Cannabidiol as a Therapeutic Target: Evidence of its Neuroprotective and Neuromodulatory Function in Parkinson’s Disease

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 15, 2020

The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit both animals and humans. BG subcortical structures that regulate initiation, execution, orientation movement. CBRs dopaminergic transmission nigro-striatal pathway and, thus, also. functioning is affected pathologies related to movement disorders, especially those occurring Parkinson's disease (PD), which produces motor non-motor symptoms involving GABAergic, glutamatergic, neural networks. To date, most effective medication PD levodopa (l-DOPA); however, long-term treatment causes type dyskinesias, l-DOPA-induced dyskinesias (LIDs). With neuromodulation offering novel strategy patients, research has focused on endocannabinoid (ECS), it participates physiological order control have shown inhibit neurotransmitter release, while endocannabinoids (eCBs) play key role synaptic regulation BG. In past decade, cannabidiol (CBD), non-psychotropic phytocannabinoid, compensatory effects ECS neuromodulator neuroprotector models such 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), reserpine, well other models. Although CBD-induced neuroprotection observed animal attributed activation CB1 receptor, recent conducted at molecular level CBD capable activating receptors, CB2 TRPV-1 neurons pathway. These findings open new lines scientific inquiry into communication. Cannabidiol activates PPARγ, GPR55, GPR3, GPR6, GPR12, GPR18 causing variety biochemical, molecular, behavioral due broad range CNS. Given low number alternatives currently available, search molecules with therapeutic potential improve neuronal communication crucial. Therefore, investigation mechanisms involved its function required ascertain whether receptor could be LID.

Language: Английский

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Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog Interaction

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: Nov. 5, 2019

Abstract We tested whether cannabinoids (CBs) potentiate alcohol-induced birth defects in mice and zebrafish, explored the underlying pathogenic mechanisms on Sonic Hedgehog (Shh) signaling. The CBs, Δ 9 -THC, cannabidiol, HU-210, CP 55,940 caused alcohol-like effects craniofacial brain development, phenocopying Shh mutations. Combined exposure to even low doses of alcohol with THC, or a greater incidence defects, particularly eyes, than did either treatment alone. Consistent hypothesis that these are by deficient Shh, we found CBs reduced signaling inhibiting Smoothened (Smo), while mRNA CB1 receptor antagonist attenuated CB-induced defects. Proximity ligation experiments identified novel CB1-Smo heteromers, suggesting allosteric interactions. In addition raising concerns about safety cannabinoid during early embryonic this study establishes link between two distinct pathways has widespread implications for as well diseases such addiction cancer.

Language: Английский

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Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches

International Journal of Biological Macromolecules, Journal Year: 2020, Volume and Issue: 168, P. 474 - 485

Published: Dec. 6, 2020

Language: Английский

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A systematic review of minor phytocannabinoids with promising neuroprotective potential

British Journal of Pharmacology, Journal Year: 2020, Volume and Issue: 177(19), P. 4330 - 4352

Published: July 1, 2020

Embase and PubMed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, apart from cannabidiol Δ9 -tetrahydrocannabinol, including -tetrahydrocannabinolic acid, -tetrahydrocannabivarin, cannabidiolic cannabidivarin, cannabichromene, cannabichromenic cannabichromevarin, cannabigerol, cannabigerolic cannabigerivarin, cannabigerovarinic cannabichromevarinic cannabidivarinic cannabinol. Out 2,341 studies, 31 met inclusion criteria. Cannabigerol (range 5 to 20 mg·kg-1 ) cannabidivarin 0.2 400 displayed efficacy in models Huntington's disease epilepsy. Cannabichromene (10-75 ), acid (20 tetrahydrocannabivarin 0.025-2.5 showed promise seizure hypomobility, Parkinson's disease. Limited mechanistic data its derivatives VCE.003 VCE.003.2, mediated some their effects through PPAR-γ, but no other receptors probed. Further studies with these combinations, are warranted across a range neurodegenerative disorders.

Language: Английский

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Access to cannabidiol without a prescription: A cross-country comparison and analysis

International Journal of Drug Policy, Journal Year: 2020, Volume and Issue: 85, P. 102935 - 102935

Published: Sept. 9, 2020

Recent legislative change has allowed increased access to cannabis products in many jurisdictions. In some locations, this includes over-the-counter (OTC) and/or online containing cannabidiol (CBD), a non-intoxicating cannabinoid with therapeutic properties. Here we compared the availability of CBD and associated regulatory background nine selected countries. Accessibility was examined USA, Canada, Germany, Ireland, United Kingdom, Switzerland, Japan, Australia, New Zealand as May 2020. Regulatory other relevant documents were obtained from government agency websites related sources. Relevant commercial physical retailers visited verify CBD-containing nature available. A range appeared be accessible without prescription seven out countries reviewed. Australia exceptions where clinician required any product. commonly available included oils, gel capsules, purified crystal topical products. The daily recommended doses orally administered non-prescription typically well below 150 mg substantially lower than reported have effects published clinical trials (e.g., 300-1500 mg). legal foundations enabling several often unclear, marketed sometimes failing meet requirements for sale. There an obvious disparity between federal directives both USA European examined. are variety approaches how manage Many appear permit OTC but clarity. As consumer demand escalates, improved legislation, guidelines quality control would seem prudent together exploring benefits lower-dose formulations.

