Category Archives: Epilepsy

Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence.

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“Review evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy.

Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL).

Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5-55 years).

Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17).

CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs.

Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed.”

https://www.ncbi.nlm.nih.gov/pubmed/29511052

http://jnnp.bmj.com/content/early/2018/02/05/jnnp-2017-317168

“Cannabis Compounds Reduce Epileptic Seizure Frequency In Children And Teenagers” http://www.iflscience.com/health-and-medicine/cannabis-compounds-reduce-epileptic-seizure-frequency-in-children-and-teenagers/

“Cannabis ingredient ‘reduces epilepsy seizures'”  https://www.webmd.boots.com/news/20180307/cannabis-ingredient-for-epilepsy-seizures

“Marijuana Derivative Successfully Treats Teen Epilepsy in New Experiments”  https://www.inverse.com/article/41985-cbd-marijuana-treat-seizures-epilepsy

Cannabidiol Regulates Long Term Potentiation Following Status Epilepticus: Mediation by Calcium Stores and Serotonin.

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“Epilepsy is a devastating disease, with cognitive and emotional consequences that are not curable.

In recent years, it became apparent that cannabinoids help patients to cope with epilepsy.

We have studied the effects of cannabidiol (CBD) on the ability to produce long term potentiation (LTP) in stratum radiatum of CA1 region of the mouse hippocampus.

Exposure to seizure-producing pilocarpine reduced the ability to generate LTP in the slice.

Pre-exposure to CBD prevented this effect of pilocarpine.

Furthermore, CBD caused a marked increase in ability to generate LTP, an effect that was blocked by calcium store antagonists as well as by a reduction in serotonin tone. Serotonin, possibly acting at a 5HT1A receptor, or fenfluramine (FFA), which causes release of serotonin from its native terminals, mimicked the effect of CBD.

It is proposed that CBD enhances non-NMDA LTP in the slice by facilitating release of serotonin from terminals, consequently ameliorating the detrimental effects of pilocarpine.”

 https://www.ncbi.nlm.nih.gov/pubmed/29467619
https://www.frontiersin.org/articles/10.3389/fnmol.2018.00032/full

Cannabis as an anticonvulsant

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BMJ Journals“There are records of the cannabis plant being used for medicinal purposes in ancient times, and in the 19th century it was used as an effective anti-epileptic drug (AED) in children.

However, because of its abuse potential, most countries imposed laws restricting its cultivation and use, and this has greatly inhibited research into possible therapeutic uses.

Things are now changing, and cannabis derivatives are now used legally to treat, for example, pain, nausea and spasticity.

The plant contains over 100 biologically active compounds, and recently it has been possible to isolate these and identify the neurochemical mechanisms by which some of them operate: one in particular, cannabidiol”

https://www.ncbi.nlm.nih.gov/pubmed/29449212

http://adc.bmj.com/content/early/2018/02/15/archdischild-2018-314921

Cannabis for paediatric epilepsy: challenges and conundrums.

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“Research is expanding for the use of cannabidiol as an anticonvulsant drug. The mechanism of cannabidiol in paediatric epilepsy is unclear but is thought to play a role in modulation of synaptic transmission. Evidence for its efficacy in treating epilepsy is limited but growing, with a single pharmaceutical company-funded randomised double-blind controlled trial in children with Dravet syndrome. Progress towards the use of medicinal cannabinoids incorporates a complex interplay of social influences and political and legal reform. Access to unregistered but available cannabidiol in Australia outside of clinical trials and compassionate access schemes is state dependent and will require Therapeutic Goods Administration approval, although the cost may be prohibitive. Further clinical trials are needed to clearly define efficacy and safety, particularly long term.”

https://www.ncbi.nlm.nih.gov/pubmed/29438649

Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center.

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“Medically refractory epilepsy continues to be a challenge worldwide, and despite an increasing number of medical therapies, approximately 1 in 3 patients continues to have seizures.

Cannabidiol (CBD), one of many constituents of the Cannabis sativa or marijuana plant, has received renewed interest in the treatment of epilepsy. While highly purified CBD awaits Food and Drug Administration (FDA) approval, artisanal formulations of CBD are readily available and are seeing increased use in our patient population.

Although randomized controlled trials of CBD are ongoing and promising, data regarding artisanal formulations of CBD are minimal and largely anecdotal. Here, we report a retrospective study to define the efficacy of artisanal CBD preparations in children with epilepsy.

Given the known interaction between CBD and clobazam, we also conducted a subgroup comparison to determine if clobazam use was related to any beneficial effects of CBD. Additionally, we compared response rates with CBD and with clobazam alone within an overlapping patient cohort. A pediatric cohort with epilepsy of 108 patients was identified through a medical record search for patients using CBD oil.

The addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The responder rate for clobazam was similar. No patients achieved CBD monotherapy, although the weaning of other antiepileptic drugs (AEDs) became possible in 22% of patients. A comparable proportion had AED additions during CBD therapy. With concomitant use of clobazam, 44% of patients had a 50% reduction in seizures upon addition of CBD compared with 33% in the population not taking clobazam; this difference was not statistically significant. The most common reported side effect of CBD was sedation in less than 4% of patients, all of whom were also taking clobazam.

Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. Benefits were more marked in the CBD alone group, in contrast to the CBD and clobazam group, but this difference was not statistically significant.

