ArticleLiterature Review

Cannabinoids and drug metabolizing enzymes: potential for drug-drug interactions and implications for drug safety and efficacy

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Abstract

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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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).
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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.
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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.
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(-)-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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
Article
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.
Article
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.
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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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.