CBD: A New Hope?

 ACS Medicinal Chemistry Letters“The nonpsychoactive phytocannabinoid, CBD, was recently approved by the Food and Drug Administration for the treatment of children with drug-resistant epilepsy. This milestone opens new avenues for cannabinoid research. In this Viewpoint, we provide an overview of recent progress in the field highlighting molecular insights into CBD’s mechanism of action, as well as its therapeutic potential.”

https://www.ncbi.nlm.nih.gov/pubmed/31097982

https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00127

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Cannabinoid interactions with ion channels and receptors.

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“Cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, acts on a diverse selection of membrane proteins with promising therapeutic potential in epilepsy and chronic pain. In this review, we will outline the studies that report reproducible results of CBD and other cannabinoids changing membrane channel function, with particular interest on Nav. Nav are implicated in fatal forms of epilepsy and are also associated with chronic pain. This makes Nav potential targets for CBD interaction since it has been reported to reduce pain and seizures. This discovery will not only prompt further research towards CBD’s characterization, but also promotes the application of cannabinoids as potentially therapeutic compounds for diseases like epilepsy and pain.” https://www.ncbi.nlm.nih.gov/pubmed/31088312
https://www.tandfonline.com/doi/full/10.1080/19336950.2019.1615824

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Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy.

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“Dogs in the CBD group had a significant reduction in seizure frequency, compared with the placebo group”
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Cannabidiol: A Review of Clinical Efficacy and Safety in Epilepsy.

Pediatric Neurology

“Several new antiepileptic medicines became available for clinical use in the last two decades. However, the prognosis of epilepsy remains unchanged, with approximately one-third of patients continuing to have drug-resistant seizures. Because many of these patients are not candidates for curative epilepsy surgery, there is a need for new seizure medicines with better efficacy and safety profile.

Recently, social media and public pressure sparked a renewed interest in cannabinoids, which had been used for epilepsy since ancient times. However, physicians have significant difficulty prescribing cannabinoids freely because of the paucity of sound scientific studies.

Among the two most common cannabinoids, cannabidiol has better antiepileptic potential than tetrahydrocannabinol. The exact antiepileptic mechanism of cannabidiol is currently not known, but it modulates a number of endogenous systems and may have a novel anticonvulsant effect. However, it has broad drug-drug interactions with several agents, including inducer and inhibitor of CYP3A4 or CYP2C19. Cannabidiol can cause liver enzyme elevation, especially when co-administered with valproate.

The US Food and Drug Administration (FDA) has approved pharmaceutical-grade cannabidiol oil for two childhood-onset catastrophic epilepsies: Dravet syndrome and Lennox-Gastaut syndrome.

The Drug Enforcement Agency also reclassified this product as a schedule V agent. However, other cannabidiol products remain as a schedule I substance and are primarily used without regulation. Additionally, the FDA-approved pharmaceutical-grade cannabidiol oil is expensive, and insurance companies might approve this only for the designated indications.

In despair, many individuals may resort to unregulated medical cannabis products in an attempt to control seizures. Rather than spontaneous treatment without medical supervision, adequate medical oversight is indicated to monitor and manage the proper dose, side effects, validity of the product, and drug-drug interactions.”

https://www.ncbi.nlm.nih.gov/pubmed/31053391

https://www.pedneur.com/article/S0887-8994(18)31168-8/fulltext

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Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy.

“Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population.

OBJECTIVE:

The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy.

RESULTS:

Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2-6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%).

CONCLUSIONS:

Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated.”

https://www.ncbi.nlm.nih.gov/pubmed/31049885

https://link.springer.com/article/10.1007%2Fs40263-019-00624-4

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Higher cannabidiol plasma levels are associated with better seizure response following treatment with a pharmaceutical grade cannabidiol.

“The objective of this study was to determine the relationship between cannabidiol (CBD) dose, CBD plasma level, and seizure control in a large open-label single-center study.

METHODS:

All participants with treatment-refractory epilepsy participating in our expanded access program (EAP) were approached for participation. Highly purified grade CBD (Epidiolex®) dosing was weight-based and could be increased every 2 weeks by 5 mg/kg/day up to a maximum dosage of 50 mg/kg/day depending on tolerance and seizure control. Seizure counts were obtained at each visit with frequency calculated per 2-week periods. Cross-sectional plasma peak levels of CBD were obtained ~4 h after dosing in consecutively presenting patients.

RESULTS:

We evaluated 56 adults and 44 children (100 total; 54 female) at two time points – one before initiating CBD and one at the time of CBD plasma level testing. There was a positive linear correlation between CBD dosage (range from 5 to 50 mg/kg/day) and level (range from 7.1-1200 ng/mL) in all participants (r = 0.640; p < 0.001). The quantile regression model supported the notion of increased CBD levels being associated with improvement in seizure frequency after adjusting for age – specifically, a 100 ng/mL increase in CBD level was associated with approximately two counts reduction in seizure frequency per time period (1.87 96% confidence interval [CI] 0.34-3.39; p = 0.018). In participants with the same CBD level, differences in seizure improvement did not depend on age (p = 0.318).

