Cannabidiol and Serum Antiepileptic Drug Levels: The ABCs of CBD With AEDs.
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ABSTRACT:
SUBMITTER: Chang BS
PROVIDER: S-EPMC5967591 | biostudies-literature | 2018 Jan-Feb
REPOSITORIES: biostudies-literature
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Cannabidiol and Serum Antiepileptic Drug Levels: The ABCs of CBD With AEDs.
Epilepsy currents 20180101 1
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Project description:Recently, cannabinoids, such as cannabidiol (CBD) and Δ9 -tetrahydrocannabinol (THC), have been the subject of intensive research and heavy scrutiny. Cannabinoids encompass a wide array of organic molecules, including those that are physiologically produced in humans, synthesized in laboratories, and extracted primarily from the Cannabis sativa plant. These organic molecules share similarities in their chemical structures as well as in their protein binding profiles. However, pronounced differences do exist in their mechanisms of action and clinical applications, which will be briefly compared and contrasted in this review. The mechanism of action of CBD and its potential applications in cancer therapy will be the major focus of this review article.
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Project description:Purpose of reviewThis review will address the many uncertainties surrounding the medical use of cannabidiol (CBD). We will begin with an overview of the legal and commercial environment, examine recent preclinical and clinical evidence on CBD, explore questions concerning CBD raised by healthcare professionals and patients, investigate dosing regimens and methods of administration, and address current challenges in the accumulation of sound evidence.Recent findingsCBD has potential for relief of symptoms of pain, sleep, and mood disturbance in rheumatology patients, but sound clinical evidence is lacking. CBD is safe when accessed from a regulated source, whereas wellness products are less reliable regarding content and contaminants. Dosing for symptom relief has not yet been established. As many rheumatology patients are trying CBD as a self-management strategy, the healthcare community must urgently accrue sound evidence for effect.
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Project description:Introduction: Despite US FDA approval of cannabidiol (CBD) liquid (Epidiolex®), patients with epilepsy still supplement prescription treatments with dispensary CBD. This study aimed to evaluate therapeutic effectiveness of dispensary CBD. Methods: We retrospectively collected dosage information, CBD serum levels, efficacy, and adverse effects from patient charts (children, adolescents, adults) (n = 18). Results: All 18 patients showed no clinical benefit from dispensary CBD as detectable serum levels never reached a therapeutic range of 150 ng/mL (6 patients had barely detectable levels that were below laboratory reporting thresholds). Minute levels of tetrahydrocannabinol (THC) were found in 3 patients, and moderate levels were found in 1 patient. Conclusion: Dispensary CBD failed to reach effective therapeutic levels in all of these patients. The presence of THC demonstrates the current lack of regulation of dispensary CBD. Anecdotal reports of clinical effectiveness should be considered an effect of concomitant prescription antiseizure medications and not dispensary CBD.
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Project description:This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health products and CBD-associated health claims lacks a rigorous scientific foundation. CBD's reputation as a cure-all puts it in the same class as other "natural" panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the "natural" label. Literature evidence associates CBD with certain semiubiquitous, broadly screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.
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Project description:Cannabis-based products have experienced notable increases in co-usage alongside tobacco products. Several cannabinoids exhibit inhibition of a number of cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes, but few studies have examined their inhibition of enzymes involved in nicotine metabolism. The goal of the present study was to examine potential drug-drug interactions occurring in the nicotine metabolism pathway perpetrated by cannabidiol (CBD) and its active metabolite, 7-hydroxy-CBD (7-OH-CBD). The inhibitory effects of CBD and 7-OH-CBD were tested in microsomes from HEK293 cells overexpressing individual metabolizing enzymes and from human liver tissue. Assays with overexpressing microsomes demonstrated that CBD and 7-OH-CBD inhibited CYP-mediated nicotine metabolism. Binding-corrected IC50,u values for CBD inhibition of nicotine metabolism to cotinine and nornicotine, and cotinine metabolism to trans-3'-hydroxycotinine (3HC), were 0.27 ± 0.060, 0.23 ± 0.14, and 0.21 ± 0.14 μM, respectively, for CYP2A6; and 0.26 ± 0.17 and 0.029 ± 0.0050 μM for cotinine and nornicotine formation, respectively, for CYP2B6. 7-OH-CBD IC50,u values were 0.45 ± 0.18, 0.16 ± 0.08, and 0.78 ± 0.23 μM for cotinine, nornicotine, and 3HC formation, respectively, for CYP2A6, and 1.2 ± 0.44 and 0.11 ± 0.030 μM for cotinine and nornicotine formation, respectively, for CYP2B6. Similar IC50,u values were observed in HLM. Inhibition (IC50,u = 0.37 ± 0.06 μM) of 3HC to 3HC-glucuronide formation by UGT1A9 was demonstrated by CBD. Significant inhibition of nicotine metabolism pathways by CBD and 7-OH-CBD suggests that cannabinoids may inhibit nicotine metabolism, potentially impacting tobacco addiction and cessation.
