Category Archives: Epilepsy

Pharmacology of Medical Cannabis.

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 “The Cannabis plant has been used for many of years as a medicinal agent in the relief of pain and seizures. It contains approximately 540 natural compounds including more than 100 that have been identified as phytocannabinoids due to their shared chemical structure. The predominant psychotropic component is Δ9-tetrahydrocannabinol (Δ9-THC), while the major non-psychoactive ingredient is cannabidiol (CBD). These compounds have been shown to be partial agonists or antagonists at the prototypical cannabinoid receptors, CB1 and CB2. The therapeutic actions of Δ9-THC and CBD include an ability to act as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds and as protective agents in neurodegeneration. However, there is a lack of well-controlled, double blind, randomized clinical trials to provide clarity on the efficacy of either Δ9-THC or CBD as therapeutics. Moreover, the safety concerns regarding the unwanted side effects of Δ9-THC as a psychoactive agent preclude its widespread use in the clinic. The legalization of cannabis for medicinal purposes and for recreational use in some regions will allow for much needed research on the pharmacokinetics and pharmocology of medical cannabis. This brief review focuses on the use of cannabis as a medicinal agent in the treatment of pain, epilepsy and neurodegenerative diseases. Despite the paucity of information, attention is paid to the mechanisms by which medical cannabis may act to relieve pain and seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/31332738

https://link.springer.com/chapter/10.1007%2F978-3-030-21737-2_8

A systematic review of cannabidiol dosing in clinical populations.

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British Journal of Clinical Pharmacology banner“Cannabidiol is a cannabis-derived medicinal product with potential application in a wide-variety of contexts, however its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of cannabidiol in a variety of medical contexts.

RESULTS:

A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. 23 studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 – 50 mg/Kg/day. Plasma concentrations were not provided in any publication. Cannabidiol was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of cannabidiol on reducing seizure frequency or severity (average 15 mg/Kg/day within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n=6-62) assessing diabetes, Crohn’s disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/Kg/day) were used in these studies.

CONCLUSION:

This review highlights cannabidiol has a potential wide range of activity in several pathologies. Pharmacokinetic studies as well as conclusive phase III trials to elucidate effective plasma concentrations within medical contexts are severely lacking and highly encouraged.”

https://www.ncbi.nlm.nih.gov/pubmed/31222854

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.14038

Cognitive functioning following long-term cannabidiol use in adults with treatment-resistant epilepsy.

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“Cognitive dysfunction is a common comorbidity in adults with treatment-resistant epilepsy (TRE).

Recently, cannabidiol (CBD) has demonstrated efficacy in epilepsy treatment. However, our understanding of CBD’s cognitive effects in epilepsy is limited.

We examined long-term cognitive effects of CBD in adults with TRE as part of an ongoing prospective, open-label safety study.

Longitudinal analysis revealed no significant group change across the two global composite scales. Of the seven individual cognitive tests, none changed significantly over time. No correlation was found between the cognitive change scores and CBD dose (all P’s ≥; 0.2). Change in cognitive test performance was not associated change in seizure severity rating.

These findings are encouraging and indicate that long-term administration of pharmaceutical grade CBD is overall cognitively well-tolerated in adults with TRE.”

https://www.ncbi.nlm.nih.gov/pubmed/31220785

https://www.epilepsybehavior.com/article/S1525-5050(18)30931-4/fulltext

Investigating the Therapeutic Mechanism of Cannabidiol in a Human Induced Pluripotent Stem Call (iPSC)-Based Cellular Model of Dravet Syndrome.

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Current Issue

“Dravet syndrome is an infantile epileptic encephalopathy primarily caused by loss-of-function variants of the gene SCN1A Standard treatment regimens have very limited efficacy to combat the life-threatening seizures in Dravet syndrome or the behavioral-cognitive comorbidities of the disease. Recently there has been encouraging progress in developing new treatments for this disorder.

One of the clinical advances is cannabidiol (CBD), a compound naturally found in cannabis and shown to further reduce convulsive seizures in patients when used together with existing drug regimens. Like many other natural products, the exact therapeutic mechanism of CBD remains undefined.

Previously we have established a human cellular model of Dravet syndrome by differentiating patient-derived induced pluripotent stem cells (iPSCs) into telencephalic inhibitory and excitatory neurons. Here we have applied this model to investigate the antiepileptic mechanism(s) of CBD at the cellular level.

We first determined the effect of escalating the concentrations of CBD on neuronal excitability, using primary culture of rat cortical neurons. We found modulatory effects on excitability at submicromolar concentrations and toxic effects at high concentrations (15 µM). We then tested CBD at 50 nM, a concentration that corresponds to the estimated human clinical exposure, in telencephalic neurons derived from a patient iPSC line and control cell line H9. This 50 nM of CBD increased the excitability of inhibitory neurons but decreased the excitability of excitatory neurons, without changing the amplitude of sodium currents in either cell type.

Our findings suggest a cell type-dependent mechanism for the therapeutic action of CBD in Dravet syndrome that is independent of sodium channel activity.”

https://www.ncbi.nlm.nih.gov/pubmed/31186344

http://symposium.cshlp.org/content/early/2019/06/11/sqb.2018.83.038174

Purified Cannabidiol for Treatment of Refractory Epilepsies in Pediatric Patients with Developmental and Epileptic Encephalopathy.

