Contemplating cannabis? The complex relationship between cannabinoids and hepatic metabolism resulting in the potential for drug-drug interactions
1Marijuana Investigations for Neuroscientific Discovery (MIND) Program, McLean Imaging Center, McLean Hospital, Belmont, MA, United States
2Department of Psychiatry, Harvard Medical School, Boston, MA, United States
*Correspondence: Staci A. Gruber, gruber@mclean.harvard.eduAbstract
The majority of states have fully legalized the use of medical cannabis (MC), and nearly all other states allow limited access to cannabidiol (CBD), a non-intoxicating constituent of cannabis often touted for a range of therapeutic indications. Further, the Agricultural Improvement Act of 2018 legalized hemp-derived products in all 50 states; typically high in CBD, these products are derived from cannabis varieties containing ≤0.3% delta-9-tetrahydrocannabinol (THC) by weight. The recent “green rush” has resulted in a striking increase in cannabis use among patients and consumers who often use a wide variety of novel product types, each with a unique blend of cannabinoid constituents. Importantly, however, several cannabinoids have the potential to cause drug-drug interactions (DDI) with other medications, primarily due to their involvement with the hepatic cytochrome P450 (CYP450) system. This article examines the potential for individual cannabinoids, particularly CBD, to interact with the hepatic metabolic system, which is concerning given its involvement in the metabolism of commonly-prescribed medications. CBD and other cannabinoids are metabolized extensively by the CYP450 system, and also inhibit many of these enzymes, potentially leading to variable serum levels of other medications, as well as variable levels of cannabinoids when other medications modify the system. As access and interest in cannabinoid-based products continues to increase, critical questions remain unanswered regarding their safety. The complex relationship between cannabinoids and the hepatic metabolic system, including common potential DDI resulting from cannabinoid exposure, are explored along with the clinical significance of these potential interactions and monitoring or mitigation strategies.
1. Introduction
Cannabis sativa is comprised of over 400 constituents, including more than 100 phytocannabinoids, many of which are known to have effects in the human body and demonstrate therapeutic potential (1). Until recently, despite widespread cannabis use, little research had elucidated the effects of cannabinoids on various biological processes. Two primary cannabinoids found in the plant are delta-9-tetrahydrocannabinol (THC), the most abundant cannabinoid and the primary intoxicating constituent, which has also demonstrated therapeutic benefits as an anti-emetic for chemotherapy-induced nausea and vomiting, pain, and muscle spasticity (2); and cannabidiol (CBD), often the second most abundant cannabinoid which is non-intoxicating and has been touted as therapeutic for a range of indications, including seizure disorders, anxiety, pain, and inflammation (3). In addition to THC and CBD, dozens of “minor” cannabinoids are found in the plant which are also often present in cannabis products, including cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), and the acid forms of THC and CBD (THCA and CBDA), among others. While little work thus far has focused on minor cannabinoids, studies have shown that these compounds have a variety of biological effects (1, 4), and the presence of minor cannabinoids in medical cannabis (MC) products is increasing (5–7) as consumers and patients become aware of their potential utility.
Medical cannabis use has increased dramatically in recent years; in the U.S., almost all states have passed legislation allowing the use of MC or CBD-containing products. The rapid legalization of MC has coincided with a significant increase in MC use; state registry data indicates a 4.5 fold increase in registered MC patients from 2016 to 2020 (8), and use among older adults has increased particularly rapidly (9). As of November 2022, 37 states plus the District of Columbia (D.C.) have fully legalized the use of MC; in addition, 21 states plus D.C. have legalized adult or recreational use of cannabis (10, 11). Additionally, the Agricultural Improvement Act of 2018 (colloquially known as the “Farm Bill”) legalized hemp-derived products containing <0.3% THC by weight (12). While a synthetic form (dronabinol) and an analog (nabilone) of THC were approved by the U.S. Food and Drug Administration (FDA) in 1985 for treating chemotherapy-related nausea and vomiting, in 2018, the FDA approved Epidiolex, a plant-derived, purified CBD isolate for treatment-resistant, pediatric-onset seizure disorders. Epidiolex is the first (and only, to date) FDA-approved, cannabis-derived medication available in the U.S., while Sativex, a plant-derived 1:1 CBD:THC buccal spray, is available in several other countries (13). The convergence of legalization of cannabis and hemp, along with the more recent approval and availability of Epidiolex and Sativex, has resulted in a rapid increase in cannabinoid-based products available for purchase in dispensaries, through online retailers, and by prescription.
