Selective electrochemical detection of cannabidiol (CBD) and tetrahydrocannabinol (THC) at molecular-imprinted mesoporous Pt-Ir surfaces.

To CBD or not to CBD?: What pharmacists need to know

Decision letter: Cannabidiol activates neuronal Kv7 channels

Editor's evaluation: Cannabidiol activates neuronal Kv7 channels

Background: Cannabidiol (CBD) and tetrahydrocannabinol (THC) are cannabinoids used predominately for medicinal and recreational purposes, respectively. Because these cannabinoids are often co-consumed with conventional drugs, there is concern for deleterious cannabinoid-drug interactions. Both cannabinoids and their major circulating metabolites (7-OH CBD or 11-OH THC) are potent inhibitors of CYPs, but their potency to inhibit UGTs has not been investigated. Objective The objective of the study was to predict the potential for CBD and THC to precipitate UGT-mediated drug interactions using an IVIVE approach. The aims were to determine the following for CBD, THC, and their metabolites: 1) fraction unbound in incubations (fu,inc) containing recombinant UGT (rUGTs) and 0.2% BSA and 2) unbound UGT inhibitory potency (IC50,u). These data were used to predict the potential for interactions between each cannabinoid and UGT-metabolized drugs after typical doses used orally or by inhalation. Methods Fraction unbound (fu,inc) of CBD, THC, or metabolite in incubations containing rUGTs and 0.2% BSA was determined by ultracentrifugation. The inhibition extent (at 10 μM) or potency (IC50,u) of CBD, 7-OH CBD, 7-COOH CBD, THC, 11-OH THC, or 11-COOH THC towards the glucuronidation of estradiol (UGT1A1), chenodeoxycholic acid (UGT1A3), trifluoperazine (UGT1A4), 4-OH indole (UGT1A6), propofol (UGT1A9), gemfibrozil (UGT2B4), naloxone (UGT2B7), amitriptyline (UGT2B10), oxazepam (UGT2B15), or testosterone (UGT2B17) was determined using rUGTs. Estimated IC50,u and unbound hepatic inlet (oral dose) or systemic plasma (inhaled dose) concentrations were used to predict the potential for interactions between CBD (700 mg) or THC (20 mg) and drugs metabolized by UGT with fm values of 0.25, 0.5, or 0.75. Results fu,inc of CBD, 7-OH CBD, and THC was 0.05, 0.20, and 0.04, respectively. CBD, 7-OH CBD, THC, and 11-OH THC at 10 μM inhibited all UGTs tested (by 30-98%), whereas 7-COOH CBD inhibited only UGT2B7 (by 25%) and 11-COOH THC inhibited only UGT1A1, 1A4, and 1A9 (by 20-35%). IC50,u of CBD, 7-OH CBD, and THC against UGT1A9, 2B4, and 2B7 ranged from 0.002-0.02 μM, 0.6-1.6 μM, and 0.07-0.13 μM, respectively. IC50,u of CBD against UGT1A4, 1A6, 2B10, and 2B15 was < 1.3 μM. A mechanistic static model predicted strong in vivo interactions (AUC ratio > 3.3) between CBD and drugs extensively metabolized (fm = 0.75) by UGT1A9, 2B4, or 2B7. CBD was also predicted to result in moderate or weak interactions (1.3 ≥ AUC ratio ≤ 2.0) with drugs not extensively metabolized by these UGTs (fm = 0.25 or 0.5). In contrast, oral or inhaled THC was not predicted to precipitate UGT-mediated drug interactions (AUC ratio < 1.2). UGT inhibition by 7-OH CBD did not change the predicted potential of CBD-drug interactions. Conclusion This study is the first to determine the UGT inhibition potencies of cannabinoids. CBD was a potent inhibitor of UGT1A9, 2B4, and 2B7 and was predicted to interact with drugs metabolized by these UGTs. Further investigation via dynamic PBPK modeling and simulation and clinical evaluation is warranted to verify these predictions.

THC and CBD in blood samples and seizures in Norway: Does CBD affect THC-induced impairment in apprehended subjects?

Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder caused by oxidative stress and dysregulation of lipid metabolism. The endocannabinoid system (ECS), particularly the type 1 cannabinoid (CB1) receptor, plays a crucial role in NAFLD progression. Cannabinoids, such as cannabidiol (CBD) and tetrahydrocannabinol (THC), along with terpenes, such as beta-myrcene and d-limonene, have shown potential therapeutic effects on liver health, particularly in reducing oxidative stress and modulating lipid metabolism. This study aimed to analyse the effects of five cannabis oils (COs), each with different CBD:THC ratios and terpenes content, on hypertension, dyslipidemia, hepatic steatosis, oxidative stress, and CB1 receptor expression in an experimental model of NAFLD induced by a sucrose-rich diet (SRD) in Wistar rats for 3 weeks. Male Wistar rats were fed either a: (1) reference diet (RD; standard commercial laboratory diet) or a: (2) sucrose-rich diet (SRD) for 3 weeks. 3 to 7 SRD + CO as following: (3) SRD + THC; (4) SRD + CBD; (5) SRD + CBD:THC 1:1; (6) SRD + CBD:THC 2:1; and (7) SRD + CBD:THC 3:1. The COs were administered orally at a dose of 1.5mg total cannabinoids/kg body weight daily. The cannabinoid and terpenes content of all COs used in the study was determined. The terpenes found in COs were beta-myrcene, d-limonene, terpinolene, linalool, beta-caryophyllene, alpha-humulene, (-)-guaiol, (-)-alpha-bisabolol. During the experimental period, body weight, food intake and blood pressure were measured. Serum glucose, triglyceride, total cholesterol, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP) levels were evaluated. Liver tissue histology, NAFLD activity score (NAS), triglyceride and cholesterol content, lipogenic enzyme activities, enzyme related to mitochondrial fatty acid oxidation, reactive oxygen species (ROS), thiobarbituric acid reactive substance (TBARS), and antioxidant enzyme activities were also evaluated. The CB1 receptor expression was also determined. The results showed that SRD-fed rats developed hypertension, dyslipidemia, liver damage, hepatic steatosis, lipid peroxidation, and oxidative stress. This was accompanied by upregulation of liver CB1 receptor expression. CBD-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO and CBD:THC 3:1 ratio CO showed antihypertensive properties. THC-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO showed the greatest beneficial effects against hepatic steatosis and liver damage. All COs exhibited antioxidant effects in liver tissue. This was associated with normal liver CB1 receptor expression. This study demonstrated that COs, particularly THC-rich CO, CBD:THC ratio 1:1 CO, CBD:THC ratio 2:1 CO and terpenes, can effectively reduce dyslipidemia, liver damage and hepatic steatosis in SRD-induced NAFLD. COs with a higher proportion of CBD in their composition showed antihypertensive properties. All the COs exhibited antioxidant properties. These findings suggest that COs, especially those with CBD:THC ratios of 1:1 and 2:1 and terpenes, may represent a promising therapeutic approach for managing NAFLD and preventing its progression to more severe liver disease.

The marijuana plant produces over 100 different cannabinoids, including Δ9− tetrahydrocannabinol (THC) and cannabidiol (CBD). THC concentrations in retail marijuana have risen dramatically, while CBD levels have declined. High concentrations of THC and high ratios of THC:CBD in marijuana are thought to be associated with more robust psychoactive effects, while CBD has been reported to attenuate THC‐induced effects. The current study sought to compare the behavioral and molecular effects of THC alone and THC combined with CBD in adolescent nonhuman primates in order to investigate, across a wide range of parameters, whether CBD modulates the effects of THC.Twelve male adolescent squirrel monkeys (2.3 – 2.5 years) were divided into three treatment groups: vehicle control, THC, or THC+CBD (n=4/group). Initially they were treated with low doses of THC or THC+CBD weekly for four weeks. Thereafter, at the onset of the testing regimen, animals received THC (1 mg/kg) or THC+CBD (1 mg/kg+3mg/kg) daily for 4 months. The following parameters were measured: 1. Cognitive ability: Animals were trained to engage in touchscreen‐based cognitive tasks according to previously established methods from our laboratory. 2. Observed behavior: behavior was video‐taped weekly in a Plexiglass observation chamber and rated by an observer blinded to the drug regimen. 3. Blood THC, CBD, and THC metabolites were measured four times over the course of the experiment. THC levels in two brain regions were measured following euthanasia. 4. mRNA levels in selected brain regions were assessed by bulk RNAseq and confirmed by RT‐qPCR.THC and THC+CBD compromised initial learning of a repeated acquisition task. On the first day of daily treatment, THC alone induced emesis, but emesis was attenuated by the co‐administration of CBD. THC or THC+CBD suppressed locomotion and foraging; tolerance developed to the behaviorally suppressant effects during continuous daily exposure. Blood levels of THC and CBD remained relatively stable over 100 days of treatment. On the first day of treatment, levels of 11‐OH‐THC, an active THC metabolite, were lower in subjects that received THC+CBD than those that received THC alone; however this effect was not present at any other time point. Brain levels of THC were approximately 2 times higher than blood levels, and levels of THC were not affected significantly when CBD was co‐administered. Furthermore, daily THC or THC+CBD administered to adolescent monkeys for four months was associated with an altered mRNA transcriptome across multiple brain regions.CBD attenuates some but not all THC‐induced effects in nonhuman primates. Attenuation is unlikely to be related to disrupted THC metabolism or brain entry. Our findings warrant further research into the pharmacological and potential pathological consequences of THC and CBD after long term use, and a comparison of adolescent and adult responses to such cannabinoid exposure.Support or Funding InformationThis work was supported by NIDA grant DA042178.