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“A pharmaceutical grade formulation of cannabidiol (CBD) has been approved for the treatment of Dravet syndrome and Lennox-Gastaut syndrome; however, this formulation is not yet available to patients outside the USA. In addition, CBD is thought to have broad anti-seizure properties that may be beneficial for other types of intractable epilepsy.

OBJECTIVE:

The aim of this study was to evaluate the efficacy, safety and tolerability of artisanal medical CBD oil in patients with developmental and epileptic encephalopathy (DEE) at the tertiary epilepsy center of Bambino Gesù Children’s Hospital in Rome, Italy.

RESULTS:

Twenty-nine patients were enrolled in this study (41.4% male). The mean duration of exposure to artisanal CBD was 11.2 months [range 6-25 months; standard deviation (SD) ± 4.4 months]. Mean age at study enrollment was 9.3 years (range 1.9-16.3 years; SD ± 4.7 years). Eleven out of 29 patients (37.9%) had a ≥ 50% improvement in seizure frequency; one patient became seizure free. None of the patients reported worsening seizure frequency; however, 18 patients (62.1%) experienced no beneficial effect regarding seizure frequency. Adverse effects were reported in seven patients (24.14%), most commonly somnolence, decreased appetite and diarrhea. Adverse events were mild and transient, and no dose modification of CBD or other AEDs was required.

CONCLUSIONS:

These data suggest that CBD may have beneficial effects in patients with DEE and an acceptable safety profile. Placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in patients with DEE.”

 https://www.ncbi.nlm.nih.gov/pubmed/31179531
https://link.springer.com/article/10.1007%2Fs40272-019-00341-x

Cannabinoids, hippocampal excitability and efficacy for the treatment of epilepsy.

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Pharmacology & Therapeutics

“Interest in cannabis and its related cannabinoids THC and CBD for use as anti-convulsant therapy has been progressively increasing. While the destigmatization of cannabis and cannabis related research have progressed in the last few decades, there are still many questions that remain answered. This review seeks to summarize the progress made in cannabis research in the past four decades and to identify possible directions for future research that are critical for the development of cannabinoid-based therapy in epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/31176695

https://www.sciencedirect.com/science/article/pii/S0163725819301093?via%3Dihub

Medical Marijuana in the Pediatric Population With Epilepsy—What You Should Know

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Journal of Pediatric Health Care Home

“This article discusses the controversial but promising topic of medical marijuana (MM) use in the pediatric population with epilepsy. Included is the importance of MM throughout history, the pharmacodynamics and pharmacokinetics, and a literature review that provides anecdotal evidence of the positive effect MM has on children suffering from seizures. From this literature review, dosage for treatment and management is provided. Also discussed is the recent FDA-approved pharmaceutical grade CBD product, Epidiolex, for treatment of two pediatric-onset seizure syndromes, Lennox-Gastaut and Dravet. Clinical implications regarding adverse side effects of MM use are also discussed. The aim of this article is to arm providers with contemporary knowledge on the risks and benefits of MM use in the pediatric population with epilepsy, which may boost their skills and confidence in educating and advocating for children with seizures. This novel, ever-changing medication is in the forefront of history and the news, making this topic especially important for review.”

 https://www.jpedhc.org/article/S0891-5245(18)30699-0/fulltext 

Synthetic, non-intoxicating 8,9-dihydrocannabidiol for the mitigation of seizures.

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 Scientific Reports“There can be a fine line between therapeutic intervention and substance abuse, and this point is clearly exemplified in herbal cannabis and its products. Therapies involving cannabis have been the treatment of last resort for some cases of refractory epilepsy, and this has been among the strongest medical justifications for legalization of marijuana. In order to circumvent the narcotic effects of Δ9-tetrahydrocannabinol (THC), many studies have concentrated on its less intoxicating isomer cannabidiol (CBD). However, CBD, like all natural cannabinoids, is a controlled substance in most countries, and its conversion into THC can be easily performed using common chemicals. We describe here the anticonvulsant properties of 8,9-dihydrocannibidiol (H2CBD), a fully synthetic analogue of CBD that is prepared from inexpensive, non-cannabis derived precursors. H2CBD was found to have effectiveness comparable to CBD both for decreasing the number and reducing the severity of pentylenetetrazole-induced seizures in rats. Finally, H2CBD cannot be converted by any reasonable synthetic route into THC, and thus has the potential to act as a safe, noncontroversial drug for seizure mitigation.”

https://www.ncbi.nlm.nih.gov/pubmed/31123271

https://www.nature.com/articles/s41598-019-44056-y

[Medicinal cannabis].

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“The use of cannabis products for medical purposes is rapidly increasing in the Netherlands. Studies suggest that these products have positive effects in the treatment of chronic neuropathic pain, multiple-sclerosis-related spasticity, certain epilepsy syndromes and chemotherapy-related nausea and vomiting.”

https://www.ncbi.nlm.nih.gov/pubmed/31120212

CBD: A New Hope?

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 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