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Project description:Background: Cannabidiol (CBD) is an approved treatment for childhood epilepsies and a candidate treatment for several other CNS disorders. However, it has poor oral bioavailability. We investigated the effect of a novel lipid formulation on its absorption in humans and on its tissue distribution in mice. Methods: In a double-blind crossover study in fasting healthy volunteers, we compared the pharmacokinetics of a single dose of 1000 mg of CBD in the lipid formulation and in a powder formulation (ClinicalTrials.gov: NCT05032807). In a second study, male CD1 mice were administered CBD in either the lipid formulation or dissolved in water, via oral gavage (n = 1 per timepoint). The tissue distribution of CBD was assessed using matrix-assisted laser desorption/ionization mass spectrometric imaging. Results: Plasma exposure (AUC0-48) of CBD was nine times greater for the lipid formulation than the powder formulation (611.1 ng·h/mL [coefficient of variation {CV%}: 104.6] and 66.8 ng·h/mL [CV%: 50.7], respectively). With the powder formulation, the AUC0-48 was related to the concentration of specific gastrointestinal bacteria and bile acids. These associations were attenuated with the lipid formulation. In the animal study, after treatment with the lipid formulation, measurable concentrations of CBD were identified in all organs. For the aqueous formulation, tissue concentrations of CBD were below the limit of quantification. Conclusions: Administering oral CBD in a lipid formulation was associated with an increase in its gastrointestinal absorption, as well as an attenuation of the relationship between its absorption and features of the gut microbiome.
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Project description:BackgroundJuvenile idiopathic arthritis (JIA) is common and difficult to treat. Cannabidiol (CBD) is now widely available, but no studies to date have investigated the use of CBD for JIA.MethodsWe performed a chart review to identify patients with JIA at a Midwestern medical institution between 2017 and 2019. We surveyed primary caregivers of JIA patients using an anonymous, online survey with questions on caregiver knowledge and attitudes towards CBD. We compared respondents with no interest in CBD use vs. those contemplating or currently using CBD using descriptive statistics.ResultsOf 900 reviewed charts, 422 met inclusion criteria. Of these, 236 consented to be sent a survey link, and n=136 (58%) completed surveys. Overall, 34.5% (n=47) of respondents reported no interest in using a CBD product for their child's JIA, while 54% (n=79) reported contemplating using CBD and 7% (n=10) reported currently giving their child CBD. Only 2% of respondents contemplating or actively using a CBD product learned about CBD from their child's rheumatologist, compared with television (70%) or a friend (50%). Most respondents had not talked to their child's rheumatologist about using CBD. Of those currently using CBD, most used oral or topical products, and only 10% of respondents (n=1) knew what dose they were giving their child.ConclusionsOur results show infrequent use but a large interest in CBD among caregivers of children with JIA. Given CBD's unknown safety profile in children with JIA, this study highlights a need for better studies and education around CBD for pediatric rheumatologists.
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Project description:Cannabidiol (CBD) is a non-intoxicating phytocannabinoid from cannabis sativa that has demonstrated anti-inflammatory effects in several inflammatory conditions including arthritis. However, CBD binds to several receptors and enzymes and, therefore, its mode of action remains elusive. In this study, we show that CBD increases intracellular calcium levels, reduces cell viability and IL-6/IL-8/MMP-3 production of rheumatoid arthritis synovial fibroblasts (RASF). These effects were pronounced under inflammatory conditions by activating transient receptor potential ankyrin (TRPA1), and by opening of the mitochondrial permeability transition pore. Changes in intracellular calcium and cell viability were determined by using the fluorescent dyes Cal-520/PoPo3 together with cell titer blue and the luminescent dye RealTime-glo. Cell-based impedance measurements were conducted with the XCELLigence system and TRPA1 protein was detected by flow cytometry. Cytokine production was evaluated by ELISA. CBD reduced cell viability, proliferation, and IL-6/IL-8 production of RASF. Moreover, CBD increased intracellular calcium and uptake of the cationic viability dye PoPo3 in RASF, which was enhanced by pre-treatment with TNF. Concomitant incubation of CBD with the TRPA1 antagonist A967079 but not the TRPV1 antagonist capsazepine reduced the effects of CBD on calcium and PoPo3 uptake. In addition, an inhibitor of the mitochondrial permeability transition pore, cyclosporin A, also blocked the effects of CBD on cell viability and IL-8 production. PoPo3 uptake was inhibited by the voltage-dependent anion-selective channel inhibitor DIDS and Decynium-22, an inhibitor for all organic cation transporter isoforms. CBD increases intracellular calcium levels, reduces cell viability, and IL-6/IL-8/MMP-3 production of RASF by activating TRPA1 and mitochondrial targets. This effect was enhanced by pre-treatment with TNF suggesting that CBD preferentially targets activated, pro-inflammatory RASF. Thus, CBD possesses anti-arthritic activity and might ameliorate arthritis via targeting synovial fibroblasts under inflammatory conditions.
