cannabidiol and cannabidiolic-acid

The endocannabinoid system (ECS) is an integral neuromodulatory system involved in neuronal development, synaptic plasticity, and homeostasis regarding immunity, as well as brain and other physiological functions such as anxiety, pain, metabolic regulation, and bone growth. Cannabis is a plant that contains exogenous cannabinoids, which have the potential for profound interplay within the ECS as enzymatic inhibitors or receptor-mediated interactions. Activation of cannabinoid receptors leads to various intracellular signaling processes that are involved in cellular functions, but those interactions are diverse due to different affinities of each cannabinoid with relevant receptors. Among the exogenous cannabinoids, cannabidiol (CBD) has drawn attention due to its potential anticancer, antiangiogenic, anti-inflammatory, and antiseizure properties using in vitro and in vivo models. Although scientific evidence is limited in dogs, there appears to be cautious optimism regarding the utilization of CBD in conjunction with other therapeutics for a range of disorders. This review will primarily focus on current scientific research on the efficacy of CBD on seizure, anxiety, osteoarthritis, and atopic dermatitis, following a brief discussion of endo- and exogenous cannabinoids, ECS, their molecular mechanism, and potential side effects in veterinary medicine. Cannabinoid pharmacology and pharmacokinetics will be addressed in the companion Currents in One Health by Schwark and Wakshlag, AJVR, May 2023.

Topics: Animals; Cannabidiol; Cannabinoids; Cannabis; Dog Diseases; Dogs; Humans; Seizures

Topics: Cannabidiol; Cannabinoids; Esters; Humans; Nausea; Vomiting

Considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of fiber-type cannabis plant, and it has been reported to possess diverse biological activities. Although CBD is obtained from non-enzymatic decarboxylation of its parent molecule, cannabidiolic acid (CBDA), several studies have investigated whether CBDA itself is biologically active. In the present report, the author summarizes findings indicating that; 1) CBDA is a selective cyclooxygenase-2 (COX-2) inhibitor, and ii) CBDA possesses an anti-migrative potential for highly invasive cancer cells, apparently through a mechanism involving inhibition of cAMP-dependent protein kinase A, coupled with an activation of the small GTPase, RhoA. Further, the author introduces recent findings on the medicinal chemistry and pharmacology of the CBD derivative, CBD-2',6'-dimethyl ether (CBDD), that exhibits inhibitory activity toward 15-lipoxygenase (15-LOX), an enzyme responsible for the production of oxidized low-density lipoprotein (LDL). These studies establish CBD as both an important experimental tool and as a lead compound for pharmaceutical development. In this review, the author further discusses the potential uses of CBD and its derivatives in future medicines.

Topics: Animals; Breast Neoplasms; Cannabidiol; Cannabinoids; Cannabis; Cell Movement; Cells, Cultured; Chemistry, Pharmaceutical; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 2 Inhibitors; Decarboxylation; Drug Discovery; Female; Humans; Lipoproteins, LDL; Lipoxygenase Inhibitors; Phytotherapy; rhoA GTP-Binding Protein

