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ArticleLiterature Review
Cannabinoids and drug metabolizing enzymes: potential for drug-drug interactions and implications for drug safety and efficacy
Expert Review of Clinical Pharmacology 15(11)
Keti Bardhi
Shelby Coates
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Christy J.W. Watson
Philip Lazarus
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Introduction Cannabis is an increasingly popular recreational and medicinal drug in the USA. While cannabis is still a Schedule 1 drug federally, many states have lifted the ban on its use. With its increased usage, there is an increased potential for potential drug-drug interactions (DDI) that may occur with concomitant use of cannabis and pharmaceuticals. Area covered This review focuses on the current knowledge of cannabis induced DDI, with a focus on pharmacokinetic DDI arising from enzyme inhibition or induction. Phase I and phase II drug metabolizing enzymes, specifically cytochromes P450, carboxylesterases, and uridine-5'-diphosphoglucuronosyltransferases, have historically been the focus of research in this field, with the much of the current knowledge of the potential for cannabis to induce DDI within these families of enzymes coming from in vitro enzyme inhibition studies. Together with a limited number of in vivo clinical studies and in silico investigations, current research suggests that cannabis exhibits the potential to induce DDI under certain circumstances. Expert opinion Based upon the current literature, there is a strong potential for cannabis-induced DDI among major drug-metabolizing enzymes.
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Potency and Therapeutic THC and CBD Ratios: U.S. Cannabis Markets Overshoot
Katharine Cunnane
Mary Catherine Cash
Sarah D. Pennypacker
E. Alfonso Romero-Sandoval
Background and aims: The effects exuded by cannabis are a result of the cannabinoids trans-Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), and is dependent upon their pharmacological interaction and linked to the two cannabinoids' concentrations and ratios. Based on current literature and trends of increasing cannabis potency, we postulate that most medical cannabis products with THC and CBD have ratios capable of producing significant acute intoxication and are similar to recreational products. We will test this by organizing products into clinically distinct categories according to TCH:CBD ratios, evaluating the data in terms of therapeutic potential, and comparing the data obtained from medical and recreational programs and from states with differing market policies. Methods: We utilized data encompassing online herbal dispensary product offerings from nine U.S. states. The products were analyzed after being divided into four clinically significant THC:CBD ratio categories identified based on the literature: CBD can enhance THC effects (THC:CBD ratios ≥1:1), CBD has no significant effect on THC effects (ratios ∼ 1:2), CBD can either have no effect or can mitigate THC effects (ratios 1:>2 < 6), or CBD is protective against THC effects (ratios ≤1:6). Results: A significant number of products (58.5%) did not contain any information on CBD content. Across all states sampled, the majority (72–100%) of both medical and recreational products with CBD (>0%) fall into the most intoxicating ratio category (≥1:1 THC:CBD), with CBD likely enhancing THC's acute effects. The least intoxicating categories (1:>2 < 6 and ≤1:6 THC:CBD) provided the smallest number of products. Similarly, the majority of products without CBD (0%) contained highly potent amounts of THC (>15%). These results were consistent, regardless of differing market policies in place. Conclusions: Despite the distinct goals of medical and recreational cannabis users, medical and recreational program product offerings are nearly identical. Patients seeking therapeutic benefits from herbal cannabis products are therefore at a substantial risk of unwanted side effects, regardless of whether they obtain products from medical or recreational programs. Efforts are needed to better inform patients of the risks associated with high potency cannabis and the interaction between THC and CBD, and to help shape policies that promote more therapeutic options.
Cannabidiol (CBD) Dosing: Plasma Pharmacokinetics and Effects on Accumulation in Skeletal Muscle, Liver and Adipose Tissue
Robert B. Child
Mark Tallon
Oral cannabidiol (CBD) consumption is widespread in North America and Europe, as it has analgesic, neuroprotective and antitumor effects. Although oral CBD consumption in humans affords beneficial effects in epileptic and inflammatory states, its pharmacokinetics and subsequent uptake into tissue are largely unknown. This study investigated plasma pharmacokinetics and accumulation of CBD in gastrocnemius muscle, liver and adipose tissue in adult rats following oral gavage. CBD was fed relative to body mass at 0 (control), 30, 115, or 230 mg/Kg/day for 28 days; with 6 males and 6 females per dosing group. Pharmacokinetics were assessed on day 1 and day 28 in the group receiving CBD at 115 mg/Kg/day. The rise in tissue CBD was closely related to specific pharmacokinetic parameters, and adipose tissue levels were ~10 to ~100 fold greater than liver or muscle. Tissue CBD levels were moderately correlated between adipose and muscle, and adipose and liver, but were highly correlated for liver and muscle. CBD feeding resulted in several gender-specific effects, including changes in pharmacokinetics, relationships between pharmacokinetic parameters and tissue CBD and differences in tissue CBD levels. CBD accumulation in mammalian tissues has the potential to influence receptor binding and metabolism; therefore, the present findings may have relevance for developing oral dosing regimens.
Understanding Cannabis sativa L.: Current Status of Propagation, Use, Legalization, and Haploid-Inducer-Mediated Genetic Engineering
David Charles Simiyu
Jin Hoon Jang
Ok Ran Lee
Cannabis sativa L. is an illegal plant in many countries. The worldwide criminalization of the plant has for many years limited its research. Consequently, understanding the full scope of its benefits and harm became limited too. However, in recent years the world has witnessed an increased pace in legalization and decriminalization of C. sativa. This has prompted an increase in scientific studies on various aspects of the plant's growth, development, and use. This review brings together the historical and current information about the plant's relationship with mankind. We highlight the important aspects of C. sativa classification and identification, carefully analyzing the supporting arguments for both monotypic (single species) and polytypic (multiple species) perspectives. The review also identifies recent studies on suitable conditions and methods for C. sativa propagation as well as highlighting the diverse uses of the plant. Specifically, we describe the beneficial and harmful effects of the prominent phytocannabinoids and provide status of the studies on heterologous synthesis of phytocannabinoids in different biological systems. With a historical view on C. sativa legality, the review also provides an up-to-date worldwide standpoint on its regulation. Finally, we present a summary of the studies on genome editing and suggest areas for future research.
Observational study of medical marijuana as a treatment for treatment‐resistant epilepsies
Orrin Devinsky
Angelica Marmanillo
Theresa Hamlin
George Todd
Objectives: Medical cannabis formulations with cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are widely used to treat epilepsy. We studied the safety and efficacy of two formulations. Methods: We prospectively observed 29 subjects (12 to 46 years old) with treatment-resistant epilepsies (11 Lennox-Gastaut syndrome; 15 with focal or multifocal epilepsy; three generalized epilepsy) were treated with medical cannabis (1THC:20CBD and/or 1THC:50CBD; maximum of 6 mg THC/day) for ≥24 weeks. The primary outcome was change in convulsive seizure frequency from the pre-treatment baseline to the stable optimal dose phase. Results: There were no significant differences during treatment on stable maximal doses for convulsive seizure frequency, seizure duration, postictal duration, or use of rescue medications compared to baseline. No benefits were seen for behavioral disorders or sleep duration; there was a trend for more frequent bowel movements compared to baseline. Ten adverse events occurred in 6/29 patients, all were transient and most unrelated to study medication. No serious adverse events were related to study medication. Interpretation: Our prospective observational study of two high-CBD/low-THC formulations found no evidence of efficacy in reducing seizures, seizure duration, postictal duration, or rescue medication use. Behavioral disorders or sleep duration was unchanged. Study medication was generally well tolerated. The doses of CBD used were lower than prior studies. Randomized trials with larger cohorts are needed, but we found no evidence of efficacy for two CBD:THC products in treating epilepsy, sleep, or behavior in our population.
Expression and Functions of the CB2 Receptor in Human Leukocytes
Mélissa Simard
Volatiana Rakotoarivelo
Vincenzo Di Marzo
Nicolas Flamand
The cannabinoid CB 2 receptor was cloned from the promyeloid cell line HL-60 and is notably expressed in most, if not all leukocyte types. This relatively restricted localization, combined to the absence of psychotropic effects following its activation, make it an attractive drug target for inflammatory and autoimmune diseases. Therefore, there has been an increasing interest in the past decades to identify precisely which immune cells express the CB 2 receptor and what are the consequences of such activation. Herein, we provide new data on the expression of both CB 1 and CB 2 receptors by human blood leukocytes and discuss the impact of CB 2 receptor activation in human leukocytes. While the expression of the CB 2 mRNA can be detected in eosinophils, neutrophils, monocytes, B and T lymphocytes, this receptor is most abundant in human eosinophils and B lymphocytes. We also review the evidence obtained from primary human leukocytes and immortalized cell lines regarding the regulation of their functions by the CB 2 receptor, which underscore the urgent need to deepen our understanding of the CB 2 receptor as an immunoregulator in humans.
Case report: Medical cannabis-warfarin drug-drug interaction
Tyan Thomas
Evdokia S Metaxas
Thu Nguyen
Alice Lim Scaletta
Aim A case of an 85-year-old patient with concurrent use of warfarin and medical cannabis containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is described. Warfarin continues to be a cornerstone of anticoagulation treatment despite the recent addition of FDA-approved anticoagulant agents. It is well known that warfarin has numerous drug interactions; however, much remains unknown about its interaction with THC and CBD. A literature review was conducted to identify documented cases of possible interactions between cannabis and warfarin. The case reports we identified noted that cannabis may potentially increase warfarin's effect. Therefore, we aimed to determine why an effect was not seen on our patient's warfarin dose despite daily use of medical cannabis. Case This case report describes an 85-year-old patient who despite starting an oromucosal medical cannabis regimen of THC and CBD (which provided 0.3 mg of THC and 5.3 mg CBD once daily and an additional 0.625 mg of THC and 0.625 mg CBD once daily as needed) had minimal INR fluctuations from October 2018 to September 2019. Conclusion Despite the introduction and use of medical cannabis therapy, with both THC and CBD components, an elderly patient with concurrent warfarin use did not see major INR fluctuations, in contrast to published literature. The potential for warfarin and THC/CBD interactions may be dependent on route of administration and dose of the cannabis product.
