover, CBD can INHIBIT the metabolism of
OTHER medications by cytochrome P450 CYP2C8,
CYP2C9 (e.g., phenytoin), and CYP2C19 (see Table5).
CBD can also increase the effect of OTHER medications
that are metabolized by CYP2C19 SUBSTRATES (e.g.,
diazepam). Since this may increase the risk of adverse
events, a reduction in dose of the CYP2C19 SUBSTRATE
medication should be considered. CBD can also INHIBIT
the metabolism of OTHER medications by the UGT1A9
enzyme (e.g., diflunisal, propofol, and fenofibrate) and
UGT2B7 enzyme (e.g., gemfibrozil, lamotrigine, mor-
phine, and lorazepam).
Since the coadministration of clobazam with CBD
(Epidiolex®) increases the CBD active metabolite (7-OH-
CBD) and produces a 3-fold increase in plasma concen-
trations of N-desmethylclobazam, (the active metabolite
of clobazam and a SUBSTRATE of CYP2C19), a reduc-
tion in dose of clobazam may need to be considered [28].
When CBD was coadministered with valproate, there was
no effect on valproate exposure; however, there is an in-
creased incidence of liver enzyme elevations with a rec-
ommendation to discontinue either agent or reduce the
dose of either agent [28]. Additionally, the PI states that
there is insufficient data to assess the risk of concomitant
administration of other hepatotoxic medications and
CBD (Epidiolex®) [28].
Kocis/Vrana
Med Cannabis Cannabinoids 2020;3:61–73
68
DOI: 10.1159/000507998
Nabiximols 1:1 ∆9-THC and CBD (Sativex®)
As described in the SmPC, nabiximols (Sativex®) is a
reversible INHIBITOR of CYP3A4, CYP1A2, CYP2B6,
CYP2C9, and CYP2C19 at concentrations far in excess of
those likely to be achieved clinically [29]. In vitro, nabix-
imols has potential for time-dependent INHIBITION of
CYP3A4 at clinically relevant concentrations. The co-
administration of nabiximols with other CYP3A4 SUB-
STRATES with an NTI may result in an increase in the
effect of the concomitant drug [29]. Nabiximols was also
found to INHIBIT UGT1A9 and UGT2B7 at concentra-
tions that could be achieved in clinic. Care should be tak-
en when prescribing nabiximols with concomitant medi-
cations solely metabolized by both or either of these UGT
enzymes (e.g., propofol and certain antivirals). The ∆9-
THC and CBD plasma concentration from clinical doses
of nabiximols could be sufficient to INDUCE CYP1A2,
CYP2B6, and CYP3A4 at the mRNA level, so a review of
the dosing regimen of these medications listed in Table2
is advised. Additionally, nabiximols can INDUCE the
metabolism of hormonal contraceptives.
With nabiximols (Sativex®) containing approximately
50% v/v of ethanol, each actuation contains up to 0.04 g
of ethanol. The PI states that a small glass of wine (125
mL) contains 12% v/v and, thus, contains 12 g of ethanol
[29]. Therefore, most patients taking up to 12 sprays/day
would ingest <0.5 g of ethanol, and thus, this amount of
ethanol is NOT expected to produce a disulfiram-like re-
action that is possible with the dronabinol (Syndros®)
alcohol-containing formulation [29].
Cannabinoid Drug-Drug Interactions
Drug-drug interactions, associated with cannabinoid-
containing products, should not be simply limited to the
additional dizziness, confusion, sedation, and somno-
lence when taken concomitantly with alcohol or other
central nervous system-sedating medications (e.g., ben-
zodiazepines, muscle relaxants, barbiturates). Addition-
ally, there can be additive cardiac side effects (e.g., hypo-
tension, hypertension, syncope, and tachycardia) when
taken with other medications having similar cardiovascu-
lar adverse events.
The cannabinoid frequency of use, route of adminis-
tration, gastrointestinal absorption, hepatic metabolism,
renal excretion, and a patient’s genomic profile can all
influence the cannabinoid metabolism and influence the
extent of a drug-drug interaction and any resulting ad-
verse events. If a potential drug-drug interaction is identi-
fied, it does not necessarily translate into a contraindi-
cated combination nor a clinically significant interaction,
but an opportunity to evaluate the dose of either the can-
nabinoid or concomitantly PI.
Clinically relevant drug-drug interactions will gener-
ally arise when a cannabinoid INHIBITS, INDUCES, or
serves as a competing SUBSTRATE for a metabolic en-
zyme of an OTC, herbal, or prescription medication.