Cannabidiol (CBD) and cannabidiolic acid (CBDA) are reported to have antinociceptive, immunomodulatory and anti-inflammatory actions.. To determine if CBD/CBDA is an effective therapy for canine atopic dermatitis (cAD).. Thirty-two privately owned dogs with cAD.. Prospective, randomised, double-blinded, placebo-controlled study. Concurrent therapies were allowed if remained unchanged. Dogs were randomly assigned to receive either 2 mg/kg of an equal mix of CBD/CBDA (n = 17) or placebo for 4 weeks. On Day (D)0, D14 and D28, Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) and pruritus Visual Analog Scale (pVAS) scores were determined by investigators and owners, respectively. Complete blood count, serum biochemistry profiles and cytokine bioassays were performed on serum collected on D0 and D28.. There was no significant difference in CADESI-04 from D0 to D14 (p  = 0.42) or D28 (p  = 0.51) in either group. pVAS scores were significantly lower for the treatment group at D14 (p  = 0.04) and D28 (p  = 0.01) and a significant change in pVAS from baseline was seen at D14 (p  = 0.04) and not D28 (p  = 0.054) between groups. There was no significant difference in serum levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein - 1, IL-31 or IL-34 between groups at D0 or D28. Elevated alkaline phosphatase was observed in four of 17 treatment group dogs.. CBD/CBDA as an adjunct therapy decreased pruritus, and not skin lesions associated with cAD in dogs.. Contexte - Le cannabidiol (CBD) et l'acide cannabidiolique (CBDA) auraient des actions antinociceptives, immunomodulatrices et anti-inflammatoires. Objectifs - Déterminer si le CBD/CBDA est une thérapie efficace pour la dermatite atopique canine (cAD). Animaux - Trente-deux chiens de propriétaires privés atteints de cAD Matériels et méthodes - Étude prospective, randomisée, en double aveugle, contrôlée versus placebo. Les thérapies concomitantes étaient autorisées si elles restaient inchangées. Les chiens ont été répartis au hasard pour recevoir soit 2 mg/kg d'un mélange égal de CBD/CBDA (n = 17) soit un placebo pendant quatre semaines. Aux jours (J)0, J14 et J28, les scores Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) et prurit Visual Analog Scale (pVAS) ont été déterminés respectivement par les investigateurs et les propriétaires. Une formule sanguine complète, des profils biochimiques sériques et des dosages biologiques des cytokines ont été réalisés sur le sérum prélevé à J0 et J28. Résultats - Il n'y avait pas de différence significative au CADESI-04 de J0 à J14 (P = 0,42) ou J28 (P = 0,51) dans les deux groupes. Les scores pVAS étaient significativement inférieurs pour le groupe de traitement à J14 (P = 0,04) et J28 (P = 0,01) et un changement significatif de la pVAS par rapport à l'inclusion a été observé à J14 (P = 0,04) et non à J28 (P = 0,054) entre les groupes. Il n'y avait pas de différence significative dans les taux sériques d'interleukine (IL)-6, IL-8, protéine chimiotactique des monocytes-1, IL-31 ou IL-34 entre les groupes à J0 ou J28. Une phosphatase alcaline élevée a été observée chez quatre des 17 chiens du groupe de traitement. Conclusions et pertinence clinique - Le CBD/CBDA en tant que traitement d'appoint a diminué le prurit, et non les lésions cutanées associées à la DAC chez les chiens.. Introducción- se ha descrito que el cannabidiol (CBD) y el ácido cannabidiólico (CBDA) tienen acciones antinociceptivas, inmunomoduladoras y antiinflamatorias. Objetivos- determinar si el CBD/CBDA es una terapia eficaz para la dermatitis atópica canina (CAD). Animales - Treinta y dos perros de propietarios privados con cAD Materiales y métodos - Estudio prospectivo, aleatorio, doble ciego, controlado con placebo. Se permitieron terapias concurrentes si permanecían sin cambios. Los perros fueron asignados al azar para recibir 2 mg/kg de una mezcla igual de CBD/CBDA (n = 17) o placebo durante cuatro semanas. En el día (D)0, D14 y D28, los investigadores y los propietarios determinaron las puntuaciones del índice de extensión y gravedad de la dermatitis atópica canina, cuarta