Hemp Chemotype Definition by Cannabinoids Characterization Using LC-ESI(+)-LTQ-FTICR MS and Infrared Multiphoton Dissociation
Filomena Lelario
Raffaella Pascale
Giuliana Bianco
Sabino Aurelio Bufo
The development and application of advanced analytical methods for a comprehensive analysis of Cannabis sativa L. extracts plays a pivotal role in order to have a reliable evaluation of their chemotype definition to guarantee the efficacy and safety in pharmaceutical use. This paper deals with the qualitative and quantitative determination of cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), and cannabigerol (CBG) based on a liquid chromategraphy-mass spectrometry (LC-MS) method using electrospray ionization in positive mode (ESI+), coupled with a hybrid quadrupole linear ion trap (LTQ) and Fourier transform ion cyclotron resonance mass spectrometer (FTICR-MS). For the first time, structural information of phytocannabinoids is available upon precursor ions' isolation within the FTICR trapping cell and subsequent fragmentation induced by infrared multiphoton dissociation (IRMPD). Such fragmentation and accurate mass measurement of product ions, alongside collision-induced dissociation (CID) within LTQ, was advantageous to propose a reliable fragmentation pattern for each compound. Then, the proposed LC-ESI(+)-LTQ-FTICR MS method was successfully applied to the hemp chemotype definition of three registered Italian accessions of hemp C. sativa plants (Carmagnola C.S., Carmagnola, and Eletta Campana), thus resulting in the Eletta Campana accession being the best one for cannabis product manufacturing.
Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses
Kenneth B. Walsh
Amanda E. McKinney
Andrea E. Holmes
The medicinal use of Cannabis sativa L. can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids trans -Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ ⁹ -THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ ⁹ -THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT 1a receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.
Inhibition of UDP-Glucuronosyltransferase Enzymes by Major Cannabinoids and Their Metabolites
Shamema Nasrin
The UDP-glucuronosyltransferase (UGT) family of enzymes play a central role in the metabolism and detoxification of a wide range of endogenous and exogenous compounds. UGTs exhibit a high degree of structural similarity and display overlapping substrate specificity, often making estimations of potential drug-drug interactions difficult to fully elucidate. One such interaction yet to be examined may be occurring between UGTs and cannabinoids, as the legalization of recreational and medicinal cannabis and subsequent co-usage of cannabis and therapeutic drugs increases in the U.S. and internationally. In the present study, the inhibition potential of the major cannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), as well as their major metabolites, was determined in microsomes isolated from HEK293 cells over-expressing individual recombinant UGTs and in microsomes from human liver and kidney specimens. The highest inhibition was seen by CBD against the glucuronidation activity of UGTs 1A9, 2B4,1A6 and 2B7, with binding- corrected IC50,u values of 0.12 {plus minus} 0.020 µM, 0.22 {plus minus} 0.045 µM, 0.40 {plus minus} 0.10 µM and 0.82 {plus minus} 0.15 µM, respectively. Strong inhibition of UGT1A9 was also demonstrated by THC and CBN, with IC50,u values of 0.45 {plus minus} 0.12 µM and 0.51 {plus minus} 0.063 µM, respectively. Strong inhibition of UGT2B7 was also observed for THC and CBN; no or weak inhibition was observed with cannabinoid metabolites. This inhibition of UGT activity suggests that in addition to playing an important role in drug-drug interactions, cannabinoid exposure may have important implications in patients with impaired hepatic or kidney function.
Cannabinoid Metabolites as Inhibitors of Major Hepatic CYP450 Enzymes, with Implications for Cannabis-Drug Interactions
Yadira X Pérez Páramo
The legalization of cannabis in many parts of the United States and other countries has led to a need for a more comprehensive understanding of cannabis constituents and their potential for drug-drug interactions. While (-)-trans-Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are the most abundant cannabinoids present in cannabis, THC metabolites are found in plasma at higher concentrations and for a longer duration than that of the parent cannabinoids. To understand the potential for drug-drug interactions, the inhibition potential of major cannabinoids and their metabolites on major hepatic cytochrome P450 (CYP) enzymes was examined. In vitro assays with CYP-overexpressing cell microsomes demonstrated that the major THC metabolites 11-hydroxy-∆9-tetra-hydrocannabinol (11-OH-THC) and 11-COO-Δ9-THC-glucuronide (THC-COO-Gluc) competitively inhibited several major CYP enzymes, including CYP2B6, CYP2C9, and CYP2D6 (apparent Ki,u values = 0.086 {plus minus} 0.066 µM and 0.90 {plus minus} 0.54 µM, 0.057 {plus minus} 0.044 µM and 2.1{plus minus} 0.81 µM, 0.15 {plus minus} 0.067 µM and 2.3 {plus minus} 0.54 µM, respectively). 11-nor-9-carboxy-Δ9- tetrahydrocannabinol (THC-COOH) exhibited no inhibitory activity against any CYP450 tested. THC competitively inhibited CYPs 1A2, 2B6, 2C9, and 2D6, CBD competitively inhibited CYPs 3A4, 2B6, 2C9, 2D6, and 2E1, and CBN competitively inhibited CYPs 2B6, 2C9, and 2E1. THC and CBD showed mixed-type inhibition for CYP2C19 and CYP1A2, respectively. These data suggest that cannabinoids and major THC metabolites are able to inhibit the activities of multiple CYP enzymes, and basic static modelling of these data suggest the possibility of pharmacokinetic interactions between these cannabinoids and xenobiotics extensively metabolized by CYP2B6, CYP2C9 and CYP2D6. Significance Statement Major cannabinoids and their metabolites found in the plasma of cannabis users inhibit several CYP enzymes, including CYP2B6, CYP2C9, and CYP2D6. This study is the first to show the inhibition potential of the most abundant plasma cannabinoid metabolite, THC-COO-Gluc, and suggests that circulating metabolites of cannabinoids play an essential role in CYP450 enzyme inhibition as well as drug-drug interactions.
Cannabis constituents interact at the drug efflux pump BCRP to markedly increase plasma cannabidiolic acid concentrations
Maia G. Etchart
Dilara Bahceci
Lyndsey L. Anderson
Jonathon C Arnold
Cannabis is a complex mixture of hundreds of bioactive molecules. This provides the potential for pharmacological interactions between cannabis constituents, a phenomenon referred to as "the entourage effect" by the medicinal cannabis community. We hypothesize that pharmacokinetic interactions between cannabis constituents could substantially alter systemic cannabinoid concentrations. To address this hypothesis we compared pharmacokinetic parameters of cannabinoids administered orally in a cannabis extract to those administered as individual cannabinoids at equivalent doses in mice. Astonishingly, plasma cannabidiolic acid (CBDA) concentrations were 14-times higher following administration in the cannabis extract than when administered as a single molecule. In vitro transwell assays identified CBDA as a substrate of the drug efflux transporter breast cancer resistance protein (BCRP), and that cannabigerol and Δ⁹-tetrahydrocannabinol inhibited the BCRP-mediated transport of CBDA. Such a cannabinoid-cannabinoid interaction at BCRP transporters located in the intestine would inhibit efflux of CBDA, thus resulting in increased plasma concentrations. Our results suggest that cannabis extracts provide a natural vehicle to substantially enhance plasma CBDA concentrations. Moreover, CBDA might have a more significant contribution to the pharmacological effects of orally administered cannabis extracts than previously thought.
Cannabinoid Interactions with Cytochrome P450 Drug Metabolism: a Full-Spectrum Characterization
AAPS J
Peter T. Doohan
Lachlan Oldfield
Medicinal cannabis use has increased exponentially with widespread legalization around the world. Cannabis-based products are being used for numerous health conditions, often in conjunction with prescribed medications. The risk of clinically significant drug-drug interactions (DDIs) increases in this setting of polypharmacy, prompting concern among health care providers. Serious adverse events can result from DDIs, specifically those affecting CYP-mediated drug metabolism. Both cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), major constituents of cannabis, potently inhibit CYPs. Cannabis-based products contain an array of cannabinoids, many of which have limited data available regarding potential DDIs. This study assessed the inhibitory potential of 12 cannabinoids against CYP-mediated drug metabolism to predict the likelihood of clinically significant DDIs between cannabis-based therapies and conventional medications. Supersomes™ were used to screen the inhibitory potential of cannabinoids in vitro. Twelve cannabinoids were evaluated at the predominant drug-metabolizing isoforms: CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2B6, and CYP2C19. The cannabinoids exhibited varied effects and potencies across the CYP isoforms. CYP2C9-mediated metabolism was inhibited by nearly all the cannabinoids with estimated Ki values of 0.2–3.2 μM. Most of the cannabinoids inhibited CYP2C19, whereas CYP2D6, CYP3A4, and CYP2B6 were either not affected or only partially inhibited by the cannabinoids. Effects of the cannabinoids on CYP2D6, CYP1A2, CYP2B6, and CYP3A4 metabolism were limited so in vivo DDIs mediated by these isoforms would not be predicted. CYP2C9-mediated metabolism was inhibited by cannabinoids at clinically relevant concentrations. In vivo DDI studies may be justified for CYP2C9 substrates with a narrow therapeutic index.
