The Other Side of the Leaf: Seizures Associated with Synthetic Cannabinoid Use

There has recently been a marked rise in the medicinal use of cannabis for epilepsy and multiple other conditions. While seizures have been reported in association with synthetic cannabinoids, the clinical features and prognosis have not been studied.

Thirty patients with a history of seizures occurring within 24 h of synthetic cannabinoid use were identified from a first seizure clinic database in Perth, Western Australia between 2011 and 2016. Eight had a prior history of seizures, three related to synthetic cannabinoid use, with an additional three patients having risk factors for seizures. The presenting event was a tonic-clonic seizure in 27 patients (90%). “Kronic” was the synthetic cannabinoid used by 16 patients. Absorption was via smoking in all cases, with seizures occurring within 30 min of inhalation in 14 patients (46%).

Electroencephalography (EEG) showed epileptiform abnormalities in 11%, and neuroimaging revealed epileptogenic lesions in 12%. Nine of 24 patients with follow-up had subsequent seizures, occurring in the setting of further synthetic cannabinoid use in two patients. This seizure recurrence rate is similar to seizures provoked by other acute systemic insults. In conclusion, smoking of some synthetic cannabinoids is associated with seizures, and this may relate to an intrinsic proconvulsant effect.

Study Finds Cannabidiol (Epidiolex®) Effective in Subjects with Refractory Epilepsy with or without Simultaneous Use of Clobazam

OBJECTIVE: To evaluate the efficacy of open-label, highly purified cannabidiol (CBD, Epidiolex®) in treating refractory epilepsy relative to the concomitant use of clobazam (CLB) as well as the clinical implications of changes in CLB and norclobazam (nCLB) levels.

METHODS: Data were examined retrospectively, in patients who either used CBD with concomitant CLB or without concomitant CLB after two months of treatment with CBD and at the point of best seizure control within the first year of treatment with CBD. Responder rates (percentage of subjects with a 50 % or greater reduction in weekly seizures from their baseline) and mean reduction in weekly seizure frequency were calculated and compared between those who concomitantly used CLB and those who did not. The relationship between the change in CLB and nCLB levels and change in mean weekly seizure frequency was also investigated within the group of subjects using concomitant CLB and CBD.

RESULTS: Researchers analyzed data from 47 subjects between the ages of 2.5-51 years. There was no significant difference between the concomitant CLB (n = 32) and no concomitant CLB (n = 15) groups in terms of demographics (age (p = 0.4344), race (p = 1.0000), sex (p = 0.7507)) or most epilepsy characteristics (underlying condition (all p > 0.05), mean baseline seizure frequency (p = 0.6483)). There was only one significant difference between groups regarding seizure types (more subjects with epileptic spasms in concomitant CLB group (p = 0.0413)). Concomitant AED usage was not significantly different in the two groups (all p > 0.05). Mean reduction in weekly seizure frequency was greater at the best point of seizure control within the first year than at two months of treatment with CBD, regardless of concomitant CLB usage (all p > 0.05). There was no significant difference in reduction of mean weekly seizure frequency between those who took concomitant CLB and those who did not at either time point (all p > 0.05). There was a significantly greater responder rate for subjects taking CBD and CLB than those taking CBD without CLB only at the point of best seizure control within the first year of CBD treatment (p = 0.0240). There was no strong, significant correlation between change in nCLB or CLB levels and change in seizure frequency at either time point (all p < 0.22).

SIGNIFICANCE: With or without concomitant clobazam, cannabidiol can be effective in reducing seizure frequency. Changes in norclobazam and clobazam levels do not have a clinically significant correlation with changes in weekly seizure frequency for those taking cannabidiol with clobazam.

Study Provides Insights on the Effects of Cannabidiol on Severe Form of Epilepsy, LGS

Results from a study published in the British Journal of Clinical Pharmacology may help explain why cannabidiol (CBD)—a chemical component of marijuana with no psychoactive properties—reduces the frequency of seizures in patients with a severe form of epilepsy. The effect may be explained by a drug-drug interaction between cannabidiol and the anti-seizure medication clobazam.

The form of epilepsy examined in the study is called Lennox–Gastaut syndrome. Investigators conducted clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on seizure frequency in patients with this syndrome.