revisión (CADESI-04) y la escala análoga visual de prurito (pVAS), respectivamente. Se realizaron hemogramas completos, perfiles bioquímicos séricos y bioensayos de citoquinas en suero obtenido en D0 y D28. Resultados- no hubo diferencias significativas en CADESI-04 de D0 a D14 (P = 0,42) o D28 (P = 0,51) en ninguno de los grupos. Las puntuaciones de pVAS fueron significativamente más bajas para el grupo de tratamiento en D14 (P = 0.04) y D28 (P = 0.01) y se observó un cambio significativo en pVAS desde el inicio en D14 (P = 0.04) y no en D28 (P = 0.054) entre grupos . No hubo diferencias significativas en los niveles séricos de interleuquina (IL)-6, IL-8, proteína quimioatrayente de monocitos-1, IL-31 o IL-34 entre los grupos en D0 o D28. Se observó fosfatasa alcalina elevada en cuatro de los 17 perros del grupo de tratamiento. Conclusiones y relevancia clínica- CBD/CBDA como terapia adjunta disminuyó el prurito y no las lesiones cutáneas asociadas con la CAD en perros.. 背景 - カンナビジオール (CBD) およびカンナビジオール酸 (CBDA) は、抗侵害受容作用、免疫調節作用、抗炎症作用を有すると報告されている。 目的 - 本研究の目的は、CBD/CBDAが犬アトピー性皮膚炎 (cAD) に対して有効な治療法であるかどうかを明らかにすることであった。 被検動物 - cAD を有するオーナー所有犬 32 頭 材料と方法 - 前向き無作為化二重盲検プラセボ対照試験。併用療法は、変化がない場合は許可された。犬はCBD/CBDAの等量混合物2mg/kg(n = 17) またはプラセボのいずれかを4週間投与するよう無作為に割り当てられた。D0、D14およびD28に、犬アトピー性皮膚炎の程度および重症度指数 (CADESI-04)、痒みのビジュアルアナログスケール (pVAS) スコアをそれぞれ調査員、飼い主が決定した。D0とD28に採取した血清について、全血球数、血清生化学プロファイル、サイトカイン・バイオアッセイ法を実施した。 結果 - CADESI-04のD0からD14(P = 0.42) またはD28(P = 0.51) まで、いずれの群でも有意差はなかった。pVASスコアはD14(P = 0.04) およびD28(P = 0.01) で治療群に有意に低く、ベースラインからのpVASの有意変化はD14(P = 0.04) で見られ、D28(P = 0.054) では認められなかった。インターロイキン (IL)-6、IL-8、単球走化性タンパク質-1、IL-31、IL-34の血清レベルには、D0とD28で群間に有意な差はなかった。アルカリフォスファターゼの上昇が17頭中4頭で観察された。 結論および臨床的意義 - CBD/CBDAを補助療法として投与することで、cADに関連する皮膚病変ではなく、犬の痒みを減少させることができた。.. 背景-据报告, 大麻二醇(CBD)和大麻二酚酸(CBDA)具有镇痛、免疫调节和抗炎作用。 目的-确定CBD/CBDA是否是犬特应性皮炎(cAD)的有效疗法。 动物-32只患有cAD的私家犬。 材料和方法-前瞻性、随机、双盲、安慰剂对照研究。如果保持不变, 允许合并治疗。将犬随机分配至2 mg/kg CBD/CBDA等混合物组(n = 17)或安慰剂组, 持续4周。在第(D)0天、第14天和第28天, 由研究者和犬主人分别测定犬特应性皮炎程度和严重指数、第4版(CADESI-04)和瘙痒视觉模拟量表(pVAS)评分。对D0和D28采集的血清进行全血细胞计数、血清生化特征和细胞因子生物测定。 结果-两组中从D0至D14(P = 0.42)或D28(P = 0.51)的CADESI-04无显著差异。治疗组在D14(P = 0.04)和D28(P = 0.01)的pVAS评分显著降低, 在D14(P = 0.04)而非D28(P = 0.01)观察到pVAS相对于基线的显著变化.054) 。D0或D28时, 组间血清白细胞介素(IL)-6、IL-8、单核细胞趋化蛋白-1、IL-31或IL-34水平无显著差异。在17只治疗组犬的4只中观察到碱性磷酸酶升高。 结论和临床相关性-CBD/CBDA作为辅助治疗减少了犬中的瘙痒, 而对cAD相关的皮肤病变无效。.. Contexto - O canabidiol (CBD) e ácido canabidiólico (CBDA) são relatados como tendo ações antinociceptivas, imunomoduladoras e anti-inflamatórias. Objetivos - Determinar se CBD/CBDA é eficaz no tratamento da dermatite atópica canina (CAD) Animais - Trinta e dois cães de propriedade privada com DAC. Materiais e métodos - Estudo prospectivo, randomizado, duplo-cego, placebo-controle. As terapias concomitantes foram permitidas se permanecessem inalteradas. Os cães foram divididos aleatoriamente em dois grupos, o que receberia 2 mg/kg de uma mistura igual de CBD/CBDA (n = 17) ou placebo durante quatro semanas. No Dia (D) 0, D14 e D28, o Índice de Extensão e Gravidade da Dermatite Atópica Canina, 4ª iteração (CADESI-04) e os escores da Escala Visual Analógica de Prurido (pVAS) foram determinados pelos investigadores e proprietários, respectivamente. Hemograma completo, perfis bioquímicos séricos e ensaios de citocinas foram realizados no soro coletado em D0 e D28. Resultados - Não houve diferença significativa no CADESI-04 de D0 a D14 (P = 0,42) ou D28 (P = 0,51) em nenhum dos grupos. Os escores de pVAS foram significativamente menores para o grupo de tratamento no D14 (P = 0,04) e D28 (P = 0,01) e observou-se uma alteração significativa no pVAS do D0 comparado ao D14 (P = 0,04) e não ao D28 (P = 0,054) entre os grupos. Não houve diferença significativa nos níveis séricos de interleucina (IL)-6, IL-8, proteína quimiotática de monócitos-1, IL-31 ou IL-34 entre os grupos em D0 ou D28. Elevação na fosfatase alcalina foi observada em quatro dos 17 cães do grupo de tratamento. Conclusões e relevância clínica - CBD e CBDA como uma terapia adjuvante é capaz de reduzir prurido, mas não lesões cutâneas associadas à DAC em cães.