Citalopram and Cannabidiol: In Vitro and In Vivo Evidence of Pharmacokinetic Interactions Relevant to the Treatment of Anxiety Disorders in Young People
J CLIN PSYCHOPHARM
Iain S Mcgregor
Background: Cannabidiol (CBD), a major nonintoxicating constituent of cannabis, exhibits anxiolytic properties in preclinical and human studies and is of interest as a novel intervention for treating anxiety disorders. Existing first-line pharmacotherapies for these disorders include selective serotonin reuptake inhibitor and other antidepressants. Cannabidiol has well-described inhibitory action on cytochrome P450 (CYP450) drug-metabolizing enzymes and significant drug-drug interactions (DDIs) between CBD and various anticonvulsant medications (eg, clobazam) have been described in the treatment of epilepsy. Here, we examined the likelihood of DDIs when CBD is added to medications prescribed in the treatment of anxiety. Methods: The effect of CBD on CYP450-mediated metabolism of the commonly used antidepressants fluoxetine, sertraline, citalopram, and mirtazapine were examined in vitro. Cannabidiol-citalopram interactions were also examined in vivo in patients (n = 6) with anxiety disorders on stable treatment with citalopram or escitalopram who received ascending daily doses of adjunctive CBD (200-800 mg) over 12 weeks in a recent clinical trial. Results: Cannabidiol minimally affected the metabolism of sertraline, fluoxetine, and mirtazapine in vitro. However, CBD significantly inhibited CYP3A4 and CYP2C19-mediated metabolism of citalopram and its stereoisomer escitalopram at physiologically relevant concentrations, suggesting a possible in vivo DDI. In patients on citalopram or escitalopram, the addition of CBD significantly increased citalopram plasma concentrations, although it was uncertain whether this also increased selective serotonin reuptake inhibitor-mediated adverse events. Conclusions: Further pharmacokinetic examination of the interaction between CBD and citalopram/escitalopram is clearly warranted, and clinicians should be vigilant around the possibility of treatment-emergent adverse effects when CBD is introduced to patients taking these antidepressants.
A Change in Blood Carbamazepine Levels Associated With Cannabis Use: Implications for Clinical Practice
J CLIN PSYCHIAT
Kathryn K. Ridout
Kelly C Young-Wolff
Samuel J Ridout
A Phase 1 Open-Label, Fixed-Sequence Pharmacokinetic Drug Interaction Trial to Investigate the Effect of Cannabidiol on the CYP1A2 Probe Caffeine in Healthy Subjects
Ching Thai
David Critchley
Bola Tayo
This pharmacokinetic (PK) drug-interaction trial investigated the effects of repeated dosing of a plant-derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the United States and Epidyolex in Europe; 100 mg/mL oral solution) on caffeine clearance via modulation of cytochrome P450 (CYP) 1A2 activity in healthy adults. In this phase 1 open-label, fixed-sequence trial, all subjects received a single 200 mg caffeine dose and placebo on day 1. Subjects then titrated CBD from 250 mg once daily to 750 mg twice daily between days 3 and 11 and took 750 mg CBD twice daily between days 12 and 27. On day 26, subjects received a single 200-mg caffeine dose with their morning CBD dose. Plasma concentrations of caffeine and its CYP1A2-mediated metabolite, paraxanthine, were determined on days 1 and 26 and PK parameters derived using noncompartmental analysis. Safety was monitored throughout. Sixteen subjects enrolled, and 9 completed treatment. When caffeine was administered with steady-state CBD, caffeine exposure increased by 15% for Cmax and 95% for AUC0-∞ , tmax increased from 1.5 to 3.0 hours, and t1/2 increased from 5.4 to 10.9 hours compared with caffeine administered with placebo. Under the same conditions, paraxanthine exposure decreased by 22% for Cmax and increased by 18% for AUC0-∞ , tmax increased from 8.0 to 14.0 hours, and t1/2 increased from 7.2 to 13.7 hours. Overall, there were no unexpected adverse events; diarrhea was most common, and 6 subjects discontinued because of elevated liver transaminases. These data suggest that CBD is an inhibitor of CYP1A2.
Identification of Phenotypic Characteristics in Three Chemotype Categories in the Genus Cannabis
HORTSCIENCE
Philippe Henry
Jacqueline Shan
Dan Jin
Jie Chen
Modern Cannabis cultivars are morphologically distinguished by their leaflet shapes (wide for "Indica" and narrow for "Sativa") by users and breeders. However, there are no scientific bases or references for determining the shape of these leaflets. In addition, these two categories contained mostly THC dominant (high THC) cultivars while excluded CBD dominant (high CBD) and intermediate (intermediate level of both THC and CBD) cultivars. This study investigated the phenotypic variation in 21 Cannabis cultivars covering three chemical phenotypes, referred to as chemotypes, grown in a commercial greenhouse. Thirty morphological traits were measured in the vegetative, flowering, and harvest stages on live plants and harvested inflorescences. The collected data were subjected to correlation analysis, hierarchical clustering, principal component analysis, and canonical correlation analysis with preassigned chemotypes. Canonical correlation analysis assigned individual plants to their chemotypes with 92.9% accuracy. Significant morphological differences were identified. Traits usable as phenotype markers for CBD dominant cultivars included light-green and narrow leaflets, a greater number of primary and secondary serrations, loose inflorescences, dense and resinous trichomes, and Botrytis cinerea resistance. Traits for intermediate cultivars included deep-green and medium-wide leaflets, more primary and secondary serrations, medium compact inflorescences, trichomes that are less dense and less resinous, and Botrytis cinerea resistance. Traits for THC dominant cultivars included deep-green and wide leaflets, large and compact inflorescences, dense and resinous trichomes, and Botrytis cinerea susceptibility. The results of this study provide a comprehensive profile of morphological traits of modern Cannabis cultivars and provides the first such profile for CBD dominant and intermediate cultivars. Additionally, this study included the traits of inflorescences, which have not been compared between three chemotypes in the literature. Phenotype markers identified in this study can facilitate preliminary cultivar identification and selection on live plants before or as a supplement to chemical and genetic analysis.
In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa
Ayat Zagzoog
Kawthar Mohamed
Hye Ji J. Kim
Robert B Laprairie
The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆⁹-tetrahydrocannabinol (∆⁹-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆⁹-THC is known to bring about the 'high' associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆⁹-THC, ∆⁹-tetrahydrocannabinolic acid (∆⁹-THCa), ∆⁹-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.
Cannabis Legalization and Acute Harm From High Potency Cannabis Products: A Narrative Review and Recommendations for Public Health
Justin Matheson
Bernard Le Foll
Legalization and commercial sale of non-medical cannabis has led to increasing diversity and potency of cannabis products. Some of the American states that were the first to legalize have seen rises in acute harms associated with cannabis use, e.g. Colorado has seen increases in emergency department visits for cannabis-related acute psychological distress and severe vomiting (hyperemesis), as well as a number of high-profile deaths related to ingestion of high doses of cannabis edibles. Over-ingestion of cannabis is related to multiple factors, including the sale of cannabis products with high levels of THC and consumers' confusion regarding labelling of cannabis products, which disproportionately impact new or inexperienced users. Based on our review of the literature, we propose three approaches to minimizing acute harms: early restriction of cannabis edibles and high-potency products; clear and consistent labelling that communicates dose/serving size and health risks; and implementation of robust data collection frameworks to monitor harms, broken down by cannabis product type (e.g. dose, potency, route of administration) and consumer characteristics (e.g. age, sex, gender, ethnicity). Ongoing data collection and monitoring of harms in jurisdictions that have existing legal cannabis laws will be vital to understanding the impact of cannabis legalization and maximizing public health benefits.
Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs
Philip Patsalos
Jerzy P. Szaflarski
Barry E Gidal
Gilmour Morrison
Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.
Δ-9-Tetrahydrocannabinol Dose Increase leads to Warfarin Drug Interaction and Elevated INR
Geoff Brown
Terrance J Bellnier
Maria Janda
Kyle Miskowitz
Objective We have reported a case of a drug-drug interaction (DDI) involving warfarin and Δ-9-tetrahydrocannabinol (THC) that resulted in a supratherapeutic international normalized ratio (INR) level. The purpose of this case report is to highlight the possibility of a pharmacokinetic DDI between THC and warfarin. Case summary A 67-year-old Caucasian man suffering from chronic pain presented to a dispensary in Buffalo, NY, for a refill of his medical cannabis (MC). The patient asked to speak with the pharmacist, and during their discussion the patient stated that he had a supratherapeutic INR level of 5.2 measured at home with a self-test device. The patient had no evidence of bleeding, and administration of warfarin was held for 2 days before the INR level returned to a normal range. The supratherapeutic level occurred when the patient was self-titrating his dose of THC and scored an 8, or "probable," on the Naranjo Adverse Drug Effect Probability Scale. Practice implications Warfarin and cannabinoids such as THC are both metabolized by cytochrome P450 (CYP) isozymes present in the liver and gastrointestinal tract. In the case described, a dose increase of 7.35 mg THC preceded an INR elevation of 5.2, but did not result in any bleeding. These observations are suggestive of a DDI involving warfarin and THC. Clinicians involved with MC should have adequate knowledge of the drugs that act as substrates, inhibitors, and inducers of CYP enzymes, including the major cannabinoids.