While the use of cannabinoid-containing products has increased significantly, relatively little work has focused on assessing potential drug-drug interactions (DDI) between cannabinoids and conventional medications. DDI can result in variable serum levels of substrates, leading to unexpected side effects, stronger drug effects than intended, or incomplete symptom relief due to lower efficacy (14). Several studies have demonstrated that cannabinoids interact with the cytochrome P450 (CYP450) enzyme system, the hepatic system responsible for the metabolism of most common medications, and the second phase of metabolism which further processes compounds for excretion (15–21). As these pathways are commonly implicated in DDI, increased cannabinoid use results in a major public health concern regarding potential DDI that has yet to be addressed. This article will provide a brief overview of the hepatic metabolic process and discuss potential areas of concern for interactions with cannabinoids (particularly CBD), the clinical significance of these interactions, and potential monitoring or mitigation strategies to minimize interactions which may help address public health concerns regarding DDI.
4. Future directions
As access to MC products, particularly high CBD-containing products, continues to expand, critical questions remain unanswered regarding their safety. Although few studies have assessed the clinical significance of common DDI related to CBD exposure, evidence suggests moderate to strong interaction risks between CBD and drugs metabolized by a variety of CYP450 enzymes (15, 16), indicating that interactions are likely at clinically-relevant doses of CBD. Future studies are needed to fully evaluate the potential for cannabinoids to cause DDI; in vivo studies and human pharmacokinetic/pharmacodynamic (PK/PD) studies involving co-administration of multiple medications with cannabinoids will be particularly valuable in determining the clinical significance of any interactions. As DDI are also more likely with drugs with a narrow TI (17, 18, 22), additional co-administration studies are warranted, particularly for CYP2C9 substrates with a narrow TI (17). In addition, studies are necessary to assess whether DDI that result in changes in bioavailability actually lead to adverse outcomes in various clinical populations.
To date, potential mitigation strategies have not been studied. It is unlikely that an offset between administration of cannabinoids and concomitant medications of concern would completely address the issue, given the extremely long half-life of certain cannabinoids, which are lipophilic and remain detectable for days to weeks after use (42, 43); however, this should be evaluated directly. Monitoring strategies, including serial blood draws assessing serum levels of concomitant medications, and monitoring LFTs to avoid potential hepatic damage, could be utilized to minimize potential negative outcomes. Importantly, as the majority of older adults take medications involving the CYP450 system (44), this group is particularly important to monitor upon initiation of cannabinoid use. Consumers and health care providers alike should be informed regarding the potential for DDI when considering cannabis and cannabinoid use, and efforts should be made to eliminate or limit potential risk and harm.
5. Conclusion
The proliferation of medical cannabis and hemp-derived products has resulted in thousands of commercially available cannabinoid-based options in the marketplace. Many consider cannabis and cannabinoid-based products relatively harmless, especially those high in CBD which is non-intoxicating and often touted for its medical benefits. Unfortunately, concerns regarding the potential safety issues associated with their use in conjunction with other medications are often overlooked. While there is great promise in the use of cannabis and cannabinoid-based products for a range of conditions, researchers and healthcare providers should be aware of the potential for significant DDI and should counsel their patients regarding potential interactions whenever the use of cannabinoid-based products is disclosed or considered. As cannabis and cannabinoid use increases, particularly vulnerable groups (e.g., older adults) should understand the potential risks associated with using these products with concomitant medications.
Data availability statement
The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Acknowledgements
The authors acknowledge M. Kathryn Dahlgren and Kelly A. Sagar for their review and critical feedback of the manuscript.
Conflict of interest
SG reported grants from the National Institute on Drug Abuse, Charles Robert Broderick III Phytocannabinoid Research Initiative, Foria/Praxis Ventures, Charlotte’s Web, and private donations outside the submitted work. Over the last 5 years, SG has reported receiving fees from the Coalition for Cannabis Policy, Education, and Regulation (CPEAR), Beth Israel Deaconess, Fenway Health, Greenwich Biosciences Cannabis Education Working Group, the National Academy of Neuropsychology, McMaster University, Harvard Health Publications, Cannabis Clinical Outcomes Research Conference, AdCare Educational Institute of New England and the Massachusetts College of Pharmacy and Health Sciences, all related to presentations/projects outside the submitted work. SG is also a scientific advisor for Ajna Biosciences. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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