In summary, these findings support efficacy of artisanal CBD preparations in seizure reduction with few significant side effects. The response to CBD was independent of concurrent clobazam use, although clobazam may contribute to the sedation seen with concurrent CBD use.”

 https://www.ncbi.nlm.nih.gov/pubmed/29429908
“In this retrospective study, we report that artisanal CBD is helpful in the treatment of medically refractory seizures.”
http://www.epilepsybehavior.com/article/S1525-5050(18)30009-X/fulltext

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.

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“Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications.

No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome.

We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients.

Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated.“

https://www.ncbi.nlm.nih.gov/pubmed/29395273

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30136-3/fulltext

“This study is registered with ClinicalTrials.gov, number NCT02224690.”

“Cannabidiol for drop seizures in Lennox-Gastaut syndrome”  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30135-1/fulltext

“Cannabidiol Reduces Drop Seizures in Lennox-Gastaut Syndrome”  https://www.neurologyadvisor.com/epilepsy/cannabidiol-reduces-drop-seizures-in-lennox-gastaut-syndrome/article/739544/

“Cannabidiol helps reduce drop attacks in people with Lennox-Gastaut syndrome, study shows” https://www.epilepsy.org.uk/news/news/cannabidiol-helps-reduce-drop-attacks-people-lennox-gastaut-syndrome-study-shows-68090

“‘Pharma Grade’ CBD Effective in Lennox-Gastaut”  https://www.medscape.com/viewarticle/891810

“Cannabidiol Efficacious for Lennox-Gastaut Drop Seizures”  https://www.doctorslounge.com/index.php/news/pb/78004

Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities.

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Molecular Neurobiology

“The hippocampus is one of the most susceptible regions in the brain to be distraught with status epilepticus (SE) induced injury. SE can occur from numerous causes and is more frequent in children and the elderly population.

Administration of a combination of antiepileptic drugs can abolish acute seizures in most instances of SE but cannot prevent the morbidity typically seen in survivors of SE such as cognitive and mood impairments and spontaneous recurrent seizures. This is primarily due to the inefficiency of antiepileptic drugs to modify the evolution of SE-induced initial precipitating injury into a series of epileptogenic changes followed by a state of chronic epilepsy.

Chronic epilepsy is typified by spontaneous recurrent seizures, cognitive dysfunction, and depression, which are associated with persistent inflammation, significantly waned neurogenesis, and abnormal synaptic reorganization. Thus, alternative approaches that are efficient not only for curtailing SE-induced initial brain injury, neuroinflammation, aberrant neurogenesis, and abnormal synaptic reorganization but also for thwarting or restraining the progression of SE into a chronic epileptic state are needed.

In this review, we confer the promise of cannabidiol, an active ingredient of Cannabis sativa, for preventing or easing SE-induced neurodegeneration, neuroinflammation, cognitive and mood impairments, and the spontaneous recurrent seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/29372545

 https://link.springer.com/article/10.1007%2Fs12035-018-0898-y

Cannabidiol for drug-resistant seizures in the Dravet syndrome

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Journal of Paediatrics and Child Health

“Dravet syndrome (severe myoclonic epilepsy of infancy) is characterised by difficult-to-control seizures. Media reports and small clinical trials suggest that cannabidiol, a non-toxic extract of cannabis, can reduce seizure frequency. A recent multicentre randomised controlled trial of 120 children aged 2–18 years with Dravet syndrome supports its efficacy.

Over a 14-week period, children taking 20 mg/kg/day of cannabidiol had a 22.8% reduction (95% confidence interval 5.4–41.1) in seizure frequency compared to a 4-week baseline period. Median convulsive frequency fell from 12.4 to 5.9 per month on cannabidiol, while the placebo group had no change from baseline. No attempt was made to measure non-convulsive seizures (e.g. absences). Subjects took a median of three other anti-convulsant drugs during the trial. Adverse effects were common with cannabidiol, particularly somnolence, fatigue, loss of appetite, vomiting and diarrhoea. Eight patients in the cannabidiol group withdrew compared to one in the placebo group.

Nevertheless, 62% of caregivers in the cannabidiol group felt the patient’s overall condition had improved, using a validated global score, compared to 34% in the placebo group (P = 0.02). Unfortunately, the high rate of adverse events may have led to widespread loss of caregiver blinding, and the study is relatively short term. Nevertheless, the reduction in seizures is clinically relevant, and further longer-term randomised controlled trials are clearly warranted. ” https://www.ncbi.nlm.nih.gov/pubmed/29314377  http://onlinelibrary.wiley.com/doi/10.1111/jpc.13803/full

Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview.

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“Cannabinoid-based medications provide not only relief for specific symptoms, but also arrest or delay of disease progression in patients with pain, multiple sclerosis, and other conditions. Although they also seem to hold potential as anticonvulsant agents, evidence of their efficacy in epilepsy is supported by several evidences.

The data reviewed herein lend support to the notion that the endocannabinoid signalling system plays a key modulation role in the activities subserved by the hippocampus, which is directly or indirectly affected in epilepsy patients.

The notion is supported by a variety of anatomical, electrophysiological, biochemical and pharmacological findings. These data suggest the need for developing novel treatments using compounds that selectively target individual elements of the endocannabinoid signalling system.” https://www.ncbi.nlm.nih.gov/pubmed/29290836

“The data reviewed herein demonstrate that cannabinoids provide neuroprotection against brain excitability. They seem to induce at least partial restoration of neurotransmitter dysfunction, inducing an anticonvulsant effect that may be the biological substrate of the complex neurochemical effects reported in experimental and clinical studies. A large body of data suggests that cannabinoids can be harnessed as antiepileptic agents. Finally, among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events and it might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy.”
https://benthamopen.com/FULLTEXT/TONEUJ-11-61