Topics: Animals; Cannabidiol; Cannabinoids; Dermatitis, Atopic; Dog Diseases; Dogs; Prospective Studies; Pruritus

"Light cannabis" is a product legally sold in Europe with Δ9-tetrahydrocannabinol (THC) concentration <0.2% and variable cannabidiol (CBD) content. In this study, we aimed to assess the time courses of THC and metabolites (11-nor-9-carboxy-THC and 11-hydroxy-THC) and CBD and metabolites (CBD-7-oic acid, 7-hydroxy-CBD, 6α-hydroxy-CBD and 6β-hydroxy-CBD) in whole blood of 10 healthy participants after smoking one or four light cannabis cigarettes (0.16% THC and 5.8% CBD). Blood samples were collected 0.5-4 h after administration. Blood analysis was performed by reversed-phase ultra-performance liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode after glucuronide hydrolysis and liquid-liquid extraction in basic and acidic conditions. The method was validated following the most recent guidelines in toxicology: the method was linear, accurate, precise and sensitive (lower limits of quantification ranged from 0.005 to 0.01 ng/mL); carryover, matrix effect, recovery, process efficiency and dilution integrity were also assessed. As previously reported, the main metabolites of THC were THC-COOH and then 11-OH-THC, and the main metabolites of CBD were 7-OH-CBD and then 7-COOH-CBD. The time of the first collection, which likely occurred after the maximal concentration of most of the analytes, and the short monitoring time, up to 4 h after smoking, limited the evaluation of the pharmacokinetic parameters.

Topics: Cannabidiol; Cannabis; Chromatography, High Pressure Liquid; Dronabinol; Hallucinogens; Humans; Smokers; Tandem Mass Spectrometry

Decarboxylation of Δ. The production of Δ. These findings indicated that TBA improved the production of Δ

Topics: Cannabidiol; Decarboxylation; Dronabinol; Ethanol; Solvents

To determine the pharmacokinetics of 8 cannabinoids and 5 metabolites after oral administration of single and multiple doses of a cannabidiol (CBD)-cannabidiolic acid (CBDA)-rich hemp extract to orange-winged Amazon parrots (Amazona amazonica) as well as to evaluate the extract's adverse effects.. 12 birds.. Based on pilot studies, a single-dose study based on 30/32.5 mg/kg of cannabidiol/cannabidiolic acid of a hemp extract was administered orally to 8 fasted parrots, and 10 blood samples were collected over 24 hours after administration. After a 4-week washout period, the hemp extract was administered orally to 7 birds at the previous dose every 12 hours for 7 days, and blood samples were collected at the previous time points. Cannabidiol, Δ9-tetrahydrocannabinol, cannabinol, cannabichromene, cannabigerol, cannabidiolic acid, cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, and 5 specific metabolites were measured by liquid chromatography-tandem/mass-spectrometry, and pharmacokinetic parameters were calculated. Adverse effects and changes in the plasma biochemistry and lipid panels were evaluated.. Pharmacokinetic parameters for cannabidiol, cannabidiolic acid, Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabinolic acid, and the metabolite 11-hydroxy-9-tetrahydrocannabinol were established. For the multiple-dose study, cannabidiol/cannabidiolic acid mean Cmax was 337.4/602.1 ng/mL with a tmax of 30 minutes and a terminal half-life of 8.6/6.29 hours, respectively. No adverse effects were detected during the multidose study. The predominant metabolite was 11-hydroxy-9-tetrahydrocannabinol.. Twice daily oral administration of the hemp extract based on 30 mg/kg/32.5 mg/kg of cannabidiol/cannabidiolic acid was well tolerated and maintained plasma concentrations considered to be therapeutic in dogs with osteoarthritis. Findings suggest different cannabinoid metabolism from mammals.

Topics: Administration, Oral; Amazona; Animals; Cannabidiol; Cannabinoids; Cannabis; Dogs; Dronabinol; Mammals; Plant Extracts

The pathophysiology of major depressive disorder (MDD) is diverse and multi-factorial, yet treatment strategies remain limited. While women are twice as likely to develop the disorder as men, many animal model studies of antidepressant response rely solely on male subjects. The endocannabinoid system has been linked to depression in clinical and pre-clinical studies. Cannabidiolic Acid-Methyl Ester (CBDA-ME, EPM-301) demonstrated anti-depressive-like effects in male rats. Here, we explored acute effects of CBDA-ME and some possible mediating mechanisms, using a depressive-like genetic animal model, the Wistar-Kyoto (WKY) rat. In Experiment 1, Female WKY rats underwent the Forced swim test (FST) following acute CBDA-ME oral ingestion (1/5/10 mg/kg). In Experiment 2, Male and female WKY rats underwent the FST after injection of CB1 (AM-251) and CB2 (AM-630) receptor antagonists 30 min before acute CBDA-ME ingestion (1 mg/kg, males; 5 mg/kg, females). Serum levels of Brain-Derived Neurotrophic Factor (BDNF), numerous endocannabinoids and hippocampal Fatty Acid Amide Hydrolase (FAAH) levels were assessed. Results indicate that females required higher doses of CBDA-ME (5 and 10 mg/kg) to induce an anti-depressive-like effect in the FST. AM-630 blocked the antidepressant-like effect in females, but not in males. The effect of CBDA-ME in females was accompanied by elevated serum BDNF and some endocannabinoids and low hippocampal expression of FAAH. This study shows a sexually diverse behavioral anti-depressive response to CBDA-ME and possible underlying mechanisms in females, supporting its potential use for treating MDD and related disorders.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cannabidiol; Depressive Disorder, Major; Disease Models, Animal; Endocannabinoids; Female; Male; Rats; Rats, Inbred WKY; Receptor, Cannabinoid, CB2