Conversely, metabolism of the cannabinoid-containing
medications can be affected by OTHER medications.
These drug-drug interactions can be quite complicated
when they involve a number of medications, their corre-
sponding metabolizing enzymes, and use within the med-
Table 5. Cannabinoid medication (as the PRECIPITANT) affect-
ing the metabolic enzyme levels/activity/drug effect of substrate
medications (OBJECT) with a Narrow Therapeutic Index (NTI)
Cannabinoid
(as PRECIPI-
TANT)
Affects the metabolism of the following
SUBSTRATES with a Narrow Therapeutic
Index (NTI)
Dronabinol
(Marinol® and
Syndros®)
CYP2C9 SUBSTRATES
CYP3A4 SUBSTRATES
Nabilone
(Cesamet®)Nabilone is a (WEAK) INHIBITOR
CYP2E1 SUBSTRATES
CYP3A4 SUBSTRATES
Nabilone is a (MODERATE) INHIBITOR
CYP2C8 SUBSTRATES
CYP2C9 SUBSTRATES
CBD
(Epidiolex®)CBD INHIBITS and INDUCES
CYP1A2 SUBSTRATES
CYP2B6 SUBSTRATES
CBD INHIBITS
CYP2C8 SUBSTRATES
CYP2C9 SUBSTRATES
CYP2C19 SENSITIVE SUBSTRATES
UGT1A9 SUBSTRATES
UGT2B7 SUBSTRATES
Nabiximols
(Sativex®)Nabiximols INHIBITS
CYP2C8 SUBSTRATESa
CYP3A4 SUBSTRATES
UGT1A9 SUBSTRATES
UGT2B7 SUBSTRATES
Nabiximols INDUCES
CYP1A2 SUBSTRATES
CYP2B6 SUBSTRATES
CYP3A4 SUBSTRATES
CBD, cannabidiol; PI, prescribing information. aListed in the
CBD (Epidiolex®) PI.
THC and CBD Drug-Drug Interactions
69
Med Cannabis Cannabinoids 2020;3:61–73
DOI: 10.1159/000507998
ically complex patient population (e.g., oncology, AIDS,
epilepsy, and geriatric). In addition to the drug-drug in-
teractions involving OTC, herbal, and prescription med-
ications, there can be DIETARY-drug interactions such
as when grapefruit INHIBITS the metabolism of another
medication by the CYP3A4 enzyme. There is potential
HERBAL-drug interaction when St. John’s Wort IN-
DUCES the metabolism of another medication by the
CYP3A4 enzyme [38, 39]. Additionally, herbal supple-
ments (e.g., Black Cohosh and Echinacea) are sometimes
paired with cannabis. Unfortunately, these added herbal
supplements themselves also have known drug-drug in-
teractions [40].
Cannabinoid (as PRECIPITANT) Affecting Metabolism
of OTHER Medications
The online supplementary material provides a list of
139 medications that could have a potential drug-drug in-
teraction with a cannabinoid (prescription, OTC, or illicit)
(see www.karger.com/doi/10.1159/000507998 for all on-
line suppl. material). Figure 2 provides a detailed illustra-
tion of this online supplementary material. These medica-
tions are presented in alphabetical order and primarily
identify the cannabinoid as a PRECIPITANT medication
that either INHIBITS, INDUCES, or competes as a SUB-
STRATE for a specific enzyme/receptor of an OBJECT
medication. Colors, directional arrows, and capitalization
are all utilized to provide visual cues to identify the type of
drug-drug interaction. Additionally, the source and date of
this information are provided.
Although two or more medications may compete for
the same enzyme, this may not be clinically significant
when a medication has a broad therapeutic concentration
range and with minor fluctuations having minimal clini-
cal impact. Therefore, in an effort to reduce any potential
false alerts, alert fatigue, and to provide a manageable
drug-drug interaction list, the medications that only have
an NTI are highlighted in this report.
The supplementary material list can be viewed online
at the Penn State College of Medicine, Department of
Pharmacology website. It is anticipated that as new med-
ications are approved and evidence provided for ob-
served/replicated cannabinoid drug-drug interactions,
one of the goals of this project was to create a single list
that is periodically updated.
This list is further categorized by the PRECIPITANT
medications (dronabinol, nabilone, CBD, and nabixi-
mols), the cannabinoid class (THC/CBD) that it belongs
to, as well as illustrating a potential increase (↑) and/or
decrease (↓) of the drug effect of the OBJECT medication.
