cannabidiol and Epilepsy

Marijuana, also known as cannabis, is the second most widely used illegal psychoactive substance smoked worldwide after tobacco, mainly due to the psychoactive effects induced by D-9-tetrahydrocannabinol (9-THC). Cannabidiol (CBD) is extracted from cannabis and may be used as an anti-inflammatory agent. Some patents on cannabidiol are discussed in this review. The cannabinoid is a non-psychoactive isomer of the more infamous tetrahydrocannabinol (THC); and is available in several administration modes, most known as CBD oil.. This study aims to provide an enhanced review of cannabidiol properties used in treating inflammation. This review also emphasises the current safety profile of cannabidiol.. Cannabis is also called Marijuana. It is the second most commonly used illegal psychoactive substance in the universe after tobacco. D-9-tetrahydrocannabinol (9-THC) present in cannabis produces psychoactive effects. Cannabidiol (CBD) extracted from cannabis is used for antiinflammatory purposes. Cannabis smoking causes various types of cancer, such as lung, tongue, and jaw. The current review took literature from Google Scholar, PubMed, and Google Patents. Many clinical investigations are included in this review.. After analysing the literature on cannabis, it has been suggested that although cannabis is banned in some countries, it may be included in the treatment and mitigation of some diseases and symptoms like pain management, epilepsy, cancer, and anxiety disorder. Mild side effects were frequently observed in cannabis medications, which included infertility in females, liver damage, etc. Conclusion: Cannabis contains chemical compounds such as the cannabinoids delta-9- tetrahydrocannabinol (THC), a psychoactive substance, and non-psychoactive cannabidiol (CBD). Cannabidiol has been confirmed as an efficient treatment of epilepsy in several clinical trials, with one pure CBD product named Epidiolex. It is also used in treating anxiety and acne, as a pain reliever, and has anti-inflammatory properties.

Topics: Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Epilepsy; Female; Humans

Antiseizure medications (ASMs) are the mainstay for the treatment of seizure disorders. However, about one-third of people with epilepsy remain refractory to current ASMs. Cannabidiol (CBD) has recently been approved as ASM for three refractory epilepsy syndrome indications in children and adults. In this study, we evaluated the overall clinical potential of an oral CBD to treat refractory epilepsy in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC) through a systematic review and meta-analysis. A comprehensive search of databases was conducted, including randomized controlled trials (RCTs) assessing the effect of CBD in epilepsy patients. The review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review focused on RCTs involving patients receiving highly purified oral CBD (Epidiolex, 10 to 50 mg/kg/day) for up to 16 weeks. A subgroup analysis by syndrome and CBD with or without concomitant clobazam was conducted. The key outcomes were reduction in seizure frequency, differences in 50% responder rates, adverse events, and interactions with clobazam as co-therapy. Odds ratio (OR) with 95% confidence interval (CI) were estimated. Of 1183 articles screened, we included 6 RCTs meeting our eligibility criteria. All studies were considered to have a low risk of bias. In the pooled analysis, CBD treatment was found to be more efficacious compared to placebo (OR = 2.45, 95% CI =1.81-3.32, p < 0.01). Subgroup analysis by syndrome demonstrated the odds of ≥50% reduction in seizures with CBD treatment in patients with DS (OR = 2.26, 95% CI:1.38-3.70), LGS (OR = 2.98, 95% CI:1.83-4.85) and TSC (OR = 1.99, 95% CI = 1.06-3.76). Compared with placebo, CBD was associated with increased adverse events (OR = 1.81, 95% CI = 1.33-2.46) such as diarrhea, somnolence, and sedation, and any serious adverse events (OR = 2.86, 95% CI = 1.63-5.05). Other factors, including dosage and clobazam co-therapy, were significantly associated with a greater effect on seizure control and side effects of CBD. In conclusion, the study shows that CBD is highly efficacious both as standalone and adjunct therapy with clobazam for controlling seizures in DS, LGS, and TSC conditions while limiting side effects. Further pharmacodynamic investigation of CBD actions, drug interaction assessments, and therapeutic management guidelines are warranted.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Clobazam; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures; Treatment Outcome

Novel and effective antiseizure medications are needed to treat refractory and rare forms of epilepsy. Cannabinoids, which are obtained from the cannabis plant, have a long history of medical use, including for neurologic conditions. In 2018, the US Food and Drug Administration approved the first phytocannabinoid, cannabidiol (CBD, Epidiolex), which is now indicated for severe seizures associated with three rare forms of developmental and epileptic encephalopathy: Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. Compelling evidence supports the efficacy of CBD in experimental models and patients with epilepsy. In randomized clinical trials, highly-purified CBD has demonstrated efficacy with an acceptable safety profile in children and adults with difficult-to-treat seizures. Although the underlying antiseizure mechanisms of CBD in humans have not yet been elucidated, the identification of novel antiseizure targets of CBD preclinically indicates multimodal mechanisms that include non-cannabinoid pathways. In addition to antiseizure effects, CBD possesses strong anti-inflammatory and neuroprotective activities, which might contribute to protective effects in epilepsy and other conditions. This article provides a succinct overview of therapeutic approaches and clinical foundations of CBD, emphasizing the clinical utility of CBD for the treatment of seizures associated with refractory and rare epilepsies. CBD has shown to be a safe and effective antiseizure medicine, demonstrating a broad spectrum of efficacy across multiple seizure types, including those associated with severe epilepsies with childhood onset. Despite such promise, there are many perils with CBD that hampers its widespread use, including limited understanding of pharmacodynamics, limited exposure-response relationship, limited information for seizure freedom with continued use, complex pharmacokinetics with drug interactions, risk of adverse effects, and lack of expert therapeutic guidelines. These scientific issues need to be resolved by further investigations, which would decide the unique role of CBD in the management of refractory epilepsy.

Topics: Adult; Anticonvulsants; Cannabidiol; Cannabinoids; Child; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Over 30 antiseizure medicines (ASMs) have been uncovered in a diversity of preclinical seizure and epilepsy models, with several critical inflection points in the 20th century fundamentally transforming ASM discovery. This commentary aims to review the historical relevance of cannabidiol's (CBD; Epidiolex) approval for epilepsy in the context of other ASMs brought to market. Further, we highlight how CBD's approval may represent an inflection point for 21st century ASM discovery. CBD is one of the main phytocannabinoids of Cannabis sativa. Unlike its related phytocannabinoid, Δ9-tetrahydrocannabinol, CBD does not exert any euphorigenic, tolerance, or withdrawal effects at anticonvulsant doses. CBD also possess marked anti-inflammatory effects, offering the tantalizing potential of a new pharmacological approach in epilepsy. For decades, hints of the anticonvulsant profile of CBD had been suggested with a small handful of studies in rodent seizure models, yet difficulties in formulation, compounded by the social and regulatory pressures related to medical use of cannabis plant-derived agents constrained any clinical implementation. Nonetheless, CBD possesses a broad antiseizure profile in preclinical seizure and epilepsy models, but the transformative impact of CBD'-s approval came because of studies in a rodent model of the orphan disease Dravet syndrome (DS). DS is a pediatric developmental epileptic encephalopathy with high mortality, frequent spontaneous recurrent seizures, and marked resistance to conventional ASMs, such as phenytoin and carbamazepine. CBD was approved for DS by the US Food and Drug Administration in 2018 after convincing efficacy was established in randomized, placebo-controlled trials in children. Because of the clinical approval of CBD as a novel, cannabis plantderived ASM for DS, CBD has revealed a new strategy in ASM discovery to reignite 21st century therapeutic development for epilepsy. In this commentary, we review the major preclinical and clinical milestones of the late 20th century that made CBD, a compound historically subjected to regulatory restrictions, a key driver of a new discovery strategy for epilepsy in the 21st century.

Topics: Anticonvulsants; Cannabidiol; Cannabinoid Receptor Agonists; Epilepsies, Myoclonic; Epilepsy; Humans; Seizures

Compelling evidence from preclinical and clinical studies supports the therapeutic role of cannabidiol (CBD) in several medical disorders. We reviewed the scientific evidence on CBD-related toxicity and adverse events (AEs) in 2019, at the beginning of the spike in clinical studies involving CBD. However, CBD safety remained uncertain.. With the benefit of hindsight, we aimed to provide an update on CBD-related toxicity and AEs in humans.. A systematic literature search was conducted following PRISMA guidelines. PubMed, Cochrane, and Embase were accessed in October 2022 to identify clinical studies mentioning CBDrelated toxicity/AEs from February 2019 to September 2022. Study design, population characteristics, CBD doses, treatment duration, co-medications, and AEs were compiled.. A total of 51 reports were included. Most studies investigated CBD efficacy and safety in neurological conditions, such as treatment-resistant epilepsies, although a growing number of studies are focusing on specific psychopathological conditions, such as substance use disorders, chronic psychosis, and anxiety. Most studies report mild or moderate severity of AEs. The most common AEs are diarrhea, somnolence, sedation, and upper respiratory disturbances. Few serious AEs have been reported, especially when CBD is co-administered with other classes of drugs, such as clobazam and valproate.. Clinical data suggest that CBD is well tolerated and associated with few serious AEs at therapeutic doses both in children and adults. However, interactions with other medications should be monitored carefully. Additional data are needed to investigate CBD's long-term efficacy and safety, and CBD use in medical conditions other than epilepsy syndromes.

Topics: Adult; Anticonvulsants; Anxiety; Cannabidiol; Child; Epilepsy; Humans

Cannabidiol (CBD), a nonpsychotropic phytocannabinoid that was once largely disregarded, is currently the subject of significant medicinal study. CBD is found in Cannabis sativa, and has a myriad of neuropharmacological impacts on the central nervous system, including the capacity to reduce neuroinflammation, protein misfolding and oxidative stress. On the other hand, it is well established that CBD generates its biological effects without exerting a large amount of intrinsic activity upon cannabinoid receptors. Because of this, CBD does not produce undesirable psychotropic effects that are typical of marijuana derivatives. Nonetheless, CBD displays the exceptional potential to become a supplementary medicine in various neurological diseases. Currently, many clinical trials are being conducted to investigate this possibility. This review focuses on the therapeutic effects of CBD in managing neurological disorders like Alzheimer's disease, Parkinson's disease and epilepsy. Overall, this review aims to build a stronger understanding of CBD and provide guidance for future fundamental scientific and clinical investigations, opening a new therapeutic window for neuroprotection. Please cite this article as: Tambe SM, Mali S, Amin PD, Oliveira M. Neuroprotective potential of Cannabidiol: Molecular mechanisms and clinical implications. J Integr Med. 2023; 21(3): 236-244.

Topics: Cannabidiol; Cannabinoids; Cannabis; Epilepsy; Humans; Neuroprotection; Neuroprotective Agents

Topics: Animals; Cannabidiol; Cannabinoid Receptor Agonists; Cannabis; Dronabinol; Epilepsy; Humans; Pain

Epilepsy is one of the most common neurologic disorders globally. Cannabidiol (CBD) has been approved for the treatment of epilepsy, but its use has been associated with several different adverse events (AEs).. To investigate the frequency and risk of AEs developing in patients with epilepsy who are using CBD.. PubMed, Scopus, Web of Science, and Google Scholar were searched for relevant studies published from database inception up to August 4, 2022. The search strategy included a combination of the following keywords: (cannabidiol OR epidiolex) AND (epilepsy OR seizures).. The review included all randomized clinical trials that investigated at least 1 AE from the use of CBD in patients with epilepsy.. Basic information about each study was extracted. I2 statistics were calculated using Q statistics to assess the statistical heterogeneity among the included studies. A random-effects model was used in cases of substantial heterogeneity, and a fixed-effects model was used if the I2 statistic for the AEs was lower than 40%. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.. Frequency of each AE and risk of developing each AE in patients with epilepsy using CBD.. Nine studies were included. Overall incidences of 9.7% in the CBD group and 4.0% in the control group were found for any grade AEs. The overall risk ratios (RRs) for any grade and severe grade AEs were 1.12 (95% CI, 1.02-1.23) and 3.39 (95% CI, 1.42-8.09), respectively, for the CBD group compared with the control group. Compared with the control group, the CBD group had a greater risk for incidence of serious AEs (RR, 2.67; 95% CI, 1.83-3.88), AEs resulting in discontinuation (RR, 3.95; 95% CI, 1.86-8.37), and AEs resulting in dose reduction (RR, 9.87; 95% CI, 5.34-14.40). Because most of the included studies had some risk of bias (3 raised some concerns and 3 were at high risk of bias), these findings should be interpreted with some caution.. In this systematic review and meta-analysis of clinical trials, the use of CBD to treat patients with epilepsy was associated with an increased risk of several AEs. Additional studies are needed to determine the safe and effective CBD dosage for treating epilepsy.

Topics: Bias; Cannabidiol; Epilepsy; Humans; Seizures

Cannabidiol (CBD) is one of the major phytocannabinoids present in the cannabis plant, with no acute psychotropic effects and a favorable safety and abuse liability profile. Animal and limited controlled human studies have demonstrated CBD to have analgesic, anxiolytic, anti-inflammatory, antipsychotic, and anticonvulsant effects, to name a few possible indications. There is growing evidence for the use of CBD to treat neurological disorders such as epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. It has been suggested that CBD improves cognition and neurogenesis. Cognitive impairment is associated with numerous disorders and can involve deficits in learning, memory, executive functioning, and attention. The purpose of this review will be to evaluate the available preclinical and clinical data on CBD for the treatment of the cognitive impairment associated with several disorders including schizophrenia, epilepsy, Alzheimer's disease, and others. Preclinical, but not clinical, studies found evidence for an improvement in cognitive performance after treatment with CBD. More research is needed to determine whether CBD can be effectively used as a monotherapy to treat cognitive dysfunction. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Topics: Alzheimer Disease; Animals; Cannabidiol; Cognitive Dysfunction; Epilepsy; Humans; Schizophrenia

Epilepsy is one of the most prevalent neurological human diseases, affecting 1% of the population in all age groups. Despite the availability of over 25 anti-seizure medications (ASMs), which are approved in most industrialized countries, approximately 30% of epilepsy patients still experience seizures that are resistant to these drugs. Since ASMs target only limited number of neurochemical mechanisms, drug-resistant epilepsy (DRE) is not only an unmet medical need, but also a formidable challenge in drug discovery.. In this review, we examine recently approved epilepsy drugs based on natural product (NP) such as cannabidiol (CBD) and rapamycin, as well as NP-based epilepsy drug candidates still in clinical development, such as huperzine A. We also critically evaluate the therapeutic potential of botanical drugs as polytherapy or adjunct therapy specifically for DRE.. Articles related to ethnopharmacological anti-epileptic medicines and NPs in treating all forms of epilepsy were collected from PubMed and Scopus using keywords related to epilepsy, DRE, herbal medicines, and NPs. The database clinicaltrials.gov was used to find ongoing, terminated and planned clinical trials using herbal medicines or NPs in epilepsy treatment.. A comprehensive review on anti-epileptic herbal drugs and natural products from the ethnomedical literature is provided. We discuss the ethnomedical context of recently approved drugs and drug candidates derived from NPs, including CBD, rapamycin, and huperzine A. Recently published studies on natural products with preclinical efficacy in animal models of DRE are summarized. Moreover, we highlight that natural products capable of pharmacologically activating the vagus nerve (VN), such as CBD, may be therapeutically useful to treat DRE.. The review highlights that herbal drugs utilized in traditional medicine offer a valuable source of potential anti-epileptic drug candidates with novel mechanisms of action, and with clinical promise for the treatment of drug-resistant epilepsy (DRE). Moreover, recently developed NP-based anti-seizure medications (ASMs) indicate the translational potential of metabolites of plant, microbial, fungal and animal origin.

