Introduction
Polypharmacy, defined as the use of 5 – 9 drugs [1], [2], and hyperpolypharmacy, defined as the use of 10 or more drugs, are common among
patients [3]. In this context, drug interactions are more prevalent and can lead to reduced efficacy
or adverse effects. These interactions can occur during both the pharmacokinetic and
pharmacodynamic phases, where drug absorption, distribution, metabolism, or excretion
may be altered, or where drugs influence each otherʼs receptor sites and biological
activity [4], [5], [6].
CBD (cannabidiol), a compound derived from Cannabis sativa L. (Cannabaceae), is known for its therapeutic effects, such as anticonvulsant and anti-inflammatory
properties [7]. However, it also has a high potential for drug interactions. CBD is primarily metabolized
by cytochrome P450 (CYP) enzymes, including CYP2C19 and CYP3A4, which convert CBD
into its active and inactive metabolites. Additionally, CBD inhibits CYP2C19, CYP3A4,
and other isoforms, leading to increased plasma concentrations of co-administered
drugs and potential adverse effects [6], [7], [8]. CBD has also been shown to inhibit drug transport via P-glycoprotein (P-gp), which
can impact the absorption and distribution of other drugs [9], [10].
Beyond pharmacokinetic interactions, CBD also interacts in the pharmacodynamic phase
by acting as a negative allosteric modulator of CB1 and CB2 receptors while increasing
the availability of endogenous cannabinoids [11]. These interactions may enhance or prolong drug effects and can result in synergistic,
additive, or antagonistic outcomes depending on the drugs involved [7].
Despite the increasing prescription of CBD, there is a lack of specific guidelines
for healthcare professionals regarding its interactions with other medications [12]. The potential for adverse events is particularly concerning in cases of polypharmacy
[13], [14].
This study aims to address the gap in knowledge by systematically mapping the current
literature on CBD drug interactions across different pharmacological classes. A key
focus is to provide practical insights for clinicians and pharmacologists, offering
a foundation to guide pharmaceutical care and mitigate risks associated with CBD use
in polypharmacy contexts.
Results and Discussion
From the search in the databases, we identified 3723 records. Of these, 136 were included
in the review. Complete information on included studies is summarized in the Open
Science Framework [15]. [Fig. 1] summarizes the study selection process, and Supplementary Material Fig. 2S describes the reason for excluding studies after full-text selection (n = 113).
Fig. 1 Study selection process.
Characteristics of the studies
[Table 1] outlines the characteristics of the studies included in this scoping review. Most
studies (91.91%) were published in the last 10 years, and only a few randomized clinical
trials were identified (n = 7; 5.15%). We identified 271 potential drug interactions,
with 203 occurring in the pharmacokinetic phase.
Table 1 General characteristics of the included studies (n = 136).
|
Characteristics
|
N
|
%
|
|
Year of publication
|
|
1973 – 2010
|
11
|
8.09
|
|
2011 – 2023
|
125
|
91.91
|
|
Type of study
|
|
Literature review
|
61
|
44.85
|
|
Pré-clinical studies
|
44
|
32.35
|
|
Non-randomized clinical studies
|
24
|
17.65
|
|
Randomized clinical trials
|
7
|
5.15
|
|
Potenzial drug interactions
|
|
Pharmacokinetics
|
203
|
74.91
|
|
Pharmacodynamics
|
68
|
25.09
|
Pharmacokinetic interactions
[Table 2] summarizes potential drug interactions between CBD and other drugs during the pharmacokinetic
phase, organized according to the ATC classification. Anticonvulsants (N03) represented
10.84% (n = 22) of the identified interactions, primarily due to CBDʼs inhibition
of CYP2C19 and CYP3A4, resulting in elevated plasma levels of clobazam and valproate.
While these interactions may enhance therapeutic efficacy, they also increase the
risk of sedation and hepatotoxicity. Additionally, although CYP2C19 and CYP3A4 are
the main enzymes involved in CBD metabolism, evidence suggests that other CYP isoforms,
such as CYP2C8, may also contribute [16].