It is interesting to note that, for several OBJECT med-
ications (e.g., acenocoumarol), there is the potential to
increase (↑) and/or decrease (↓) drug effects based on a
number of different metabolic enzymes and the fact that
the PRECIPITANT may INHIBIT but also INDUCE
expression of enzyme activity (e.g., CYP1A2, CYP2C9,
CYP2C19, and CYP3A4). The check mark “√” identifies
whether the PRECIPITANT is an INHIBITOR or IN-
DUCER of a specific metabolizing enzyme.
The FDA Center for Drug Evaluation and Research
(CDER) draft guidance document titled “Clinical Drug
Interaction Studies - Study Design, Data Analysis, and
Clinical Implications Guidance for Industry” describes a
WEAK INHIBITOR “√ (Weak)” as “a drug that increases
(↑) the Area Under the Curve (AUC) of a sensitive index
SUBSTRATE of a given metabolic pathway by ≥1.25-fold
to <2-fold.” The MODERATE INHIBITOR “√ (Mod)” is
defined by the FDA as a “drug that increases (↑) the AUC
of a sensitive index SUBSTRATE of a given metabolic
pathway by ≥2-fold to <5-fold.” [41]. Finally, the source
of the drug-drug interaction information (e.g., PI, FDA.
gov, and DrugBank.ca) and date are provided.
Medical Marijuana, Unregulated CBD Oil, and
Recreational Marijuana
Prior discussions within this article have been predi-
cated on information gathered from regulatory agency
approved cannabinoid manufacturer PI, supplemented
with the FDA “Drug Development and Drug Interac-
tions: Table of Substrates, Inhibitors and Inducers” on-
line document [22] and the DrugBank database [23].
While these drug-drug interactions are important for the
relatively small patient populations for which the drugs
are intended, perhaps the broader importance is derived
from the recent deregulation of CBD oil (hemp oil) and
the steady increase in states and countries legalizing rec-
reational and medical marijuana.
The use of medical marijuana (whether smoked or in
extracts), CBD oil, or recreational marijuana can deliver
a highly variable cannabinoid concentration. As has been
seen in Colorado, there has been a concerted effort to in-
crease the ∆9-THC content of recreational marijuana
[42]. While typical Marinol® (∆9-THC) prescriptions are
dispensed as 2.5 mg, 5 mg, or 10 mg capsules, recreation-
al marijuana will provide cannabinoids at concentrations
10- to 100-fold higher; therefore, potential drug-drug in-
Kocis/Vrana
Med Cannabis Cannabinoids 2020;3:61–73
70
DOI: 10.1159/000507998
teractions will be exacerbated. Patients may be less likely
to accurately report their recreational marijuana frequen-
cy and amount of use. Therefore, it is incumbent on the
healthcare provider to inquire as to this use. For example,
screening for use of cannabinoid-containing products is
now advocated for select cardiovascular patient popula-
tions [43]. Finally, plant-derived products may contain
myriad other compounds (e.g., cannabinoids, flavonoids,
and terpenes) that may increase the risk of unintended
drug-drug interactions.
Limitations
While every attempt has been made to provide the most
up-to-date and comprehensive list of drug-drug interac-
tions, there may be OTC, herbal, and prescription medica-
tions that are not included within this publication or online
supplementary material. Except for selected instances, the
medications contained in these lists do not describe their
active metabolites and associated metabolizing enzymes.