Topics: Animals; Anticonvulsants; Biological Products; Cannabidiol; Drug Resistant Epilepsy; Epilepsy; Ethnopharmacology; Evidence-Based Medicine; Humans; Plant Extracts; Plants, Medicinal

Epileptic syndromes affecting children can sometimes be refractory to pharmacological treatments. Cannabinoids, especially cannabidiol, began to be studied to contribute to the treatment of these syndromes, configuring an expanding research area. The aim of this paper was to evaluate the scientific evidence available in the literature regarding the use of cannabinoids in the therapy of children with epilepsy.. This is a systematic literature review, carried out according to the structure of the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA), in the SCIELO, Cochrane Library, and MEDLINE databases. Observational studies or clinical trials were included, conducted in humans, addressing the use of cannabinoids in pediatric patients with epilepsy, published in the last 10 years.. In all, 626 studies were found and analyzed, of which 29 were considered eligible for the research; studies indicated good efficacy, safety, and tolerability of cannabidiol in several syndromes, with emphasis on Lennox-Gastaut and Dravet syndromes, in addition to practical issues were perceived regarding the applicability and expectations of patients and physicians.. The use of cannabidiol was considered effective and safe, yet the studies were mostly carried out in the same countries.

Topics: Anticonvulsants; Cannabidiol; Cannabinoids; Child; Epilepsies, Myoclonic; Epilepsy; Humans

Cannabidiol (CBD), derived from Cannabis sativa, has gained remarkable attention for its potential therapeutic applications. This thorough analysis explores the increasing significance of CBD in treating neurological conditions including epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease, which present major healthcare concerns on a worldwide scale. Despite the lack of available therapies, CBD has been shown to possess a variety of pharmacological effects in preclinical and clinical studies, making it an intriguing competitor. This review brings together the most recent findings on the endocannabinoid and neurotransmitter systems, as well as anti-inflammatory pathways, that underlie CBD's modes of action. Synthesized efficacy and safety assessments for a range of neurological illnesses are included, covering human trials, in vitro studies, and animal models. The investigation includes how CBD could protect neurons, control neuroinflammation, fend off oxidative stress, and manage neuronal excitability. This study emphasizes existing clinical studies and future possibilities in CBD research, addressing research issues such as regulatory complications and contradicting results, and advocates for further investigation of therapeutic efficacy and ideal dose methodologies. By emphasizing CBD's potential to improve patient well-being, this investigation presents a revised viewpoint on its suitability as a therapeutic intervention for neurological illnesses.

Topics: Alzheimer Disease; Animals; Cannabidiol; Epilepsy; Humans

Cannabis is used in the treatment of several human conditions; however, its use is still less explored in veterinary medicine. This systematic review aims to summarize the evidence of efficacy and safety of the use of cannabis for the treatment of animal disease. A literature search was performed for studies published until 16 March 2021 in five databases. Randomized clinical trials (RCTs) that reported the efficacy or safety of cannabis in the treatment of animal disease were included. The RoB 2 Tool was used to assess the risk of bias. A total of 2427 records were identified, of which six studies fully met the eligibility criteria. RCTs were conducted in dogs with osteoarthritis (

Topics: Animals; Cannabidiol; Cannabis; Dog Diseases; Dogs; Epilepsy; Humans; Osteoarthritis; Randomized Controlled Trials as Topic

The aim of this current report was to present a critical review of the use of cannabidiol (CBD) in the treatment of refractory epilepsies in the pediatric population.. Literature review was carried out in the Medline (PubMed), Cochrane, and Scientific Electronic Library Online (SciELO) databases with the descriptors "Cannabidiol" and "Epilepsy." The search was not limited by the date of publication, language, or study design. A total of 69 articles were included in the review.. The efficacy of CBD in treating epileptic seizures has been confirmed by randomized controlled trials for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. The incidence of side effects reported in subjects of the studies is high. However, most studies indicate a good safety profile and tolerance to the drug, with most of the adverse effects being mild to moderate and transient.. There is no consensus on the release of CBD as a therapeutic tool by the drug regulatory agencies worldwide. However, the use of CBD is promising since it has presented satisfactory results in crisis control in well-designed studies. In addition, this drug has a good safety and tolerance profile. However, further studies with a long follow-up period are needed to confirm its usefulness and the long-term safety in pediatric patients.

Topics: Anticonvulsants; Cannabidiol; Child; Drug Resistant Epilepsy; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Humans; Lennox Gastaut Syndrome

Cannabidiol (CBD) has become a promising therapeutic option in the treatment of epilepsy. Recent studies provide robust evidence that CBD is effective and safe. Limitations in current knowledge and regulatory issues still limit CBD use. CBD use regarding epilepsy types still lacks clear guidelines.. To critically review the main current pharmacological features and clinical issues regarding CBD use in epilepsy, to provide current regulatory background regarding CBD use in Brazil, and to suggest a practical CBD therapeutic guide in Brazil.. Non-systematic literature review (up to February 2022) of current concepts of CBD and epilepsy, including the authors' personal experience.. Five pivotal trials have led to CBD approval as an adjunctive treatment for Dravet and Lennox-Gastaut syndromes, and for the tuberous sclerosis complex. Efficacy of CBD in other drug-resistant epilepsies remains not completely understood. CBD adverse event profile and drug interactions are better understood. CBD is well tolerated. In Brazil, CBD is not classified as a medication, but as a product subject to a distinct regulatory legislation. CBD is still not offered by the National Brazilian health system, but can be purchased in authorized pharmacies or imported under prescription and signed informed consent.. CBD is a recognized novel treatment for epilepsy. Future well-designed studies and public health strategies are needed to offer widespread access to CBD, and to improve the quality of life of people living with epilepsy in Brazil.

Topics: Anticonvulsants; Brazil; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Quality of Life

In February 2020 parliament passed the Cannabis Regulation Bill (2020) which regulates the cultivation and production of industrial hemp and medical cannabis. The country will only fully benefit from this development if the medical and scientific community can take the lead in enabling the country to exploit the plant's potential to help address some of our economic and public health challenges. This special communication provides some basic information on cannabis and discusses its history and medical uses. Cannabidiol (CBD) has emerged as one of the most important cannabis-derived phytochemicals and has formed the basis for the growth of the medical cannabis industry. The scientific data on the mechanisms of the effects of CBD on the human neuroendocrine-immune network is reviewed and the first effective cannabis-based FDA-approved treatment for epilepsy discussed. Some clinical research that is being done on the antipsychotic and neuroprotective properties of CBD is also reviewed. A case is made for the potential of CBD as a neuroprotective adjunctive therapy for the prevention of neuropsychological sequelae associated with complicated malaria. The safety profile of CBD is reviewed and finally, the potential importance of the re-medicalization of cannabis-based therapies for the broader field of phytomedicine is pointed out.

Topics: Cannabidiol; Cannabis; Epilepsy; Humans; Malawi; Medical Marijuana

Epilepsy is a common neurological condition, affecting over 70 million individuals worldwide.. The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies.. Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.

Topics: Adult; Animals; Anticonvulsants; Cannabidiol; Epilepsies, Partial; Epilepsy; Humans; Lennox Gastaut Syndrome; Spasms, Infantile; Tuberous Sclerosis

We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.

Topics: Breast Feeding; Cannabidiol; Carbamazepine; Child; Clobazam; Clonazepam; Epilepsy; Ethosuximide; Everolimus; Felbamate; Female; Fenfluramine; Gabapentin; Humans; Infant; Lacosamide; Lamotrigine; Levetiracetam; Oxcarbazepine; Phenobarbital; Phenytoin; Prospective Studies; Tiagabine; Topiramate; Valproic Acid; Vigabatrin; Zonisamide

The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures.. This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses.. Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%.. This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures; Tuberous Sclerosis

The use of Cannabis for medicinal purposes has been documented since ancient times, where one of its principal cannabinoids extracted from

Topics: Anticonvulsants; Cannabidiol; Cannabinoids; Cannabis; Epilepsy; Humans

Epilepsy is a chronic neurological disease characterized by recurrent epileptic seizures. Studies have shown the complexity of epileptogenesis and ictogenesis, in which immunological processes and epigenetic and structural changes in neuronal tissues have been identified as triggering epilepsy. Cannabidiol (CBD) is a major active component of the Cannabis plant and the source of CBD-enriched products for the treatment of epilepsy and associated diseases. In this review, we provide an up-to-date discussion on cellular and molecular mechanisms triggered during epilepsy crises, and the phytochemical characteristics of CBD that make it an attractive candidate for controlling rare syndromes, with excellent therapeutic properties. We also discuss possible CBD anticonvulsant mechanisms and molecular targets in neurodegenerative disorders and epilepsy. Based on these arguments, we conclude that CBD presents a biotecnological potential in the anticonvulsant process, including decreasing dependence on health care in hospitals, and could make the patient's life more stable, with regard to neurological conditions.

Topics: Anticonvulsants; Cannabidiol; Cannabis; Epilepsy; Humans; Seizures

Voltage-gated sodium (Nav) channels initiate action potentials in excitable tissues. Altering these channels' function can lead to many pathophysiological conditions. Nav channels are composed of several functional and structural domains that could be targeted pharmacologically as potential therapeutic means against various neurological conditions. Mutations in Nav channels have been suggested to underlie various clinical syndromes in different tissues and in association with conditions ranging from epileptic to muscular problems. Treating those mutations that increase the excitability of Nav channels requires inhibitors that could effectively reduce channel firing. The main non-psychotropic constituent of the cannabis plant, cannabidiol (CBD), has recently gained interest as a viable compound to treat some of the conditions that are associated with Nav malfunctions. In this review, we discuss an overview of Nav channels followed by an in-depth description of the interactions of CBD and Nav channels. We conclude with some clinical implications of CBD use against Nav hyperexcitability based on a series of preclinical studies published to date, with a focus on Nav/CBD interactions.

Topics: Action Potentials; Cannabidiol; Epilepsy; Humans; Voltage-Gated Sodium Channels

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

Topics: Anticonvulsants; Cannabidiol; Carbamazepine; Clobazam; COVID-19; COVID-19 Drug Treatment; Drug Interactions; Epilepsy; Humans; Nutrients; SARS-CoV-2

Research on endocannabinoid signaling has greatly advanced our understanding of how the excitability of neural circuits is controlled in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses excitability by inhibiting glutamate release, while that at inhibitory synapses promotes excitability by inhibiting GABA release, although there are some exceptions in genetically epileptic animal models. In the epileptic brain, the physiological distributions of endocannabinoid signaling molecules are disrupted during epileptogenesis, contributing to the occurrence of spontaneous seizures. However, it is still unknown how endocannabinoid signaling changes during seizures and how the redistribution of endocannabinoid signaling molecules proceeds during epileptogenesis. Recent development of cannabinoid sensors has enabled us to investigate endocannabinoid signaling in much greater spatial and temporal details than before. Application of cannabinoid sensors to epilepsy research has elucidated activity-dependent changes in endocannabinoid signaling during seizures. Furthermore, recent endocannabinoid research has paved the way for the clinical use of cannabidiol for the treatment of refractory epilepsy, such as Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Cannabidiol significantly reduces seizures and is considered to have comparable tolerability to conventional antiepileptic drugs. In this article, we introduce recent advances in research on the roles of endocannabinoid signaling in epileptic seizures and discuss future directions.

Topics: Animals; Anticonvulsants; Cannabidiol; Endocannabinoids; Epilepsy; Seizures

This review focuses on the possible roles of phytocannabinoids, synthetic cannabinoids, endocannabinoids, and "transient receptor potential cation channel, subfamily V, member 1" (TRPV1) channel blockers in epilepsy treatment. The phytocannabinoids are compounds produced by the herb Cannabis sativa, from which Δ

Topics: Animals; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Epilepsy; Humans

The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they are likely to be multifactorial and to include, among others, antagonism of G protein-coupled receptor, desensitization of transient receptor potential vanilloid type 1 channels, potentiation of adenosine-mediated signaling, and enhancement of GABAergic transmission. CBD has a low and highly variable oral bioavailability, and can be a victim and perpetrator of many drug-drug interactions. A pharmaceutical-grade formulation of purified CBD derived from Cannabis sativa has been evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Interpretation of results of these trials, however, has been complicated by the occurrence of an interaction with clobazam, which leads to a prominent increase in the plasma concentration of the active metabolite N-desmethylclobazam in CBD-treated patients. Despite impressive advances, significant gaps in knowledge still remain. Areas that require further investigation include the mechanisms underlying the antiseizure activity of CBD in different syndromes, its pharmacokinetic profile in infants and children, potential relationships between plasma drug concentration and clinical response, interactions with other co-administered medications, potential efficacy in other epilepsy syndromes, and magnitude of antiseizure effects independent from interactions with clobazam. This article is part of the special issue on 'Cannabinoids'.

Topics: Animals; Anticonvulsants; Biomedical Research; Cannabidiol; Drug Interactions; Epilepsy; Evidence-Based Medicine; Fatigue; Humans; Randomized Controlled Trials as Topic

Anecdotal reports addressing the successful seizure treatment of severe epilepsies with cannabidiol (CBD) have increased both public interest and academic research. Placebo-controlled, randomized, controlled trials proved the efficacy of pharmaceutical-grade CBD in epilepsy treatment, thus leading to pharmaceutical-grade CBD approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of seizures in Dravet syndrome and Lennox-Gastaut syndrome as well as for tuberous complex syndrome by the Food and Drug Administration only. However, the CBD market is confusing because an array of products of different origins, purity, and concentration is available. Additionally, the results from the pivotal studies with plant-derived, pharmaceutical-grade CBD cannot simply be transferred to other epilepsy types or CBD of any origin. Because of the high demands and expectations that patients with epilepsy and their caregivers have regarding CBD, information outlining the proven facts and potential risks is essential. The aim of this article is to thoroughly review available research data and practical recommendations to provide the treating physician with the necessary information for counseling patients with epilepsy.

Topics: Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures; United States; United States Food and Drug Administration

Cannabidiol (CBD), which is one major constituent of the Cannabis sativa plant, has anti-seizure properties and does not produce euphoric or intrusive side effects. A plant-derived, highly purified CBD formulation with a known and constant composition has been approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. In the European Union, the drug has been authorized by the European Medicines Agency for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome, in conjunction with clobazam, and is under regulatory review for the treatment of seizures in patients with tuberous sclerosis complex.. This systematic review aimed to summarize the currently available body of knowledge about the use of this US Food and Drug Administration/European Medicines Agency-approved oral formulation of pharmaceutical-grade CBD in patients with epileptic conditions, especially developmental and epileptic encephalopathies other than Dravet syndrome and Lennox-Gastaut syndrome.. The relevant studies were identified through MEDLINE and the US National Institutes of Health Clinical Trials Registry in October 2020. There were no date limitations or language restrictions. The following types of studies were included: clinical trials, cohorts, case-control, cross-sectional, clinical series, and case reports. Participants had to meet the following criteria: any sex, any ethnicity, any age, diagnosis of epilepsy, receiving plant-derived, highly purified (> 98% w/w) CBD in a sesame oil-based oral solution for the treatment of seizures. Data extracted from selected records included efficacy, tolerability, and safety outcomes.. Five hundred and seventy records were identified by database and trial register searching. Fifty-seven studies were retrieved for detailed assessment, of which 42 were eventually included for the review. The participants of the studies included patients of both pediatric and adult age. Across the trials, purified CBD was administered at dosages up to 50 mg/kg/day. In a randomized double-blind controlled trial in patients with tuberous sclerosis complex, CBD was associated with a significantly greater percent reduction in seizure frequency than placebo over the treatment period. Open-label studies suggested the effectiveness of CBD in the treatment of children and adults presenting with other epilepsy syndromes than those addressed by regulatory trials, including CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences. The most common adverse events observed during treatment with CBD included somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.. The currently available data suggest that response to treatment with a highly purified, plant-derived CBD oil-based solution can be seen in patients across a broad range of epilepsy disorders and etiologies. The existing evidence can provide preliminary support for additional research.