Cannabis is commercially cultivated for both therapeutic and recreational purposes in a growing number of jurisdictions. The main cannabinoids of interest are cannabidiol (CBD) and delta-9 tetrahydrocannabidiol (THC), which have applications in different therapeutic treatments. The rapid, nondestructive determination of cannabinoid levels has been achieved using near-infrared (NIR) spectroscopy coupled to high-quality compound reference data provided by liquid chromatography. However, most of the literature describes prediction models for the decarboxylated cannabinoids, e.g., THC and CBD, rather than naturally occurring analogues, tetrahydrocannabidiolic acid (THCA) and cannabidiolic acid (CBDA). The accurate prediction of these acidic cannabinoids has important implications for quality control for cultivators, manufacturers and regulatory bodies. Using high-quality liquid chromatography-mass spectroscopy (LCMS) data and NIR spectra data, we developed statistical models including principal component analysis (PCA) for data quality control, partial least squares regression (PLS-R) models to predict cannabinoid concentrations for 14 different cannabinoids and partial least squares discriminant analysis (PLS-DA) models to characterise cannabis samples into high-CBDA, high-THCA and even-ratio classes. This analysis employed two spectrometers, a scientific grade benchtop instrument (Bruker MPA II-Multi-Purpose FT-NIR Analyzer) and a handheld instrument (VIAVI MicroNIR Onsite-W). While the models from the benchtop instrument were generally more robust (99.4-100% accuracy prediction), the handheld device also performed well (83.1-100% accuracy prediction) with the added benefits of portability and speed. In addition, two cannabis inflorescence preparation methods were evaluated: finely ground and coarsely ground. The models generated from coarsely ground cannabis provided comparable predictions to that of the finely ground but represent significant timesaving in terms of sample preparation. This study demonstrates that a portable NIR handheld device paired with LCMS quantitative data can provide accurate cannabinoid predictions and potentially be of use for the rapid, high-throughput, nondestructive screening of cannabis material.

Topics: Cannabidiol; Cannabinoids; Cannabis; Spectroscopy, Near-Infrared

The evaluation of the chiral composition of phytocannabinoids in the cannabis plant is particularly important as the pharmacological effects of the (+) and (-) enantiomers of these compounds are completely different. Chromatographic attempts to assess the presence of the minor (+) enantiomers of the main phytocannabinoids, cannabidiolic acid (CBDA) and trans-Δ

Topics: Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Medical Marijuana

The goal of pharmacokinetic (PK) studies is to provide a basis for appropriate dosing regimens with novel therapeutic agents. With a knowledge of the desired serum concentration for optimum pharmacological effect, the amount and rate of drug administration can be tailored to maintain that concentration based on the 24-hour PK modeling (eg, every 24 hours, every 12 hours) to achieve therapeutic ranges. This dosing and PK information are tailored to maintain that concentration. Typically, these optimum serum concentrations pertain across species. Single-dose PK modeling provides fundamental parameters to suggest dosing regimes. Multiple-dose PK studies provide information on steady-state serum levels to assure that desired therapeutic levels are maintained during chronic administration. Clinical trials using dosing suggested by these PK determinations provide proof that the compound is producing the desired therapeutic effect. A number of PK studies with cannabinoids in humans and domestic animals have been conducted with the goal of determining appropriate clinical use with these plant-derived products. The following review will focus on the PK of cannabidiol (CBD) and the lesser-known precursor of CBD, cannabidiolic acid (CBDA). Although Δ9-tetrahydrocannabinol (THC) has profound pharmacological effects and may be present at variable and potentially violative concentrations in hemp products, PK studies with THC will not be a major consideration. Because, in domestic animals, hemp-CBD products are usually administered orally, that route will be a focus. When available, PK results with CBD administered by other routes will be summarized. In addition, the metabolism of CBD across species appears to be different in carnivorous species compared with omnivorous/herbivorous species (including humans) based on current information, and the preliminary information related to this will be explained with the therapeutic implication being addressed in Currents in One Health by Ukai et al, JAVMA, May 2023.