The source of data may, at times, be inherently outdated
due to the publication date or revision date of the sourced
information (e.g., PI). When compiling this list of drug-
drug interactions, tables within the FDA “Drug Develop-
Cannabinoid (PRECIPITANT) the Metabolism of Another (OBJECT)
Pennsylvania State University, of Medicine, Dept of (Hershey, PA)
Generic Name Medica�on
(OBJECT)
Drug Effect
(OBJECT)
Cannabinoid
Class
(PRECIPITANT)
Cannabinoid as the
(PRECIPITANT)
Enzyme
Inhibitor
Enzyme
Inducer Enzyme/Metabolism CYP1A2 CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2E1 CYP3A4 UGT1A9 UGT2B7 Source Source
Date
(VKA) CBD Cannabidiolol CYP1A2 a
(VKA) CBD Cannabidiolol CYP2C19 a
(VKA) CBD Cannabidiolol CYP2C9 a
(VKA) THC Dronabinol CYP2C9 a
(VKA) THC Dronabinol or Nabilone 4A3PYC)aeW( a
(VKA) THC Nabilone 9C2PYC)doM( a
(VKA) D Nabiximols CYP1A2 a
(VKA) D Nabiximols CYP3A4 a
alfentanil THC Dronabinol or Nabilone A3PYC)aeW( (Table 3-1) v
alfentanil THC Dronabinol or Nabilone 4A3PYC)aeW( a
alfentanil D Nabiximols CYP3A (Table 3-1) v
alfentanil D Nabiximols CYP3A4 a
alosetron CBD Cannabidiolol CYP1A2 (Table 3-1) v
alosetron D Nabiximols CYP1A2 (Table 3-1) v
alprazolam THC Dronabinol or Nabilone ) CYP3A Moderate (Table 3-1) v
alprazolam THC Dronabinol or Nabilone 4A3PYC)aeW( a
alprazolam D Nabiximols CYP3A Moderate (Table 3-1) v
alprazolam D Nabiximols CYP3A4 a
aminophylline CBD Cannabidiolol CYP1A2 a
aminophylline THC Dronabinol or Nabilone 4A3PYC)aeW( a
aminophylline D Nabiximols CYP1A2 a
aminophylline D Nabiximols CYP3A4 a
amiodarone CBD Cannabidiolol CYP1A2 a
amiodarone CBD Cannabidiolol CYP2C19 a
amiodarone CBD Cannabidiolol CYP2C8 a
amiodarone THC Dronabinol or Nabilone 4A3PYC)aeW( a
amiodarone THC Nabilone 8C2PYC)doM( a
amiodarone D Nabiximols CYP1A2 a
amiodarone D Nabiximols CYP3A4 a
amitriptyline CBD Cannabidiolol CYP1A2 a
amitriptyline CBD Cannabidiolol CYP2B6 a
amitriptyline CBD Cannabidiolol CYP2C19 a
amitriptyline THC Dronabinol or Nabilone 4A3PYC)aeW( a
amitriptyline D Nabiximols CYP1A2 a
amitriptyline D Nabiximols CYP2B6 a
amitriptyline D Nabiximols CYP3A4 a
amphotericin B nietorPlonibanorDCHT (LexiCom
p
® Clinical Info) m
aprepitant THC Dronabinol or Nabilone ) CYP3A Moderate (Table 3-1) v
aprepitant THC Dronabinol or Nabilone 4A3PYC)aeW( a
aprepitant D Nabiximols CYP3A Moderate (Table 3-1) v
aprepitant D Nabiximols CYP3A4 a
THC Dronabinol or Nabilone 4A3PYC)aeW( a
D Nabiximols CYP3A4 a
astemizole THC Dronabinol or Nabilone 4A3PYC)aeW( a
astemizole D Nabiximols CYP3A4 a
THC Dronabinol or Nabilone ) CYP3A Moderate (Table 3-1) v
D Nabiximols CYP3A Moderate (Table 3-1) v
THC Dronabinol or Nabilone A3PYC)aeW( (Table 3-1) v
THC Dronabinol or Nabilone 4A3PYC)aeW( a
D Nabiximols CYP3A (Table 3-1) v
D Nabiximols CYP3A4 a
THC Dronabinol or Nabilone 4A3PYC)aeW( a
D Nabiximols CYP3A4 a
e
THC Dronabinol or Nabilone A3PYC)aeW( (Table 3-1) v
e
THC Dronabinol or Nabilone 4A3PYC)aeW( a
e
D Nabiximols CYP3A (Table 3-1) v
e
D Nabiximols CYP3A4 a
CBD Cannabidiolol CYP2B6 (Table 3-1) v
THC Dronabinol or Nabilone A3PYC)aeW( (Table 3-1) v
THC Dronabinol or Nabilone 4A3PYC)aeW( a
D Nabiximols CYP3A (Table 3-1) v
D Nabiximols CYP3A4 a
THC Dronabinol or Nabilone 4A3PYC)aeW( a
D Nabiximols CYP3A4 a
CBD Cannabidiolol CYP1A2 Index (Table 2-1) v
CBD Cannabidiolol CYP1A2 (Table 3-1) v
D Nabiximols CYP1A2 Index (Table 2-1) v
D Nabiximols CYP1A2 (Table 3-1) v
carbamazepin
e
CBD Cannabidiolol CYP1A2 a
carbamazepin
e
CBD Cannabidiolol UGT2B7 a
carbamazepin
e
THC Dronabinol or Nabilone 4A3PYC)aeW( a
While every has been made to provide the most comprehensive list of -
there may be OTC, herbal, and not within this
List Updated April 13, 2020
1 of 7
Fig. 2. Cannabinoid (PRECIPITANT) Medication Affecting the Metabolism of Another (OBJECT) Medication
(see www.karger.com/doi/10.1159/000507998).