“The effects of cannabidiol on seizure frequency in Lennox-Gastaut patients could be explained entirely through estimated elevations of blood levels of clobazam, which might mean that cannabidiol in itself may not have any, or at best limited, antiepileptic effects,” said senior author Geert Jan Groeneveld, MD, PhD, of the Centre for Human Drug Research, in The Netherlands.

Cannabis-based Zygel Helps Reduce Seizures in Childhood Epilepsy Syndromes, Trial Reports

A cannabis-based gel formulation developed by Zynerba Pharmaceuticals can significantly reduce seizures by up to six months in children and adolescents with developmental and epileptic encephalopathies, according to Phase 2 trial data.

Developmental and epileptic encephalopathies, or DEE, is an umbrella term that includes a heterogeneous group of rare pediatric epilepsy syndromes, such as Dravet and Lennox-Gastaut syndrome, among others.

The open-label BELIEVE 1 clinical trial was designed to explore the long-term safety and efficacy of Zygel in children and adolescents with DEE. To date, the study has enrolled, by invitation, 48 participants between 3 and 16 years old, who had confirmed DEE as classified by the International League Against Epilepsy.

The participants were initially dosed daily with 250 or 500 mg of Zygel, based on their weight, but the dosage could be increased up to a maximum of 1,000 mg daily. The treatment was directly applied to the skin (transdermal delivery) on the shoulders and upper arms.

Zygel was generally well-tolerated, and the safety profile was consistent with data from previous clinical studies.

Prospective Evaluation of Oral Cannabis Extracts in Children with Epilepsy Shows

PURPOSE: Interest in the use of artisanal cannabinoids in pediatric epilepsy has increased but safety and utility data are lacking. The aim of this study was to prospectively characterize the use of oral cannabis extracts (OCE) in a refractory pediatric epilepsy population.

METHODS: Families considering the use of an OCE were enrolled in a prospective observational study. Baseline seizure frequency was assessed over a period of 4 weeks. Seizure frequency, CBD and THC-COOH levels were assessed every 4 weeks during a 12-week treatment period. Response was defined as at least a 50% reduction in seizure frequency over the final 8 weeks of the study relative to baseline.

RESULTS: Consent was obtained in 32 children; 11 were excluded from analysis (3 failed to complete baseline data, 3 started OCE before completing baseline period and 5 did not start OCE) leaving 21 to be included in subsequent analyses. Median age was 10.3 years (IQR 6.8-12.6), 13 (62%) were male and median seizure frequency was 2.7 seizures/day during the baseline period. The median of the high dose of CBD that was administered during the observation period was of 0.9 (0.6-2.2) mg/kg/day. Of the 21 subjects who were included in the analysis, 5 (24%) were responders. OCE was stopped early in 3 subjects (14%) due to a perceived increase in seizures. THC-COOH and CBD blood levels did not have a significant association with response status (p = 0.95 CBD, p = 0.53 THC-COOH, N = 14).

CONCLUSION: The observed response rate [at least a 50% reduction in seizure frequency over the final 8 weeks of the study relative to baseline] in this study is similar to placebo rates in prospective randomized trials of pharmaceutical grade products and the withdrawal rate is greater than rates obtained with retrospective methods. Doses of oral cannabis extracts administered were lower than doses used in randomized trials.

Oral Cannabidiol Epidyolex Approved in Europe as Add-on Treatment for Dravet, Lennox-Gastaut Syndromes

The European Commission has approved Epidyolex (cannabidiol) as an add-on therapy to clobazam (brand names Onfi and Sympazan) for the treatment of seizures associated with Dravet syndrome and Lennox?Gastaut syndrome (LGS) in patients 2 and older.

This decision, which follows the favorable opinion of the Committee for Medicinal Products for Human Use — an arm of the European Medicines Agency (EMA) — is valid in all 28 E.U. member countries, along with Norway, Iceland, and Liechtenstein. The U.S. Food and Drug Administration had reached a similar decision to approve the treatment, under the brand name Epidiolex, in June 2018.

GW Pharmaceuticals’ Epidyolex is a purified and oral form of cannabidiol (CBD), the most common non-psychoactive cannabinoid compound in the cannabis plant. CBD is able to mimic natural compounds by acting on brain receptors, which may cause seizures when faulty.