Language: Английский

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Use and Perceptions of Cannabidiol Products in Canada and in the United States

Cannabis and Cannabinoid Research, Journal Year: 2020, Volume and Issue: 7(3), P. 355 - 364

Published: Nov. 23, 2020

Objectives: This study aimed to characterize use and perceptions of cannabidiol (CBD) products. Materials Methods: Participants aged 16–65 years in Canada (n=15,042) the United States (n=30,288) completed measures on prevalence patterns CBD product oil as part 2019 International Cannabis Policy Study online survey. Results: Past 12-month was significantly more prevalent among respondents (26.1%) than (16.2%). Consumers reported using a range products, including drops (46.3% vs. 47.3%, respectively), topicals (26.0% 16.7%), edibles/foods (23.8% 17.6%), vape oils (18.9% 13.3%), capsules (13.3% dried flower (10.1% 16.1%). most commonly for management pain, anxiety, depression. Over half consumers both countries that beneficial health. Conclusions: Use products is common Canada, primarily manage self-reported health conditions which there little or no evidence efficacy. Clearer public messaging regarding therapeutic effects warranted.

Language: Английский

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Cannabidiol use and effectiveness: real-world evidence from a Canadian medical cannabis clinic

Journal of Cannabis Research, Journal Year: 2021, Volume and Issue: 3(1)

Published: June 23, 2021

Abstract Background Cannabidiol (CBD) is a primary component in the cannabis plant; however, recent years, interest CBD treatments has outpaced scientific research and regulatory advancement resulting confusing landscape of misinformation unsubstantiated health claims. Within limited results from randomized controlled trials, lack trust product quality known clinical guidelines dosages, real-world evidence (RWE) countries with robust frameworks may fill critical need for patients healthcare professionals. Despite growing interest, no data (RWD) studies have yet investigated patients’ reports impact on symptom control common expression pain, anxiety, depression, poor wellbeing. The objective this study to assess CBD-rich treatment burden, as measured specific assessment scale (ESAS-r). Methods This retrospective observational examined depression symptoms, wellbeing 279 participants over 18 years old, prescribed at network clinics dedicated medical Quebec, Canada. Data were collected baseline, 3 (FUP1), 6 (FUP2) month after initiation. Groups formed based severity (mild vs moderate/severe) changes plan FUP1 (CBD THC:CBD). Two-way mixed ANOVAs used ESAS-r scores differences between groups visits. Results All average decreased baseline (all p s < 0.003). addition delta-9-tetrahydrocannabinol (THC) during first follow-up had effect changes. Patients moderate/severe symptoms experienced important improvement 0.001), whereas those mild actually increased. Differences FUP2 not statistically different. Conclusion suggests beneficial well overall only moderate severe symptoms; observed symptoms. contribute address myths about demand further investigation.

Language: Английский

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Cytochrome P450–Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol

Drug Metabolism and Disposition, Journal Year: 2021, Volume and Issue: 49(10), P. 882 - 891

Published: July 30, 2021

Cannabidiol (CBD) is a naturally occurring nonpsychotoxic phytocannabinoid that has gained increasing attention as popular consumer product and for its use in Food Drug Administration–approved Epidiolex (CBD oral solution) the treatment of Lennox-Gastaut syndrome Dravet syndrome. CBD was previously reported to be metabolized primarily by CYP2C19 CYP3A4, with minor contributions from UDP-glucuronosyltransferases. 7-Hydroxy-CBD (7-OH-CBD) primary active metabolite equipotent activity compared CBD. Given polymorphic nature CYP2C19, we hypothesized variable expression may lead interindividual differences metabolism 7-OH-CBD. The objectives this study were further characterize roles cytochrome P450 enzymes metabolism, specifically 7-OH-CBD, investigate impact CYP2C19 polymorphism on genotyped human liver microsomes. results reaction phenotyping experiments recombinant P450–selective chemical inhibitors indicated both CYP2C9 are capable CYP3A played major role metabolic clearance via oxidation at sites other than 7-position. In microsomes, 7-OH-CBD formation positively correlated but not associated genotype. subset single-donor microsomes moderate low activity, inhibition significantly reduced formation, suggesting play greater 7-hydroxylation thought. Collectively, these data indicate important contributors

SIGNIFICANCE STATEMENT

This demonstrates involved CYP3A4 contributor through pathways 7-hydroxylation. microsomal genotype, found contribute generation. These findings have implications patients taking who risk clinically P450–mediated drug interactions.

Language: Английский

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The safety and efficacy of low oral doses of cannabidiol: An evaluation of the evidence

Clinical and Translational Science, Journal Year: 2022, Volume and Issue: 16(1), P. 10 - 30

Published: Oct. 19, 2022

Global interest in the non-intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a diversity health conditions. At present, there sufficient clinical trial evidence to support use high oral doses CBD (e.g., 10-50 mg/kg) treating intractable childhood epilepsies. However, question remains as whether "low-dose" products confer any benefits. This an important answer, low-dose are widely available many countries, often nutraceutical formulations. The present review therefore evaluated efficacy and safety low CBD. includes interventional studies that measured condition and/or tolerability dosed at less than or equal 400 mg per day adult populations (i.e., ≥18 years age). Studies were excluded if product administered had Δ

Language: Английский

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Cannabidiol activates neuronal Kv7 channels

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Feb. 18, 2022

Cannabidiol (CBD), a chemical found in the Cannabis sativa plant, is clinically effective antiepileptic drug whose mechanism of action unknown. Using fluorescence-based thallium flux assay, we performed large-scale screen and enhancement through heterologously expressed human Kv7.2/7.3 channels by CBD. Patch-clamp recordings showed that CBD acts at submicromolar concentrations to shift voltage dependence hyperpolarizing direction, producing dramatic current voltages near –50 mV. enhanced native M-current mouse superior cervical ganglion starting 30 nM also rat hippocampal neurons. The potent Kv2/7.3 may contribute its effectiveness as an reducing neuronal hyperexcitability.

Language: Английский

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