THC and CBD Drug-Drug Interactions
71
Med Cannabis Cannabinoids 2020;3:61–73
DOI: 10.1159/000507998
ment and Drug Interactions: Table of Substrates, Inhibi-
tors and Inducers,” online document [22] were last updat-
ed on September 26, 2016 and other tables updated on
December 3rd, 2019. The DrugBank database [23], which
is updated frequently, was last accessed between Novem-
ber 2019 and February 2020. At times, the format of the
∆9-THC and CBD cannabinoid PI varied; therefore, the
drug-drug interaction information was at times challeng-
ing to compare and contrast. The pharmaceutical canna-
binoid manufacturer did not, at times, undertake formal
drug-drug interaction studies and report only general and
nonspecific case reports (e.g., marijuana smoking).
Discussion
Although the focus of this article was to identify and
describe specific ∆9-THC and CBD cannabinoid drug-
drug interactions, there are physiologic effects that can be
attributed to cannabinoid use that may impact the cardio-
vascular, cerebrovascular, respiratory, temperature, and
coagulation systems for the hospitalized and surgical pa-
tients [44]. The patient’s current use of cannabinoids
(whether it be prescription, OTC, and/or illicit) should be
taken into consideration when medically managing a pa-
tient during a hospital stay or when selecting a medica-
tion to treat pain, nausea, and/or vomiting in the outpa-
tient setting [45, 46]. The withdrawal of a cannabinoid
(more specific to heavy recreational cannabis use) may
precipitate the cannabis withdrawal syndrome [44]. In
addition, there have been reports of patients who regu-
larly use recreational cannabis and then require higher
doses of propofol for sedation [47].
There have been various published case reports and
journal articles listing P-gp [48], oncology [17, 49], psycho-
tropic [16], transplant [20, 50], and other miscellaneous
lists of cannabinoid drug-drug interactions [21]. Currently,
there is not a comprehensive list of medications that is
closely aligned with the cannabinoid manufacturer regula-
tory agency approved PI. Enzyme SUBSTRATES that have
an NTI were included in these drug-drug interaction lists
to reduce any potential false alerts, alert fatigue, and to pro-
vide a manageable list of the more clinically significant
drug-drug interactions. DrugBank was used to identify
SUBSTRATES with an NTI. These lists of potential drug-
drug interactions include medications that are metabolized
by the cytochrome P450 enzymes, the UGT enzymes and
those that compete as metabolism SUBSTRATES with
medications that have an NTI. Additionally, other potential
drug-drug interactions are the result of those highly pro-
tein-bound medications, those metabolized by the CYP1A2
enzyme SUBSTRATE, and further INDUCED by smoking.
Conclusions
With a paucity of formal drug-drug interaction studies,
especially in medically complex patient populations (e.g.,
oncology, HIV, epilepsy, and geriatric), these detailed lists
of cannabinoid prescription drug-drug interactions are
meant to provide a readily accessible resource for evaluat-
ing the use of prescription cannabinoids, as well as OTC
and/or illicit or unregulated ∆9-THC and CBD cannabi-
noid products. While the online supplementary material
contains a comprehensive and detailed list of drug-drug in-
teractions, Table2 provides a concise list of 57 medications,
with an NTI, that should be considered in patients taking
prescription cannabinoids and/or therapeutic/recreational
marijuana. While developing these drug-drug interaction
data tables, it was evident there can be multiple drug-drug
interactions as the result of the many possible combination
of medications and their corresponding metabolizing en-
zymes. Table2 provides a starting point for consideration.
This comprehensive drug-drug interaction list is in-
tended to provide a reference when reviewing a patient’s
medication regimen containing OTC, herbal, and pre-
scription medications and, perhaps, also factoring in the
illicit or unregulated use of cannabinoid-containing prod-
ucts. These lists of potential drug-drug interactions are
NOT intended to be a substitute for medical decision
making, since individual patient characteristics (e.g., gen-
der, age, genomic profile, ethnicity, hepatic function, re-
nal function, and disease state) need to be considered. The
specific drug-drug interaction information that is provid-
ed in this article and supplementary material is also host-
ed online at the Pennsylvania State University, College of
Medicine, Department of Pharmacology Web site via the
following URL: https://sites.psu.edu/cannabinoid.