Table 2 Drug interactions in the pharmacokinetic phase between CBD and other drugs (n = 203).
|
Therapeutic classes (ATC)
|
Pharmacokinetic drug interactions
N (%)
|
|
Anticonvulsants (N03)
|
22 (10.8)
|
|
Psychoanaleptics (N 06)
|
20 (9.8)
|
|
Antivirals for systemic use (J05)
|
16 (7.8)
|
|
Antineoplastic agents (L01)
|
15 (7.3)
|
|
Psycholeptics (N05)
|
15 (7.3)
|
|
Antibacterials for systemic use (J01)
|
12 (5.9)
|
|
Analgesics (N02)
|
10 (4.9)
|
|
Immunosuppressants (L04)
|
9 (4.4)
|
|
Antidiabetics (A10)
|
9 (4.4)
|
|
Lipid modifying agents (C10)
|
8 (3.9)
|
|
Drugs for acid-related disorders (A02)
|
7 (3.4)
|
|
Anti-inflammatory and Antirheumatic (M01)
|
7 (3.4)
|
|
Antimycotics for systemic use (J02)
|
6 (2.9)
|
|
Antithrombotic agents (B01)
|
4 (1.9)
|
|
Antimycobacterials (J04)
|
4 (1.9)
|
|
Agents that act on the renin-angiotensin system (C09)
|
3 (1.4)
|
|
Antiprotozoários (P01)
|
3 (1.4)
|
|
Calcium channel blockers (C08)
|
3 (1.4)
|
|
Corticosteroids for systemic use (H02)
|
3 (1.4)
|
|
Cardiac therapy (C01)
|
3 (1.4)
|
|
Hormone therapy (L02)
|
3 (1.4)
|
|
Antidiarrheals, intestinal anti-inflammatories/anti-infectives (A07)
|
2 (0.9)
|
|
Antihypertensives (C02)
|
2 (0.9)
|
|
Nervous system drugs – Others (N07)
|
2 (0.9)
|
|
Antitussive and anti-flu medications (R05)
|
2 (0.9)
|
|
Agentes beta bloqueadores (C07)
|
2 (0.9)
|
|
Drugs for obstructive airway diseases (R03)
|
2 (0.9)
|
|
General anesthetics (N01)
|
1 (0.4)
|
|
Antiemetics and Antinauseants (A04)
|
1 (0.4)
|
|
Antihistamine for systemic use (R06)
|
1 (0.4)
|
|
Sex hormones and modulators of the genital system (G03)
|
1 (0.4)
|
|
Other respiratory system products (R07)
|
1 (0.4)
|
|
Muscle relaxants (M03)
|
1 (0.4)
|
|
Diuretics (C03)
|
1 (0.4)
|
|
Thyroid therapy (H03)
|
1 (0.4)
|
|
Urological (G04)
|
1 (0.4)
|
Similarly, interactions commonly reported with antineoplastic agents (L01) are associated
with CBD-mediated inhibition of P-gp, leading to increased plasma concentrations of
substrates such as paclitaxel and vincristine, which may result in dose-limiting toxicities
(Supplementary Material Figs. 3S and 4S).
In addition to the interactions mediated by cytochrome P450 enzymes, CBD also influences
drug transport by inhibiting the breast cancer resistance protein (BCRP) and the bile
salt export pump (BSEP). Evidence suggests that the most abundant inactive metabolite
of CBD, 7-COOH-CBD, may inhibit these transporters [17].
Inhibition of BSEP by CBD may elevate the plasma concentrations of drugs such as carvedilol,
ketoconazole, digoxin, and others, thereby increasing the risk of toxicity. This is
especially concerning for drugs with a narrow therapeutic index, like digoxin and
paclitaxel. Conversely, inhibition of BCRP may enhance the tissue distribution and
reduce the efflux of drugs in excretory organs, potentially amplifying their therapeutic
effects but also increasing the risk of adverse reactions. These interactions underscore
the importance of careful monitoring of drug levels in patients using CBD, particularly
in polypharmacy settings, where the risk of clinically significant interactions is
elevated [1], [2], [3], [17].