CONCLUSIONS:

In this open-label study, we found evidence of a linear correlation between CBD dosage and plasma levels, and that higher dose/levels are associated with a higher response rate for seizure improvement. Children and adults responded to CBD similarly. However, seizure control response rates suggest children may respond to lower dosages/plasma levels than adults. Findings reported in this study are specific to Epidiolex® and should not be extrapolated to other CBD products.”

https://www.ncbi.nlm.nih.gov/pubmed/31048098

https://www.epilepsybehavior.com/article/S1525-5050(19)30051-4/fulltext

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Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results.

Epilepsy Research

“Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice.

We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016.

CONCLUSIONS:

Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.”

https://www.ncbi.nlm.nih.gov/pubmed/31022635

https://www.sciencedirect.com/science/article/pii/S0920121118305837?via%3Dihub

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Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials.

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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.”

https://www.ncbi.nlm.nih.gov/pubmed/31013866

https://www.mdpi.com/1420-3049/24/8/1459

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Quality of life in adults enrolled in an open-label study of cannabidiol (CBD) for treatment-resistant epilepsy.

“Treatment-resistant epilepsy (TRE) is associated with low quality of life (QOL). Cannabidiol (CBD) may improve QOL, but it is unclear if such improvements are independent of improvements in seizure control. Our aim was to compare QOL at baseline and after 1 year of treatment with CBD. We hypothesized that QOL would improve independent of changes in seizure frequency (SF) or severity, mood, or adverse events. We assessed QOL using Quality of Life in Epilepsy-89 (QOLIE-89) in an open-label study of purified CBD (Epidiolex®) for the treatment of TRE. All participants received CBD, starting at 5 mg/kg/day and titrated to 50 mg/kg/day in increments of 5 mg/kg/day. We collected QOLIE-89 in adult participants at enrollment and after 1 year of treatment, or at study exit if earlier. We analyzed if the change in QOLIE-89 total score could be explained by the change in SF, seizure severity (Chalfont Seizure Severity Scale, CSSS), mood (Profile of Moods States, POMS), or adverse events (Adverse Event Profile, AEP). Associations among the variables were assessed using bivariate tests and multiple regression. Fifty-three participants completed enrollment and follow-up testing, seven at study termination. Mean QOLIE-89 total score improved from enrollment (49.4 ± 19) to follow-up (57 ± 21.3; p = .004). We also saw improvements in SF, POMS, AEP, and CSSS (all p ≤ .01). Multivariable regression results showed QOLIE-89 at follow-up associated with improvements in POMS at follow-up (p = .020), but not with AEP, CSSS, or SF (p ≥ .135). Improvement in QOL after treatment with CBD is associated with better mood but not with changes in SF, seizure severity, or AEP. Cannabidiol may have beneficial effects on QOL and mood that are independent of treatment response.”

https://www.ncbi.nlm.nih.gov/pubmed/31003195

https://www.epilepsybehavior.com/article/S1525-5050(19)30116-7/fulltext

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Cost-effectiveness of cannabinoids for pediatric drug-resistant epilepsy: protocol for a systematic review of economic evaluations.

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“Drug-resistant epilepsy negatively impacts the quality of life and is associated with increased morbidity and mortality and high costs to the healthcare system. Cannabis-based treatments may be effective in reducing seizures in this population, but whether they are cost-effective is unclear. In this systematic review, we will search for cost-effectiveness analyses involving the treatment of pediatric drug-resistant epilepsy with cannabis-based products to inform decision-making by public healthcare payers about reimbursement of such products. We will also search for cost-effectiveness analyses of other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as estimates of healthcare resource use, costs, and utilities, for use in a subsequent cost-utility analysis to address this decision problem.

METHODS:

We will search the published and gray literature for economic evaluations of cannabis-based products and other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as resource utilization and utility studies. Two independent reviewers will screen the title and abstract of each identified record and the full-text version of any study deemed potentially relevant. Study and population characteristics, the incremental cost-effectiveness ratio (ICER), as well as total costs and benefits, will be extracted, and quality will be assessed by use of the Drummond and CHEERS checklists; context-specific issues will also be considered. From model-based cost-utility and cost-effectiveness analyses, we will extract and summarize the model structure, including health states, time horizon, and cycle length. From resource utilization studies, we will extract data about the frequency of resource use (e.g., neurology visits, emergency department visits, admissions to hospital). From utility studies, we will extract the utility for each health state, the source of the preferences (e.g., child, parent, patient, general public), and the method of elicitation.

DISCUSSION:

Drug-resistant epilepsy in children is associated with important costs to the healthcare system, and decision-makers require high-quality evidence on which to base reimbursement decisions. The results of this review will be useful to both decision-makers considering the decision problem of whether to reimburse cannabis-based products through public formularies and to analysts conducting studies in this area.”

https://www.ncbi.nlm.nih.gov/pubmed/30917869

https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-019-0990-z

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