CBD Alleviates Seizures in Animal Model of Angelman Syndrome, a Severe Neurodevelopmental Condition

University of North Carolina School of Medicine researchers show that CBD may alleviate seizures and normalize brain rhythms in Angelman syndrome, a rare neurodevelopmental condition. Published in the Journal of Clinical Investigation, the research conducted using Angelman syndrome animal models shows that CBD could benefit kids and adults with this serious condition, which is characterized by intellectual disability, lack of speech, brain rhythm dysfunction, and deleterious and often drug-resistant epilepsy.

“There is an unmet need for better treatments for kids with Angelman syndrome to help them live fuller lives and to aid their families and caregivers,” said Ben Philpot, Ph.D., Kenan Distinguished Professor of Cell Biology and Physiology and associate director of the UNC Neuroscience Center. “Our results show CBD could help the medical community safely meet this need.”

MGC Pharmaceuticals will Study Low THC Formula for Epilepsy Treatment

MGC Pharmaceuticals has received Human Research Ethics Committee approval to conduct a head-to-head clinical study to compare the effectiveness of its low tetrahydrocannabinol formula for the treatment of drug-resistant epilepsy to its 100% cannabidiol product.

The low tetrahydrocannabinol product is a proprietary pharmaceutical-grade phytocannabinoid-derived medicine authorized for prescription as an Investigational Medicinal Product in Australia and the UK, while the 100% cannabidiol product is currently available under Australia’s Special Access Scheme.

Management said the study, which will be carried out together with Cannabis Access Clinics and Epilepsy Action Australia, will be one of the first clinical opportunities in the world to assess and collect several data points.

These data points include the long-term safety of tetrahydrocannabinol treatments, the efficacy of cannabinoid treatments compared to currently available treatments and doctors’ assessments on cannabinoid medicine’s long-term impact on the quality of treatment and quality of life.

MGC said the study would be carried out on 100 patients from Cannabis Access Clinics for 12 months.

MGC Pharma to Test Cannabis Epilepsy Drug on Driving Performance

CannEpil is an approved drug currently being sold in Australia and parts of Europe and South America for the treatment of refractory, drug-resistant epilepsy.

And now the company has received approval from the Human Research Ethics Committee — which must sign off on all clinical trials before they can proceed — to conduct a controlled trial on its effects on driver competency and performance.

Data from the trial, if successful, will then form part of the application to be submitted to the Australian Therapeutic Goods Administration (TGA) and the European Medicines Agency (EMA) for product registration.

It will be one of the first trials globally to assess the impact of medicinal cannabis products on driving competency.

The hope is that it will allow patients taking CannEpil and other similar products to still drive while under treatment. Australian law currently prohibits patients consuming medicinal cannabis from driving.

Study Recommends Physicians and Healthcare Providers Better Educate Patients about Epilepsy and Cannabis

INTRODUCTION: Medical cannabis is increasingly discussed as an alternative treatment option in neurological diseases, e.g. epilepsy. Supporters and opponents base their propositions mostly on subjective estimates, they confuse cannabis in whole versus extracts and botanical versus synthesized.

METHODS: Two hundred seventy five patients with any kind of epilepsy (56% female, 44% seizure free, 91% on medication) answered a survey on the knowledge, expectations, fears, and willingness to be treated with medical cannabis. Data were analyzed with regard to patient characteristics and clinical data from patient files.

RESULTS: Overall, 70.5% of the patients were familiar with the possibility of medical cannabis treatment, 36.7% with its use in epilepsy. A minority of 10.9% gained the information from their physicians. The majority knew about organic compared to synthetic cannabis. The interest in further information is high (71.3%). Regression analysis (explaining 53.8% of the variance) indicated that positive expectations (in the order of relevance) were seizure control, relaxation, mood, and tolerability whereas fears mostly concerned addiction and delirant intoxication. Men showed a greater interest than women.

CONCLUSION: Many epilepsy patients knew about medical cannabis, were interested in this treatment, and wanted more information. Expectations, however, appear to be based on the connotations of the whole substance cannabis with tetrahydrocannabidiol and its commonly known effects. Unfortunately, patients did not get their information from physicians, but mostly by other sources. In order to avoid prejudices and potentially harmful self-medication, physicians and healthcare providers are called to become familiar with the substance and to inform patients adequately.