Topics: Anticonvulsants; Cannabidiol; Case-Control Studies; Cross-Sectional Studies; Double-Blind Method; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Seizures

Epilepsy is a neurological disorder mainly characterised by recurrent seizures that affect the entire population diagnosed with the condition. Currently, there is no cure for the disease and a significant proportion of patients have been deemed to have treatment-resistant epilepsy (TRE). A patient is deemed to have TRE if two or more antiepileptic drugs (AEDs) fail to bring about seizure remission. This inefficacy of traditional AEDs, coupled with their undesirable side effect profile, has led to researchers considering alternative forms of treatment. Phytocannabinoids have long served as therapeutics with delta-9-THC (Δ

Topics: Adolescent; Anticonvulsants; Cannabidiol; Cannabis; Epilepsy; Humans; Seizures

To provide an up-to-date summary of the benefits and harms of cannabis-based products for epilepsy in children.. We updated our earlier systematic review, by searching for studies published up to May 2019. We included randomized controlled trials (RCTs) and non-randomized studies (NRS) involving cannabis-based products administered to children with epilepsy. Outcomes were seizure freedom, seizure frequency, quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and emergency room visits.. Thirty-five studies, including four RCTs, have assessed the benefits and harms of cannabis-based products in pediatric epilepsy (12 since April 2018). All involved cannabis-based products as adjunctive treatment, and most involved cannabidiol. In the RCTs, there was no statistically significant difference between cannabidiol and placebo for seizure freedom (relative risk 6.77, 95 % confidence interval [CI] 0.36-128.38), quality of life (mean difference [MD] 0.6, 95 %CI -2.6 to 3.9), or sleep disruption (MD -0.3, 95 %CI -0.8 to 0.2). Data from both RCTs and NRS suggest that cannabidiol reduces seizure frequency and increases treatment response; however, there is an increased risk of gastrointestinal adverse events.. Newly available evidence supports earlier findings that cannabidiol probably reduces the frequency of seizures among children with drug-resistant epilepsy.. CRD42018084755.

Topics: Cannabidiol; Cannabinoid Receptor Modulators; Child; Epilepsy; Humans; Medical Marijuana

Epilepsy is a neurological disorder characterized by the presence of seizures and neuropsychiatric comorbidities. Despite the number of antiepileptic drugs, one-third of patients did not have their seizures under control, leading to pharmacoresistance epilepsy. Cannabis sativa has been used since ancient times in Medicine for the treatment of many diseases, including convulsive seizures. In this context, Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been a promising compound for treating epilepsies due to its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. In this review, we summarize evidence of the CBD anticonvulsant activities present in a great diversity of animal models. Special attention was given to behavioral CBD effects and its translation to human epilepsies. CBD anticonvulsant effects are associated with a great variety of mechanisms of action such as endocannabinoid and calcium signaling. CBD has shown effectiveness in the clinical scenario for epilepsies, but its effects on epilepsy-related comorbidities are scarce even in basic research. More detailed and complex behavioral evaluation about CBD effects on seizures and epilepsy-related comorbidities are required.

Topics: Animals; Anticonvulsants; Cannabidiol; Disease Models, Animal; Epilepsy; Seizures

Multiple medications have recently been approved or are nearing US Food and Drug Administration approval for treatment of pediatric epilepsy, while a number of other compounds are in development. Many of these therapies are seeking indications in rare epilepsy syndromes and present novel mechanisms of action for the treatment of epilepsy.. Data related to drugs in development or under study were accessed following literature search via PubMed or author knowledge of publically available data.. Several new compounds are recently approved or under study for epilepsy in children.. The following is a brief overview of the new and emerging medications for the treatment of pediatric epilepsy.

Topics: Anticonvulsants; Cannabidiol; Child; Dioxolanes; Epilepsy; Fenfluramine; Humans; Piperidines; Pregnanolone; Pyridines

Herein, 11 general types of natural cannabinoids from Cannabis sativa as well as 50 (-)-CBD analogues with therapeutic potential were described. The underlying molecular mechanisms of CBD as a therapeutic candidate for epilepsy and neurodegenerative diseases were comprehensively clarified. CBD indirectly acts as an endogenous cannabinoid receptor agonist to exert its neuroprotective effects. CBD also promotes neuroprotection through different signal transduction pathways mediated indirectly by cannabinoid receptors. Furthermore, CBD prevents the glycogen synthase kinase 3β (GSK-3β) hyperphosphorylation caused by Aβ and may be developed as a new therapeutic candidate for Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Biological Products; Cannabidiol; Cannabis; Epilepsy; Humans; Neuroprotective Agents

Recent trials using cannabidiol (CBD) have shown that most acute and prolonged adverse effects of CBD are mild to moderate, with rare serious adverse effects (SAEs). This review focused on analyzing SAEs of CBD and their possible relation to drug-drug interactions.. We systematically analyzed the SAEs reported in randomized controlled trials (RCTs) involving the administration of oral CBD for at least 1 week in both healthy volunteers and clinical samples.. SAEs related to CBD in RCT are rare and include mainly elevated transaminases, convulsion, sedation, lethargy, and upper respiratory tract infections. Elevated transaminases are related to concomitant valproate use, while sedation, lethargy, and upper respiratory tract infections are related to concomitant clobazam use. Epileptic patients should be monitored when using CBD concomitantly with these and other antiepileptic drugs for other possible drug-drug interactions.

Topics: Administration, Oral; Anticonvulsants; Cannabidiol; Drug Interactions; Drug Therapy, Combination; Epilepsy; Humans; Randomized Controlled Trials as Topic

Topics: Animals; Anticonvulsants; Cannabidiol; Dog Diseases; Dogs; Epilepsy; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Cannabidiol (CBD), which is nonintoxicating pharmacologically relevant constituents of Cannabis, demonstrates several beneficial effects. It has been found to have antioxidative, anti-inflammatory, and neuroprotective effects. As the medicinal use of CBD is gaining popularity for treatment of various disorders, the recent flare-up of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology. Currently, as lot of clinical trials are underway, CBD demonstrates remarkable potential to become a supplemental therapy in various neurological conditions. It has shown promise in the treatment of neurological disorders such as anxiety, chronic pain, trigeminal neuralgia, epilepsy, and essential tremors as well as psychiatric disorders. While recent FDA-approved prescription drugs have demonstrated safety, efficacy, and consistency enough for regulatory approval in spasticity in multiple sclerosis (MS) and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges still remain. In the current review, the authors have shed light on the application of CBD in the management and treatment of various neurological disorders.

Topics: Anticonvulsants; Cannabidiol; Cannabis; Epilepsy; Humans; Lennox Gastaut Syndrome

The compounds present in cannabis have been in use for both recreational and medicinal purposes for many centuries. Changes in the legislation in South Africa have led to an increase in the number of people interested in using these compounds for self-medication. Many of them may approach their general practitioner as the first source of information about possible therapeutic effects. It is important that medical professionals are able to give patients the correct information. Cannabidiol (CBD) is one of the main compounds in cannabis plants, and there is evidence that it can successfully treat certain patients with epilepsy. This review looks at the most recent evidence on the use of CBD in the treatment of epilepsy and explores the mechanisms behind these beneficial effects.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabis; Epilepsy; Humans; South Africa

In the United States, access to marijuana and its related products has been outlawed since passing the Controlled Substance Act (CSA) in 1970. Under this act, marijuana is classified as Schedule I substance and is considered to have a high potential for dependency and abuse as well as unaccepted medical use. From that time, multiple states have taken measures to legalize and decriminalize the use of marijuana. In June 2018, Epidiolex® (cannabidiol, CBD) was the first cannabis-derived drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe forms of epilepsy, Lennox-Gastaut syndrome, or Dravet syndrome. In December 2018, Farm Bill was significant progress in cannabis-related law by which hemp was removed from the definition of marijuana in the CSA. This paper provides an up-to-date overview of the legal status of cannabis-related aspects, including medical marijuana, home cultivation, patient registration, and hemp-derived CBD from the medical perspective in the United States.

Topics: Cannabidiol; Cannabis; Epilepsy; Humans; Lennox Gastaut Syndrome; Medical Marijuana; United States

In recent years, there has been a growing appreciation by regulatory authorities that cannabis-based medicines can play a useful role in disease therapy. Although often conflagrated by proponents of recreational use, the legislative rescheduling of cannabis-derived compounds, such as cannabidiol (CBD), has been associated with the steady increase in the pursuit of use of medicinal cannabis. One key driver in this interest has been the scientific demonstration of efficacy and safety of CBD in randomised, placebo-controlled clinical trials in children and young adults with difficult-to-treat epilepsies, which has encouraged increasing numbers of human trials of CBD for other indications and in other populations. The introduction of CBD as the medicine Epidiolex in the United States (in 2018) and as Epidyolex in the European Union (in 2019) as the first cannabis-derived therapeutic for the treatment of seizures was underpinned by preclinical research performed at the University of Reading. This work was awarded the British Pharmacological Society Sir James Black Award for Contributions to Drug Discovery 2019 and is discussed in the following review article.

Topics: Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Young Adult

To review the history, pharmacology, and clinical science of cannabidiol (CBD) in the treatment of epilepsy.. Phase III randomized controlled trials and prospective open label trials have provided efficacy and safety data for the use of CBD in pediatric onset severe epilepsies. The product that was studied in the vast majority of these published trials, Epidiolex (>99% of CBD and <0.10% Δ9-tetrahydrocannabinol (THC); GW pharmaceuticals, Cambridge, UK), has now been FDA approved based on this published data.. Identification of CBD, Δ9-THC, and the endocannabinoid system in the mid-20th century has led to advancement of cannabis-based therapies for epilepsy. Based on clinical trial data, Epidiolex is the first CBD medication approved by a national regulatory agency (US Food and Drug Administration for Dravet and Lennox Gastaut syndrome; European Medicines Agency for Lennox Gastaut syndrome). Approval of CBD as a treatment for these rare and severe pediatric-onset epilepsy syndromes is an important milestone, but the complete spectrum of use of cannabis-derived products, and the use of CBD for other epilepsy syndromes remains to be determined.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabinoids; Clinical Trials, Phase III as Topic; Epilepsy; Humans; Randomized Controlled Trials as Topic

Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from

Topics: Anti-Anxiety Agents; Anticonvulsants; Antipsychotic Agents; Cannabidiol; Cannabis; Clinical Trials as Topic; Epilepsy; Humans; Seizures

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. One such protein is the voltage-gated sodium channel (Na

Topics: Animals; Brain; Cannabidiol; Cannabinoids; Epilepsy; Humans; Protein Binding; Voltage-Gated Sodium Channels

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 unanswered. 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.

Topics: Animals; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Epilepsy; Hippocampus; Humans

Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.

Topics: Animals; Cannabidiol; Double-Blind Method; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures

Over the past decade there has been an increasing interest in using cannabinoids to treat a range of epilepsy syndromes following reports of some remarkable responses in individual patients. The situation is complicated by the fact that these agents do not appear to work via their attachment to endogenous cannabinoid receptors. Their pharmacokinetics are complex, and bioavailability is variable, resulting in difficulty in developing a suitable formulation for oral delivery. Drug interactions also represent another complication in their everyday use. Nevertheless, recent randomized, placebo-controlled trials with cannabidiol support its efficacy in Dravet and Lennox-Gastaut syndromes. Further placebo-controlled studies are underway in adults with focal epilepsy using cannabidivarin. The many unanswered questions in the use of cannabinoids to treat epileptic seizures are briefly summarized in the conclusion.

Topics: Anticonvulsants; Biological Availability; Cannabidiol; Cannabinoids; Drug Interactions; Epilepsies, Myoclonic; Epilepsies, Partial; Epilepsy; Humans; Lennox Gastaut Syndrome

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.

Topics: Animals; Cannabidiol; Comorbidity; Disease Models, Animal; Epilepsy; Humans; Status Epilepticus

Pediatric epilepsy, including treatment-resistant forms, has a major effect on the quality of life, morbidity, and mortality of affected children. Interest has been growing in the use of medical cannabis as a treatment for pediatric epilepsy, yet there has been no comprehensive review of the benefits and harms of cannabis use in this population. In this systematic review, we will search for, synthesize, and assess the published and gray literature in order to provide usable and relevant information to parents, clinicians, and policy makers.. We will perform a living systematic review of studies involving the use of cannabis to treat pediatric epilepsy. We will search the published and gray literature for studies involving children with any type of epilepsy taking any form of cannabis. Studies will be selected for inclusion by two independent reviewers. The primary outcome is seizure freedom. Secondary outcomes are seizure frequency, quality of life (child, caregiver), quality and quantity of sleep, status epilepticus, tonic-clonic seizures, death (all-cause, sudden unexpected death in epilepsy), gastrointestinal adverse events (diarrhea, vomiting), and visits to the emergency room. The quality of each included study will be assessed. If data are sufficient in quantity and sufficiently similar, we will conduct pairwise random-effects meta-analysis. We will repeat the literature search every 6 months to identify studies published after the previous search date. Sequential meta-analysis will be performed as necessary to update the review findings.. Our review aims to provide a comprehensive and up-to-date summary of the available evidence to inform decisions about the use of cannabis in children with treatment-resistant epilepsy. The results of this review will be of use to parents, clinicians, and policy makers as they navigate this rapidly evolving area.. PROSPERO CRD42018084755.

Topics: Anticonvulsants; Cannabidiol; Cannabis; Child; Epilepsy; Humans; Quality of Life; Seizures

For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.. While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. U

Topics: Anticonvulsants; Cannabidiol; Cannabis; Drug Resistant Epilepsy; Endocannabinoids; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Medical Marijuana; Randomized Controlled Trials as Topic; Retrospective Studies; Seizures; Spasms, Infantile; Treatment Outcome; TRPV Cation Channels

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting approximately 1 in 6,000 people, and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first 12 months of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique opportunity to monitor EEG before the onset of clinical seizures, thus enabling early intervention in the process of epileptogenesis. In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and present recommendations of American and European experts in the field of epilepsy.

Topics: Anticonvulsants; Cannabidiol; Cognitive Dysfunction; Diet, Ketogenic; Electroencephalography; Epilepsy; Humans; Infant; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Vagus Nerve Stimulation

Topics: Animals; Anxiety; Brazil; Cannabidiol; Cannabis; Clinical Trials as Topic; Epilepsy; Humans; Neuroprotective Agents; Parkinson Disease; Psychotic Disorders; Translational Research, Biomedical

Click here to listen to the Podcast The one-third of people who do not gain seizure control through current treatment options need a revolution in epilepsy therapeutics. The general population appears to be showing a fundamental and rapid shift in its opinion regarding cannabis and cannabis-related drugs. It is quite possible that cannabidiol, licensed in the USA for treating rare genetic epilepsies, may open the door for the widespread legalisation of recreational cannabis. It is important that neurologists understand the difference between artisanal cannabidiol products available legally on the high street and the cannabidiol medications that have strong trial evidence. In the UK in 2018 there are multiple high-profile reports of the response of children taking cannabis-derived medication, meaning that neurologists are commonly asked questions about these treatments in clinic. We address what an adult neurologist needs to know now, ahead of the likely licensing of Epidiolex in the UK in 2019.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabis; Epilepsy; Humans

Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.. The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.. Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).. Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy; Female; Humans; Lennox Gastaut Syndrome; Male; Middle Aged; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection. The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from

Topics: Animals; Astrocytes; Biomarkers; Cannabidiol; Cannabinoids; Cell Communication; Epilepsy; Humans; Mental Disorders; Neurodegenerative Diseases; Neurogenesis; Receptors, Cannabinoid

Cannabis-derived cannabinoids such as cannabidiol (CBD) have anticonvulsant properties. Recently, there has been an emerging interest in the use of CBD-enriched products for treatment of drug-resistant epilepsy. Some pilot trials of CBD have proved beneficial for refractory epilepsy, but its efficacy is yet to be confirmed by standard placebo-controlled trials. However, the mechanisms underlying the seizure protection efficacy claims of CBD remain unclear. This review briefly describes the clinical utility of CBD in the treatment of refractory epilepsy.

Topics: Animals; Anticonvulsants; Cannabidiol; Clinical Trials as Topic; Epilepsy; Half-Life; Humans; Medical Marijuana; Metabolic Clearance Rate; Pilot Projects; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Topics: Cannabidiol; Epilepsy; Humans; Nervous System Diseases; Neurology; Pediatrics; Zika Virus Infection

Cannabis has been associated with the treatment of epilepsy throughout history, and if ancient Assyrian sources referring to "hand of ghost" are considered credible, this relationship may span four millennia. A tradition of usage continued in Arabic medicine and Ayurvedic practice in India, which led, in turn, to early experiments in Europe and North America with "Indian hemp." Lack of standardization, bioavailability issues, and ultimately prohibition were all factors in cannabis-based medicines failing to maintain mainstream usage in seizure treatment, but investigation was resumed in the 1970s with interesting signals noted in both laboratory and clinical settings. Early case studies showed promise, but lacked sufficient rigor. Resumption of research coupled with mass experimentation by families of epilepsy patients has led to intense interest in cannabis-based medicines for its treatment once more, with greatest focus on cannabidiol, but additional investigation of tetrahydrocannabinol, tetrahydrocannabinolic acid, and other phytocannabinoids. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".