Toxicogenetic analysis of Δ9-THC-metabolizing enzymes
INT J LEGAL MED
Angela Gasse
Marielle Vennemann
H Köhler
Jennifer Schürenkamp
While the impact of genetic polymorphisms on the metabolism of various pharmaceuticals is well known, more data are needed to better understand the specific influence of pharmacogenetics on the metabolism of delta 9-tetrahydocannabinol (Δ9-THC). Therefore, the aim of the study was to analyze the potential impact of variations in genes coding for phase I enzymes of the Δ9-THC metabolism. First, a multiplex assay for genotyping different variants of genes coding for phase I enzymes was developed and applied to 66 Δ9-THC-positive blood samples obtained in cases of driving under the influence of drugs (DUID). Genetic and demographic data as well as plasma concentrations of Δ9-THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-Δ9-THC), and 11-nor-9-carboxy-Δ9-THC (Δ9-THC-COOH) were combined and statistically investigated. For cytochrome P450 2C19 (CYP2C19) variants, no differences in analyzed cannabinoid concentrations were found. There were also no differences in the concentrations of Δ9-THC and 11-OH-Δ9-THC for the different allelic CPY2C9 status. We recognized significantly lower Δ9-THC-COOH concentrations for CYP2C9*3 (p = 0.001) and a trend of lower Δ9-THC-COOH concentrations for CYP2C9*2 which did not reach statistical significance (p = 0.068). In addition, this study showed significantly higher values in the ratio of Δ9-THC/Δ9-THC-COOH for the carriers of the CYP2C9 variants CYP2C9*2 and CYP2C9*3 compared with the carriers of the corresponding wild-type alleles. Therefore, an impact of variations of the CYP2C9 gene on the interpretation of cannabinoid plasma concentrations in DUID cases should be considered.
Delta-9-Tetrahydrocannabinol and Cannabidiol Drug-Drug Interactions
Paul T Kocis
Kent E. Vrana
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).
Predicting the Potential for Cannabinoids to Precipitate Pharmacokinetic Drug Interactions via Reversible Inhibition or Inactivation of Major Cytochromes P450
Sumit Bansal
Jashvant Unadkat
Neha Maharao
Mary F. Paine
Cannabis is used for both recreational and medicinal purposes. The most abundant constituents are the cannabinoids - cannabidiol (CBD, nonpsychoactive) and (-)-trans-Δ9-tetrahydrocannabinol (THC, psychoactive). Both have been reported to reversibly inhibit or inactivate cytochrome P450 (CYPs) enzymes. However, the low aqueous solubility, microsomal protein binding, and nonspecific binding to labware were not considered, potentially leading to an underestimation of CYPs inhibition potency. Therefore, the binding-corrected reversible (IC50,u) and irreversible (K I,u ) inhibition potency of each cannabinoid toward major CYPs were determined. The fraction unbound of CBD and THC in the incubation mixture was 0.12 ± 0.04 and 0.05 ± 0.02, respectively. The IC50,u for CBD toward CYP1A2, 2C9, 2C19, 2D6, and 3A was 0.45 ± 0.17, 0.17 ± 0.03, 0.30 ± 0.06, 0.95 ± 0.50, and 0.38 ± 0.11 µM, respectively; the IC50,u for THC was 0.06 ± 0.02, 0.012 ± 0.001, 0.57 ± 0.22, 1.28 ± 0.25, and 1.30 ± 0.34 µM, respectively. Only CBD showed time-dependent inactivation (TDI) of CYP1A2, 2C19, and CYP3A, with inactivation efficiencies (kinact/KI,u) of 0.70 ± 0.34, 0.11 ± 0.06, and 0.14 ± 0.04 minutes-1 µM-1, respectively. A combined (reversible inhibition and TDI) mechanistic static model populated with these data predicted a moderate to strong pharmacokinetic interaction risk between orally administered CBD and drugs extensively metabolized by CYP1A2/2C9/2C19/2D6/3A and between orally administered THC and drugs extensively metabolized by CYP1A2/2C9/3A. These predictions will be extended to a dynamic model using physiologically based pharmacokinetic modeling and simulation and verified with a well-designed clinical cannabinoid-drug interaction study. SIGNIFICANCE STATEMENT: This study is the first to consider the impact of limited aqueous solubility, nonspecific binding to labware, or extensive binding to incubation protein shown by cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) on their true cytochrome P450 inhibitory potency. A combined mechanistic static model predicted a moderate to strong pharmacokinetic interaction risk between orally administered CBD and drugs extensively metabolized by CYP1A2, 2C9, 2C19, 2D6, or 3A and between orally administered THC and drugs extensively metabolized by CYP1A2, 2C9, or 3A.
A Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers
EUR J DRUG METAB PH
Daniel Perkins
Juliet Butler
Katherine S Ong
Brian Lilley
Background There is increasing interest in the use of purified cannabidiol (CBD) as a treatment for a wide range of conditions due to its reported anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties.Objective The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single ascending dose of a new lipid-based oral formulation of CBD in healthy volunteers after a high-fat meal.MethodsA total of 24 eligible healthy volunteers (aged 18–48 years) were randomised to one of three sequential cohorts (each with six active and two placebo subjects). Cohort 1 received 5 mg/kg CBD or placebo, cohort 2 received 10 mg/kg CBD or placebo (cohort 2), and cohort 3 received 20 mg/kg CBD or placebo. Data relating to adverse events, vital signs, clinical laboratory assessments, 12-lead ECGs, physical examinations and concomitant medications were collected to assess safety and tolerability. Blood samples were collected up to 8 days postdose and plasma was analysed by liquid chromatography and mass spectrometry to assess the pharmacokinetics of the CBD formulation.ResultsCBD was well tolerated in the healthy volunteers (mean age: 24.0 years) treated with a single oral dose of CBD. There were no safety concerns with increasing the dose and the safety profiles of the CBD-treated and placebo-treated subjects were similar. The most frequently reported treatment emergent adverse events (TEAEs) were headache (17%) and diarrhoea (8%). There were no reported serious adverse events (SAEs) and no clinical laboratory findings, vital signs, ECGs or physical examination findings that were reported as TEAEs or were of clinical significance during the study. After a high-fat meal, CBD was detected in plasma samples at 15 min postdose; the median time to maximum plasma concentration (Tmax) was 4 h across all three CBD dose cohorts. The CBD plasma exposure [maximum observed plasma concentration (Cmax) and the area under the concentration–time curve (AUC)] increased in a dose-proportional manner and declined to levels approaching the lower level of quantification by day 8. The terminal elimination half-life was approximately 70 h, suggesting that 2–3 weeks are needed to fully eliminate CBD.Conclusions This new CBD formulation demonstrated a favourable safety and tolerability profile in healthy volunteers that was consistent with the profiles reported for other purified CBD products. No severe or serious AEs were observed in this study and there were no safety concerns.Trial RegistrationACTRN12618001424291. Registered August 2018.
Cannabinoids, Blood–Brain Barrier, and Brain Disposition
Fabrizio Calapai
Luigi Cardia
Emanuela Elisa Sorbara
Carmen Mannucci
Potential therapeutic actions of the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are based on their activity as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds. THC and CBD lipophilicity and their neurological actions makes them candidates as new medicinal approaches to treat central nervous system (CNS) diseases. However, they show differences about penetrability and disposition in the brain. The present article is an overview about THC and CBD crossing the blood-brain barrier (BBB) and their brain disposition. Several findings indicate that CBD can modify the deleterious effects on BBB caused by inflammatory cytokines and may play a pivotal role in ameliorating BBB dysfunction consequent to ischemia. Thus supporting the therapeutic potential of CBD for the treatment of ischemic and inflammatory diseases of CNS. Cannabinoids positive effects on cognitive function could be also considered through the aspect of protection of BBB cerebrovascular structure and function, indicating that they may purchase substantial benefits through the protection of BBB integrity. Delivery of these cannabinoids in the brain following different routes of administration (subcutaneous, oral, and pulmonary) is illustrated and commented. Finally, the potential role of cannabinoids in drug-resistance in the clinical management of neurological or psychiatric diseases such as epilepsy and schizophrenia is discussed on the light of their crossing the BBB.
Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes
Kaiping Dai
Zhen Xie
Cannabis research has historically focused on the most prevalent cannabinoids. However, extracts with a broad spectrum of secondary metabolites may have increased efficacy and decreased adverse effects compared to cannabinoids in isolation. Cannabis's complexity contributes to the length and breadth of its historical usage, including the individual application of the leaves, stem barks, and roots, for which modern research has not fully developed its therapeutic potential. This study is the first attempt to profile secondary metabolites groups in individual plant parts comprehensively. We profiled 14 cannabinoids, 47 terpenoids (29 monoterpenoids, 15 sesquiterpenoids, and 3 triterpenoids), 3 sterols, and 7 flavonoids in cannabis flowers, leaves, stem barks, and roots in three chemovars available. Cannabis inflorescence was characterized by cannabinoids (15.77–20.37%), terpenoids (1.28–2.14%), and flavonoids (0.07–0.14%); the leaf by cannabinoids (1.10–2.10%), terpenoids (0.13–0.28%), and flavonoids (0.34–0.44%); stem barks by sterols (0.07–0.08%) and triterpenoids (0.05–0.15%); roots by sterols (0.06–0.09%) and triterpenoids (0.13–0.24%). This comprehensive profile of bioactive compounds can form a baseline of reference values useful for research and clinical studies to understand the "entourage effect" of cannabis as a whole, and also to rediscover therapeutic potential for each part of cannabis from their traditional use by applying modern scientific methodologies.
Marijuana legalization and historical trends in marijuana use among US residents aged 12-25: Results from the 1979-2016 National Survey on drug use and health
Bin Yu
Xinguang Chen
Xiangfan Chen
Hong Yan
Background: Marijuana is the most commonly used illicit drug in the United States. More and more states legalized medical and recreational marijuana use. Adolescents and emerging adults are at high risk for marijuana use. This ecological study aims to examine historical trends in marijuana use among youth along with marijuana legalization. Method: Data (n = 749,152) were from the 31-wave National Survey on Drug Use and Health (NSDUH), 1979-2016. Current marijuana use, if use marijuana in the past 30 days, was used as outcome variable. Age was measured as the chronological age self-reported by the participants, period was the year when the survey was conducted, and cohort was estimated as period subtracted age. Rate of current marijuana use was decomposed into independent age, period and cohort effects using the hierarchical age-period-cohort (HAPC) model. Results: After controlling for age, cohort and other covariates, the estimated period effect indicated declines in marijuana use in 1979-1992 and 2001-2006, and increases in 1992-2001 and 2006-2016. The period effect was positively and significantly associated with the proportion of people covered by Medical Marijuana Laws (MML) (correlation coefficients: 0.89 for total sample, 0.81 for males and 0.93 for females, all three p values < 0.01), but was not significantly associated with the Recreational Marijuana Laws (RML). The estimated cohort effect showed a historical decline in marijuana use in those who were born in 1954-1972, a sudden increase in 1972-1984, followed by a decline in 1984-2003. Conclusion: The model derived trends in marijuana use were coincident with the laws and regulations on marijuana and other drugs in the United States since the 1950s. With more states legalizing marijuana use in the United States, emphasizing responsible use would be essential to protect youth from using marijuana.
