Category Archives: Epilepsy

Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies

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“Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.

Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson’s disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.

Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/37843213/

https://journals.lww.com/nrronline/fulltext/2024/04000/cannabinoids_and_endocannabinoids_as_therapeutics.22.aspx

Phytocannabinoids Reduce Seizures in Larval Zebrafish and Affect Endocannabinoid Gene Expression

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“Cannabis has demonstrated anticonvulsant properties, and about thirty percent of epileptic patients do not have satisfactory seizure management with standard treatment and could potentially benefit from cannabis-based intervention. Here, we report the use of cannabinoids to treat pentylenetetrazol (PTZ)-induced convulsions in a zebrafish model, their effect on gene expression, and a simple assay for assessing their uptake in zebrafish tissues. Using an optimized behavioral assay, we show that cannabidiol (CBD) and cannabichromene (CBC) and cannabinol (CBN) are effective at reducing seizures at low doses, with little evidence of sedation, and our novel HPLC assay indicates that CBC is effective with the lowest accumulation in larval tissues. All cannabinoids tested were effective at higher concentrations. Pharmacological manipulation of potential receptors demonstrates that Gpr55 partially mediates the anticonvulsant effects of CBD. Treatment of zebrafish larvae with endocannabinoids, such as 2-arachidonoylglycerol (2-AG) and anandamide (AEA), altered larvae movement, and the expression of genes that regulate their metabolism was affected by phytocannabinoid treatment, highlighting the possibility that changes to endocannabinoid levels may represent one facet of the anticonvulsant effect of phytocannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/37759798/

https://www.mdpi.com/2218-273X/13/9/1398

Highly purified cannabidiol in the treatment of drug-resistant epilepsies: A real-life impact on seizure frequency, quality of life, behavior, and sleep patterns from a single Italian center

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“Seizure frequency in treatment-resistant epilepsies seems to be decreased by cannabidiol (CBD), but contrasting data are available on its effect on sleep, behavior, and quality of life (QoL), and no data is reported on its effect on parental stress in patients with epilepsy (PWE). Thus, we conducted a retrospective study on a cohort of children and adults with drug-resistant epilepsy (DRE) who had been treated with highly purified, pharmaceutical-grade CBD to evaluate its effects on seizure frequency, QoL, behavior, parental stress, and sleep. Eighteen patients (12 adults and 6 children) were included in the cohort and followed for a median of 9 months. At the last follow-up (Tn), nine patients (50%) were considered CBD responders with at least a 50% decrease in seizure frequency. No serious adverse effects were found. No statistically significant differences were found concerning sleep, including daytime sleepiness, and no statistically significant effect was found on parental stress at Tn. An improvement was found for social interaction in quality of life (p < 0.05) for all patients.

Our results demonstrate that CBD is a safe and effective antiseizure medication (ASM).

CBD doesn’t seem to affect sleep measures in adults and children or worsen daytime sleepiness. However, CBD improves specific QoL measures, which could indicate a possible use of CBD for other childhood disabilities. No impact of CBD was seen on parental stress, which could possibly be due to the limited follow-up or could mean that parental stress is not dependent on seizure frequency.”

https://pubmed.ncbi.nlm.nih.gov/37677907/

“Cannabidiol (CBD) is a safe and effective antiseizure medication (ASM).”

https://www.epilepsybehavior.com/article/S1525-5050(23)00328-1/fulltext

Efficacy and tolerance of cannabidiol in the treatment of epilepsy in patients with Rett syndrome

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“We aim to assess the efficacy and tolerance of cannabidiol as adjunctive therapy for Rett syndrome (RTT) patients with epilepsy. We conducted a longitudinal observational study through a monocentric cohort of 46 patients with RTT. Patients were recruited from March 2020 to October 2022 and were treated with Epidyolex® (cannabidiol, CBD, 100 mg/ml oral solution). In our cohort, 26 patients had associated epilepsy (26/46 (56%)), and 10/26 (38%) were treated with CBD, in combination with clobazam in 50% of cases. The median dose at their last follow-up was 15 mg/kg/d. The median treatment duration was 13 months (range, 1-32 mo.). CBD reduced the incidence of seizures in seven out of ten patients (70%) with one seizure-free patient, two patients with a reduction of seizures of more than 75%, and four patients with a decrease of more than 50%. No aggravation of symptoms or adverse effects were observed. Only one patient experienced a transitory drooling and somnolence episode at the CBD initiation. Half of the patients showed a reduction in agitation and/or anxiety attacks, and an improvement in spasticity was reported in 4/10 (40%) of patients. CBD appears to have potential therapeutic value for the treatment of drug-resistant epilepsy in Rett syndrome. CBD is well tolerated and, when used in combination with clobazam, may increase the effectiveness of clobazam alone.”