Topics: Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Drug Combinations; Epilepsy; Europe; History, Ancient; Humans; India; Medical Marijuana; North America; Seizures

The use of cannabis products in the treatment of epilepsy has long been of interest to researchers and clinicians alike; however, until recently very little published data were available to support its use. This article summarizes the available scientific data of pharmacology from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including ∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), ∆9-tetrahydrocannabivarin (∆9-THCV), cannabidivarin (CBDV), and ∆9-tetrahydrocannabinolic acid (Δ9-THCA). It has long been known that ∆9-THC has partial agonist activity at the endocannabinoid receptors CB1 and CB2, though it also binds to other targets which may modulate neuronal excitability and neuroinflammation. The actions of Δ9-THCV and Δ9-THCA are less well understood. In contrast to ∆9-THC, CBD has low affinity for CB1 and CB2 receptors and other targets have been investigated to explain its anticonvulsant properties including TRPV1, voltage gated potassium and sodium channels, and GPR55, among others. We describe the absorption, distribution, metabolism, and excretion of each of the above mentioned compounds. Cannabinoids as a whole are very lipophilic, resulting in decreased bioavailability, which presents challenges in optimal drug delivery. Finally, we discuss the limited drug-drug interaction data available on THC and CBD. As cannabinoids and cannabis-based products are studied for efficacy as anticonvulsants, more investigation is needed regarding the specific targets of action, optimal drug delivery, and potential drug-drug interactions. This article is part of a Special Issue titled Cannabinoids and Epilepsy.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Drug Combinations; Epilepsy; Humans; Receptor, Cannabinoid, CB1; Treatment Outcome

There has been a dramatic surge in the interest of utilizing cannabis for epilepsy treatment in the US. Yet, access to cannabis for research and therapy is mired in conflicting regulatory policies and shifting public opinion. Understanding the current state of affairs in the medical cannabis debate requires an examination of the history of medical cannabis use. From ancient Chinese pharmacopeias to the current Phase III trials of pharmaceutical grade cannabidiol, this review covers the time span of cannabis use for epilepsy therapy so as to better assess the issues surrounding the modern medical opinion of cannabis use. This article is part of a Special Issue titled Cannabinoids and Epilepsy.

Topics: Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Drug Combinations; Epilepsy; History, Ancient; Humans; Medical Marijuana

Recent interest for the use of cannabis-derived products as therapeutic agents in the treatment of epilepsies has necessitated a reevaluation of their effects on brain and behavior. Overall, prolonged cannabis use is thought to result in functional and structural brain alterations. These effects may be dependent on a number of factors: e.g., which phytocannabinoid is used (e.g., cannabidiol (CBD) vs. tetrahyrocannabinol (THC)), the frequency of use (occasional vs. heavy), and at what age (prenatal, childhood, adulthood) the use began. However, due to the fact that there are over seven hundred constituents that make up the Cannabis sativa plant, it is difficult to determine which compound or combination of compounds is responsible for specific effects when studying recreational users. Therefore, this review focuses only on the functional MRI studies investigating the effects of specific pharmacological preparations of cannabis compounds, specifically THC, tetrahydrocannabivarin (THCV), and CBD, on brain function in healthy individuals and persons with epilepsy with references to non-epilepsy studies only to underline the gaps in research that need to be filled before cannabis-derived products are considered for a wide use in the treatment of epilepsy. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".

Topics: Brain; Cannabidiol; Cannabinoids; Cannabis; Comprehension; Dronabinol; Drug Combinations; Epilepsy; Humans; Marijuana Smoking; Medical Marijuana; Neuroimaging

In the United States, federal and state laws regarding the medical use of cannabis and cannabinoids are in conflict and have led to confusion among patients, caregivers, and healthcare providers. Currently, cannabis is legal for medical purposes in 50% of the states, and another seventeen states allow products that are high in cannabidiol (CBD) and low in THC (tetrahydrocannabinol) for medical use. Many of these artisanal products are sold in dispensaries or over the internet. However, none of these products has been approved by the Food and Drug Administration (FDA). Understanding how federal laws apply to clinical research and practice can be challenging, and the complexity of these laws has resulted in particular confusion regarding the legal status of CBD. This paper provides an up-to-date overview (as of August 2016) of the legal aspects of cannabis and cannabidiol, including cultivation, manufacture, distribution, and use for medical purposes. This article is part of a Special Issue title, Cannabinoids and Epilepsy.

Topics: Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Epilepsy; Federal Government; Humans; Marijuana Use; Medical Marijuana; State Government; United States

This is the third of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper focuses on treatment issues that arise during the course of childhood epilepsy and make the process of transition to adult care more complicated. Some AEDs used during childhood, such as stiripentol, vigabatrin, and cannabidiol, are unfamiliar to adult epilepsy specialists. In addition, new drugs are being developed for treatment of specific childhood onset epilepsy syndromes and have no indication yet for adults. The ketogenic diet may be effective during childhood but is difficult to continue in adult care. Regional adult epilepsy diet clinics could be helpful. Polytherapy is common for patients transitioning to adult care. Although these complex AED regimes are difficult, they are often possible to simplify. AEDs used in childhood may need to be reconsidered in adulthood. Rescue medications to stop prolonged seizures and clusters of seizures are in wide home use in children and can be continued in adulthood. Adherence/compliance is notoriously difficult for adolescents, but there are simple clinical approaches that should be helpful. Mental health issues including depression and anxiety are not always diagnosed and treated in children and young adults even though effective treatments are available. Attention deficit hyperactivity disorder and aggressive behavior disorders may interfere with transition and successful adulthood but these can be treated. For the majority, the adult social outcome of children with epilepsy is unsatisfactory with few proven interventions. The interface between pediatric and adult care for children with epilepsy is becoming increasingly complicated with a need for more comprehensive transition programs and adult epileptologists who are knowledgeable about special treatments that benefit this group of patients.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Cannabidiol; Child; Congresses as Topic; Diet, Ketogenic; Dioxolanes; Epilepsy; Humans; Transition to Adult Care; Treatment Outcome; Vigabatrin; Young Adult

Recently, cannabis has been suggested as a potential alternative therapy for refractory epilepsy, which affects 30% of epilepsy, both adults and children, who do not respond to current medications. There is a large unmet medical need for new antiepileptics that would not interfere with normal function in patients with refractory epilepsy and conditions associated with refractory seizures. The two chief cannabinoids are Δ-9-tetrahyrdrocannabinol, the major psychoactive component of marijuana, and cannabidiol (CBD), the major nonpsychoactive component of marijuana. Claims of clinical efficacy in epilepsy of CBD-predominant cannabis or medical marijuana come mostly from limited studies, surveys, or case reports. However, the mechanisms underlying the antiepileptic efficacy of cannabis remain unclear. This article highlights the pharmacological basis of cannabis therapy, with an emphasis on the endocannabinoid mechanisms underlying the emerging neurotherapeutics of CBD in epilepsy. CBD is anticonvulsant, but it has a low affinity for the cannabinoid receptors CB1 and CB2; therefore the exact mechanism by which it affects seizures remains poorly understood. A rigorous clinical evaluation of pharmaceutical CBD products is needed to establish the safety and efficacy of their use in the treatment of epilepsy. Identification of mechanisms underlying the anticonvulsant efficacy of CBD is also critical for identifying other potential treatment options.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabis; Epilepsy; Humans; Medical Marijuana

Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remains still poor. Unfortunately, besides several advantages, these new AEDs have not satisfactorily reduced the number of refractory patients. Therefore, the need for different other therapeutic options to manage epilepsy is still a current issue. To this purpose, emphasis has been given to phytocannabinoids, which have been medicinally used since ancient time in the treatment of neurological disorders including epilepsy. In particular, the nonpsychoactive compound cannabidiol (CBD) has shown anticonvulsant properties, both in preclinical and clinical studies, with a yet not completely clarified mechanism of action. However, it should be made clear that most phytocannabinoids do not act on the endocannabinoid system as in the case of CBD. In in vivo preclinical studies, CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures, whereas restricted data exist in chronic models of epilepsy as well as in animal models of epileptogenesis. Likewise, clinical evidence seems to indicate that CBD is able to manage epilepsy both in adults and children affected by refractory seizures, with a favourable side effect profile. However, to date, clinical trials are both qualitatively and numerically limited, thus yet inconsistent. Therefore, further preclinical and clinical studies are undoubtedly needed to better evaluate the potential therapeutic profile of CBD in epilepsy, although the actually available data is promising.

Topics: Animals; Anticonvulsants; Cannabidiol; Epilepsy; Humans

States and the federal government are under growing pressure to legalize the use of cannabis products for medical purposes in the United States. Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted ∆(9) -tetrahydrocannabinol (∆(9) -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader. This review provides an overview of the pharmacology and toxicology of CBD; summarizes some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and assesses the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States. Unlike Δ(9) -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors, whose activation results in the psychotropic effects characteristic of Δ(9) -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use. CBD exhibits neuroprotective, antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties. In combination with Δ(9) -THC, CBD has received regulatory approvals in several European countries and is currently under study in trials registered by the U.S. Food and Drug Administration in the United States. A number of states have passed legislation to allow for the use of CBD-rich, limited Δ(9) -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications. Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain.

Topics: Cannabidiol; Dronabinol; Endocannabinoids; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Receptors, Cannabinoid

Several antiepileptic drugs (AEDs), about 25, are currently clinically available for the treatment of patients with epilepsy. Despite this armamentarium and the many recently introduced AEDs, no major advances have been achieved considering the number of drug resistant patients, while many benefits have been indeed obtained for other clinical outcomes (e.g. better tolerability, less interactions). Cannabinoids have long been studied for their potential therapeutical use and more recently phytocannabinoids have been considered a valuable tool for the treatment of several neurological disorders including epilepsy. Among this wide class, the most studied is cannabidiol (CBD) considering its lack of psychotropic effects and its anticonvulsant properties.. Analyse the currently available literature on CBD also in light of other data on phytocannabinoids, reviewing data spanning from the mechanism of action, pharmacokinetic to clinical evidences.. Several preclinical studies have tried to understand the mechanism of action of CBD, which still remains largely not understood. CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures; beneficial effects were reported also in animal models of epileptogenesis and chronic models of epilepsy, although not substantial. In contrast, data coming from some studies raise questions on the effects of other cannabinoids and above all marijuana.. There is indeed sufficient supporting data for clinical development and important antiepileptic effects and the currently ongoing clinical studies will permit the real usefulness of CBD and possibly other cannabinoids. Undoubtedly, several issues also need to be addressed in the next future (e.g. better pharmacokinetic profiling). Finally, shading light on the mechanism of action and the study of other cannabinoids might represent an advantage for future developments.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabis; Epilepsy; Humans

Antiepileptic drugs often produce serious adverse effects, and many patients do not respond to them properly. Phytocannabinoids produce anticonvulsant effects in preclinical and preliminary human studies, and appear to produce fewer adverse effects than available antiepileptic drugs. The present review summarizes studies on the anticonvulsant properties of phytocannabinoids.. Literature search using the PubMed database to identify studies on phytocannabinoids and epilepsy.. Preclinical studies suggest that phytocannabinoids, especially cannabidiol and cannabidivarin, have potent anticonvulsant effects which are mediated by the endocannabinoid system. Human studies are limited in number and quality, but suggest that cannabidiol has anticonvulsant effects in adult and infantile epilepsy and is well tolerated after prolonged administration.. Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects. Cannabidiol and cannabidivarin should be tested in randomized, controlled clinical trials, especially in infantile epileptic syndromes.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabinoids; Cerebral Cortex; Clinical Trials as Topic; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Evaluation, Preclinical; Endocannabinoids; Epilepsy; Humans; Phytotherapy; Plant Extracts

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Epilepsy; Humans; Medical Marijuana

The antiepileptic potential of Cannabis sativa preparations has been historically recognized. Recent changes in legal restrictions and new well-documented cases reporting remarkably strong beneficial effects have triggered an upsurge in exploiting medical marijuana in patients with refractory epilepsy. Parallel research efforts in the last decade have uncovered the fundamental role of the endogenous cannabinoid system in controlling neuronal network excitability raising hopes for cannabinoid-based therapeutic approaches. However, emerging data show that patient responsiveness varies substantially, and that cannabis administration may sometimes even exacerbate seizures. Qualitative and quantitative chemical variability in cannabis products and personal differences in the etiology of seizures, or in the pathological reorganization of epileptic networks, can all contribute to divergent patient responses. Thus, the consensus view in the neurologist community is that drugs modifying the activity of the endocannabinoid system should first be tested in clinical trials to establish efficacy, safety, dosing, and proper indication in specific forms of epilepsies. To support translation from anecdote-based practice to evidence-based therapy, the present review first introduces current preclinical and clinical efforts for cannabinoid- or endocannabinoid-based epilepsy treatments. Next, recent advances in our knowledge of how endocannabinoid signaling limits abnormal network activity as a central component of the synaptic circuit-breaker system will be reviewed to provide a framework for the underlying neurobiological mechanisms of the beneficial and adverse effects. Finally, accumulating evidence demonstrating robust synapse-specific pathophysiological plasticity of endocannabinoid signaling in epileptic networks will be summarized to gain better understanding of how and when pharmacological interventions may have therapeutic relevance.

Topics: Animals; Anticonvulsants; Brain; Cannabidiol; Cannabinoid Receptor Agonists; Endocannabinoids; Epilepsy; Humans; Marijuana Smoking; Medical Marijuana; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Signal Transduction; Treatment Outcome

Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it is effective in patients with epilepsy. Some states in the United States of America have explicitly approved its use for epilepsy.. To assess the efficacy and safety of cannabinoids when used as monotherapy or add-on treatment for people with epilepsy.. We searched the Cochrane Epilepsy Group Specialized Register (9 September 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 8), MEDLINE (Ovid) (9 September 2013), ISI Web of Knowledge (9 September 2013), CINAHL (EBSCOhost) (9 September 2013), and ClinicalTrials.gov (9 September 2013). In addition, we included studies we personally knew about that were not found by the searches, as well as searched the references in the identified studies.. Randomized controlled trials (RCTs) whether blinded or not.. Two authors independently selected trials for inclusion and extracted the data. The primary outcome investigated was seizure freedom at one year or more, or three times the longest interseizure interval. Secondary outcomes included responder rate at six months or more, objective quality of life data, and adverse events.. We found four randomized trial reports that included a total of 48 patients, each of which used cannabidiol as the treatment agent. One report was an abstract and another was a letter to the editor. Anti-epileptic drugs were continued in all studies. Details of randomisation were not included in any study report. There was no investigation of whether the control and treatment participant groups were the same or different. All the reports were low quality.The four reports only answered the secondary outcome about adverse effects. None of the patients in the treatment groups suffered adverse effects.. No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to small numbers of patients generally for short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Randomized Controlled Trials as Topic

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ(9) -Tetrahydrocannabinol (Δ(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Topics: Animals; Anticonvulsants; Brain; Cannabidiol; Cannabinoids; Epilepsies, Myoclonic; Epilepsy; Humans; Intellectual Disability; Lennox Gastaut Syndrome; Mental Disorders; Phytotherapy; Plant Extracts; Seizures; Spasms, Infantile

Recreational cannabis use in adults with epilepsy is widespread. The use of cannabis for medicinal purposes is also becoming more prevalent. For this purpose, various preparations of cannabis of varying strengths and content are being used. The recent changes in the legal environment have improved the availability of products with high cannabidiol (CBD) and low tetrahydrocannabinol (THC) concentrations. There is some anecdotal evidence of their potential efficacy, but the mechanisms of such action are not entirely clear. Some suspect an existence of synergy or "entourage effect" between CBD and THC. There is strong evidence that THC acts via the cannabinoid receptor CB1. The mechanism of action of CBD is less clear but is likely polypharmacological. The scientific data support the role of the endocannabinoid system in seizure generation, maintenance, and control in animal models of epilepsy. There are clear data for the negative effects of cannabis on the developing and mature brain though these effects appear to be relatively mild in most cases. Further data from well-designed studies are needed regarding short- and long-term efficacy and side effects of CBD or high-CBD/low-THC products for the treatment of seizures and epilepsy in children and adults.