A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol
Cinzia Citti
Pasquale Linciano
Fabiana Russo
Giuseppe Cannazza
(-)-Trans-Δ9-tetrahydrocannabinol (Δ9-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ9-THC with a longer side chain have shown cannabimimetic properties far higher than Δ9-THC itself. In the attempt to define the phytocannabinoids profile that characterizes a medicinal cannabis variety, a new phytocannabinoid with the same structure of Δ9-THC but with a seven-term alkyl side chain was identified. The natural compound was isolated and fully characterized and its stereochemical configuration was assigned by match with the same compound obtained by a stereoselective synthesis. This new phytocannabinoid has been called (-)-trans-Δ9-tetrahydrocannabiphorol (Δ9-THCP). Along with Δ9-THCP, the corresponding cannabidiol (CBD) homolog with seven-term side alkyl chain (CBDP) was also isolated and unambiguously identified by match with its synthetic counterpart. The binding activity of Δ9-THCP against human CB1 receptor in vitro (Ki = 1.2 nM) resulted similar to that of CP55940 (Ki = 0.9 nM), a potent full CB1 agonist. In the cannabinoid tetrad pharmacological test, Δ9-THCP induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating a THC-like cannabimimetic activity. The presence of this new phytocannabinoid could account for the pharmacological properties of some cannabis varieties difficult to explain by the presence of the sole Δ9-THC.
A Phase I, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics, Safety, and Tolerability of Cannabidiol in Subjects with Mild to Severe Renal Impairment
Farhad Sahebkar
Lesley Taylor
Introduction As patients who receive cannabidiol (CBD) may have co-existing renal morbidities, it is important to understand whether dose adjustments are necessary to mitigate the risk of exposure-related toxicity. This study was conducted to evaluate the pharmacokinetics, safety, and tolerability of CBD in patients with renal impairment. Methods The pharmacokinetics and safety of a single oral 200 mg dose of a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (Epidiolex® in the USA; 100 mg/mL) were assessed in subjects with mild, moderate, or severe renal impairment (n = 8/group) relative to matched subjects with normal renal function (n = 8). Blood samples were collected until 48 h post-dose and evaluated by liquid chromatography with tandem mass spectrometry. Analysis of variance was used to compare primary pharmacokinetic parameters (maximum measured plasma concentration [Cmax], oral clearance of drug from plasma [CL/F], renal clearance [CLR], area under the plasma concentration–time curve [AUC] from time zero to last measurable concentration [AUCt], and AUC from time zero to infinity [AUC∞]); descriptive analysis was used for secondary pharmacokinetic parameters (time to Cmax [tmax], terminal [elimination] half-life [t½], cumulative amount excreted from time zero to the last quantifiable sample [Aelast], and fraction of the systemically available drug excreted into the urine [fe]). Results No statistically significant differences were observed in Cmax, AUCt, AUC∞, or tmax values between subjects with mild, moderate, or severe renal impairment and subjects with normal renal function for CBD or its major metabolites, 7-carboxy-CBD (7-COOH-CBD) and 7-hydroxy-CBD (7-OH-CBD), and minor metabolite, 6-hydroxy-CBD (6-OH-CBD); geometric mean ratio for Cmax values ranged from 0.68 to 1.35. No differences were observed for other secondary parameters (Aelast and fe). CBD, 7-COOH-CBD, 7-OH-CBD, and 6-OH-CBD were highly protein bound (> 90%); binding was similar in all subject groups. Urine analysis for CBD recorded no appreciable amount, and thus no urinary pharmacokinetic parameters could be derived. Adverse events (AEs) affected two subjects; all five AEs were mild in severity and resolved during the trial. There were no serious AEs or discontinuations due to AEs. Laboratory, physical examination, vital sign, and 12-lead electrocardiogram findings were not clinically significant. Conclusion Renal impairment had no effect on the metabolism of CBD after a single oral 200 mg dose. CBD was generally well tolerated in subjects with varying degrees of renal function. Registration European Union Clinical Trials Register (EudraCT) no. 2015-002122-39.
Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions
Nathan L. Absalom
Sarah V. Abelev
Objective: Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. Methods: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a+/- mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a+/- mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together. Results: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation. Significance: Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.
The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications
Bill J. Gurley
Yuli Qian
John S Markowitz
Purpose: Increased cannabis use and recent drug approvals pose new challenges for avoiding drug interactions between cannabis products and conventional medications. This review aims to identify drug-metabolizing enzymes and drug transporters that are affected by concurrent cannabis use and, conversely, those co-prescribed medications that may alter the exposure to one or more cannabinoids. Methods: A systematic literature search was conducted utilizing the Google Scholar search engine and MEDLINE (PubMed) database through March 2019. All articles describing in vitro or clinical studies of cannabis drug interaction potential were retrieved for review. Additional articles of interest were obtained through cross-referencing of published bibliographies. Findings: After comparing the in vitro inhibition parameters to physiologically achievable cannabinoid concentrations, it was concluded that CYP2C9, CYP1A1/2, and CYP1B1 are likely to be inhibited by all 3 major cannabinoids Δ-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). The isoforms CYP2D6, CYP2C19, CYP2B6, and CYP2J2 are inhibited by THC and CBD. CYP3A4/5/7 is potentially inhibited by CBD. Δ-Tetrahydrocannabinol also activates CYP2C9 and induces CYP1A1. For non-CYP drug-metabolizing enzymes, UGT1A9 is inhibited by CBD and CBN, whereas UGT2B7 is inhibited by CBD but activated by CBN. Carboxylesterase 1 (CES1) is potentially inhibited by THC and CBD. Clinical studies suggest inhibition of CYP2C19 by CBD, inhibition of CYP2C9 by various cannabis products, and induction of CYP1A2 through cannabis smoking. Evidence of CBD inhibition of UGTs and CES1 has been shown in some studies, but the data are limited at present. We did not identify any clinical studies suggesting an influence of cannabinoids on drug transporters, and in vitro results suggest that a clinical interaction is unlikely. Conclusions: Medications that are prominent substrates for CYP2C19, CYP2C9, and CYP1A2 may be particularly at risk of altered disposition by concomitant use of cannabis or 1 or more of its constituents. Caution should also be given when coadministered drugs are metabolized by UGT or CES1, on which subject the information remains limited and further investigation is warranted. Conversely, conventional drugs with strong inhibitory or inductive effects on CYP3A4 are expected to affect CBD disposition.
Probable Interaction Between Warfarin and Inhaled and Oral Administration of Cannabis
Amy Hsu
Nathan A. Painter
Objective To report a probable interaction between warfarin and edible cannabis that resulted in an elevated international normalized ratio (INR) without bleeding complications. Case Summary A 35-year-old Middle Eastern male on warfarin long term with an INR goal of 2.5 (accepted range: 2.0-3.0). The patient has generally been stable on warfarin 10 mg daily from 2010 to 2018, until INR suddenly increased to 7.2 following 1 month of edible cannabis ingestion and cannabis smoking. Patient denied any signs and symptoms of bleeding. No other reasonable causes of the elevation in INR were apparent. The patient was advised to hold 2 doses of warfarin and discontinue cannabis use. The INR dropped below 4 upon discontinuation of cannabis with dose adjustments to warfarin. Discussion The elevation in INR can be explained by the inhibition of CYP2C9 by cannabis use causing decreased metabolism of warfarin. The interaction between warfarin and cannabis was determined to be probable using the Horn Drug Interaction Probability Scale. Conclusions There are no previous reports of interactions between edible cannabis and warfarin, with very few case reports describing the interaction with other forms of cannabis. Close monitoring of INR in patients with concomitant cannabis is recommended for proper warfarin management.
Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials
Serena Silvestro
Santa Mammana
Eugenio Cavalli
Emanuela Mazzon
Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from Cannabis sativa. CBD is a terpenophenol and it has received a great scientific interest thanks to its medical applications. This compound showed efficacy as anti-seizure, antipsychotic, neuroprotective, antidepressant and anxiolytic. The neuroprotective activity appears linked to its excellent anti-inflammatory and antioxidant properties. The purpose of this paper is to evaluate the use of CBD, in addition to common anti-epileptic drugs, in the severe treatment-resistant epilepsy through an overview of recent literature and clinical trials aimed to study the effects of the CBD treatment in different forms of epilepsy. The results of scientific studies obtained so far the use of CBD in clinical applications could represent hope for patients who are resistant to all conventional anti-epileptic drugs.