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Project description:To investigate effects of smoking cannabidiol (CBD)-rich marijuana on driving ability and determine free CBD and Δ9-tetrahydrocannabinol (THC) concentrations in capillary blood samples, a randomised, double-blind, placebo-controlled, two-way crossover pilot study was conducted with 33 participants. Participants smoked a joint containing 500 mg of tobacco and either 500 mg of CBD-rich marijuana (16.6% total CBD; 0.9% total THC) or 500 mg of a placebo substance, then performed three different dimensions of the Vienna Test System TRAFFIC examining reaction time, behaviour under stress, and concentration performance. For further assessment of participants' fitness to drive, three tests of balance and coordination were evaluated and vital signs (blood pressure and pulse) were measured. Dried blood spot samples of capillary blood were taken after smoking and after completion of the tests to determine the cannabinoid concentrations (CBD, THC and THC-metabolites). The results revealed no significant differences between the effects of smoking CBD-rich marijuana and placebo on reaction time, motor time, behaviour under stress, or concentration performance. Maximum free CBD and THC concentrations in capillary blood were detected shortly after smoking, ranging between 2.6-440.0 ng/mL and 6.7-102.0 ng/mL, respectively. After 45 min, capillary blood concentrations had already declined and were in the range of 1.9-135.0 ng/mL (free CBD) and 0.9-38.0 ng/mL (free THC). Although the observed levels of free THC concentrations have been reported to cause symptoms of impairment in previous studies in which THC-rich marijuana was smoked, no signs of impairment were found in the current study. This finding suggests that higher CBD concentrations cause a negative allosteric effect in the endocannabinoid system, preventing the formation of such symptoms. Nevertheless, it is recommended that consumers refrain from driving for several hours after smoking CBD-rich marijuana, as legal THC concentration limits may be exceeded. Supplemental data for this article is available online at https://doi.org/10.1080/20961790.2021.1946924 .
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Project description:Importance:Use of cannabidiol (CBD) has markedly increased in the past 5 years, concurrent with marketing claims that over-the-counter CBD can be used to treat almost any health condition. However, the reasons why individuals use CBD remain unclear. Objective:To assess whether individuals are using CBD for diagnosable conditions that have evidence-based therapies. Design, Setting, and Participants:This case series assessed claimed treatment applications reported by CBD users in public testimonials shared on the Reddit forum r/CBD. The r/CBD forum was selected because it includes a large, naturally occurring sample of 104?917 registered individuals who publicly discuss their experiences using CBD. All r/CBD posts were obtained from January 1, 2014, through August 31, 2019. A random sample of posts was drawn (n?=?3000) and filtered to include posts in which self-identified CBD users testified why they take CBD (n?=?376). Exposures:Self-reported use of CBD for medicinal purposes. Main Outcomes and Measures:Cannabidiol testimonials were divided into 11 subcategories corresponding with the condition's medical subspecialty and 2 subcategories corresponding with wellness benefits. Posts were allowed to receive more than 1 label. Results:Of the 376 posts labeled as testimonials, 90.0% (95% CI, 86.8%-92.8%) of testimonials claimed that CBD treated the individual's diagnosable conditions. Psychiatric conditions (eg, autism or depression) were the most frequently cited subcategory, mentioned in 63.9% (95% CI, 59.0%-69.1%) of testimonials, followed by orthopedic (26.4%; 95% CI, 21.8%-31.1%), sleep (14.6%; 95% CI, 11.3%-18.5%), and neurological (6.9%; 95% CI, 4.4%-9.6%) conditions. Testimonials also claimed that CBD treated gastroenterological conditions (3.9%; 95% CI, 1.9%-6.1%), as well as addiction, cardiological, dermatological, ophthalmological, oral health, and sexual health conditions (<2.0% each). By contrast, just 29.5% (95% CI, 24.8%-34.2%) of testimonies claimed any wellness benefit, with most citing mental wellness (eg, "quieting my mind") (29.5% [95% CI, 24.2%-34.4%]); 1.4% (95% CI, 0.3%-2.8%) claimed a physical wellness benefit (eg, "exercise performance"). Conclusions and Relevance:The findings of this case series suggest a need for regulation of factors associated with CBD being used to treat diagnosable conditions, engagement of health care professionals with patients on their potential CBD use, and implementation of public health campaigns that encourage the public to seek treatment advice from health care professionals regarding evidence-based therapies.
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