Topics: Animals; Cannabidiol; Dronabinol; Epilepsy; Humans; Medical Marijuana; Seizures

Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it is effective in patients with epilepsy. Some states in the United States of America have explicitly approved its use for epilepsy.. To assess the efficacy of marijuana, or one of marijuana's constituents in the treatment of people with epilepsy.. We searched the Cochrane Epilepsy Group Specialized Register (May 15, 2012), the Cochrane Central Register of Controlled Trials (CENTRAL issue 4 of 12, The Cochrane Library 2012),MEDLINE (PubMed, searched on May 15, 2012), ISI Web of Knowledge (May 15, 2012), CINAHL (EBSCOhost, May 15, 2012), and ClinicalTrials.gov (May 15, 2012). In addition, we included studies we personally knew about that were not found by the searches, as well as references in the identified studies.. Randomized controlled trials (RCTs), whether blinded or not.. Two authors independently selected trials for inclusion and extracted data. The primary outcome investigated was seizure freedom at one year or more, or three times the longest interseizure interval. Secondary outcomes included: responder rate at six months or more, objective quality of life data, and adverse events.. We found four randomized reports which included a total of 48 patients, each of which used cannabidiol as the treatment agent. One report was an abstract, and another was a letter to the editor. Anti-epileptic drugs were continued in all. Details of randomisation were not included in any study. There was no investigation of whether control and treatment groups were the same or different. All the reports were low quality.The four reports only answered the secondary outcome about adverse effects. None of the patients in the treatment groups suffered adverse effects.. No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to small numbers of patients, for generally short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Randomized Controlled Trials as Topic

Recent work aimed at the introduction of natural and synthetic cannabinoids as drugs is reviewed. Delta1-Tetrahydrocannabinol (delta1-THC) is mainly investigated as a potential drug against glaucoma and asthma, and as an antiemetic agent in cancer chemotherapy. Cannabidiol is being tried in the clinic against epilepsy and as a hypnotic. Numerous synthetic cannabinoids are currently being investigated as analgetics and as sedative-relaxants.

Topics: Analgesics; Anti-Inflammatory Agents; Antiemetics; Asthma; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Epilepsy; Glaucoma; History, Ancient; History, Medieval; History, Modern 1601-; Humans; Hypertension; Medicine, Arabic; Medicine, East Asian Traditional; Phytotherapy; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship

People with epilepsy may experience episodes of frequent seizure activity (seizure clusters, acute repetitive seizures), and benzodiazepines are the cornerstone of rescue treatment. Cannabidiol (CBD) can be used as an adjunctive treatment for epilepsy, and it may interact with other antiseizure drugs, such as benzodiazepines. Here, we examined the safety and effectiveness of intermittent use of diazepam nasal spray in patients with seizure clusters who also received CBD treatment. This analysis included data from patients aged 6 to 65 years enrolled in a phase 3, long-term safety study of diazepam nasal spray. Age- and weight-based dosing of diazepam nasal spray were administered during a 12-month treatment period. Concomitant CBD use was recorded, and treatment-emergent adverse events (TEAEs) were collected. Of 163 treated patients, 119 (73.0%) did not receive CBD, 23 (14.1%) received the US Food and Drug Administration-approved highly purified CBD and 21 (12.9%) received another form of CBD. On average, patients receiving highly purified CBD were younger and more likely to have epileptic encephalopathies, including Dravet syndrome or Lennox-Gastaut syndrome, than patients who received another CBD preparation or no CBD. Rates of TEAEs and serious TEAEs were greater in patients who received any form of CBD (90.9% and 45.5%, respectively) compared with no CBD (79.0% and 26.1%, respectively). However, the lowest rates of TEAEs attributed to diazepam nasal spray were reported in patients who received highly purified CBD (13.0%), and this result was maintained in those who received concomitant clobazam. Use of second doses of diazepam nasal spray, a proxy for effectiveness, was lowest in the highly purified-CBD group (8.2%) compared with the no-CBD (11.6%) and other-CBD groups (20.3%). These results suggest that CBD does not alter the safety and effectiveness of diazepam nasal spray and supports concomitant use in appropriate patients.

Topics: Anticonvulsants; Cannabidiol; Diazepam; Epilepsy; Humans; Nasal Sprays; Seizures; Treatment Outcome

Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking.. To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy.. A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018.. Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years.. Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period.. A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants; 390-mg cannabidiol, 62 participants; placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days; least squares mean difference, 0.014; 95% CI, -0.175 to 0.203; P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days; least squares mean difference, 0.096; 95% CI, -0.093 to 0.285; P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, -6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension.. Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery.. ACTRN12616000510448 (double-blind); ACTRN12616001455459 (open-label).

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Female; Humans; Male; Seizures; Treatment Outcome

In recent randomized, placebo-controlled, phase III trials, highly purified cannabidiol demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome. It is anticipated that antiepileptic drugs such as stiripentol and valproate will be administered concomitantly with cannabidiol.. This trial evaluated the effect of cannabidiol on steady-state pharmacokinetics of stiripentol or valproate in patients with epilepsy, and the safety and tolerability of cannabidiol.. In total, 35 patients were recruited to the stiripentol arm (n = 14) or the valproate arm (n = 21). Both the safety and the pharmacokinetic populations of the stiripentol arm comprised 14 patients (2 placebo; 12 cannabidiol). The safety population of the valproate arm comprised 20 patients (4 placebo; 16 cannabidiol; one withdrew before receiving treatment); the pharmacokinetic population comprised 15 patients (3 placebo; 12 cannabidiol). Concomitant cannabidiol led to a small increase in stiripentol exposure (17% increase in maximum observed plasma concentration [C. The clinical relevance of the increase in stiripentol exposure is unknown; patients receiving cannabidiol and stiripentol concomitantly should be monitored for adverse reactions as individual patient responses may vary. Coadministration of cannabidiol did not affect the pharmacokinetics of valproate or its metabolite, 4-ene-VPA, in adult patients with epilepsy. Safety results were consistent with the known safety profile of cannabidiol at a dose of 20 mg/kg/day. Clinicaltrials.gov: NCT02607891.

Topics: Adolescent; Adult; Anticonvulsants; Area Under Curve; Cannabidiol; Dioxolanes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Valproic Acid; Young Adult

Topics: Adult; Anticonvulsants; Cannabidiol; Clobazam; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged

To assess the effect of oral cannabidiol (CBD) administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with idiopathic epilepsy.. Randomized blinded controlled clinical trial.. 26 client-owned dogs with intractable idiopathic epilepsy.. Dogs were randomly assigned to a CBD (n = 12) or placebo (14) group. The CBD group received CBD-infused oil (2.5 mg/kg [1.1 mg/lb], PO) twice daily for 12 weeks in addition to existing antiepileptic treatments, and the placebo group received noninfused oil under the same conditions. Seizure activity, adverse effects, and plasma CBD concentrations were compared between groups.. 2 dogs in the CBD group developed ataxia and were withdrawn from the study. After other exclusions, 9 dogs in the CBD group and 7 in the placebo group were included in the analysis. Dogs in the CBD group had a significant (median change, 33%) reduction in seizure frequency, compared with the placebo group. However, the proportion of dogs considered responders to treatment (≥ 50% decrease in seizure activity) was similar between groups. Plasma CBD concentrations were correlated with reduction in seizure frequency. Dogs in the CBD group had a significant increase in serum alkaline phosphatase activity. No adverse behavioral effects were reported by owners.. Although a significant reduction in seizure frequency was achieved for dogs in the CBD group, the proportion of responders was similar between groups. Given the correlation between plasma CBD concentration and seizure frequency, additional research is warranted to determine whether a higher dosage of CBD would be effective in reducing seizure activity by ≥ 50%.

Topics: Animals; Anticonvulsants; Cannabidiol; Dog Diseases; Dogs; Drug Therapy, Combination; Epilepsy; Seizures

In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8 health human volunteers. Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting. Neurological and physical examinations, blood and urine analysis, ECG and EEG were performed at weekly intervals. In phase 2 of the study, 15 patients suffering from secondary generalized epilepsy with temporal focus were randomly divided into two groups. Each patient received, in a double-blind procedure, 200-300 mg daily of CBD or placebo. The drugs were administered for along as 4 1/2 months. Clinical and laboratory examinations, EEG and ECG were performed at 15- or 30-day intervals. Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment, although these drugs no longer controlled the signs of the disease. All patients and volunteers tolerated CBD very well and no signs of toxicity or serious side effects were detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved. The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed.

Topics: Adult; Cannabidiol; Cannabinoids; Double-Blind Method; Drug Evaluation; Electrocardiography; Electroencephalography; Epilepsy; Ethanol; Female; Humans; Male; Sleep

Topics: Animals; Anticonvulsants; Cannabidiol; Child; Disease Models, Animal; Epilepsy; Epilepsy, Temporal Lobe; Humans; Mice; Seizures

Cannabidiol (CBD) oil has been used for the treatment of refractory epilepsy for a long time. In this study, we aimed to investigate the quality and reliability of YouTube videos pertaining to the use of CBD oil in the treatment of epilepsy.. A total of 100 videos were reviewed. Evaluation of the videos were performed by two experienced neurologists at the same time, but in different settings in order to prevent bias. Videos' image type, video content, video length, upload date, daily view count, comment and like counts, qualification of uploaders, DISCERN, and GQS scores were recorded.. The videos were found to be uploaded by physicians (46 %), health channels (33 %), TV channels (7 %), patients (2 %), and other persons (12 %). The mean DISCERN score was found as 3.71 ± 1.17 and the mean GQS score was found as 3.21 ± 1.05 in all videos. According to the DISCERN scale, the videos uploaded by doctors were scored as 3.82 ± 1.02 and the videos uploaded by non-doctors as 3.07 ± 1.12 (p < 0.001). According to the GQS scale, the videos uploaded by doctors were scored as 3.51 ± 1.02 and the videos uploaded by non-doctors as 3.01 ± 1.17 (p < 0.001).. Thirty-two (32%) videos were poor, 43 (43%) videos were moderate, and only 25 (25%) videos were good in terms of quality and reliability. YouTube videos related to health issues need to be audited strictly before they can become publicly accessible.

Topics: Cannabidiol; Epilepsy; Humans; Information Dissemination; Information Sources; Reproducibility of Results; Social Media; Video Recording

Topics: Adult; Anticonvulsants; Benzodiazepines; Cannabidiol; Child; Drug Resistant Epilepsy; Epilepsies, Partial; Epilepsy; Female; Humans; Male; Midazolam; Neurosteroids; Seizures

Cannabidiol (CBD) expanded access program, initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsies (TREs) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019.. Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/ml oral solution), increasing from 2 to 10 mg/kg/day to tolerance or maximum 25-50 mg/kg/day dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit.. Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (range = 0-74.5), and patients were taking a median of three (range = 0-10) antiseizure medications (ASMs) at baseline; the most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/day; median exposure duration was 694 days. Median percentage reduction from baseline ranged 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) ranged 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. The most common AEs (≥20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%).. Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of TREs.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Epilepsy; Humans; Infant; Infant, Newborn; Middle Aged; Seizures; Treatment Outcome; Young Adult

Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest antiseizure effects also beyond these three epilepsy syndromes.. In a retrospective multicenter study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers.. The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0-72) years (235 children and adolescents, 76 adults). Therapy with CBD was off-label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co-medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%).. Our study highlights that CBD has an antiseizure effect comparable to other antiseizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children <2 years of age.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Cannabidiol; Child; Clobazam; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Humans; Middle Aged; Retrospective Studies; Seizures; Young Adult

Marijuana-based therapies (MBTs) have been shown to reduce seizure frequency in patients with severe and drug-resistant epilepsy (DRE). Pharmaceutical-grade CBD (Epidiolex. Thirty patients were identified as taking more than 1 type of MBT. Our findings suggest that seizure frequencies do not change significantly from baseline to after the first MBT and to after the second MBT (p = .4). However, we did find that patients with greater baseline seizure frequency were significantly more likely to respond to treatment after the second MBT (p = .03). To our second endpoint of side effect profile, we found that patients who experienced side effects after a second MBT had significantly greater seizure frequency compared to those who did not (p = .04).. We found no significant seizure frequency reduction from baseline to after a second MBT in patients who tried at least 2 different formulations of MBT. This suggests a low probability of seizure frequency reduction with a second MBT therapy in patients with epilepsy who tried at least two different MBTs. While these findings need to be replicated in a larger sample, they suggest that clinicians should not delay care by trying alternative MBT formulations after a patient has already tried one. Instead, it may be more prudent to attempt an alternative class of therapy.

Topics: Anticonvulsants; Cannabidiol; Cannabis; Child, Preschool; Drug Resistant Epilepsy; Epilepsy; Humans; Lennox Gastaut Syndrome; Retrospective Studies; Seizures

Lennox-Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy associated with numerous neurological signs and symptoms. Altered postural tone and the need for a caregiver-assisted wheelchair are features characterizing patients with LGS. Highly purified cannabidiol (CBD) is a novel antiseizure medication (ASM) recommended for seizure treatment, in combination with clobazam, in patients with LGS. Adding CBD to the previous ASM treatment helps in reducing seizure frequency, specifically drop seizures, in patients with LGS in both clinical trials and real-world studies. However, no data about drug effects on postural tone, motor activity, gait, and stability are available. In this case series, three adult patients diagnosed with LGS were treated with CBD as an add-on. During the follow-up, a slight improvement in seizure frequency was observed. Unexpectedly, an amelioration in postural tone and stability, measured using the validated Gross Motor Function Classification System, was also detected. Our case series suggests that CBD may help in managing patients with LGS regarding seizure control and in improving other aspects of the clinical spectrum of the disease, such as postural tone and stability. The mechanisms at the basis of this improvement may be related, other than seizure reduction, to the drug's effect on the brain locomotor centers, as demonstrated in animal model studies.

Topics: Animals; Anticonvulsants; Cannabidiol; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Cannabidiol (CBD) is the main active ingredient in the cannabis plant used for treating epilepsy and related diseases. However, how CBD ameliorates epilepsy and its effect on the hippocampus remains unknown. Herein, we evaluated how CBD ameliorates seizure degree in pentylenetetrazol (PTZ) induced epilepsy mice after being exposed to CBD (10 mg/kg p.o). In addition, transcriptome and metabolomic analysis were performed on the hippocampus. Our results suggested that CBD could alleviate PTZ-induced seizure, of which the NPTX2, Gprc5c, Lipg, and Stc2 genes were significantly down-regulated in mice after being exposed to PTZ. Transcriptome analysis showed 97 differently expressed genes (CBD) and the PTZ groups. Metabonomic analysis revealed that compared with the PTZ group, 41 up-regulated and 67 down-regulated metabolites were identified in the hippocampus of epileptic mice exposed to CBD. The correlation analysis for transcriptome and metabolome showed that (±) 15-HETE and carnitine C6:0 were at the core of the network and were involved in the positive or negative regulation of the related genes after being treated with CBD. In conclusion, CBD ameliorates epilepsy by acting on the metabolism, calcium signaling pathway, and tuberculosis pathways in the hippocampus. Our study provided a practical basis for the therapeutic potential of treating epilepsy using CBD.

Topics: Animals; Anticonvulsants; Cannabidiol; Epilepsy; Mice; Multiomics; Pentylenetetrazole; Seizures

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.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epilepsies, Partial; Epilepsy; Humans; Lennox Gastaut Syndrome; Prospective Studies; Quality of Life

The 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), 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.