Topics: Animals; Animals, Domestic; Biotransformation; Cannabidiol; Cannabinoids; Dronabinol; Humans; One Health

Most studies related to hemp are focused on Cannabidiol (CBD) and Tetrahydrocannabinol (THC); however, up to 120 types of phytocannabinoids are present in hemp. Hemp leaves contain large amounts of Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA), which are acidic variants of CBD and THC and account for the largest proportion of CBDA. In recent studies, CBDA exhibited anti-hyperalgesia and anti-inflammatory effects. THCA also showed anti-inflammatory and neuroprotective effects that may be beneficial for treating neurodegenerative diseases. CBDA and THCA can penetrate the blood-brain barrier (BBB) and affect the central nervous system. The purpose of this study was to determine whether CBDA and THCA ameliorate Alzheimer's disease (AD)-like features in vitro and in vivo. The effect of CBDA and THCA was evaluated in the Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Memory Disorders; Mice; Neuroprotective Agents

Cannabidiol (CBD) and cannabidiolic acid (CBDA) are non-psychoactive components of the cannabis plant. CBD has been well characterised to have anxiolytic and anticonvulsant activity, whereas the behavioural effects of CBDA are less clear. Preclinical and clinical data suggests that CBD has antipsychotic properties and reduces methamphetamine self-administration in rats. An animal model that is commonly used to mimic the neurochemical changes underlying psychosis and drug dependence is methamphetamine (METH) sensitisation, where repeated administration of the psychostimulant progressively increases the locomotor effects of METH.. The aim of this study was to determine whether CBD or CBDA attenuate METH-induced sensitisation of locomotor hyperactivity in rats.. Eighty-six male Sprague Dawley rats underwent METH sensitisation protocol where they were subjected to daily METH (1 mg/kg on days 2 and 8, 5 mg/kg on days 3-7; i.p.) injections for 7 days. After 21 days of withdrawal, rats were given a prior injection of CBD (0, 40 and 80 mg/kg; i.p.) or CBDA (0, 0.1, 10 and 1000 µg/kg; i.p.) and challenged with acute METH (1 mg/kg; i.p.). Locomotor activity was then measured for 60 min.. Rats displayed robust METH sensitisation as evidenced by increased locomotor activity to METH challenge in METH-pretreated versus SAL-pretreated rats. CBD (40 and 80 mg/kg) reduced METH-induced sensitisation. There was no effect of any CBDA doses on METH sensitisation or acute METH-induced hyperactivity.. These results demonstrate that CBD, but not CBDA, reduces METH sensitisation of locomotor activity in rats at pharmacologically effective doses, thus reinforcing evidence that CBD has anti-addiction and antipsychotic properties.

Topics: Animals; Antipsychotic Agents; Cannabidiol; Cannabinoids; Male; Methamphetamine; Rats; Rats, Sprague-Dawley

To determine the pharmacokinetics of a solution containing cannabidiol (CBD) and cannabidiolic acid (CBDA), administered orally in 2 single-dose studies (with and without food), in the domestic rabbit (Oryctolagus cuniculus).. 6 healthy New Zealand White rabbits.. In phase 1, 6 rabbits were administered 15 mg/kg CBD with 16.4 mg/kg CBDA orally in hemp oil. In phase 2, 6 rabbits were administered the same dose orally in hemp oil followed by a food slurry. Blood samples were collected for 24 hours to determine the pharmacokinetics of CBD and CBDA. Quantification of plasma CBD and CBDA concentrations was determined using a validated liquid chromatography-mass spectrometry (LC-MS) assay. Pharmacokinetics were determined using noncompartmental analysis.. For CBD, the area under the curve extrapolated to infinity (AUC)0-∞ was 179.8 and 102 hours X ng/mL, the maximum plasma concentration (Cmax) was 30.4 and 15 ng/mL, the time to Cmax (tmax) was 3.78 and 3.25 hours, and the terminal half-life (t1/2λ) was 7.12 and 3.8 hours in phase 1 and phase 2, respectively. For CBDA, the AUC0-∞ was 12,286 and 6,176 hours X ng/mL, Cmax was 2,573 and 1,196 ng/mL, tmax was 1.07 and 1.12 hours, and t1/2λ was 3.26 and 3.49 hours in phase 1 and phase 2, respectively. Adverse effects were not observed in any rabbit.. CBD and CBDA reached a greater Cmax and had a longer t1/2λ in phase 1 (without food) compared with phase 2 (with food). CBDA reached a greater Cmax but had a shorter t1/2λ than CBD both in phase 1 and phase 2. These data may be useful in determining appropriate dosing of cannabinoids in the domestic rabbit.