AHA's new statement focuses on cannabis and brain health

Mid-infrared spectroscopy as process analytical technology tool for estimation of THC and CBD content in Cannabis flowers and extracts

Cannabis-Based Medicines ??? GW Pharmaceuticals

Tea is a recommended way of administration of prescribed cannabis plant products in Denmark. We aimed to investigate the cannabinoid and terpene doses contained in different teas. We analysed tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), and terpene concentrations in three repeated preparations of each type of tea, and in plant material. In standard tea, concentrations of THC were [median (min-max)] 9.5 (2.3-15), 19 (13-34), and 36 (26-57) μg/mL for products with a labelled content of 6.3%, 14%, and 22% total THC (THC + THCA), respectively. The CBD concentration in tea from a product labelled with 8% total CBD (CBD + CBDA) was 7.5 (1.9-10) μg/mL. Based on this, the recommended starting amount of 0.2L of the different teas would contain between 0.46 and 11.3mg THC, and 0.38 to 2.0mg CBD. Adding creamer before, but not after boiling, increased the THC and CBD concentration 2.3-4.4 and 2.1-fold, respectively. Terpenes were detected in plant material, but not in tea. The study elucidates THC and CBD doses in different teas, which may assist the clinician's choice of cannabis product. Moreover, it underscores the need for caution as administration as tea can result in exposure to different doses, even when the same cannabis product is used.

Regulatory approaches to cannabidiol in the European Union: are market developments sowing the seeds of confusion?

Background Cannabis products are used for recreational and medicinal purposes. The major cannabinoids, cannabidiol (CBD) and tetrahydrocannabinol (THC), are inhibitors of several cytochromes P450 (CYPs). However, their low aqueous solubility and significant binding to human liver microsomes (HLM)/proteins or labware have not been considered. Moreover, CYP inhibition by their circulating metabolites, 7-OH CBD/7-COOH CBD and 11-OH THC/11-COOH THC, has not been evaluated. We hypothesized that the inhibitory potencies of CBD and THC and their potential to precipitate CYP-mediated drug interactions have been underestimated. Objectives Our objective was to assess potential CYP-mediated cannabinoid-drug interactions using an IVIVE approach. The aims were to determine the following for each cannabinoid and metabolite: 1) binding to HLM proteins, labware, and plasma; 2) unbound reversible CYP inhibitory potency (IC50,u); and 3) unbound time-dependent CYP inhibition (TDI) potency (KI,u) and apparent maximum inactivation rate constant (kinact,app). These data were used to predict the magnitude of cannabinoid-drug interactions for oral or inhaled doses used for recreational or medicinal purposes. Methods Fraction unbound of CBD, THC, or metabolite in incubations containing HLM and BSA (fu,inc) or plasma (fu,p) was determined by ultracentrifugation. IC50,u,KI,u, andkinact,app were estimated by assessing the effect of varying concentrations of CBD, THC, or metabolite on the formation of CYP-mediated metabolites of phenacetin (CYP1A2), coumarin (CYP2A6), bupropion (CYP2B6), amodiaquine (CYP2C8), diclofenac (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and testosterone (CYP3A) using HLM. These data, along with expected intestinal and unbound hepatic inlet (oral dose) or systemic plasma (inhaled dose) concentrations, were used to predict the potential for interactions between typical doses of CBD (700 mg) or THC (20 mg) and drugs predominantly metabolized by these enzymes. Results fu,inc of CBD, 7-OH CBD, and THC was 0.03, 0.02, and 0.13, respectively; corresponding fu,p was 0.01, 0.02, and 0.01. CBD or THC inhibited all the tested CYPs (IC50,u < 0.68 μM). Comparatively, 7-OH CBD or 11-OH THC were less potent inhibitors (IC50,u < 5.3 μM). Both CBD and 7-OH CBD showed TDI of CYP2C19 and CYP3A; CBD showed TDI of CYP1A2. A mechanistic static model predicted in vivo interactions (AUC ratio > 1.4) between CBD and drugs significantly metabolized by CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A. Oral THC was predicted to interact with drugs metabolized by CYP2C9 and 3A (AUC ratio > 1.7), whereas inhaled THC is unlikely to interact with these drugs. CYP inhibition by CBD or THC metabolites had no effect on the predicted magnitude of CBD- or THC-drug interactions. Conclusion This study is the first to consider binding of CBD, THC, and metabolites to microsomal protein and labware to estimate CYP inhibition potential. A clinical study is ongoing to verify our static model predictions of cannabinoid-drug interactions.