These interactions highlight the importance of careful monitoring of drugs transported
by BCRP and BSEP in patients using CBD, particularly in polypharmacy settings where
the risk of clinically significant interactions is high (Supplementary Material Figs. 3S and 4S).
Pharmacodynamic interactions
Of the 68 drug interactions identified in the pharmacodynamic phase, antineoplastic
agents (L01) (n = 16; 23.53%) and anticonvulsants (N03) (n = 12; 17.65%) were the
most commonly reported in studies on potential drug interactions involving CBD ([Table 3]). CBD exhibited synergistic effects with drugs such as cisplatin, paclitaxel, and
doxorubicin, suggesting a potential role in enhancing the efficacy of chemotherapy.
Synergy with clobazam improved anticonvulsant efficacy by modulating GABA-A receptors,
although sedative effects were amplified (Supplementary Material Fig. 5S).
Table 3 Drug interactions in the pharmacodynamic phase between CBD and other drugs (n = 68).
|
Therapeutic classes (ATC)
|
Pharmacodynamics drug interactions
N(%)
|
|
Antineoplastic agents (L01)
|
16 (23.5)
|
|
Anticonvulsants (N03)
|
12 (17.65)
|
|
Immunosuppressants (L04)
|
5 (7.3)
|
|
Antivirals for systemic use (J05)
|
5 (7.3)
|
|
Psycholeptics (N05)
|
5 (7.3)
|
|
Psicoanalépticos (Antidepressivos) (N06)
|
4 (5.8)
|
|
Analgesics (N02)
|
4 (5.8)
|
|
Antibacterials for systemic use (J01)
|
4 (5.8)
|
|
Antiprotozoal Agents (P01)
|
3 (4.4)
|
|
Antithrombotic agents (B01)
|
2 (2.9)
|
|
Hormone therapy (L02)
|
2 (2.9)
|
|
Anesthetics (N01)
|
1 (1.4)
|
|
Antidiabetics (A10)
|
1 (1.4)
|
|
Antimycobacterials (J04)
|
1 (1.4)
|
|
Antimycotics for systemic use (J02)
|
1 (1.4)
|
|
Corticosteroids for systemic use (H02)
|
1 (1.4)
|
|
Nervous system drugs-Others (N07)
|
1 (1.4)
|
Main findings
This scoping review highlights numerous potential drug–drug interactions involving
CBD, derived primarily from preclinical evidence and literature reviews, with limited
support from primary clinical studies. While these findings shed light on the pharmacokinetic
and pharmacodynamic mechanisms underlying CBD interactions, they do not confirm causality
or clinical relevance. The complexities of polypharmacy in patients using CBD remain
insufficiently addressed, highlighting the urgent need for further research.
Managing CBD use in polypharmacy requires individualized strategies to mitigate risks
and improve therapeutic outcomes. Regular monitoring of plasma drug levels and liver
function is crucial, particularly for drugs metabolized by CYP450 and UGT enzymes.
Comparison with literature
Some of the observed interactions deserve special attention due to their frequency
in the literature. The class of anticonvulsants was the most frequently identified
in pharmacokinetic interactions and the second most frequent in pharmacodynamic interactions.
This can be explained by the historical use of cannabis for medicinal purposes in
treating seizures since 1800 B. C. Furthermore, the first pharmaceutical-grade CBD-based
medication for the treatment of refractory epilepsy was approved by the Food and Drug
Administration (FDA) in the United States in 2018 [18], [19].
Among the pharmacokinetic interactions found, those involving the absorption phase
were represented by interactions with P-gp, BCRP, and BSEP. Zhu et al. (2006) showed
that CBD significantly inhibits P-gp-mediated drug transport, suggesting that CBD
could potentially influence the absorption and disposition of other co-administered
compounds that are P-gp substrates [19], as observed in this review: atorvastatin, azithromycin, dabigatran, dasatinib,
desipramine, digoxin, doxorubicin, irinotecan, loperamide, lopinavir/ritonavir, methotrexate,
paclitaxel, sofosbuvir, tiagabine, topiramate, and vincristine.