Acknowledgement
Our sincere appreciation for the feedback received from the
Pharmacists of the Medical Marijuana Advisory Workgroup prac-
ticing in the Commonwealth of Pennsylvania.
Disclosure Statement
None by P.T.K. K.E.V. receives a sponsored research agree-
ment from PA Options for Wellness (a medical marijuana com-
pany in the Commonwealth of Pennsylvania).
Kocis/Vrana
Med Cannabis Cannabinoids 2020;3:61–73
72
DOI: 10.1159/000507998
Funding Sources
This work was supported, in part, by a sponsored research
agreement (to KEV) from PA Options for Wellness (Harrisburg,
PA, USA).
Author Contributions
P.T.K. and K.E.V. both contributed equally to the conception,
design, acquisition of data, analysis, and the interpretation of the
data. Additionally, P.T.K. and K.E.V. contributed equally to the
drafting and revision of the journal article for its intellectual con-
tent.
Disclaimer
While every attempt has been made to provide the most up-to-
date and comprehensive list of drug-drug interactions, there may
be OTC, herbal, illicit, and prescription medications that are not
included. This list of potential drug-drug interactions is intended
to provide a reference when reviewing a patient’s medication reg-
imen containing OTC, herbal, and prescription medications and,
perhaps, also factoring in the illicit or unregulated use of cannabi-
noid-containing products. These potential drug-drug interactions
are NOT intended to be a substitute for medical decision-making,
since all individual patient characteristics (e.g., gender, age, ge-
nomic profile, ethnicity, hepatic function, renal function, and dis-
ease state) need to be considered.
References
1 Fraguas-Sánchez AI, Torres-Suárez AI. Med-
ical use of cannabinoids. Drugs. 2018; 78(16):
1665–703.
2 ElSohly M, Gul W. Constituents of Cannabis
sativa. Handb Cannabis. 2014; 3:1093.
3 Radwan MM, Wanas AS, Chandra S, ElSohly
MA. Natural cannabinoids of cannabis and
methods of analysis. In: Cannabis sativa L –
botany and biotechnology. Springer; 2017.
p. 161–82.
4 Corroon J, Phillips JA. A cross-sectional study
of cannabidiol users. Cannabis Cannabinoid
Res. 2018; 3(1):152–61.
5 Gaoni Y, Mechoulam R. Isolation, structure,
and partial synthesis of an active constituent of
hashish. J Am Chem Soc. 1964; 86(8):1646–7.
6 National Academies of Sciences, Engineering,
and Medicine. The health effects of cannabis
and cannabinoids: the current state of evi-
dence and recommendations for research.
National Academies Press; 2017.
7 Dai H, Richter KP. A national survey of mar-
ijuana use among US adults with medical con-
ditions, 2016–2017. JAMA Netw Open. 2019;
2(9):e1911936.
8 Hudak J. The Farm Bill, Hemp Legalization
and the Status of CBD: An explainer. The
Brookings Institution [cited 2018 Dec 14].
Available from: https://www.brookings.edu/
blog/fixgov/2018/12/14/the-farm-bill-hemp-
and-cbd-explainer/.
9 FDA warns 15 companies for illegally selling
various products containing cannabidiol as
agency details safety concerns. U.S. Food &
Drug Administration (FDA) [cited 2019 Nov
25]. Available from: https://www.fda.gov/news-
events/press-announcements/fda-warns-
15-companies-illegally-selling-various-prod-
ucts-containing-cannabidiol-agency-details.
10 Fasinu PS, Phillips S, ElSohly MA, Walker LA.
Current status and prospects for cannabidiol
preparations as new therapeutic agents. Phar-
macotherapy. 2016; 36(7):781–96.
11 Medical Cannabis: Adverse Effects & Drug In-
teractions. Government of The District of Co-
lumbia, Department of Health. Available
from: https://doh.dc.gov/sites/default/files/
dc/sites/doh/publication/attachments/Medi-
calCannabisAdverseEffectsandDrugInterac-
tions_0.pdf.
12 ElSohly MA, Mehmedic Z, Foster S, Gon C,
Chandra S, Church JC. Changes in cannabis
potency over the last 2 decades (1995–2014):
analysis of current data in the United States.
Biol Psychiatry. 2016; 79(7):613–9.
13 McPartland JM, Blanchon DJ, Musty RE.
Cannabimimetic effects modulated by cho-
linergic compounds. Addict Biol. 2008; 13(3–
4):411–5.
