Evidence of Potential Drug Interactions Between Cannabidiol and Other Drugs: A Scoping Review to Guide Pharmaceutical Care

• Abstract
• Introduction
• Results and Discussion
• Characteristics of the studies
• Pharmacokinetic interactions
• Pharmacodynamic interactions
• Main findings
• Comparison with literature
• Strengths and limitations
• Implications for research and the clinic
• Methods
• Protocol and registry
• Eligibility criteria
• Inclusion criteria
• Exclusion criteria
• Information sources
• Study selection and data extraction
• Categorization of drugs and drug interactions
• Contributorsʼ Statement
• References

Abstract

Cannabidiol (CBD), a non-psychoactive cannabinoid with therapeutic potential, is increasingly used in combination with other drugs, raising concerns about potential interactions and their impact on safety and efficacy. This scoping review aimed to map the current evidence on CBD interactions across different drug classes and assess their clinical significance. The study followed the Joanna Briggs Institute guidelines, utilizing a structured protocol based on the population, concept, and context (PCC) framework. Five databases were searched, and preclinical and clinical studies on CBD pharmacokinetic and pharmacodynamic interactions were included, with publications in English, Portuguese, or Spanish. Out of 136 studies analyzed, 91.91% were published after 2011, reflecting a sharp rise in interest in this area. A total of 271 interactions were identified, with 203 related to pharmacokinetics, primarily involving metabolism mediated by cytochrome P450 (CYP) enzymes, and 68 linked to pharmacodynamics, including additive effects such as sedation. Among the most relevant findings, CBD was shown to inhibit CYP enzymes like CYP3A4 and CYP2C19, potentially increasing plasma levels of co-administered drugs. However, only 5.15% of studies evaluated the clinical relevance of these interactions, indicating a substantial gap in knowledge regarding their safety implications. This review highlights the urgent need for rigorous clinical research to determine the clinical significance of CBD-drug interactions, particularly in patients undergoing polypharmacy. Understanding these interactions is crucial for optimizing therapeutic outcomes, minimizing adverse effects, and enabling safer clinical use of CBD in diverse treatment regimens.

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).

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.

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].

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).

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).

Contributorsʼ Statement

Conception and design of the study: L. P. N. Lopes, M. E. Matheus; data collection: F. D. Nader, L. P. N. Lopes; analysis and interpretation of the data: F. D. Nader, L. P. N. Lopes; drafting the manuscript: L. P. N. Lopes, F. D. Nader, A. Ramos-Silva, M. E. Matheus; critical revision of the manuscript: F. D. Nader, L. P. N. Lopes, A. Ramos-Silva, M. E. Matheus.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

We thank librarian Roberto Unger for the validation of the search strategy.

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  PubMed

Correspondence

Publication History

Received: 19 September 2024

Accepted after revision: 23 April 2025

Accepted Manuscript online:
23 April 2025

Article published online:
08 May 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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