Regarding BCRP and BSEP, interactions involve CBDʼs inactive and most abundant metabolite,
7-COOH-CB. The registered substrates of BSEP susceptible to this interaction include
carvedilol, ketoconazole, digoxin, glibenclamide, paclitaxel, rosiglitazone, simvastatin,
and telmisartan. The BCRP substrates identified were cyclophosphamide, cimetidine,
darunavir/cobicistat, dasatinib, dexamethasone, BCRP dipyridamole, glibenclamide,
imatinib, lopinavir/ritonavir, methotrexate, mitoxantrone, nelfinavir, nitrofurantoin,
paclitaxel, prazosin, sofosbuvir, sulfasalazine, and topotecan [20].
In the distribution stage, interactions were observed due to CBD binding to plasma
proteins. This type of interaction occurred with the drugs darunavir/cobicistat, dexamethasone,
lopinavir/ritonavir, nelfinavir, nitazoxanide, and umifenovir, which competed with
CBD for the protein and displaced it, increasing its plasma concentration.
Most drug interactions in the pharmacokinetic phase occur during the metabolization
stage. In this scoping review, we observed that almost all possible interactions involved
mechanisms related to CYP enzyme interactions. This is because, in addition to being
a substrate for CYP2C19 and CYP3A4, CBD can also inhibit these enzymes, as well as
other isoforms of the CYP450 family [21]. Therefore, CBD is subject to interactions with all drugs that are metabolized by
these enzymes, which may result in either an increase or decrease in their plasma
concentration.
While we have highlighted the main pharmacokinetic and pharmacodynamic interactions
involving CBD, a detailed examination of molecular mechanisms, particularly those
modulating cytochrome P450 enzymes, is essential for a more comprehensive understanding
of how CBD affects drug metabolism. CBD acts as a significant modulator of CYP450
enzymes, exerting inhibitory and, in some cases, inductive effects, depending on the
dose and clinical context. Recent studies suggest that CBD selectively inhibits CYP2C19
and CYP3A4 through competitive binding mechanisms, altering the metabolism of drugs
that are substrates for these enzymes and potentially increasing their activity and
plasma concentrations [22], [23], [24], [25]. Moreover, the interaction between CBD and CYP450 is not limited to direct inhibition
but also involves changes in the gene expression of these
enzymes, influenced by intracellular signaling pathways such as the pregnane X receptor
(PXR) and the constitutive androstane receptor (CAR), which are activated by lipophilic
compounds like CBD [26]. This transcriptional regulation is crucial for understanding interindividual variations
in responses to CBD, particularly in polypharmacy scenarios. Therefore, an in-depth
exploration of these molecular mechanisms will provide valuable insights into the
drug interactions of CBD and their clinical implications, allowing for the optimization
of therapy and mitigation of associated risks when used concomitantly with other drugs
metabolized by the CYP450 system.
Among the drug interactions identified in this review, the interaction between CBD
and clobazam has been extensively studied, with clinical evidence supporting its statistical
and clinical significance. Randomized clinical trials have demonstrated that CBD inhibits
CYP2C19 and CYP3A4, leading to increased serum levels of clobazam and its active metabolite,
N-desmethyl clobazam (N-CLB), which enhances its anticonvulsant and sedative effects
[27], [28], [29], [30], [31]. Therefore, it is recommended to monitor clobazam and N-CLB levels during treatment,
and dose adjustments may be necessary before initiating therapy in combination with
CBD [17], [27].
Furthermore, CBD also interacts with uridine diphosphate-glucuronosyltransferase (UGT)
enzymes, which are involved in phase II glucuronidation reactions, as observed in
this review. CBD is a potent inhibitor of UGT1A9, UGT2B4, and UGT2B7 [24], [32]. In this review, we identified that valproic acid, canagliflozin, dabigatran, dapagliflozin,
diflunisal, fenofibrate, haloperidol, ibuprofen, irinotecan, mycophenolate, paracetamol,
propofol, regorafenib, and sorafenib are substrates of UGT1A9 [24], [33]. Codeine is a substrate of UGT2B4. Valproic acid [34], azithromycin, carbamazepine, ezetimibe, gemfibrozil, hydromorphone, ibuprofen,
lamotrigine [25], [34], lorazepam, losartan, lovastatin, morphine, oxycodone, and oxymorphone are substrates
of UGT2B7 [13]. Therefore, the concomitant use of CBD with these drugs may prevent the formation
of more water-soluble, pharmacologically inactive metabolites, potentially increasing
both the therapeutic effect and adverse effects.