Topics: Animals; Biological Availability; Cannabidiol; Cannabinoids; Cannabis; Plant Extracts; Rabbits

Cannabidiolic acid (CBDa) is pharmacologically unique from cannabidiol (CBD), but its chemical instability poses challenges for potential clinical utility. Here, we used magnesium ions to stabilize two cannabidiolic acid-enriched hemp extracts (Mg-CBDa and Chylobinoid, the latter of which also contains minor cannabinoid constituents) and compared their anticonvulsant activities with CBD in the maximal electroshock seizure test (MES) in rats.. Sprague-Dawley rats received intraperitoneal (i.p.) injections of Chylobinoid, Mg-CBDa, or CBD at varying doses at discrete time points. Rats were challenged with a 0.2 s, 60 Hz, 150 mA corneal stimulation and evaluated for resultant hindlimb tonic extension. Dose-response relationships were calculated using Probit analysis and statistical significance was assessed with a two-sample z-test.. CBDa-enriched hemp extracts exhibited dose-dependent protection in the MES model at doses comparable, but not more effective than, CBD. Chylobinoid was more effective than Mg-CBDa despite lower CBDa content. Test compounds should be compared by sub-chronic dosing in the MES test in order to assess safety and pharmacokinetic profiles. CBDa should be evaluated in pharmacoresistant and chronic animal models of epilepsy.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabinoids; Plant Extracts; Rats; Rats, Sprague-Dawley; Seizures

The major phytocannabinoid cannabidiol (CBD) has anxiolytic properties and lacks tetrahydrocannabinol-like psychoactivity. Cannabidiolic acid (CBDA) is the acidic precursor to CBD, and this compound appears more potent than CBD in animal models of emesis, pain and epilepsy. In this short report, we aimed to examine whether CBDA is more potent than CBD in disrupting expression of conditioned fear and generalised anxiety-related behaviour induced by Pavlovian fear conditioning. Mice underwent fear conditioning and 24 h later were administered CBD and CBDA before testing for fear expression and generalized anxiety-like behaviour. We found that CBD and CBDA had dissociable effects; while CBD but not CBDA disrupted cued fear memory expression, CBDA but not CBD normalized trauma-induced generalized anxiety-related behaviour. Neither phytocannabinoid affected contextual fear expression. Our findings form the basis for future experiments examining whether phytocannabinoids, alone and in combination, are effective in these mouse models of fear and anxiety.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Cannabidiol; Cannabinoids; Conditioning, Classical; Fear; Male; Memory; Mice; Mice, Inbred C57BL; Wounds and Injuries

When acutely administered intraperitoneally, the non-psychoactive cannabinoid cannabidiol (CBD), its acidic precursor cannabidiolic acid (CBDA) and a stable methyl ester of CBDA (HU-580) reduce lithium chloride (LiCl)-induced conditioned gaping in male rats (a selective preclinical model of acute nausea) via activation of the serotonin 1A (5-HT. To utilise these compounds to manage nausea in the clinic, we must determine if their effectiveness is maintained when injected subcutaneously (s.c) and when repeatedly administered. First, we compared the effectiveness of each of these compounds to reduce conditioned gaping following repeated (7-day) and acute (1-day) pretreatments and whether these anti-nausea effects were mediated by the 5-HT. When administered repeatedly (7 days), CBD, CBDA and HU-580 did not lose efficacy in reducing nausea and continued to act via agonism of the 5-HT

Topics: Animals; Antiemetics; Cannabidiol; Cannabinoids; Drug Administration Schedule; Female; Lithium Chloride; Male; Nausea; Rats; Rats, Sprague-Dawley; Shrews; Treatment Outcome; Vomiting

Topics: Animals; Anticonvulsants; Brain; Cannabinoids; Epilepsies, Myoclonic; Epilepsy, Tonic-Clonic; Female; Half-Life; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NAV1.1 Voltage-Gated Sodium Channel

Aldose reductase (ALR2) is a key enzyme involved in diabetic complications and the search for new aldose reductase inhibitors (ARIs) is currently very important. The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications. Non-psychotropic phytocannabinoids exert multiple pharmacological effects with therapeutic potential in many diseases such as inflammation, cancer, diabetes. Here, we have investigated the inhibitory effects of extracts and their fractions from two Cannabis sativa L. chemotypes with high content of cannabidiol (CBD)/cannabidiolic acid (CBDA) and cannabigerol (CBG)/cannabigerolic acid (CBGA), respectively, on human recombinant and pig kidney aldose reductase activity in vitro. A molecular docking study was performed to evaluate the interaction of these cannabinoids with the active site of ALR2 compared to known ARIs. The extracts showed significant dose-dependent aldose reductase inhibitory activity (>70%) and higher than fractions. The inhibitory activity of the fractions was greater for acidic cannabinoid-rich fractions. Comparative molecular docking results have shown a higher stability of the ALR2-cannabinoid acids complex than the other inhibitors. The extracts of Cannabis with high content of non-psychotropic cannabinoids CBD/CBDA or CBG/CBGA significantly inhibit aldose reductase activity. These results may have some relevance for the possible use of C. sativa chemotypes based preparations as aldose reductase inhibitors.