https://pubmed.ncbi.nlm.nih.gov/37485779/

https://onlinelibrary.wiley.com/doi/10.1002/epi4.12796

Disease-modifying effects of cannabidiol, β-caryophyllene and their combination in Syn1-Cre/Scn1aWT/A1783V mice, a preclinical model of Dravet syndrome

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“Cannabidiol (CBD) has been recently approved as an antiseizure agent in Dravet Syndrome (DS), a pediatric epileptic encephalopathy, but CBD could also be active against associated comorbidities. Such associated comorbidities were also attenuated by the sesquiterpene β-caryophyllene (BCP). Here, we have compared the efficacy of both compounds and further initiated the analysis of a possible additive effect between both compounds in relation with these comorbidities using two experimental approaches. The first experiment was aimed at comparing the benefits of CBD and BCP, including their combination in conditional knock-in Scn1a-A1783V mice, an experimental model of DS, treated since the postnatal day 10th to 24th. As expected, DS mice showed impairment in limb clasping, delay in the appearance of hindlimb grasp reflex and additional behavioural disturbances (e.g., hyperactivity, cognitive deterioration, social interaction deficits). This behavioural impairment was associated with marked astroglial and microglial reactivities in the prefrontal cortex and the hippocampal dentate gyrus. BCP and CBD administered alone were both able to partially attenuate the behavioural disturbances and the glial reactivities, with apparently greater efficacy against glial reactivities obtained with BCP, whereas superior effects in a few specific parameters were obtained when both compounds were combined. In the second experiment, we investigated this additive effect in cultured BV2 cells treated with BCP and/or CBD and stimulated with LPS. As expected, addition of LPS induced a marked increase in several inflammation-related markers (e.g., TLR4, COX-2, iNOS, catalase, TNF-α, IL-1β), as well as elevated Iba-1 immunostaining. Treatment with BCP or CBD attenuated these elevations, but, again and in general, superior results were obtained when both cannabinoids were combined. In conclusion, our results support the interest to continue investigating the combination of BCP and CBD to improve the therapeutic management of DS in relation with their disease-modifying properties.”

https://pubmed.ncbi.nlm.nih.gov/37290534/

https://www.sciencedirect.com/science/article/pii/S0028390823001922?via%3Dihub

The therapeutic potential of purified cannabidiol

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“The use of cannabidiol (CBD) for therapeutic purposes is receiving considerable attention, with speculation that CBD can be useful in a wide range of conditions. Only one product, a purified form of plant-derived CBD in solution (Epidiolex), is approved for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Appraisal of the therapeutic evidence base for CBD is complicated by the fact that CBD products sometimes have additional phytochemicals (like tetrahydrocannabinol (THC)) present, which can make the identification of the active pharmaceutical ingredient (API) in positive studies difficult. The aim of the present review is to critically review clinical studies using purified CBD products only, in order to establish the upcoming indications for which purified CBD might be beneficial.

The areas in which there is the most clinical evidence to support the use of CBD are in the treatment of anxiety (positive data in 7 uncontrolled studies and 17 randomised controlled trials (RCTs)), psychosis and schizophrenia (positive data in 1 uncontrolled study and 8 RCTs), PTSD (positive data in 2 uncontrolled studies and 4 RCTs) and substance abuse (positive data in 2 uncontrolled studies and 3 RCTs). Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT. Limited evidence supports the use of CBD for the treatment of Parkinson’s (3 positive uncontrolled studies and 2 positive RCTs), autism (3 positive RCTs), smoking cessation (2 positive RCTs), graft-versus-host disease and intestinal permeability (1 positive RCT each). Current RCT evidence does not support the use of purified oral CBD in pain (at least as an acute analgesic) or for the treatment of COVID symptoms, cancer, Huntington’s or type 2 diabetes.

In conclusion, published clinical evidence does support the use of purified CBD in multiple indications beyond epilepsy. However, the evidence base is limited by the number of trials only investigating the acute effects of CBD, testing CBD in healthy volunteers, or in very small patient numbers. Large confirmatory phase 3 trials are required in all indications.”

https://pubmed.ncbi.nlm.nih.gov/37312194/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00186-9

Efficacy of cannabidiol in convulsive and nonconvulsive seizure types associated with treatment-resistant epilepsies in the expanded access program

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“Cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex®) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic) and nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic-absence) and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types (median percentage reduction, 47%-100%) and nonconvulsive seizure types and epileptic spasms (median percentage reduction, 50%-100%) across visit intervals through 144 weeks of treatment. Approximately 50% of patients had ≥50% reduction in convulsive and nonconvulsive seizure types and epileptic spasms at nearly all intervals. These results show a favorable effect of long-term CBD use in patients with TRE who may experience various convulsive and nonconvulsive seizure types. Future controlled trials are needed to confirm these findings.”