A Phase 1, Open‐Label, Parallel‐Group, Single‐Dose Trial of the Pharmacokinetics and Safety of Cannabidiol (CBD) in Subjects With Mild to Severe Hepatic Impairment
Julie Crockett
The pharmacokinetics and safety of a single oral dose of 200‐mg plant‐derived pharmaceutical formulation of highly purified cannabidiol (CBD) in oral solution (Epidiolex in the United States; 100 mg/mL) were assessed in subjects with mild to severe hepatic impairment (n = 8 each for mild and moderate, n = 6 for severe) relative to matched subjects with normal hepatic function (n = 8). Blood samples were collected until 48 hours after dosing and evaluated by liquid chromatography and tandem mass spectrometry. Pharmacokinetic parameters (primarily maximum measured plasma concentration, area under the plasma concentration–time curve from time zero to time t, area under the concentration‐time curve from time zero to infinity, time to maximum plasma concentration, and terminal half‐life) of CBD and its major metabolites were derived using non‐compartmental analysis. CBD was rapidly absorbed in all groups independent of hepatic function (median time to maximum plasma concentration, 2‐2.8 hours). Exposure (area under the concentration–time curve from time zero to infinity) to total CBD slightly increased in subjects with mild hepatic impairment (geometric mean ratio [GMR], 1.48; 90% confidence interval [CI], 0.90‐2.41). However, there were clinically relevant increases in subjects with moderate (GMR, 2.45; 90%CI, 1.50‐4.01) and severe (GMR, 5.15; 90%CI, 2.94‐9.00) hepatic impairment, relative to subjects with normal hepatic function. Exposure to the CBD metabolites (6‐hydroxy‐CBD and 7‐hydroxy‐CBD) also increased in subjects with moderate and severe hepatic impairment, but to a lesser extent than the parent drug. The 7‐carboxy‐CBD metabolite exposure was lower in subjects with severe hepatic impairment when compared with subjects with normal liver function. These findings indicate that dose modification is necessary in patients with moderate and severe hepatic impairment, and a lower starting dose and slower titration are necessary based on benefit‐risk. CBD was well tolerated, and there were no serious adverse events reported during the trial.
A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects
Graham Blakey
Kenneth William Sommerville
GW Pharmaceuticals' formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox‐Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open‐label, fixed‐sequence, drug‐drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady‐state pharmacokinetics of clobazam (and N‐desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7‐hydroxy‐cannabidiol [7‐OH‐CBD] and 7‐carboxy‐cannabidiol [7‐COOH‐CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure (maximum concentration [Cmax] and area under the concentration‐time curve [AUC], 1.2‐fold), N‐desmethylclobazam exposure increased (Cmax and AUC, 3.4‐fold), stiripentol exposure increased slightly (Cmax, 1.3‐fold; AUC, 1.6‐fold), while no clinically relevant effect on valproate exposure was observed. Concomitant clobazam with cannabidiol increased 7‐OH‐CBD exposure (Cmax, 1.7‐fold; AUC, 1.5‐fold), without notable 7‐COOH‐CBD or cannabidiol increases. Stiripentol decreased 7‐OH‐CBD exposure by 29% and 7‐COOH‐CBD exposure by 13%. There was no effect of valproate on cannabidiol or its metabolites. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clinically significant safety findings.
Prediction of Carboxylesterase 1 (CES1)-mediated In Vivo Drug Interaction between Methylphenidate and Cannabinoids using Static and Physiologically Based Pharmacokinetic Models
The use of cannabis products has increased substantially. Cannabis products have been perceived and investigated as potential treatments for attention-deficit/hyperactivity disorder (ADHD). Accordingly, co-administration of cannabis products and methylphenidate (MPH), a first-line medication for ADHD, is possible. Oral MPH undergoes extensive pre-systemic metabolism by carboxylesterase 1 (CES1), a hepatic enzyme which can be inhibited by two prominent cannabinoids, ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD). This prompts further investigation into the likelihood of clinical interactions between MPH and these two cannabinoids through CES1 inhibition. In the present study, inhibition parameters were obtained from a human liver S9 system and then incorporated into static and physiologically-based pharmacokinetic (PBPK) models for prediction of potential clinical significance. The inhibition of MPH hydrolysis by THC and CBD was reversible, with estimated unbound inhibition constants (Ki,u) of 0.031 and 0.091 µM, respectively. The static model predicted a mild increase in MPH exposure by concurrent THC (34%) and CBD (94%) from smoking a cannabis cigarette and ingestion of prescriptive CBD, respectively. PBPK models suggested no significant interactions between single doses of MPH and CBD (2.5 - 10 mg/kg) when administered simultaneously, while a mild interaction (AUC increased by up to 55% and Cmax by up to 45%) is likely if multiple doses of CBD (10 mg/kg twice daily) are administered. In conclusion, the pharmacokinetic disposition of MPH can be potentially influenced by THC and CBD under certain clinical scenarios. Whether the magnitude of predicted interactions translates into clinically relevant outcomes requires verification in an appropriately designed clinical study. Significance Statement This work demonstrated a potential mechanism of drug-drug interactions between methylphenidate (MPH) and two major cannabinoids (∆9-tetrahydrocannabinol [THC] and cannabidiol [CBD]) not previously reported. We predicted a mild interaction between MPH and THC when the cannabinoid exposure occurred via cannabis smoking. Mild interactions between MPH and CBD were predicted with multiple oral administrations of CBD.
Use of Marijuana: Effect on Brain Health: A Scientific Statement From the American Heart Association
Fernando D. Testai
Philip B Gorelick
Hugo Aparicio
Sarah Y. Song
Marijuana is perceived as a harmless drug, and its recreational use has gained popularity among young individuals. The concentration of active ingredients in recreational formulations has gradually increased over time, and high-potency illicit cannabinomimetics have become available. Thus, the consumption of cannabis in the general population is rising. Data from preclinical models demonstrate that cannabinoid receptors are expressed in high density in areas involved in cognition and behavior, particularly during periods of active neurodevelopment and maturation. In addition, growing evidence highlights the role of endogenous cannabinoid pathways in the regulation of neurotransmitter release, synaptic plasticity, and neurodevelopment. In animal models, exogenous cannabinoids disrupt these important processes and lead to cognitive and behavioral abnormalities. These data correlate with the higher risk of cognitive impairment reported in some observational studies done in humans. It is unclear whether the effect of cannabis on cognition reverts after abstinence. However, this evidence, along with the increased risk of stroke reported in marijuana users, raises concerns about its potential long-term effects on cognitive function. This scientific statement reviews the safety of cannabis use from the perspective of brain health, describes mechanistically how cannabis may cause cognitive dysfunction, and advocates for a more informed health care worker and consumer about the potential for cannabis to adversely affect the brain.
Comprehensive Predictions of Cytochrome P450 (P450)-Mediated In Vivo Cannabinoid-Drug Interactions Based on Reversible and Time-Dependent P450 Inhibition in Human Liver Microsomes
DRUG METAB DISPOS
Jashvant D. Unadkat
We previously reported the unbound reversible (IC50,u) and time-dependent (KI,u) inhibition potencies of cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), and THC metabolites (11-OH THC, 11-COOH THC) against the major cytochrome P450 (CYP) enzymes (1A2, 2C9, 2C19, 2D6, 3A). Here, using human liver microsomes, we determined the CYP2A6, 2B6, and 2C8 IC50,u values of the aforementioned cannabinoids and the IC50,u and KI,u of the circulating CBD metabolites, 7-OH CBD and 7-COOH CBD, against all the CYPs listed above. The IC50,u of CBD, 7-OH CBD, THC, and 11-OH THC against CYP2B6 was 0.05, 0.34, 0.40, and 0.38 µM, respectively and against CYP2C8 was 0.28, 1.02, 0.67, and 4.37 µM, respectively. 7-COOH CBD, but not 11-COOH THC, was a weak inhibitor of CYP2B6 and 2C8. All tested cannabinoids except 11-COOH THC were weak inhibitors of CYP2A6. 7-OH CBD inhibited all CYPs examined (IC50,u<2.5 µM) except CYP1A2 and inactivated CYP2C19 and CYP3A, with inactivation efficiencies (kinact/KI,u) of 0.10 and 0.14 min-1µM-1, respectively. Using several different static models, we predicted the following maximum pharmacokinetic interactions (affected CYP probe drug and AUC ratio) between oral CBD (700 mg) and drugs predominantly metabolized by CYP3A (midazolam, 14.8) >2C9 (diclofenac, 9.6) >2C19 (omeprazole, 7.3) >1A2 (theophylline, 4.0) >2B6 (ticlopidine, 2.2) >2D6 (dextromethorphan, 2.1) >2C8 (repaglinide, 1.6). Oral (130 mg) or inhaled (75 mg) THC was predicted to precipitate interactions with drugs predominately metabolized by CYP2C9 (diclofenac, 6.6 or 2.3, respectively) >3A (midazolam, 1.8) >1A2 (theophylline, 1.4). In vivo drug interaction studies are warranted to verify these predictions. Significance Statement This study, combined with our previous findings, provides for the first time a comprehensive analysis of the potential for cannabidiol, delta-9-tetrahydrocannabinol, and their metabolites to inhibit cytochrome P450 enzymes in a reversible or time-dependent manner. These analyses enabled us to predict the potential of these cannabinoids to produce drug interactions in vivo at clinical or recreational doses.
Public interest in ∆8-Tetrahydrocannabinol (delta-8-THC) increased in US states that restricted ∆9-Tetrahydrocannabinol (delta-9-THC) use
INT J DRUG POLICY
Eric Craig Leas
Alicia Nobles
Yuyan Shi
Erik Michael Hendrickson
Background There is an expanding unregulated market for a psychotropic compound called ∆⁸-Tetrahydrocannabinol (delta-8-THC) that is being derived from hemp, but there are no empirical estimates of public interest in this compound. Methods To measure public interest, we obtained yearly Google query fractions (QFs) that mentioned delta-8-THC (i.e., "delta 8," "delta-8," or "Δ8") for the past decade (from January 2011 through August 2021) for every country and territory in the world and every state in the United States (US) from Google Trends. We also obtained the same trends for the last complete month of data for all US states (July 2021) to compare across cannabis use policies. We summarized QFs across years, countries, US states and cannabis policies in US states using linear regression, means and ratios. We estimated raw search counts for the US using comscore.com. Results The global rate of delta-8-THC searches was stable between 2011 and 2019 before increasing by 257.0% from 2019 to 2020 and 705.0% from 2020 to 2021. In 2021, the rate of delta-8-THC searches in the US was at least 10 times higher than the rates in other countries or territories. In absolute terms, there were 22.3 million delta-8-THC searches in the US in the first 8 months of 2021 alone. Increases in delta-8-THC searches from 2020 to 2021 occurred in all 50 US states and the District of Columbia (Mean 854.2%; range = 256.4% – 2831.2%) but continued to vary substantially between states in 2021. In July 2021, the legal status of delta-9-THC use across US states explained 49.0% of the variance in delta-8-THC QFs between US states (R² = 0.490; p < 0.001) and was inversely associated, where delta-8-THC QFs were higher in jurisdictions with stricter cannabis use policies. Conclusion Public interest in delta-8-THC increased rapidly in 2020 and 2021 and was particularly high in US states that restricted delta-9-THC use. Jurisdictions should clarify whether delta-8-THC can be sold as a hemp product.