14 Bonn-Miller MO, Loflin MJE, Thomas BF,
Marcu JP, Hyke T, Vandrey R. Labeling ac-
curacy of cannabidiol extracts sold online.
JAMA. 2017; 318(17):1708–9.
15 Keyhani S, Steigerwald S, Ishida J, Vali M,
Cerdá M, Hasin D, et al. Risks and benefits of
marijuana use: a national survey of U.S.
adults. Ann Intern Med. 2018; 169(5):282–90.
16 Rong C, Carmona NE, Lee YL, Ragguett RM,
Pan Z, Rosenblat JD, et al. Drug-drug interac-
tions as a result of co-administering Δ. Expert
Opin Drug Saf. 2018; 17(1):51–4.
17 Alsherbiny MA, Li CG. Medicinal cannabis-
potential drug interactions. Medicines. 2018;
6(1):3.
18 Brown J, Winterstein A. Clinical medicine
potential adverse drug events and drug-drug
interactions with medical and consumer can-
nabidiol (CBD) use. J Clin Med. 2019; 8:989.
19 Srinivas M, Thirumaleswara G, Pratima S. Cy-
tochrome P450 enzymes, drug transporters and
their role in pharmacokinetic drug-drug inter-
actions of xenobiotics: a comprehensive review.
Peertechz J Med Chem Res. 2017; 3:1–11.
20 Hauser N, Sahai T, Richards R, Roberts T.
High on cannabis and calcineurin inhibitors:
a word of warning in an era of legalized mari-
juana. Case Rep Transplant. 2016; 2016:1–3.
21 Stout SM, Cimino NM. Exogenous cannabi-
noids as substrates, inhibitors, and inducers
of human drug metabolizing enzymes: a sys-
tematic review. Drug Metab Rev. 2014; 46(1):
86–95.
22 Drug Development and Drug Interactions:
Table of Substrates, Inhibitors and Inducers.
U.S. Food & Drug Administration (FDA)
[cited 2017 Nov 14]. Available from: https://
www.fda.gov/drugs/drug-interactions-label-
ing/drug-development-and-drug-interac-
tions-table-substrates-inhibitors-and-induc-
ers.
23 Wishart DS, Feunang YD, Guo AC, Lo EJ,
Marcu A, Grant JR, et al. DrugBank 5.0: a ma-
jor update to the DrugBank database for 2018.
Nucleic Acids Res. 2018; 46(D1):D1074–D82.
24 Dronabinol (Marinol®). Full Prescribing In-
formation [cited 2017 Aug]. Available from:
https://www.rxabbvie.com/pdf/marinol_
PI.pdf.
25 Dronabinol (Syndros®). Full Prescribing In-
formation [cited 2018 Sep]. Available from:
http://syndros.com/wp-content/up-
loads/2019/06/SYNDROS-label.pdf.
26 Nabilone (Cesamet®). Drug Label Informa-
tion: DailyMed. U.S. National Library of
Medicine [cited 2015 May 7]. Available from:
https://dailymed.nlm.nih.gov/dailymed/dru-
gInfo.cfm?setid=bb582d64-0f51-11df-8a39-
0800200c9a66.
27 Letter (Data on File: VV-MED-04647). Carls-
bad, CA: Greenwich Biosciences. Cannabidi-
ol (Epidiolex®).
28 Cannabidiol (Epidiolex®). Full Prescribing
Information [cited 2018 Dec]. Available from:
https://www.epidiolex.com/sites/default/
files/EPIDIOLEX_Full_Prescribing_Infor-
mation.pdf.
29 Sativex Oromucosal Spray. Summary of Prod-
uct Characteristics (SmPC). GW Pharma Ltd
[cited 2019 Sep 3]. Date of Revision of Text
2019 Apr 27. Available from: https://www.
medicines.org.uk/emc/product/602/smpc.
30 Nabiximols - DrugBank. The Canadian In-
stitutes of Health Research, Alberta Inno-
vates-Health Solutions, and The Metabolo-
mics Innovation Centre (TMIC) [updated
Version 5.1.4, Released 2019 Feb 7]. Avail-
able from: https://www.drugbank.ca/drugs/
DB14011.
THC and CBD Drug-Drug Interactions
73
Med Cannabis Cannabinoids 2020;3:61–73
DOI: 10.1159/000507998
31 Nabiximols ClinicalTrials.gov. U.S. National
Library of Medicine. Available from: https://
clinicaltrials.gov/ct2/results?cond=&
term=nabiximols& cntry=US& state=&
city=& dist=.