https://pubmed.ncbi.nlm.nih.gov/37243404/

https://onlinelibrary.wiley.com/doi/10.1111/epi.17665

Cannabidiol as an adjuvant treatment in adults with drug-resistant focal epilepsy

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“Cannabidiol oil (CBD) has been approved as an anti-seizure medication for the treatment of uncommon types of epilepsy, occurring in children: Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. There are few publications in relation to use the CBD in adult patients with focal drug-resistant epilepsy. The objective of this study was to evaluate the efficacy, tolerability, safety, and quality of life, of adjuvant treatment with CBD, in adult patients with drug-resistant focal epilepsy for at least 6 months. An open, observational, prospective cohort study was conducted using a before-after design (time series) in adult patients undergoing outpatient follow-up in a public hospital in Buenos Aires, Argentina. From a total of 44 patients, 5% of patients were seizure-free, 32% of patients reduced more than 80% of their seizures and 87% of patients reduced 50% of their monthly seizures. Eleven percent presented a decrease of less than 50% in seizure frequency. The average final dose was 335 mg/d orally administered. Thirty-four percent of patients reported mild adverse events and no patient reported severe adverse effects. At the end of the study, we found in most patients a significant improvement in the quality of life, in all the items evaluated. Adjuvant treatment with CBD in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated, and associated with a significant improvement in their quality of life.”

https://pubmed.ncbi.nlm.nih.gov/37196452/

“Most patients have a significant improvement in their quality of life.”

https://www.epilepsybehavior.com/article/S1525-5050(23)00129-4/fulltext

Cannabidiol in children with treatment-resistant epilepsy with myoclonic-atonic seizures

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“Purpose: This multicenter study aimed to evaluate the efficacy and tolerability of add-on cannabidiol (CBD) in treatment-resistant patients with epilepsy with myoclonic-atonic seizures (EMAtS) (n = 22) and Sturge Weber syndrome (SWS) with myoclonic-atonic seizures (n = 4).

Methods: Patients who met the diagnostic criteria of treatment-resistant EMAtS or SWS with myoclonic-atonic seizures were included. Cannabidiol was added in doses ranging from 8 to 40 mg/kg/day. Efficacy was assessed by comparing seizure frequency before and after initiating CBD therapy. Neurologic examinations, brain magnetic resonance imaging, repeated prolonged electroencephalography (EEG) and/or video-EEG recordings, and neurometabolic studies were performed in all patients, and genetic investigations in 15.

Results: After a mean follow-up of 19 months, 15/26 patients (57.7%) who received add-on CBD had a >50% seizure decrease; three (11.5%) became seizure-free. The remaining 11 patients (42.3%) had a 25-50% seizure reduction. Drop attacks, including myoclonic-atonic seizures and generalized tonic-clonic seizures, as well as atypical absences and nonconvulsive status epilepticus responded well to CBD. In SWS patients, focal motor seizures without consciousness impairment and focal non-motor seizures with consciousness impairment were recognized in two each; in three a 30% reduction of focal seizures was observed. Side effects were mild and did not lead to CBD discontinuation.

Conclusion: This study evaluating the use of add-on CBD in children with EMAtS or SWS with myoclonic-atonic seizures found that 15/26 (57.7%) had a >50% seizure reduction with good tolerability; three (11.5%) became seizure-free.”

https://pubmed.ncbi.nlm.nih.gov/37182500/

“Cannabidiol was safe and effective in patients with epilepsy with myoclonic-atonic seizures.

•Cannabidiol is also a good option in patients with SWS associated with myoclonic-atonic seizures.

•Cannabidiol was effective in drop-attack, generalized tonic-clonic, and non-convulsive seizures.”

https://www.epilepsybehavior.com/article/S1525-5050(23)00164-6/fulltext


Cannabidiol in the acute phase of Febrile Infection-Related Epilepsy Syndrome (FIRES)

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“Febrile infection-related epilepsy syndrome (FIRES) is a prolonged refractory status epilepticus (SE) that develops among healthy individuals after a febrile infection. FIRES treatment is challenging due to its poor response to anti-seizure medications (ASMs) and anesthetic drugs.

The use of cannabidiol (CBD) as an adjunctive treatment has been suggested, albeit data about its role in the acute phase is lacking. This report describes the use of purified CBD in the acute phase of two pediatric cases of FIRES and their long-term outcome.

Both children were treated with several ASMs, immunomodulators, anesthetics, and non-pharmacological treatment (ketogenic diet). CBD was administered, as an adjunctive treatment, through nasogastric tube about 30 days after onset. SE resolved within three days of reaching the target dose and both were seizure-free for one year after.

Although it is difficult to define the extent to which each previous therapy contributed to recovery, in both cases CBD therapy was a turning point, reinforcing its potential role as add-on treatment in the acute phase of FIRES.”

https://pubmed.ncbi.nlm.nih.gov/37042946/

https://onlinelibrary.wiley.com/doi/10.1002/epi4.12740