Among the pharmacodynamic interactions identified in this review, we observed a synergistic
effect between CBD and the following drugs: bortezomib, carfilzomib, carmustine, cyclophosphamide,
clobazam [31], desipramine, sertraline [35], docetaxel, doxorubicin [36], morphine [37], paclitaxel, panobinostat, polymyxin B, tamoxifen, temozolomide, and vinorelbine
[38]. This type of interaction can be beneficial, as the prescriber can reduce the dose
of the drug when used in conjunction with CBD.
The interactions of CBD with antineoplastic drugs, generating a synergistic effect,
suggest that CBD may be included in conventional chemotherapy regimens [38]. The only drug that demonstrated an antagonistic effect with CBD was dexamethasone.
However, this effect has been shown in in vivo anti-inflammatory models, indicating the need for studies with greater methodological
robustness to determine the clinical relevance of these interactions [39]. From a pharmacodynamic perspective, regarding clobazam, it was observed that CBD
and N-CLB increased the inhibitory function of GABAergic interneurons, as both are
positive allosteric modulators of GABA-A receptors, which enhances anticonvulsant
efficacy [40]. The co-administration of CBD with valproic acid resulted in significant changes
in liver function in patients, with increased levels of hepatic alanine and aspartate
aminotransferases (ALT and AST). The exact reason for this change is not yet known,
but one of the FDAʼs propositions is that it is due to a pharmacodynamic interaction
in the mitochondria [41].
Strengths and limitations
Among the strengths of this review, we highlight that this study followed the international
and validated guidelines of the Joanna Briggs Institute for scoping review, including
a broad bibliographic search and selection of studies, extraction, and categorization
independently by two reviewers, reducing bias selection and selective reporting [42].
On the other hand, it is important to highlight that this scoping review identified
few randomized clinical trials, or robust observational studies, with the available
evidence coming mainly from pre-clinical studies and non-systematic literature reviews.
Although preclinical evidence is useful for identifying the potential mechanisms of
these interactions and for translational research when clinical evidence is insufficient,
it presents methodological limitations that make it impossible for data to be directly
extrapolated in the clinic.
Implications for research and the clinic
As previously explained, the bulk of the studies included in the scoping review comprised
literature reviews and pre-clinical studies, indicating a significant gap in identifying
clinically relevant drug interactions associated with the increasing global use of
CBD. Further research is needed to assess the clinical evidence and causality of the
interactions, aiding healthcare professionals in appropriately managing potential
outcomes linked to drug interactions between CBD and other medications.
The use of CBD in clinical practice has expanded over the years, and its combination
with other medications underscores the necessity to delineate potential drug interactions
and their associated outcomes, as treated patients face an elevated risk of adverse
effects. Our scoping review identified 271 drug interactions, yet the majority stemmed
from preclinical evidence and non-systematic literature reviews (77.2%). Only a small
fraction originated from clinical studies (22.8%), indicating the imperative for further
methodologically robust clinical investigations to pinpoint drug interactions with
clinical significance. Such efforts will aid healthcare professionals in decision-making
and monitoring these interactions effectively.
In addressing the complexities of CBD interactions with other pharmacological agents,
it is imperative to consider the significant impact of individual differences on CBD
metabolism. Factors such as age, sex, genetic polymorphisms, and the presence of other
medical conditions play pivotal roles in modulating the pharmacokinetics of CBD. For
instance, genetic variations in the cytochrome P450 enzymes, crucial for metabolizing
many drugs including CBD, can significantly alter the metabolic clearance of CBD.
This alteration influences its plasma levels and therapeutic efficacy. Additionally,
sex differences can affect hormone levels, which modulate enzyme activity involved
in drug metabolism. Age-related changes in liver function and enzyme activity also
contribute to variations in drug interactions and responses. Therefore, personalized
approaches to CBD dosing and management of drug interactions are essential for optimizing
therapeutic outcomes and minimizing adverse effects
across diverse patient populations [43], [44], [45].
