Systematic review of drug-drug interactions of delta-9-tetrahydrocannabinol, cannabidiol, and Cannabis.

Background: The recent exponential increase in legalized medical and recreational cannabis, development of medical cannabis programs, and production of unregulated over-the-counter products (e.g., cannabidiol (CBD) oil, and delta-8-tetrahydrocannabinol (delta-8-THC)), has the potential to create unintended health consequences. The major cannabinoids (delta-9-tetrahydrocannabinol and cannabidiol) are metabolized by the same cytochrome P450 (CYP) enzymes that metabolize most prescription medications and xenobiotics (CYP3A4, CYP2C9, CYP2C19). As a result, we predict that there will be instances of drug-drug interactions and the potential for adverse outcomes, especially for prescription medications with a narrow therapeutic index. Methods: We conducted a systematic review of all years to 2023 to identify real world reports of documented cannabinoid interactions with prescription medications. We limited our search to a set list of medications with predicted narrow therapeutic indices that may produce unintended adverse drug reactions (ADRs). Our team screened 4,600 reports and selected 151 full-text articles to assess for inclusion and exclusion criteria. Results: Our investigation revealed 31 reports for which cannabinoids altered pharmacokinetics and/or produced adverse events. These reports involved 16 different Narrow Therapeutic Index (NTI) medications, under six drug classes, 889 individual subjects and 603 cannabis/cannabinoid users. Interactions between cannabis/cannabinoids and warfarin, valproate, tacrolimus, and sirolimus were the most widely reported and may pose the greatest risk to patients. Common ADRs included bleeding risk, altered mental status, difficulty inducing anesthesia, and gastrointestinal distress. Additionally, we identified 18 instances (58%) in which clinicians uncovered an unexpected serum level of the prescribed drug. The quality of pharmacokinetic evidence for each report was assessed using an internally developed ten-point scale. Conclusion: Drug-drug interactions with cannabinoids are likely amongst prescription medications that use common CYP450 systems. Our findings highlight the need for healthcare providers and patients/care-givers to openly communicate about cannabis/cannabinoid use to prevent unintended adverse events. To that end, we have developed a free online tool (www.CANN-DIR.psu.edu) to help identify potential cannabinoid drug-drug interactions with prescription medications.

CANNabinoid Drug Interaction Review (CANN-DIR™).

Non-prescription cannabidiol (CBD) and medical marijuana (cannabis) currently do not have US Food and Drug Administration (FDA)-approved prescribing information nor a dedicated resource to evaluate potential cannabinoid drug-drug interactions with other medications. The CANNabinoid Drug Interaction Review (CANN-DIR™) is a free web-based platform that has been developed to screen for potential drug-drug interactions from the perspective of how a cannabinoid delta-9-tetrahydrocannabinol (THC), CBD, or a combination of THC/CBD may affect the metabolism of another prescribed medication. CANN-DIR™ is based on FDA-approved prescribing information for the prescription cannabinoids (dronabinol, nabilone, nabiximols, and prescription CBD) and other FDA-approved prescribing information for medications sharing similar metabolic enzymes (e.g., the FDA "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers"). The Summary of Product Characteristics (SmPC) was the source of drug-drug interaction information for the combined ∆9-THC & CBD product nabiximols (Sativex®). CANN-DIR™ provides an expeditious review of cannabinoid drug-drug interaction information, and also a platform from which the patient and health care provider can print out the search results to either initiate a conversation, or for the health care provider to provide a written information sheet to supplement their verbal discussion. Additionally, to more effectively reach a global audience, the end user of CANN-DIR™ has the ability to currently navigate and print results in any of the following ten languages: Chinese, English, French, German, Nepali, Polish, Russian, Spanish, Swedish, and Vietnamese.

Drug-drug interaction between dexamethasone and direct-acting oral anticoagulants: a nested case-control study in the National COVID Cohort Collaborative (N3C).

OBJECTIVE: The goal of this work is to evaluate if there is an increase in the risk of thromboembolic events (TEEs) due to concomitant exposure to dexamethasone and apixaban or rivaroxaban. Direct oral anticoagulants (DOACs), as well as corticosteroid dexamethasone, are commonly used to treat individuals hospitalised with COVID-19. Dexamethasone induces cytochrome P450-3A4 enzyme that also metabolises DOACs apixaban and rivaroxaban. This raises a concern about possible interaction between dexamethasone and DOACs that may reduce the efficacy of the DOACs and result in an increased risk of TEE. DESIGN: We used nested case-control study design. SETTING: This study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA. PARTICIPANTS: Study participants were adults over 18 years who were exposed to a DOAC for 10 or more consecutive days. Exposure to dexamethasone was at least 5 or more consecutive days. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary exposure variable was concomitant exposure to dexamethasone for 5 or more days after exposure to either rivaroxaban or apixaban for 5 or more consecutive days. We used McNemar's Χ2 test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban. RESULTS: McNemar's Χ2 test did not find a discernible association of TEE in patients concomitantly exposed to dexamethasone and a DOAC (χ2=0.5, df=1, p=0.48). In addition, a conditional logistic regression model did not find an increase in the risk of TEE (adjusted OR 1.15, 95% CI 0.32 to 4.18). CONCLUSION: This nested case-control study did not find evidence of an association between concomitant exposure to dexamethasone and a DOAC with an increase in risk of TEE. Due to small sample size, an association cannot be completely ruled out.

Use of Hydroxychloroquine, Remdesivir, and Dexamethasone Among Adults Hospitalized With COVID-19 in the United States : A Retrospective Cohort Study.