Topics: Adolescent; Adult; Aged; Cannabidiol; Child; Child, Preschool; Compassionate Use Trials; Epilepsy; Humans; Infant; Middle Aged; Patient Safety; Seizures; Young Adult

Topics: Binding Sites; Cannabidiol; Epilepsy; Humans

Topics: Anticonvulsants; Cannabidiol; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epilepsy; Humans; Quality Improvement

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.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Disorders of Excessive Somnolence; Drug Resistant Epilepsy; Epilepsy; Humans; Quality of Life; Retrospective Studies; Seizures; Sleep

The study analyzed the lawsuits of patients who requested cannabidiol (CBD)-based products from the Brazilian Unified National Health System during the period from 2019 to 2022, describing sociodemographic, clinical, and legal characteristics. This is a cross-sectional study composed of the evaluation of the technical notes issued by the Center for Technical Support of the Judiciary (NatJus), which supports judicial decisions. The data were obtained from the e-NatJus system, of the Brazilian Ministry of Justice, using web scraping techniques. Logistic regression was used to estimate odds ratios with 95% confidence intervals. We analyzed 1,115 technical notes of the CBD plaintiffs, of which 54.7% of the male patients, with a mean age of 18.4 years, mostly from the South Region of the country (38.8%), and 49.6% sought treatment for epilepsy. Regarding the actions with favorable opinions, 28.8% had no scientific evidence, 26.5% pleaded for products without registration with the Brazilian Health Regulatory Agency, and 25.3% of those that had registration were not in compliance with the therapeutic indication. Patients from the Northeast Region had a chance of a favorable opinion increased by 3.0 times and those diagnosed with epilepsy by 2.3. The expert opinions that supported the magistrates for the judicial decisions regarding the demands of patients for cannabidiol-based products in Brazil were mostly in accordance with scientific evidence, denoting the importance of NatJus in the qualification of access to medicinal products in the country.. Este estudo analisou as ações judiciais de pacientes que solicitaram ao Sistema Único de Saúde produtos à base de canabidiol (CBD) durante o período de 2019 a 2022, descrevendo características sociodemográficas, clínicas e jurídicas. Trata-se de um estudo transversal composto pela avaliação das notas técnicas emitidas pelos Núcleos de Apoio Técnico do Judiciário (NatJus), que embasaram as decisões judiciais. Os dados foram obtidos do sistema e-NatJus, do Ministério da Justiça, utilizando técnicas de web scraping. Regressão logística foi empregada para estimar razões de chances com intervalos de 95% de confiança. Foram analisadas 1.115 notas técnicas das ações demandantes de CBD, das quais 54,7% dos pacientes eram do sexo masculino, com idade média de 18,4 anos, em sua maioria da Região Sul do país (38,8%), e 49,6% buscavam tratamento para epilepsia. Das ações com pareceres favoráveis, 28,8% não tinham evidências científicas, 26,5% pleitearam produtos sem registro na Agência Nacional de Vigilância Sanitária e 25,3% dos que tinham registro não estavam em conformidade com a indicação terapêutica. Os pacientes da Região Nordeste tiveram a chance de parecer favorável aumentada em 3 vezes; e os que tinham diagnóstico de epilepsia, em 2,3 vezes. Os pareceres técnicos que deram suporte aos magistrados para as decisões judiciais das demandas de pacientes por produtos à base de canabidiol no Brasil estavam, em sua maioria, em conformidade com evidências científicas, denotando a importância dos NatJus na qualificação do acesso a produtos medicinais no país.. El estudio analizó las acciones legales de pacientes que solicitaron al Sistema Único de Salud brasileño productos a base de cannabidiol (CBD) durante el período de 2019 a 2022, describiendo características sociodemográficas, clínicas y legales. Se trata de un estudio transversal compuesto por la evaluación de las notas técnicas emitidas por los Núcleos de Apoyo Técnico del Poder Judicial (NatJus) que basaron las decisiones judiciales. Los datos se obtuvieron del sistema e-NatJus, del Ministerio de Justicia brasileño, mediante técnicas de web scraping. La regresión logística se empleó para estimar los odds ratios con intervalos del 95% de confianza. Fueron analizadas 1.115 notas técnicas de las acciones demandantes de CBD que tenían 54,7 % de los pacientes del género masculino, con una edad media de 18,4 años, en su mayoría de la Región Sur del país (38,8%) y 49,6% buscaban tratamiento para la epilepsia. De las acciones con opiniones favorables, el 28,8% no tenían evidencias científicas, el 26,5% pleitearon productos sin registro en la Agencia Nacional de Vigilancia Sanitaria y el 25,3% de los que tenían registro, no estaban en conformidad con la indicación terapéutica. Los pacientes de la Región Nordeste tuvieron la posibilidad de opiniones favorables aumentada en 3,0 veces y los que tenían diagnóstico de epilepsia en 2,3. Los dictámenes técnicos que dieron apoyo a los magistrados para las decisiones judiciales de las demandas de los pacientes por productos a base de cannabidiol en Brasil estaban en su mayoría en conformidad con las evidencias científicas, denotando la importancia de NatJus en la calificación del acceso a productos medicinales en el país.

Topics: Adolescent; Brazil; Cannabidiol; Cross-Sectional Studies; Epilepsy; Health Services Accessibility; Humans; Male

Pediatric epilepsy is a debilitating disease cluster that is much less researched than adult epilepsy. With approximately 30% of patients with pediatric epilepsy experiencing refractory seizures, novel treatment modalities are sometimes necessary to provide benefit. The use of marijuana, and more specifically cannabidiol, in people with seizures is much more broadly researched in adults compared with pediatric patients, although several recent review articles have been published. This article seeks to provide a pathophysiological basis for cannabidiol in epilepsy, discuss commercially available products and nonpharmaceutical marijuana, and review recent evidence in pediatric epilepsy.

Topics: Anticonvulsants; Cannabidiol; Cannabis; Child; Epilepsy; Humans; Seizures

Topics: Asphyxia; Cannabidiol; Child, Preschool; Drug Resistant Epilepsy; Epilepsy; Female; Humans; Infant; Quality of Life; Seizures; Treatment Outcome

We report our findings regarding effectiveness, safety, and tolerability of cannabidiol (CBD)-enriched medical cannabis as add-on therapy in children with drug-resistant epileptic encephalopathies (DEEs) after a median follow-up of 20 months.. A prospective cohort study was conducted to assess effectiveness, safety, and tolerability of CBD-enriched medical cannabis oil added to standard antiseizure medications in children with drug-resistant DEE seen at a single center.. Between October 2018 and March 2020, 59 patients were enrolled. Mean age at enrollment was 10.5 years (range, 2-17 years). Median treatment duration was 20 months (range, 12-32). Median age at first seizure was 8 months (range, 1 day - 10 years). At the end of follow-up, 78% of the children had a ≥ 50% decrease in seizure frequency and 47.5% had a > 75% decrease. Seven patients (11.9%) were seizure free. The number of seizures was reduced from a median of 305/month to 90/month, amounting to a mean reduction of 57% and a median reduction of 71% (p < 0.0001). Adverse effects were mostly mild or moderate. CBD was discontinued in 17 patients (28.8%) due to lack of response to treatment, increased seizure frequency, intolerance to the drug, or poor compliance.. In children with drug-resistant DEEs, long-term treatment of CBD-enriched medical cannabis as an adjuvant therapy to antiseizure therapy was found to be safe, well tolerated, and effective. Sustained reductions in seizure frequency and improvement of aspects of daily living were observed compared to our preliminary findings.

Topics: Anticonvulsants; Cannabidiol; Child; Drug Resistant Epilepsy; Epilepsy; Humans; Medical Marijuana; Prospective Studies

Topics: Cannabidiol; Child; Complementary Therapies; Epilepsy; Humans; Seizures; Surveys and Questionnaires

Cannabis sativa has been cultivated for human use for about 5,000 years, and has likewise been used in the treatment of epilepsy for thousands of years.. Cannabidiol (CBD), which was isolated from cannabis sativa in 1940, has an anti-seizure effect and no psychoactive activity. Its effectiveness in reducing various types of seizures has been proven in animal seizure and epilepsy models. Recent randomised, placebo-controlled trials have confirmed its effectiveness in patients with drug-resistant epilepsy.. The aim of this position paper was to present the specific mechanism of CBD's anti-seizure action and current indications for CBD's use in epilepsy. The only cannabis-derived drug that has successfully passed clinical trials and has obtained United States Food and Drug Administration and European Medicines Agency approval for epilepsy is Epidiolex®. This paper presents the outcomes of the completed clinical trials with the use of this drug.. CBD may be an effective drug in drug-resistant epilepsy, particularly in Dravet Syndrome, Lennox- Gastaut Syndrome and seizures associated with tuberous sclerosis complex. Additional randomised, placebo-controlled studies with CBD are needed.

Topics: Animals; Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome

Medical cannabis formulations with cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are widely used to treat epilepsy. We studied the safety and efficacy of two formulations.. We prospectively observed 29 subjects (12 to 46 years old) with treatment-resistant epilepsies (11 Lennox-Gastaut syndrome; 15 with focal or multifocal epilepsy; three generalized epilepsy) were treated with medical cannabis (1THC:20CBD and/or 1THC:50CBD; maximum of 6 mg THC/day) for ≥24 weeks. The primary outcome was change in convulsive seizure frequency from the pre-treatment baseline to the stable optimal dose phase.. There were no significant differences during treatment on stable maximal doses for convulsive seizure frequency, seizure duration, postictal duration, or use of rescue medications compared to baseline. No benefits were seen for behavioral disorders or sleep duration; there was a trend for more frequent bowel movements compared to baseline. Ten adverse events occurred in 6/29 patients, all were transient and most unrelated to study medication. No serious adverse events were related to study medication.. Our prospective observational study of two high-CBD/low-THC formulations found no evidence of efficacy in reducing seizures, seizure duration, postictal duration, or rescue medication use. Behavioral disorders or sleep duration was unchanged. Study medication was generally well tolerated. The doses of CBD used were lower than prior studies. Randomized trials with larger cohorts are needed, but we found no evidence of efficacy for two CBD:THC products in treating epilepsy, sleep, or behavior in our population.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Dronabinol; Epilepsies, Myoclonic; Epilepsy; Humans; Medical Marijuana; Middle Aged; Seizures; Young Adult

To describe the presence, type, and management of drug-drug interactions (DDIs) at prescription cannabidiol (CBD) therapy initiation.. We conducted a single-center, retrospective study of patients prescribed CBD from a medical center's neurology clinic for seizure management from January 2019 through April 2020. Patients were excluded if they were enrolled in a CBD clinical trial or the insurance approval or medication fulfillment process was not completed by the center's specialty pharmacy. The primary outcomes were the numbers, types, and management of DDIs identified at the time of CBD prescribing.. Of the 136 patients included, 109 (80%) had a DDI identified at baseline. Of the 260 DDIs, 71% (n = 184) were pharmacodynamic and 29% (n = 76) were pharmacokinetic in nature. Management of the 260 DDIs detected included counseling only (89% [n = 232 interactions]), discontinuation of the interacting agent [9% (n = 22 interactions]), and dosage change for the interacting agent [2% (n = 6 interactions]). Clobazam was the most commonly identified interacting medication (n = 63, 24%), while valproic acid accounted for 10% (n = 26) of the DDIs. The population was predominantly white (n = 115, 85%), 18 years of age or younger (n = 92, 68%), and had an indication for prescription CBD treatment of Lennox-Gastaut syndrome (n = 117, 86%).. This study provides new information on the role that integrated specialty pharmacists can play in identifying and managing initial DDIs in patients starting prescription CBD.

Topics: Anticonvulsants; Cannabidiol; Drug Interactions; Epilepsy; Humans; Pharmacists; Prescriptions; Retrospective Studies

Microglia, the dynamic innate immune cells of the central nervous system, become activated in epilepsy. The process of microglial activation in epilepsy results in the creation of an inflammatory environment around the site of seizure onset, which contributes to the epileptogenic process and epilepsy progression. Cannabidiol (CBD) has been effective for use as an adjunctive treatment for two severe pediatric seizure disorders. Newly recognized as an Food and Drug Administration (FDA)-approved drug treatment in epilepsy, it has gained in popularity primarily for pain management. Although CBD is readily available in stores and online retailers, its mechanism of action and specifically its effects on microglia and their functions are yet fully understood. In this study, we examine the effects of commercially available CBD on microglia inflammatory activation and neurogenic response, in the presence and absence of seizures. We use systemic administration of kainate to elicit seizures in mice, which are assessed behaviorally. Artisanal CBD is given in different modes of administration and timing to dissect its effect on seizure intensity, microglial activation and aberrant seizure-related neurogenesis. CBD significantly dampens microglial migration and accumulation to the hippocampus. While long term artisanal CBD use does not prevent or lessen seizure severity, CBD is a promising adjunctive partner for its ability to depress epileptogenic processes. These studies indicate that artisanal CBD is beneficial as it both decreases inflammation in the CNS and reduces the number of ectopic neurons deposited in the hippocampal area post seizure.

Topics: Animals; Anticonvulsants; Cannabidiol; Epilepsy; Humans; Kainic Acid; Mice; Microglia; Neurogenesis; Seizures

Several retrospective studies on pediatric epilepsy reported positive effects of cannabidiol-enriched artisanal cannabis oil and pure cannabidiol oil on seizure reduction.. This is a retrospective study of children and adolescents with refractory epilepsy caused by various etiologies who were treated with artisanal cannabis oil during January 2014 to June 2019, with at least one year follow-up.. Of 114 patients, 84 (73.3%) reported some improvement in seizure frequency at some point during treatment. Fifty-one (59%) of the 86 patients who continued treatment for at least one year showed >50% improvement in seizure frequency. Seizure etiology, seizure type, and patients' age and sex were not found to be associated with the response to cannabidiol-enriched cannabis oil. Side effects were minor, and positive effects beyond seizure reduction were noted.. Artisanal cannabidiol-enriched cannabis may be an effective and safe long-term treatment for refractory epilepsy.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Cannabis; Child; Drug Resistant Epilepsy; Epilepsy; Humans; Retrospective Studies; Seizures

The anticonvulsant effect of cannabidiol (CBD), which has been confirmed by findings from animal models and human trials, has attracted the interest of veterinary practitioners and dog owners. Moreover, social media and public pressure has sparked a renewed awareness of cannabinoids, which have been used for epilepsy since ancient times. Unfortunately, at this moment veterinarians and veterinary neurologists have difficulty prescribing cannabinoids because of the paucity of sound scientific studies. Pharmacokinetic studies in dogs have demonstrated a low oral bioavailability of CBD and a high first-pass effect through the liver. Administering CBD in oil-based formulations and/or with food has been shown to enhance the bioavailability in dogs, rats and humans. Tolerability studies in healthy dogs and dogs with epilepsy have demonstrated that CBD was safe and well tolerated with only mild to moderate adverse effects. In this context, it should be noted that the quality of available CBD varies widely, underscoring the importance of pharmaceutical quality and its control. One clinical trial in dogs with drug-resistant idiopathic epilepsy failed to confirm a difference in response rates between the CBD group and the placebo group, while in another cross-over trial a ≥ 50 % reduction in epileptic seizure frequency was found in six of 14 dogs in the treatment phase, a reduction that was not observed during the placebo phase. Based on the current state of knowledge it is not possible to provide clear-cut recommendations for the use of CBD in canine epilepsy. Randomized controlled canine trials with large sample sizes are needed to determine the range of therapeutic plasma concentrations, develop evidence-based dosing regimens, determine the efficacy of cannabidiol in drug-refractory epilepsy, and explore potential associations between treatment effects and different etiologies, epilepsy types, and drug combinations.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabinoids; Dog Diseases; Dogs; Drug Resistant Epilepsy; Epilepsy; Humans; Rats; Rodent Diseases; Seizures

The treatment of epilepsy during early life poses unique challenges-first-line therapies leave many individuals with poorly controlled seizures. In response to the pharmaco-resistance of current first-line anti-seizure drugs (ASDs) during early life, new therapies have emerged. One such therapy is cannabidiol (CBD). While well studied in adult models of epilepsy, it is poorly studied in immature animals. Here we assessed the efficacy of CBD in immature rodent models of the epilepsies.. Pups were pre-treated with CBD (1, 10, 50, 100, 200 mg/kg) and assessed for anticonvulsant efficacy using two well-established anti-seizure screening models: the pentylenetetrazole (PTZ) and maximal electroshock (MES) models. We assessed drug efficacy in postnatal day (P)7 and P21 rats.. In the PTZ model, CBD delayed seizure onset in adolescent but not neonatal rats. By contrast, higher doses of CBD reduced seizure duration in both neonatal and adolescent rats in the MES model. The effects of CBD in both models were modest but consistent.. Efficacy of CBD increased in older as compared to younger animals, producing an age-, model-, and dose-dependent suppression of seizures. These data suggest neonatal seizures (modeled by P7 treatment) may be less responsive to CBD. They also suggest preferential efficacy against tonic seizures as compared to partial motor seizures.