Given the interaction mechanisms, strategies to mitigate risks and make prescribing
CBD safer in patients with polypharmacy include baseline and ongoing monitoring, dosage
adjustments, and patient education [44]. Before starting CBD, it is advisable to obtain baseline liver function tests and
levels of concomitant medications [45]. Monitoring should be repeated at regular intervals to detect any significant changes
that may require dosage adjustments. For medications that interact with CBD, starting
at the lower end of the dosage range and adjusting based on clinical response and
drug levels is recommended. Informing patients of potential symptoms of drug interactions,
such as excessive sedation or gastrointestinal discomfort, and advising them to report
these symptoms immediately is crucial [44].
Methods
Protocol and registry
Our scoping review followed the methodological steps proposed by the Joanna Briggs
Institute and was reported following Preferred Reporting Items for Systematic reviews
and Meta-Analyses extension for Scoping Review (PRISMAScr) recommendations (Supplementary
Material Fig. 1S) [46]. A protocol had been previously developed [15].
Eligibility criteria
Inclusion criteria
As recommended, our research question followed the population, concept, and context
(PCC) framework [46]. Therefore, pre-clinical and clinical studies evaluating or describing drug interactions
between CBD and any other drug were included, without restrictions on study design.
We adopt the concept of “drug interactions” when the administration of a drug, either
prior or concurrent, modifies the effect of another. No contextual restrictions were
applied; studies from any geographic region were included. We only included studies
in Portuguese, English, and Spanish.
Exclusion criteria
We excluded studies published in languages other than Portuguese, English, and Spanish,
as well as those suggesting a drug interaction between CBD and other drugs but not
presenting the results of the interaction.
Information sources
We consulted the following databases: MEDLINE (via PubMed), Embase, Scopus, and LILACS
(via Portal da Biblioteca Virtual de Saúde). Gray literature was searched using Google
Scholar. The search strategy employed in MEDLINE was adapted for other databases with
the assistance of an experienced librarian: (“Drug interactions” OR “Drug Interaction”
OR “Interaction, Drug” OR “Interactions, Drug”) AND (“Cannabidiol” OR “1,3-Benzenediol,2-(3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl)-5-pentyl-,(1R-trans)-”
OR “Epidiolex”). The search strategy was carried out in July 2022 and updated in November
2023.
Study selection and data extraction
All identified references were managed in EndNote software, including the deduplication
process. Subsequently, the references were imported into Rayyan, and screening based
on title and abstract was conducted. After completing this initial stage, we proceeded
to select full texts. During this final stage, reasons for excluding studies were
documented. Both steps were independently performed by two reviewers (FDN and LPNL),
and any disagreements were resolved through discussion with a third reviewer (MEM).
We extracted data using a form developed in Microsoft Excel 2016. The following variables
were obtained from the included studies: author, year, title, type of study, type
of interaction, name of the drug, and possible outcomes and/or associated mechanisms.
Two independent reviewers (FDN and LPNL) performed the extraction, and any disagreements
were resolved through consensus.
Categorization of drugs and drug interactions
Initially, we categorized all drugs according to the Anatomical Therapeutic Chemical
(ATC) classification, a system recommended by the WHO that organizes drugs at anatomical,
therapeutic, pharmacological, chemical, and product levels [47]. We also categorized the interactions into two types: pharmacokinetic and pharmacodynamic.
Pharmacokinetic interactions were defined as those affecting the absorption, distribution,
metabolism, and excretion stages of a drug when administered with another one. These
interactions result in increase or decrease in plasma concentration [6]. Pharmacodynamic interactions were identified when the interaction occurred at one
or more receptor sites, resulting in a synergistic response (greater than the sum
of individual responses), an additive response (equal to the sum of individual responses),
or an antagonistic response (lower than the expected therapeutic response) [6]. The categorization steps were carried out by one reviewer (FDN) and checked by
another (MEM and LPNL).