32 Rowland A, Miners JO, Mackenzie PI. The
UDP-glucuronosyltransferases: their role in
drug metabolism and detoxification. Int J
Biochem Cell Biol. 2013; 45(6):1121–32.
33 Kiang TK, Ensom MH, Chang TK. UDP-
glucuronosyltransferases and clinical drug-
drug interactions. Pharmacol Therapeut.
2005; 106(1):97–132.
34 Scheife RT. Protein binding: what does it
mean? DICP. 1989; 23(7–8):S27–31.
35 Zevin S, Benowitz NL. Drug interactions with
tobacco smoking. An update. Clin Pharmaco-
kinet. 1999; 36(6):425–38.
36 Dobrinas M, Cornuz J, Pedrido L, Eap CB. In-
fluence of cytochrome P450 oxidoreductase
genetic polymorphisms on CYP1A2 activity
and inducibility by smoking. Pharmacogenet
Genomics. 2012; 22(2):143–51.
37 Zhou S-F, Wang B, Yang L-P, Liu J-P. Struc-
ture, function, regulation and polymorphism
and the clinical significance of human cyto-
chrome P450 1A2. Drug Metab Rev. 2010;
42(2):268–354.
38 Kiani J, Imam SZ. Medicinal importance of
grapefruit juice and its interaction with vari-
ous drugs. Nutr J. 2007; 6:33.
39 Markowitz JS, Donovan JL, DeVane CL, Tay-
lor RM, Ruan Y, Wang J-S, et al. Effect of St
John’s wort on drug metabolism by induction
of cytochrome P450 3A4 enzyme. JAMA.
2003; 290(11):1500–4.
40 7 Medicinal Herbs to Pair With Cannabis:
Written by Anna Wilcox (Herb.co) [cited
2019 Aug 19]. Available from: https://herb.
co/learn/best-herbs-to-mix-with-weed/.
41 Clinical Drug Interaction Studies: Study De-
sign, Data Analysis, and Clinical Implica-
tions. Guidance for Industry (Draft Guidance
for Comment Purposes Only). U.S. Food &
Drug Administration (FDA) [cited 2018 Aug
24]. Available from: https://www.fda.gov/reg-
ulatory-information/search-fda-guidance-
documents/clinical-drug-interaction-stud-
ies-study-design-data-analysis-and-clinical-
implications-guidance.
42 Stuyt E. The problem with the current high
potency THC marijuana from the perspective
of an addiction psychiatrist. Mo Med. 2018;
115(6):482–6.
43 DeFilippis EM, Bajaj NS, Singh A, Malloy R,
Givertz MM, Blankstein R, et al. Marijuana
use in patients with cardiovascular disease:
JACC review topic of the week. J Am Coll Car-
diol. 2020; 75(3):320–32.
44 Echeverria-Villalobos M, Todeschini AB,
Stoicea N, Fiorda-Diaz J, Weaver T, Bergese
SD. Perioperative care of cannabis users: a
comprehensive review of pharmacological
and anesthetic considerations. J Clin Anesth.
2019; 57:41–9.
45 Beaulieu P, Boulanger A, Desroches J, Clark
AJ. Medical cannabis: considerations for the
anesthesiologist and pain physician. Can J
Anaesth. 2016; 63(5):608–24.
46 Bakshi C, Barrett AM. Impact of recreational
and medicinal marijuana on surgical patients:
a review. Am J Surg. 2019; 217(4):783–6.
47 Twardowski MA, Link MM, Twardowski
NM. Effects of cannabis use on sedation re-
quirements for endoscopic procedures. J Am
Osteopath Assoc. 2019; 119(5):307–11.
48 Zhu HJ, Wang JS, Markowitz JS, Donovan JL,
Gibson BB, Gefroh HA, et al. Characteriza-
tion of P-glycoprotein inhibition by major
cannabinoids from marijuana. J Pharmacol
Exp Ther. 2006; 317(2):850–7.
49 Bouquié R, Deslandes G, Mazaré H, Cogné M,
Mahé J, Grégoire M, et al. Cannabis and anti-
cancer drugs: societal usage and expected
pharmacological interactions: a review. Fun-
dam Clin Pharmacol. 2018; 32(5):462–84.
50 Motycka C, Egelund EF, Thomas C. The im-
pact of medical marijuana on pharmacy prac-
tice. Adv Pharmacol Pharm. 2018; 6(1):12–7.
Available via license: CC BY-NC-ND 4.0
Content may be subject to copyright.