Topics: Animals; Anticonvulsants; Cannabidiol; Disease Models, Animal; Epilepsy; Pentylenetetrazole; Rats

Epilepsy is one of the most common brain disorder and, despite the possible use of several therapeutic options, many patients continue to have seizures for their entire lifespan and they need new therapeutic approaches. In the last years the interest on the non-psychoactive compounds present in Cannabis sativa has massively increased, and cannabidiol (CBD) has been shown to be effective in the treatment of different types of neurological disorders and neurodegenerative diseases such as epilepsy, ischemia, multiple sclerosis and Alzheimer's Disease.. We investigated the effects of the selected cannabinoids, Δ9-tetrahydrocannabinol (THC), CBD and cannabigerol (CBG) in rat organotypic hippocampal slices exposed to kainate, an in vitro seizure model. Cell death in the cornu Ammonis 3 (CA3) hippocampal subregion was quantified by propidium iodide fluorescence. Morphological analysis and tissue organization were examined by immunohistochemistry and confocal microscopy and microglia activation and polarization was evaluated using flow cytometry and morphology analysis.. When present in the incubation medium, cannabidiol reduced dose-dependent CA3 injury induced by kainate. Conversely, incubation with THC exacerbated hippocampal damage. The neuroprotective effects of cannabidiol were blocked by TRPV1, TRPV2, 5-HT1A, and PPARγ antagonists. Confocal microscopy confirmed that CBD but not THC had a significant protective effect against neuronal damage and tissue disorganization caused by kainate. Cannabidiol incubation significantly block the microglia activation from the M0 to M1 phenotype observed in the kainate in-vitro seizure model, pushing toward a transition from M0 to M2.. Our results suggest that CBD mitigated neuronal damage induced by kainate and blocked the transition from the M0 to the M1 phenotype.

Topics: Animals; Cannabidiol; Dronabinol; Epilepsy; Kainic Acid; Microglia; Rats; Seizures

To evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP).. This was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation.. One hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together.. Cannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Quality of Life; Retrospective Studies; Seizures; Status Epilepticus; Treatment Outcome

Lennox Gastaut Syndrome (LGS) is an epilepsy syndrome presenting in childhood, classically characterised by a triad of cognitive or developmental impairment, multiple seizure types and EEG features of slow-spike waves (SWW), with or without paroxysmal fast activity (PFA) in sleep. There is increasing scientific opinion in favour of a less rigid approach to LGS diagnosis and this clinical audit attempts to shed light on how the LGS diagnostic criteria used may have changed over time, in a large tertiary paediatric neurology unit (Great Ormond Street Hospital (GOSH), London, UK).. Electronic patient records were reviewed for patients with a diagnosis of LGS made at GOSH within two time periods, 2014-2017 and 2018-2021. Patient demographics, aetiology, clinical features, EEG features, investigation results and medications were reviewed. Findings were compared against the International League Against Epilepsy (ILAE) Diagnostic Manual criteria for LGS diagnosis (the classical triad plus PFA in sleep). Existing GOSH data regarding total number of new epilepsy referrals to GOSH and ICD10 codes (including all epilepsy and epilepsy syndromes) per year were also used to review LGS diagnoses as proportions of new epilepsy referrals and total number of epilepsy diagnoses.. 5 LGS diagnoses were made in 2014-2017 compared to 40 diagnoses made in 2018-2021. There was a steep increase in the number of LGS diagnoses and LGS diagnoses as a proportion of total epilepsy diagnoses in the last 4 years, coinciding with the licensing of cannabidiol for management of LGS in the UK in 2018. There was a much less marked increase in LGS diagnoses as a proportion of epilepsy referrals from 2018 (and an as yet unexplained high proportion in 2014). The 2014-17 cohort fit a more classical LGS diagnostic criteria of the triad plus presence of PFA on sleep EEG (100% in 2014-17 vs 68% in 2018-21), with a more classical preceding history of infantile spasms (80% in 2014-17 vs 23% in 2018-21). Common seizure types were similar in both groups and a male preponderance was also noted in both groups. Cannabidiol use in LGS patients has also increased over time, all prescribed after 2018.. Despite the limitations of the small numbers of patients in each group, the results of this clinical audit are in keeping with changing clinical trends in favour of a broader LGS diagnostic criteria. The combination of this less rigid diagnostic criteria, the steep increase in diagnosis seen from 2018 onwards (coinciding with UK cannabidiol licencing for LGS in 2018) and the fact that most of the LGS patients in both groups are currently prescribed cannabidiol, may reflect a strategic shift in attitude towards LGS diagnosis or an increase in referrals for LGS, possibly to help facilitate access to novel treatments.

Topics: Cannabidiol; Child; Electroencephalography; Epilepsy; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Male; Seizures; Spasms, Infantile

Here we present a series of patients with WS that were refractory to antiseizure medications and the ketogenic diet and who were treated with cannabidiol-enriched cannabis oil (CBD) as add-on therapy analyzing efficacy, safety, and tolerability.. Medical records of eight patients with WS treated with CBD at a ratio of cannabidiol:Δ-9-tetrahydrocannabinol (CBD:THC) of 25:1 seen between May 2020 and March 2021 were retrospectively analyzed. In all patients CBD was started as add-on therapy.. Eight patients (six female and two male) who received CBD for treatment-resistant WS were evaluated. Ages ranged from 16 to 22 months. The etiology was unknown in five and structural in three. Initial CBD dose was 2 mg/kg/day which was uptitrated to a median dose of 12 mg/kg/day (range, 2-25). Prior to CBD initiation, patients had a mean of 63 seizures per day (range, 31-79). After a follow-up of between 6 and 13 months, a 75-99% decrease in seizure frequency was observed in two patients, a 50-74% decrease in two, a less than 50% decrease in three, and no changes in seizure frequency were seen in the remaining patient. The index of EEG abnormalities improved between 20 and 80% in seven patients concurrently with the reduction in seizures. Adverse effects were mild and transient. Somnolence was observed in one patient, nausea and vomiting in one, and behavior disturbances and irritability in another patient.. This study evaluating the use of cannabidiol-enriched cannabis oil in children with WS showed that four (50%) of eight had a more than 50% seizure reduction with good tolerability.

Topics: Anticonvulsants; Cannabidiol; Child; Drug Resistant Epilepsy; Epilepsy; Female; Humans; Infant; Male; Medical Marijuana; Retrospective Studies; Spasms, Infantile

In spite of use of cannabidiol (CBD), a non-psychoactive cannabinoid, in pediatric patients with epilepsy, preclinical studies on its effects in immature animals are very limited. In the present study we investigated anti-seizure activity of CBD (10 and 60 mg/kg administered intraperitoneally) in two models of chemically induced seizures in infantile (12-days old) rats. Seizures were induced either with pentylenetetrazol (PTZ) or N-methyl-D-aspartate (NMDA). In parallel, brain and plasma levels of CBD and possible motor adverse effects were assessed in the righting reflex and the bar holding tests. CBD was ineffective against NMDA-induced seizures, but in a dose 60 mg/kg abolished the tonic phase of PTZ-induced generalized seizures. Plasma and brain levels of CBD were determined up to 24 h after administration. Peak CBD levels in the brain (996 ± 128 and 5689 ± 150 ng/g after the 10- and 60-mg/kg doses, respectively) were reached 1-2 h after administration and were still detectable 24 h later (120 ± 12 and 904 ± 63 ng/g, respectively). None of the doses negatively affected motor performance within 1 h after administration, but CBD in both doses blocked improvement in the bar holding test with repeated exposure to this task. Taken together, anti-seizure activity of CBD in infantile animals is dose and model dependent, and at therapeutic doses CBD does not cause motor impairment. The potential risk of CBD for motor learning seen in repeated motor tests has to be further examined.

Topics: Animals; Anticonvulsants; Brain; Cannabidiol; Disease Models, Animal; Epilepsy; Male; N-Methylaspartate; Pentylenetetrazole; Rats; Rats, Wistar; Seizures

To evaluate the long-term effectiveness of cannabidiol (CBD)-enriched oil for the treatment of refractory epilepsy and to assess the development of tolerance to its anti-seizure effect.. A prospective study of 92 consecutive patients (age 1-37 years, mean-11.8 years) with treatment resistant epilepsy who were treated with cannabis oil extract (CBD/tetrahydrocannabinol [THC] ratio of 20:1). Mean monthly seizure frequency was reported by the patients/their parents during monthly clinic visits. Tolerance was defined as either the need to increase the dose by ≥30% due to reduced treatment efficacy or as an increase of ≥30% in mean monthly seizure frequency in patients treated for at least 3 months with no change in other anti-seizure medications.. Mean follow-up time was 19.8 ± 12.5 months (range 3-45). Mean CBD dose was 11.3 (4-38) mg/kg/day. Twenty-nine (31%) patients discontinued treatment due to lack of effect or adverse reactions, which were reported in 51% (47/87) of the patients. Overall responder rate (>50% seizures reduction) was 54%, whereas 8 patients (9%) became seizure-free. Eighty-four patients were included in the tolerance analysis. Tolerance was observed in 21 (25%) patients after a mean duration of 7.3 ± 5.4 months of CBD-enriched oil treatment. There was a negative correlation between epilepsy duration and tolerance development (p = 0.038).. We report for the first time the plausible appearance of tolerance to cannabidiol-enriched oil. This may limit treatment efficacy in the long-term clinical management of refractory epilepsy in both pediatric and adult population. Further studies are needed to investigate potential mechanisms.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Drug Resistant Epilepsy; Drug Tolerance; Epilepsy; Female; Humans; Infant; Israel; Male; Prospective Studies; Seizures; Treatment Outcome

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na

Topics: Animals; Anticonvulsants; Biomarkers; Cannabidiol; Cerebral Cortex; Computer Simulation; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; Female; Gamma Rhythm; Hippocampus; Interneurons; Male; Mice; Mice, Knockout; NAV1.1 Voltage-Gated Sodium Channel; Potassium Channels, Voltage-Gated; Seizures; Theta Rhythm

Therapeutic use of cannabidiol (CBD) in intractable epilepsies has increased considerably over the last ten years. As more evidence for the potentially beneficial effects of CBD on different epilepsy types is emerging, it is important to monitor potential cognitive and behavioral side effects. So far, studies including standardized neuropsychological data in the context of treatment with CBD in epilepsy patients are sparse. The present open-label study examines cognitive and behavioral effects of CBD in children and adults with treatment resistant epilepsy.. Thirty-nine patients with treatment-resistant epilepsy completed the study protocol, i.e. they were tested at baseline (T0) and after three months of CBD treatment (T1). Patients completed standardized neuropsychological tests on memory, executive functions and attention if they were capable. For cognitively impaired patients who could not complete cognitive tests, caregiver interviews were conducted and caregiver questionnaires completed.. Significant cognitive decline from T0 to T1 was observed on none of the included measures. There was a significant improvement on a measure of selective attention and on a caregiver-rated behavioral measure. More than 89% of all individual test results remained stable or showed reliable improvement from T0 to T1. Cognitive and behavioral changes from T0 to T1 were not significantly correlated with CBD dose. Improvements in short-term/working memory were significantly related to better therapy response.. No adverse group-level effects of CBD treatment were detected. On an individual level, most test results remained stable or were improved. Cognitive change was not related to CBD dose. The present results show that, from a cognitive and behavioral point of view, CBD seems to have an encouraging side-effect profile. The results need to be replicated with larger samples.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Cognition; Drug Resistant Epilepsy; Epilepsy; Executive Function; Humans

To evaluate the safety, efficacy, and tolerability of highly purified cannabidiol (CBD) for the treatment of seizures in children and adults with treatment-resistant epilepsy (TRE) in an open-label, expanded access program (EAP).. One hundred sixty-nine participants (89 children and 80 adults) with TRE received plant-derived highly purified CBD (Epidiolex® in the U.S.; 100 mg/mL oral solution) with a starting dose of 5 mg/kg/day divided twice per day and titrated to a maximum dose of 50 mg/kg/day over the study period to seizure control and tolerability and followed for up to 2 years. Seizure frequency (calendars) and severity (Chalfont Seizure Severity Score; CSSS) were collected at every study visit. Adverse Events were reported at/between study visits as required, and participants also completed Adverse Events Profile (AEP) which generates a numerical representation of AEs. Response to CBD was defined as ≥50% reduction in seizure frequency. Given non-normal distribution of seizure frequency, a log transformation was applied after which the generalized least squares regression model for longitudinal data was used.. Evidence from the adjusted model revealed a significant mean reduction in seizure frequency compared to baseline in children and adults at all time points (1 month and 1 and 2 years). Percentage of children achieving ≥50% seizure frequency reduction was 44% at month 1, and 41% at year 1, and 61% reduction at year 2, while adult responder rates were 34% at month 1, 53% at year 1, and 71% at year 2 (all P < 0.0001). CSSS showed a sustained reduction from baseline to all 3 time points. Children displayed 52% seizure reduction at month 1, a 51% reduction at year 1, and 75% reduction at year 2. Seizure reductions in adults were 60%, 81%, and 85%, respectively (all P < 0.0001). While there were no significant differences between seizure frequency reduction between children and adults at all time points, there was a significant difference in seizure severity reduction at year 1, with adults reporting greater improvement in seizure severity (P < 0.001). The most commonly reported adverse events in the study period were diarrhea, sedation, and decreased appetite. AEP revealed significant improvement from baseline at multiple time points in adults and children, and the mean AEP scores were always lower compared to baseline over the duration of the study.. Our study provides further evidence of sustained seizure frequency and severity reduction over two years of treatment with highly purified CBD in TRE. In addition, CBD was generally well tolerated with minority of participants experiencing adverse events resulting in stopping CBD.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Drug Resistant Epilepsy; Epilepsy; Humans; Seizures; Treatment Outcome

The effects of individual cannabinoids on white matter integrity are unclear. Human studies have shown white matter maturation alterations in regular recreational cannabis users with the magnitude of these effects dependent on the age of exposure. However, studies have yet to determine which phytocannabinoids are most responsible for these changes. In the current study, we analyzed the effects of pharmaceutical grade cannabidiol oral solution (CBD; Epidiolex® in the U.S.; Epidyolex® in the EU; 100 mg/mL oral solution) on white matter integrity using diffusion MRI in patients with treatment resistant epilepsy (TRE).. 15 patients with TRE underwent 3 T diffusion MRI prior to receiving CBD and then again approximately 12 weeks later while on a stable dose of CBD for at least two weeks. DTI analyzes were conducted using DSI Studio and tract-based spatial statistics (TBSS).. DTI analysis using DSI Studio showed significant increases in fractional anisotropy (FA) in the right medial lemniscus (p = 0.03), right superior cerebellar peduncle (p = 0.03) and the pontine crossing tract (p = 0.04); decreased mean diffusivity (MD) in the left uncinate fasciculus (p = 0.02) and the middle cerebellar peduncle (p = 0.04); decreased axial diffusivity (AD) in the left superior cerebellar peduncle (p = 0.05), right anterior limb of the internal capsule (p = 0.03), and right posterior limb of the internal capsule (p = 0.02); and decreased radial diffusivity (RD) in the middle cerebellar peduncle (p = 0.03) and left uncinate fasiculus (p = 0.01). The follow-up ANCOVA also yielded significant results when controlling for covariates of CBD dosage, age, sex, change in seizure frequency, and scanner type: FA increased in the pontine crossing tract (p = 0.03); RD decreased in the middle cerebellar peduncle (p = 0.04) and left uncinate fasciculus (p = 0.04). Subsequent TBSS analysis controlling for the same variables yielded no significant white matter differences between groups.. These findings indicate relatively minor short-term effects of highly-purified plant-derived CBD on white matter structural integrity in patients with TRE.