BACKGROUND: Relatively little is known about the use patterns of potential pharmacologic treatments of COVID-19 in the United States. OBJECTIVE: To use the National COVID Cohort Collaborative (N3C), a large, multicenter, longitudinal cohort, to characterize the use of hydroxychloroquine, remdesivir, and dexamethasone, overall as well as across individuals, health systems, and time. DESIGN: Retrospective cohort study. SETTING: 43 health systems in the United States. PARTICIPANTS: 137 870 adults hospitalized with COVID-19 between 1 February 2020 and 28 February 2021. MEASUREMENTS: Inpatient use of hydroxychloroquine, remdesivir, or dexamethasone. RESULTS: Among 137 870 persons hospitalized with confirmed or suspected COVID-19, 8754 (6.3%) received hydroxychloroquine, 29 272 (21.2%) remdesivir, and 53 909 (39.1%) dexamethasone during the study period. Since the release of results from the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial in mid-June, approximately 78% to 84% of people who have had invasive mechanical ventilation have received dexamethasone or other glucocorticoids. The use of hydroxychloroquine increased during March 2020, peaking at 42%, and started declining by April 2020. By contrast, remdesivir and dexamethasone use gradually increased over the study period. Dexamethasone and remdesivir use varied substantially across health centers (intraclass correlation coefficient, 14.2% for dexamethasone and 84.6% for remdesivir). LIMITATION: Because most N3C data contributors are academic medical centers, findings may not reflect the experience of community hospitals. CONCLUSION: Dexamethasone, an evidence-based treatment of COVID-19, may be underused among persons who are mechanically ventilated. The use of remdesivir and dexamethasone varied across health systems, suggesting variation in patient case mix, drug access, treatment protocols, and quality of care. PRIMARY FUNDING SOURCE: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute; and National Institute on Aging.

Delta-9-Tetrahydrocannabinol and Cannabidiol Drug-Drug Interactions.

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 exemplars or only reference a class of medications without providing any specific medication examples. In the case of medical cannabis and medicinal cannabinoids, this is further complicated by the fact that the increased therapeutic use of marijuana extracts and cannabidiol oil will not have regulatory agency approved PI. The objective of this study was to provide 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 PRECIPITANT (cannabinoid) medication that either INHIBITS/INDUCES the metabolism or competes for the same SUBSTRATE target (metabolic enzyme) of an OBJECT (OTHER) medication. In addition to a comprehensive list of drug-drug interactions, 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).

Comparison of Osteoporosis Pharmacotherapy Fracture Rates: Analysis of a MarketScan® Claims Database Cohort.

BACKGROUND: Several different classes of medications have been shown to be efficacious at preventing fractures in patients with osteoporosis. No study has compared real world efficacy at preventing fractures between all currently approved medications. OBJECTIVES: To directly compare the efficacy of all currently available osteoporosis medications by using a large population claims database. METHODS: The Truven Health Analytics MarketScan® database from 2008 - 2012 was used to identify all patients who started a new osteoporosis medication. Patients who experienced a fracture after at least 12 months of treatment were identified and risk factors for fracture for all patients were recorded. Logistic regression was used to account for and quantify the contribution of risk factors, and to make direct comparisons between different osteoporosis medications. RESULTS: A total of 51649 patients were included in the cohort, with an average age of 56 years. The overall incidence rate of fracture was 1.55 per 100 person - years of treatment. Orally administered medications had the lowest fracture rates, led by raloxifene and alendronate (1.24 and 1.54 respectively), while parenterally administered medications including teriparatide and zolerdonic acid had the highest rates (3.90 and 1.98 respectively). No statistically significant differences found between oral or parenterally administered bisphosphonate medications. CONCLUSIONS: While patients taking orally administered drugs including bisphosphonates had less frequent incident fracture no statistically significant differences were found between most drugs in head - to - head comparisons, even considering the route of administration of bisphosphonates. These findings support previous evidence that minimal differences in efficacy exist between different osteoporosis medications. This is the first study using a large database to compare all currently available osteoporosis treatments and will hopefully be augmented by further study to provide more evidence to make clinical decisions on osteoporosis medication use.

Use of Chronic Medications Among Patients with Non-Valvular Atrial Fibrillation.

BACKGROUND: Frequency of administration (once daily versus more than once daily) is believed to be an important consideration affecting drug choice. OBJECTIVE: The aim of this study was to describe the characteristics of patients with non-valvular atrial fibrillation (NVAF) and the extent to which they take chronic medications, other than anticoagulants, more frequently than once daily. METHODS: Using data from a large, national database of health insurance claims, patients with a diagnosis of NVAF between 1 July 2008 and 30 September 2011 were identified, along with their prescription medications, to determine the proportion of patients taking chronic medications more than once a day. Prescription medications, co-morbidities, and CHADS2 and CHA2DS2-VASc scores were evaluated. CHADS2 assesses the risk of stroke in NVAF patients with the following risk factors: Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, and history of prior Stroke or transient ischemic attack. The CHA2DS2-VASc score adds the following risk factors to the CHADS2 score: Age 65-74 years, Vascular Disease, and Sex Category (Female). RESULTS: Overall, 324,172 patients with NVAF with mean CHADS2 and CHA2DS2-VASc scores of 1.51 and 3.08, respectively, were included in the study. Of these patients, 299,716 (92.5 %) took chronic medications, with an average of 6.9 medications per patient, and 215,527 (66.5 % of all patients or 71.9 % of those taking chronic medications) took medications more than once per day. CONCLUSION: Use of chronic medications other than anticoagulants is common among patients with NVAF, and medications are typically taken multiple times per day. The average number of medications per patient and multiple therapeutic classes prescribed underscore the clinical complexity of NVAF patients. Hence, the choice of a once daily anticoagulant versus a more than once daily anticoagulant may be less relevant in a real world NVAF population in terms of a potential convenience benefit.