Topics: Aldehyde Reductase; Animals; Cannabidiol; Cannabinoids; Cannabis; Enzyme Inhibitors; Humans; Molecular Docking Simulation; Plant Extracts; Recombinant Proteins; Swine

In the past 50 years, Cannabis sativa (C. sativa) has gone from a substance essentially prohibited worldwide to one that is gaining acceptance both culturally and legally in many countries for medicinal and recreational use. As additional jurisdictions legalize Cannabis products and the variety and complexity of these products surpass the classical dried plant material, appropriate methods for measuring the biologically active constituents is paramount to ensure safety and regulatory compliance. While there are numerous active compounds in C. sativa the primary cannabinoids of regulatory and safety concern are (-)-Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and their respective acidic forms THCA-A and CBDA. Using the US Food and Drug Administration (FDA) bioanalytical method validation guidelines we developed a sensitive, selective, and accurate method for the simultaneous analysis CBD, CBDA, THC, and THCA-A in oils and THC & CBD in more complex matrices. This HPLC-MS/MS method was simple and reliable using standard sample dilution and homogenization, an isocratic chromatographic separation, and a triple quadrupole mass spectrometer. The lower limit of quantification (LLOQ) for analytes was 0.195 ng/mL over a 0.195-50.0 ng/mL range of quantification with a coefficient of correlation of >0.99. Average intra-day and inter-day accuracies were 94.2-112.7% and 97.2-110.9%, respectively. This method was used to quantify CBD, CBDA, THC, and THCA-A in 40 commercial hemp products representing a variety of matrices including oils, plant materials, and creams/cosmetics. All products tested met the federal regulatory restrictions on THC content in Canada (<10 μg/g) except two, with concentrations of 337 and 10.01 μg/g. With respect to CBD, the majority of analyzed products contained low CBD levels and a CBD: CBDA ratio of <1.0. In contrast, one product contained 8,410 μg/g CBD and a CBD: CBDA ratio of >1,000 (an oil-based product). Overall, the method proved amenable to the analysis of various commercial products including oils, creams, and plant material and may be diagnostically indicative of adulteration with non-hemp C. sativa, specialized hemp cultivars, or unique manufacturing methods.

Topics: Cannabidiol; Cannabinoids; Cannabis; Chromatography, High Pressure Liquid; Chromatography, Liquid; Dronabinol; Plant Extracts; Tandem Mass Spectrometry

Cannabis is commonly used by humans to relieve stress.. Here, we evaluate the potential of intraperitoneally (i.p.) administered Δ. These results suggest the anxiolytic effects of CBDA and CBD may require the presence of a specific stressor.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Male; Rats; Receptor, Serotonin, 5-HT1A; Serotonin; Serotonin 5-HT1 Receptor Antagonists

Smoked marijuana contains over 100 different cannabinoids, including the psychoactive compound Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC, CBD, and its acidic precursor, cannabidiolic acid (CBDA), have all been shown to have antiemetic properties in the Suncus murinus (S. murinus; house musk shrew). Here we show that when subthreshold antiemetic doses of CBD (2.5 mg/kg ip) or CBDA (0.05 mg/kg ip) are combined with a subthreshold antiemetic dose of THC (1 mg/kg ip) in the S. murinus, both lithium-chloride-induced vomiting and abdominal retching are dramatically suppressed. These results suggest that combined effects of these compounds may lead to better control of vomiting with fewer side effects.

Topics: Animals; Antiemetics; Cannabidiol; Cannabinoids; Disease Models, Animal; Dronabinol; Drug Therapy, Combination; Female; Lithium Chloride; Male; Shrews; Vomiting

Cannabidiol (CBD) has been shown to inhibit gastrointestinal (GI) transit in pathophysiologic in vivo models, while having no effect in physiologic controls. The actions of the precursor of CBD, cannabidiolic acid (CBDA), have not been investigated in the GI tract. The actions of these phytocannabinoids on the contractility of the GI tract of Suncus murinus were investigated in the current study. The effects of CBDA and CBD in resting state and pre-contracted isolated intestinal segments, and on the contractile effects of carbachol and electrical field stimulation (EFS) on the intestines of S. murinus were examined. CBDA and CBD induced a reduction in resting tissue tension of isolated intestinal segments which was not blocked by the cannabinoid CB1 receptor antagonist, AM251, the CB(2) receptor antagonist AM630, or tetrodotoxin. CBDA and CBD reduced the magnitude of contractions induced by carbachol and the tension of intestinal segments that were pre-contracted with potassium chloride. In tissues stimulated by EFS, CBDA inhibited contractions induced by lower frequencies (0.1-4.0 Hz) of EFS, while CBD inhibited contractions induced by higher frequencies (4.0-20.0 Hz) of EFS. The data suggest that CBDA and CBD have inhibitory actions on the intestines of S. murinus that are not neuronallymediated or mediated via CB(1) or CB(2) receptors.

Topics: Animals; Cannabidiol; Cannabinoids; Dose-Response Relationship, Drug; In Vitro Techniques; Intestines; Muscle Contraction; Muscle, Smooth; Shrews