Cytochrome P450-Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol
Jessica L. Beers
Dong Fu
Klarissa Jackson
Cannabidiol (CBD) is a naturally occurring, non-psycho-toxic phytocannabinoid that has gained increasing attention as a popular consumer product and for its use in FDA-approved Epidiolex® (CBD oral solution) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome. CBD was previously reported to be metabolized primarily by cytochrome P450 (CYP) 2C19 and CYP3A4, with minor contributions from UDP-glucuronosyltransferases. 7-Hydroxy-CBD (7-OH-CBD) is the primary active metabolite with equipotent activity compared to CBD. Given the polymorphic nature of CYP2C19, we hypothesized that variable CYP2C19 expression may lead to interindividual differences in CBD metabolism to 7-OH-CBD. The objectives of this study were to further characterize the roles of CYP enzymes in CBD metabolism, specifically to the active metabolite 7-OH-CBD, and to investigate the impact of CYP2C19 polymorphism on CBD metabolism in genotyped human liver microsomes. The results from reaction phenotyping experiments with recombinant CYP enzymes and CYP-selective chemical inhibitors indicated that both CYP2C19 and CYP2C9 are capable of CBD metabolism to 7-OH-CBD. CYP3A played a major role in CBD metabolic clearance via oxidation at sites other than the 7-position. In genotyped human liver microsomes, 7-OH-CBD formation was positively correlated with CYP2C19 activity but was not associated with CYP2C19 genotype. In a subset of single-donor human liver microsomes with moderate to low CYP2C19 activity, CYP2C9 inhibition significantly reduced 7-OH-CBD formation, suggesting that CYP2C9 may play a greater role in CBD 7-hydroxylation than previously thought. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD. Significance Statement This study demonstrates that both CYP2C19 and CYP2C9 are involved in CBD metabolism to the active metabolite 7-OH-CBD, and CYP3A4 is a major contributor to CBD metabolism through pathways other than 7-hydroxylation. 7-OH-CBD formation was associated with human liver microsomal CYP2C19 activity, but not CYP2C19 genotype, and CYP2C9 was found to contribute significantly to 7-OH-CBD generation. These findings have implications for patients taking CBD, who may be at risk for clinically important CYP-mediated drug interactions.
Mechanisms of Action and Pharmacokinetics of Cannabis
Sirichai Chayasirisobhon
None: At least 100 cannabis species are compounds known as cannabinoids, a molecule with a 21-carbon terpenophenolic skeleton. Cannabinoids produce more than 100 naturally occurring chemicals, the most abundant of which are Δ-9-tetrahydrocannabinol (THC), cannabidiol (CBD), terpenes, and flavonoids. THC and CBD bind with cannabinoid receptors (CB1 and CB2), which are present in the brain and many organs. Metabolism of cannabis is determined by the route of consumption. When inhaled, THC and its metabolites enter the bloodstream rapidly via the lungs; they achieve peak levels within 6 to 10 minutes and reach the brain and various organs. The bioavailability of inhaled THC is 10% to 35%. After THC is absorbed, it travels to the liver where most of it is eliminated or metabolized to 11-OH-THC or 11-COOH-THC. The remaining THC and its metabolites enter the circulation. The bioavailability of ingested THC is only 4% to 12%. THC is highly lipid soluble and is therefore rapidly taken up by fat tissue. The plasma half-life of THC is 1 to 3 days in occasional users and 5 to 13 days in chronic users. The bioavailability of CBD via inhalation is 11% to 45%, whereas that of oral CBD is 6%. CBD has high lipophilicity and therefore is rapidly distributed in the brain, adipose tissue, and other organs. CBD is hydroxylated to 7-OH-CBD and 7-COOH-CBD by cytochrome P450 enzymes CYP3A4 and CYP2C9 in the liver and is excreted mainly in feces and less in urine. The plasma half-life of CBD is 18 to 32 hours.
THE PHARMACOLOGICAL CASE FOR CANNABIGEROL (CBG)
Rahul Nachnani
Wesley M. Raup-Konsavage
Kent Eugene Vrana
Medical cannabis and individual cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), are receiving growing attention in both the media and the scientific literature. The Cannabis plant, however, produces over 100 different cannabinoids, and cannabigerol (CBG) serves as the precursor molecule for the most abundant phytocannabinoids. CBG exhibits affinity and activity characteristics between THC and CBD at the cannabinoid receptors, but appears to be unique in its interactions with alpha-2 adrenoceptors and 5-HT1A Studies indicate that CBG may have therapeutic potential in treating neurological disorders (e.g., Huntington's Disease, Parkinson's Disease, and multiple sclerosis), inflammatory bowel disease, as well as having antibacterial activity. There is growing interest in the commercial use of this unregulated phytocannabinoid. This review focuses on the unique pharmacology of CBG, our current knowledge of its possible therapeutic utility, and its potential toxicological hazards. Significance Statement Cannabigerol (CBG) is currently being marketed as a dietary supplement and, as with cannabidiol (CBD) before, many claims are being made about its benefits. Unlike CBD, however, little research has been performed on this unregulated molecule, and much of what is known warrants further investigation to identify potential areas of therapeutic uses and hazards.
CBD and THC: Do they complement each other like yin and yang?
Increased public access to cannabis calls for a deeper understanding of cannabis's constituents and how they interact to induce clinical effects. Whereas trans‐Δ⁹‐tetrahydrocannabinol (THC) is considered the main psychoactive component in cannabis, producing the associated "high" or "euphoria," various findings demonstrate medical potential for cannabidiol (CBD), from anxiolytic to antiepileptic implications. This has translated into a public optimism and given way to the popular opinion that CBD can provide countless other therapeutic benefits, including the potential to mitigate some of the adverse side effects of THC, such as intoxication, psychomotor impairment, anxiety, and psychotic symptoms. This is particularly relevant for patients seeking to garner therapeutic benefits from cannabis without experiencing the burden of a significant subjective high. This article thus analyzes the scientific evidence available to support or disprove the idea that presence of CBD is beneficial and can exude a protective effect against THC. A thorough review of relevant literature, a basis from which to interpret such evidence through a critical mechanistic discussion, and the implications for patients are presented in this article.
Characterization of Differential Tissue Abundance of Major Non-CYP Enzymes in Human
MOL PHARMACEUT
Abdul Basit
Naveen K. Neradugomma
Christopher Wolford
Bhagwat Prasad
The availability of assays that predict the contribution of cytochrome P450 (CYP) metabolism allows for the design of new chemical entities (NCEs) with minimal oxidative metabolism. These NCEs are often substrates of non-CYP drug metabolizing enzymes (DMEs), such as UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), carboxylesterases (CESs), and aldehyde oxidase (AO). Nearly 30% of clinically approved drugs are metabolized by non-CYP enzymes. However, knowledge about the differential hepatic versus extrahepatic abundance of non-CYP DMEs is limited. In this study, we detected and quantified the protein abundance of eighteen non-CYP DMEs (AO, CES1 and 2, ten UGTs, and five SULTs) across five different human tissues. AO was most abundantly expressed in the liver and to a lesser extent in the kidney; however, it was not detected in the intestine, heart, or lung. CESs were ubiquitously expressed with CES1 being predominant in the liver, while CES2 was enriched in the small intestine. Consistent with the literature, UGT1A4, UGT2B4, and UGT2B15 demonstrated liver-specific expression, whereas UGT1A10 expression was specific to the intestine. UGT1A1 and UGT1A3 were expressed in both the liver and intestine; UGT1A9 was expressed in the liver and kidney; and UGT2B17 levels were significantly higher in the intestine than in the liver. All five SULTs were detected in the liver and intestine, and SULT1A1 and 1A3 were detected in the lung. Kidney abundance was the most variable among the studied tissues, and overall, high interindividual variability (>15-fold) was observed for UGT2B17, CES2 (intestine), SULT1A1 (liver), UGT1A9, UGT2B7, and CES1 (kidney). These differential tissue abundance data can be integrated into physiologically based pharmacokinetic (PBPK) models for the prediction of non-CYP drug metabolism and toxicity in hepatic and extrahepatic tissues.
Cannabinoids and the expanded endocannabinoid system in neurological disorders
Luigia Cristino
Tiziana Bisogno
Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system - known as the endocannabinoidome - that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.