This study used nanofluidic protein posttranslational modification (PTM) profiling to measure the effects of six cannabidiol (CBD) oils and isolated CBD on the signaling pathways of a cultured SH-SY5Y neuronal cell line. Chemical composition analysis revealed that all CBD oils met the label claims and legal regulatory limit regarding the CBD and tetrahydrocannabinol (THC) contents, respectively. Isolated CBD was cytotoxic, with an effective concentration (EC50) of 40 µM. In contrast, the CBD oils had no effect on cell viability at CBD concentrations exceeding 1.2 mM. Interestingly, only an unadulterated CBD oil had strong and statistically significant suppressive effects on the pI3K/Akt/mTOR signaling pathway with an EC50 value of 143 µM and a slow-acting timescale requiring hours. Systematic profiling of twenty-six proteins, which served as biomarkers for nine signaling pathways, revealed that the unadulterated CBD oil downregulated seven signaling pathways but had no measurable effect on the other two signaling pathways. The remaining CBD oils, which were adulterated, and isolated CBD had weak, variable, or undetectable effects on neuronal signaling pathways. Our data clearly showed that adulteration diminished the biological activities of CBD oils. In addition, nanofluidic protein PTM profiling provided a robust means for potency assessment of CBD oils.

Cannabis constituents, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), show distinct pharmacological profiles with therapeutic relevance for neurological and psychiatric conditions. THC exerts euphoric effects primarily via CB1 receptor activation, while CBD displays non-euphoric properties affecting various pathways. This study evaluated the effects of THC, CBD, and their combination on brain functional connectivity (FC) and cerebral blood flow (CBF) using multimodal neuroimaging. Adult male Sprague Dawley rats received intraperitoneal doses of 10 mg/kg THC, 150 mg/kg CBD, 10.8:10 mg/kg THC:CBD, or vehicle. Resting-state blood oxygenation level dependent magnetic resonance imaging and arterial spin labelling assessed FC and CBF, approximately 2 h after drug administration. Graph-theory metrics and seed-based analyses identified connectivity and perfusion alterations, while plasma analyses determined cannabinoid concentrations. THC increased whole-brain FC and clustering coefficient, with elevated CBF in cortical and subcortical regions. CBD decreased FC metrics without affecting CBF, while THC:CBD induced moderate increases in both. Seed-based analysis revealed THC-driven increases in cortical-hippocampal and cortical-striatal connectivity, attenuated in the THC:CBD group. A multivariate combined analysis of FC and CBF revealed a divergent pattern of changes induced by each drug. In conclusion, we show that THC and CBD induce distinct neurophysiological profiles in rats, with THC increasing both connectivity and perfusion, moderated by CBD when combined. These findings corroborate existing knowledge about the effects of cannabinoids on the brain, while also supporting the potential of preclinical functional neuroimaging to delineate cannabinoid-induced endophenotypes, offering insights for therapeutic development.