Cannabis Use Motivations among Adults Prescribed Opioids for Pain versus Opioid Addiction
PAIN MANAG NURS
Selena N. Clem
Teresa Bigand
Marian Wilson
Background: Cannabis has been linked to reduced opioid use, although reasons for cannabis use among adults prescribed opioids are unclear. Aims: The purpose of this study was to determine whether motivations for cannabis use differ between adults prescribed opioids for persistent pain versus those receiving opioids as medication-assisted treatment for opioid use disorder. Design: A cross-sectional survey design was used. Participants: Adults prescribed opioids for persistent pain (n = 104) or opioid use disorder (n = 139) were recruited from outpatient settings. Methods: Data were collected on surveys asking about cannabis use and compared the two populations. A series of regression models examined population characteristics and cannabis use motivations using validated measures of the Marijuana Motives Measure scale. Results: More than half the sample (n = 122) reported current, daily cannabis use and 63% reported pain as a motivation for use. Adults with persistent pain were more likely to be older, female, and have higher levels of education (p < .05). Adults with opioid use disorder were more likely to report "enhancement" (p < .01) and relief of drug withdrawal symptoms (p < .001) as motivations for cannabis use. The most common reasons for cannabis use in both populations were social and recreational use and pain relief. Conclusions: Both studied populations have unmet health needs motivating them to use cannabis and commonly use cannabis for pain. Persistent pain participants were less likely to use cannabis for euphoric effects or withdrawal purposes. Nurses should assess for cannabis use, provide education on known risks and benefits, and offer options for holistic symptom management.
A marijuana-drug interaction primer: Precipitants, pharmacology, and pharmacokinetics
PHARMACOL THERAPEUT
Emily J. Cox
Gabriela Patilea-Vrana
The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms
Robyn Meech
Dong Gui Hu
Ross McKinnon
Peter Mackenzie
UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to a broad range of lipophilic molecules. This biotransformation plays a critical role in elimination of a broad range of exogenous chemicals and by-products of endogenous metabolism, and also controls the levels and distribution of many endogenous signaling molecules. In mammals, the superfamily comprises four families: UGT1, UGT2, UGT3, and UGT8. UGT1 and UGT2 enzymes have important roles in pharmacology and toxicology including contributing to interindividual differences in drug disposition as well as to cancer risk. These UGTs are highly expressed in organs of detoxification (e.g., liver, kidney, intestine) and can be induced by pathways that sense demand for detoxification and for modulation of endobiotic signaling molecules. The functions of the UGT3 and UGT8 family enzymes have only been characterized relatively recently; these enzymes show different UDP-sugar preferences to that of UGT1 and UGT2 enzymes, and to date, their contributions to drug metabolism appear to be relatively minor. This review summarizes and provides critical analysis of the current state of research into all four families of UGT enzymes. Key areas discussed include the roles of UGTs in drug metabolism, cancer risk, and regulation of signaling, as well as the transcriptional and posttranscriptional control of UGT expression and function. The latter part of this review provides an in-depth analysis of the known and predicted functions of UGT3 and UGT8 enzymes, focused on their likely roles in modulation of levels of endogenous signaling pathways.
Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites
Xinwen Wang
The escalating use of medical cannabis and significant recreational use of cannabis in recent years has led to a higher potential for metabolic interactions between cannabis or one or more of its components and concurrently used medications. Although there have been a significant number of in vitro and in vivo assessments of the effects of cannabis on cytochrome P450 and UDP-glucuronosyltransferase enzyme systems, there is limited information regarding the effects of cannabis on the major hepatic esterase, carboxylesterase 1 (CES1). In this study, we investigated the in vitro inhibitory effects of the individual major cannabinoids and metabolites ∆9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), 11-nor-THC-carboxylic acid, and 11-hydroxy-THC on CES1 activity. S9 fractions from human embryonic kidney 293 cells stably expressing CES1 were used in the assessment of cannabinoid inhibitory effects. THC, CBD, and CBN each exhibited substantial inhibitory potency, and were further studied to determine their mechanism of inhibition and kinetic parameters. The inhibition of CES1 by THC, CBD, and CBN was reversible and appears to proceed through a mixed competitive-noncompetitive mechanism. The inhibition constant (Ki) values for THC, CBD, and CBN inhibition were 0.541, 0.974, and 0.263 µM (0.170, 0.306, and 0.0817 µg/ml), respectively. Inhibition potency was increased when THC, CBD, and CBN were combined. Compared with the potential unbound plasma concentrations attainable clinically, the Ki values suggest a potential for clinically significant inhibition of CES1 by THC and CBD. CBN, however, is expected to have a limited impact on CES1. Carefully designed clinical studies are warranted to establish the clinical significance of these in vitro findings. Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
Cannabidiol as a Novel Candidate Alcohol Use Disorder Pharmacotherapy: A Systematic Review
Jasmine Turna
Sabrina Kaur Syan
Benicio N. Frey
James MacKillop
There is substantial interest in the therapeutic potential of cannabidiol (CBD), a non‐psychoactive cannabinoid found in plants of the genus Cannabis. The goal of the current systematic review was to characterize the existing literature on this topic and to evaluate the credibility of CBD as a candidate pharmacotherapy for alcohol use disorder (AUD). Using a comprehensive search strategy, 303 unique potential articles were identified and 12 ultimately met criteria for inclusion (8 using rodent models, 3 using healthy adult volunteers, and 1 using cell culture). In both rodent and cell culture models, CBD was found to exert a neuroprotective effect against adverse alcohol consequences on the hippocampus. In rodent models, CBD was found to attenuate alcohol‐induced hepatotoxicity, specifically, alcohol‐induced steatosis. Finally, findings from preclinical rodent models also indicate that CBD attenuates cue‐elicited and stress‐elicited alcohol‐seeking, alcohol self‐administration, withdrawal‐induced convulsions, and impulsive discounting of delayed rewards. In human studies, CBD was well tolerated and did not interact with the subjective effects of alcohol. Collectively, given its favorable effects on alcohol‐related harms and addiction phenotypes in preclinical models, CBD appears to have promise as a candidate AUD pharmacotherapy. This is further bolstered by the absence of abuse liability and its general tolerability. A clear limitation to the literature is the paucity of human investigations. Human preclinical and clinical studies are needed to determine whether these positive effects in model systems substantively translate into clinically‐relevant outcomes. This article is protected by copyright. All rights reserved.
Spotlight on CYP4B1
January 2023 · International Journal of Molecular Sciences
Annika Röder
Saskia Hüsken
Marco Girhard
The mammalian cytochrome P450 monooxygenase CYP4B1 can bioactivate a wide range of xenobiotics, such as its defining/hallmark substrate 4-ipomeanol leading to tissue-specific toxicities. Similar to other members of the CYP4 family, CYP4B1 has the ability to hydroxylate fatty acids and fatty alcohols. Structural insights into the enigmatic role of CYP4B1 with functions in both, xenobiotic and ... [Show full abstract] endobiotic metabolism, as well as its unusual heme-binding characteristics are now possible by the recently solved crystal structures of native rabbit CYP4B1 and the p.E310A variant. Importantly, CYP4B1 does not play a major role in hepatic P450-catalyzed phase I drug metabolism due to its predominant extra-hepatic expression, mainly in the lung. In addition, no catalytic activity of human CYP4B1 has been observed owing to a unique substitution of an evolutionary strongly conserved proline 427 to serine. Nevertheless, association of CYP4B1 expression patterns with various cancers and potential roles in cancer development have been reported for the human enzyme. This review will summarize the current status of CYP4B1 research with a spotlight on its roles in the metabolism of endogenous and exogenous compounds, structural properties, and cancer association, as well as its potential application in suicide gene approaches for targeted cancer therapy.
HepaRG cells undergo increased levels of post-differentiation patterning in physiologic conditions w...
Thomas J. DiProspero
Lauren G. Brown
Trevor D. Fachko
Matthew Ryen Lockett
Monolayer cultures of hepatocytes lack many aspects of the liver sinusoid, including a tissue-level organization that results from extracellular matrix interactions and gradients of soluble molecules that span from the portal triad to the central vein. We measured the activity and transcript levels of drug-metabolizing enzymes in HepaRG cells maintained in three different culture configurations: ... [Show full abstract] as monolayers, seeded onto paper scaffolds that were pre-loaded with a collagen matrix, and when seeded directly into the paper scaffolds as a cell-laden gel. Drug metabolism was significantly decreased in the presence of the paper scaffolds compared to monolayer configurations when cells were exposed to standard culture conditions. Despite this decreased function, transcript levels suggest the cells undergo increased polarization and adopt a biliary-like character in the paper scaffolds, including the increased expression of transporter proteins (e.g., ABCB11 and SLOC1B1 ) and the KRT19 cholangiocyte marker. When exposed to representative periportal or perivenous culture conditions, we observed in vivo zonal-like patterns, including increased cytochrome P450 (CYP) activity and transcript levels in the perivenous condition. This increased CYP activity is more pronounced in the laden configuration, supporting the need to include multiple aspects of the liver microenvironment to observe the post-differentiation processing of hepatocytes. TOC Figure
Contemplating cannabis? The complex relationship between cannabinoids and hepatic metabolism resulti...
January 2023 · Frontiers in Psychiatry
Rosemary T. Smith
Staci A. Gruber
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 ... [Show full abstract] 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.
Monolayer cultures of hepatocytes lack many aspects of the liver sinusoid, including a tissue-level organization that results from extracellular matrix interactions and gradients of soluble molecules that span from the portal triad to the central vein. We measured the activity and transcript levels of drug-metabolizing enzymes in HepaRG cells maintained in three different culture configurations: ... [Show full abstract] as monolayers, seeded onto paper scaffolds that were pre-loaded with a collagen matrix, and when seeded directly into the paper scaffolds as a cell-laden gel. Drug metabolism was significantly decreased in the presence of the paper scaffolds compared to monolayer configurations when cells were exposed to standard culture conditions. Despite this decreased function, transcript levels suggest the cells undergo increased polarization and adopt a biliary-like character in the paper scaffolds, including the increased expression of transporter proteins (e.g., ABCB11 and SLOC1B1 ) and the KRT19 cholangiocyte marker. When exposed to representative periportal or perivenous culture conditions, we observed in vivo zonal-like patterns, including increased cytochrome P450 (CYP) activity and transcript levels in the perivenous condition. This increased CYP activity is more pronounced in the laden configuration, supporting the need to include multiple aspects of the liver microenvironment to observe the post-differentiation processing of hepatocytes.
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