Topics: Anisotropy; Brain; Cannabidiol; Diffusion Tensor Imaging; Epilepsy; Humans; White Matter

Topics: Anticonvulsants; Cannabidiol; Cannabis; Child; Epilepsy; Humans

To assess the longitudinal impact of highly purified cannabidiol (CBD) on the electroencephalogram (EEG) of children and adults.. Participants received an EEG prior to starting CBD, after approximately 12 weeks of CBD (FU1) and after approximately one year of CBD therapy (FU2). Longitudinal changes in five EEG measures (background frequency, focal slowing, reactivity, frequency of interictal, and ictal discharges) were examined following CBD exposure. Data were compared between pediatric and adult groups at two follow-up time points and within groups over time. Population-averaged models with generalized estimation equations or linear mixed effects models were used to analyze data where appropriate. Correlation analysis was used to assess any association between changes in seizure frequency and changes in EEG interictal discharge (IED) frequency. An alpha level of 5% was used to assess statistical significance.. At FU1, the adult group showed significant decrease in IED/minute (IDR 0.07, 95% CI [0.04, 0.14], P < 0.001); a nonsignificant decrease was observed among children (IDR 0.87, 95% CI [0.47, 0.64], P = 0.67). The difference in changes over time between participant groups was significant after adjusting for last CBD dose (IDR 11.8, 95% CI [4.86, 28.65], P < 0.0001). At FU2 both groups showed significant reduction from baseline after controlling for last CBD dose. This decrease was more pronounced in children (IDR 15.38, 95% CI [4.93, 47.99], P < 0.001). There was no significant correlation between changes in seizure frequency and EEG IED frequency at each timepoint (P = 0.542, 0.917 and 0.989 from baseline to FU1, FU1 to FU2 and baseline to FU2, respectively).. This longitudinal EEG study shows that highly-purified plant-derived CBD has positive effects on interictal epileptiform discharge frequency but no effects on other EEG measures. The effect of CBD does not appear to be dose or treatment-duration dependent.

Topics: Adult; Cannabidiol; Child; Drug Resistant Epilepsy; Electroencephalography; Epilepsy; Humans; Seizures

Recent approval of Epidiolex® (pharmaceutical cannabidiol/CBD) for the treatment of Lennox Gastaut syndrome (LGS) and Dravet syndrome highlights a therapeutic efficacy of CBD in the treatment of epilepsy. However, a large number of patients with epilepsy elect to use alternative artisanal CBD products due to cost or access constraints. Despite widespread availability and variety of these artisanal CBD products, studies evaluating their safety or efficacy are rare, making conclusions about clinical utility uncertain. The purpose of the present study was to evaluate cross-sectional and longitudinal associations of artisanal CBD product use with quality of life, mental health, healthcare utilization, and epilepsy-specific outcomes within a large, observational cohort of people with epilepsy. Participants who reported using artisanal CBD products at baseline (Artisanal CBD Users; n = 280) and participants who used no cannabis-based products (Controls; n = 138) completed web-based assessments evaluating psychiatric symptoms, healthcare utilization, and epilepsy-specific factors. Follow-up surveys were collected in a subset of participants (n = 190) following baseline assessment for longitudinal comparison. Cross-sectionally, higher quality of life, lower psychiatric symptom severity, and improved sleep were observed among Artisanal CBD Users at baseline compared with Controls. Initiation of artisanal CBD product use was also related to improved health outcomes longitudinally. No group differences were observed for seizure control, but both groups included a high number of individuals with no past month seizures. Artisanal CBD Users reported significantly better epilepsy medication tolerability, use of fewer prescription medications overall, and reduced healthcare utilization compared with Controls. These findings are consistent with research indicating that practitioners recommending CBD in clinical care for epilepsy report integrating the use of CBD both as a means to improve patient quality of life as well as for seizure control.

Topics: Anticonvulsants; Cannabidiol; Cross-Sectional Studies; Epilepsy; Humans; Quality of Life

Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) for Dravet syndrome. Unregulated artisanal cannabis-based products used to treat children with intractable epilepsies often contain relatively low doses of CBD but are enriched in other phytocannabinoids. This raises the possibility that other cannabis constituents might have anticonvulsant properties.. We used the Scn1a. The initial screen identified three phytocannabinoids with novel anticonvulsant properties: CBGA, cannabidivarinic acid (CBDVA) and cannabigerovarinic acid (CBGVA). CBGA was most potent and potentiated the anticonvulsant effects of clobazam against hyperthermia-induced and spontaneous seizures, and was anticonvulsant in the MES threshold test. However, CBGA was proconvulsant in the 6-Hz threshold test and a high dose increased spontaneous seizure frequency in Scn1a. These results suggest that CBGA, CBDVA and CBGVA may contribute to the effects of cannabis-based products in childhood epilepsy. Although these phytocannabinoids have anticonvulsant potential and could be lead compounds for drug development programmes, several liabilities would need to be overcome before CBD is superseded by another in this class.

Topics: Animals; Anticonvulsants; Benzoates; Cannabidiol; Cannabis; Epilepsies, Myoclonic; Epilepsy; Mice; NAV1.1 Voltage-Gated Sodium Channel; Receptors, Cannabinoid; Seizures

Epidiolex™, a form of highly purified cannabidiol (CBD) derived from Cannabis plants, has demonstrated seizure control activity in patients with Dravet syndrome, without a fully elucidated mechanism of action. We have employed an unbiased approach to investigate this mechanism at a cellular level.. We use a tractable biomedical model organism, Dictyostelium, to identify a protein controlling the effect of CBD and characterize this mechanism. We then translate these results to a Dravet syndrome mouse model and an acute in vitro seizure model.. CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human glycine cleavage system component H protein, which is functionally linked to folate one-carbon metabolism (FOCM). Analysis of FOCM components identified a mechanism for CBD in directly inhibiting methionine synthesis. Analysis of brain tissue from a Dravet syndrome mouse model also showed drastically altered levels of one-carbon components including methionine, and an in vitro rat seizure model showed an elevated level of methionine that is attenuated following CBD treatment.. Our results suggest a novel mechanism for CBD in the regulating methionine levels and identify altered one-carbon metabolism in Dravet syndrome and seizure activity.

Topics: Animals; Anticonvulsants; Cannabidiol; Carbon Cycle; Dictyostelium; Epilepsy; Humans; Lennox Gastaut Syndrome; Methionine; Rats

Cannabinoids include a variety of substances, of which cannabidiol (CBD) is the main substance investigated for the treatment of epilepsy, and this will be the focus in the present review. CBD preparations exist in various forms. There are significant differences in quality control regarding content and reproducibility for an approved drug versus herbal preparations. Cannabidiol has challenging pharmacological properties, and pharmaceutical and pharmacokinetic aspects will depend on the formulation or preparation of a certain product. This article will focus on the characteristics, pharmacokinetic challenges, and interactions of standardised CBD-containing drugs based on evidence from clinical and pharmacokinetic studies.

Topics: Anticonvulsants; Cannabidiol; Cannabinoids; Drug Interactions; Drug Resistant Epilepsy; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Cannabis sativa L. is an ancient medicinal plant wherefrom over 120 cannabinoids are extracted. In the past two decades, there has been increasing interest in the therapeutic potential of cannabis-based treatments for neurological disorders such as epilepsy, and there is now evidence for the medical use of cannabis and its effectiveness for a wide range of diseases. Cannabinoid treatments for pain and spasticity in patients with multiple sclerosis (Nabiximols) have been approved in several countries. Cannabidiol (CBD), in contrast to tetra-hydro-cannabidiol (THC), is not a controlled substance in the European Union, and over the years there has been increasing use of CBD-enriched extracts and pure CBD for seizure disorders, particularly in children. No analytical controls are mandatory for CBD-based products and a pronounced variability in CBD concentrations in commercialized CBD oil preparations has been identified. Randomized controlled trials of plant-derived CBD for treatment of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) have provided evidence of anti-seizure effects, and in June 2018, CBD was approved by the Food and Drug Administration as an add-on antiepileptic drug for patients two years of age and older with LGS or DS. Medical cannabis, with various ratios of CBD and THC and in different galenic preparations, is licensed in many European countries for several indications, and in July 2019, the European Medicines Agency also granted marketing authorisation for CBD in association with clobazam, for the treatment of seizures associated with LGS or DS. The purpose of this article is to review the availability of cannabis-based products and cannabinoid-based medicines, together with current regulations regarding indications in Europe (as of July 2019). The lack of approval by the central agencies, as well as social and political influences, have led to significant variation in usage between countries.

Topics: Anticonvulsants; Cannabidiol; Cannabinoids; Child; Child, Preschool; Dronabinol; Drug Combinations; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Plant Extracts; Seizures

Despite limited evidence, cannabidiol-rich cannabis extracts have been popularly used in pediatrics. With increased use, it is critical to determine basic pharmacokinetic parameters of cannabidiol in these extracts in the pediatric population. The objective of this study was to determine the disposition of oral cannabidiol cannabis extracts and drug interactions in children with pediatric epilepsy.. We conducted a prospective observational study evaluating the disposition of oral cannabidiol in children (< 18 years of age) receiving cannabidiol extracts for epilepsy. Subjects underwent serial blood draws after oral cannabidiol administration. Cannabidiol and metabolites, along with anticonvulsant concentrations were determined.. Twenty-nine patients had sufficient pharmacokinetic data and were included in the analysis. Mean age was 9.7 years (standard deviation 4.3) and 17 patients (59%) were male. Median peak plasma cannabidiol concentrations was 13.1 ng/mL (interquartile range 6.8-39.3 ng mL); median time to peak of 2.0 h (interquartile range 2.0-4.0 h). Mean acute elimination half-life of oral cannabidiol was 6.2 h (standard deviation 1.8 h). There was an observed half-life of degradation of 533 days noted for cannabidiol concentrations when stored for 0.6-3.1 years. There was some impact on cannabidiol pharmacokinetic parameters when cannabidiol was co-administered with zonisamide (elimination rate constant and V1) and levetiracetam (elimination rate constant).. In pediatric patients using oral cannabidiol-rich cannabis extract for epilepsy, the time to peak concentration of plasma cannabidiol and average acute elimination half-life were shorter than those reported for adults. Co-administration of zonisamide and levetiracetam had some impact on cannabidiol pharmacokinetic parameters. There was an observed degradation of plasma cannabidiol in long-term storage.. ClinicalTrials.gov Identifer no. NCT02447198.

Topics: Anticonvulsants; Cannabidiol; Cannabis; Child; Epilepsy; Female; Humans; Male; Plant Extracts

Highly purified cannabidiol (CBD) (approved as Epidiolex

Topics: Anticonvulsants; Cannabidiol; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures; TRPV Cation Channels

Many epilepsy patients are refractory to conventional antiepileptic drugs. Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are enhanced by Nav1.2 epilepsy mutations. Pharmacotherapies that specifically target aberrant resurgent and/or persistent currents would likely have fewer unwanted side effects and be effective in many patients with refractory epilepsy. This study investigated the effects of cannbidiol (CBD) and GS967 (each at 1 μM) on transient, resurgent, and persistent currents in human embryonic kidney (HEK) cells stably expressing wild-type hNav1.2 channels. We found that CBD preferentially inhibits resurgent currents over transient currents in this paradigm; and that GS967 preferentially inhibits persistent currents over transient currents. Therefore, CBD and GS967 may represent a new class of more targeted and effective antiepileptic drugs.

Topics: Action Potentials; Animals; Anticonvulsants; Cannabidiol; Epilepsy; HEK293 Cells; Humans; Ion Channel Gating; Mice; Mutation; NAV1.2 Voltage-Gated Sodium Channel; Neurons; Protein Isoforms; Pyridines; Triazoles

Pathogenic variants in AIMP1 gene are rare causes of neurologic disorders. Homozygous frameshift and nonsense variants in AIMP1 have been described in severe neurodegenerative disease. This is the third report of a homozygous nonsense variant in AIMP1 [c.115 C > T (p.Gln39*)] in a girl with severe neonatal onset epileptic encephalopathy. Like the two other cases reported, our patient is also of Filipino descent. Clinical features include microcephaly, poor visual motor development, shallow breathing, severe hypertonia in extremities, severe global developmental delay, poor gag and suck reflex, failure to thrive in the neonatal period, and early onset intractable seizures. Brain MRI showed hypoplasia of corpus callosum as well as cerebellar vermis, global volume loss and diminished myelination for her age. Electroencephalogram at four months of age showed background consisting of synchronous and asynchronous intervals of burst suppression with intermittent multifocal spikes predominantly in the bi-temporal region, suggestive of Early Onset Epileptic Encephalopathy with Burst Suppression (EOEE-BS) which has not been previously associated with the c.115 C > T variant in AIMP1. Of note, she presented to us in super refractory status epilepticus which was eventually controlled after administration of ketogenic diet and Epidiolex (cannabidiol). This report expands the genetic landscape of EOEE-BS. This is the first case of this specific variant in which Epidiolex was administered, which along with Ketogenic diet aided in controlling patient's super refractory status epilepticus.

Topics: Anticonvulsants; Brain; Brain Waves; Cannabidiol; Codon, Nonsense; Cytokines; Developmental Disabilities; Diet, Ketogenic; Epilepsy; Female; Homozygote; Humans; Infant; Neoplasm Proteins; RNA-Binding Proteins

A special component of cannabis, cannabidiol (CBD), is currently in the focus of epilepsy treatment and research. In this context, we investigated patients' expectations and preferences pertaining to plant-derived versus synthetic formulation of cannabidiol, as well as their willingness to get this treatment.. One hundred and four of 153 patients with different forms of epilepsy (54 % female, mean age 40 ± 16 yrs.) responded to the survey. The survey consisted of 8 questions addressing expectations of and concerns towards CBD treatment, preferences of plant-derived versus synthetic CBD, estimated monthly costs, and willingness to buy CBD at one's own expense.. The majority (73 %) of the responding epilepsy patients wished to receive plant-derived CBD; 5 % preferred synthetic CBD. Reasons for this choice were botanic origin, lack of chemistry, and the assumption of fewer and less dangerous side effects. Eighty-two percent of the patients estimated the monthly costs of CBD treatment to be below €500. Using the willingness-to-pay approach to assess the commitment of patients, 68 % could imagine buying the drug themselves. Fifty-three percent of these would be willing to pay up to €100, 40 % €100 to €200, and another 7 % €200 to €500 per month.. There is an overwhelming preference towards plant-derived cannabidiol in epilepsy patients, driven by the idea of organic substances being safer and better tolerated than synthetic. The willingness-to-pay approach reflects the high burden and pressure of uncontrolled epilepsy and the expectation of relief. Non-realistic ideas of pricing as well as what patients would be willing and able to pay confirm this perception.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Cannabis; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Male

The purpose of this study was to evaluate whether the topic of using cannabis as a treatment option for epilepsy is relevant among adult patients with the disorder and assess the possible determinant attitudes for having a history of cannabis consumption or being inclined to try it for medical purposes.. Willing adult (≥18 years) patients with diagnosed epilepsy participated in a cross-sectional survey study at a tertiary epilepsy center. The questions were related to cannabis use and opinions towards the safety and efficacy profile of cannabis for treating epilepsy.. From 250 respondents, 41 (16.4%) reported prior use of cannabis or its preparations (15 [36.6%] for self-treatment). There were 81 (32.4%) participants further interested in cannabis use for treating epilepsy. In a binary regression model (Nagelkerke R. Among adult patients with epilepsy, we report no particularly high rate of cannabis use or interest in applying cannabis for medical purposes. In order to clarify the scientific and legal status of the preparations, treating neurologists should consult prior users and patients interested in the possibility of trying cannabis as an epilepsy remedy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Cannabidiol; Cannabis; Cross-Sectional Studies; Epilepsy; Female; Humans; Lithuania; Male; Marijuana Smoking; Medical Marijuana; Middle Aged; Surveys and Questionnaires; Tertiary Care Centers; Young Adult

In January 2019, a new plant-derived purified cannabidiol preparation, approved by the US Food and Drug Administration, became commercially available for patients ≥2 years old with Lennox-Gastaut syndrome or Dravet syndrome. Among our patients who were prescribed the new cannabidiol formulation, we observed several cases of thrombocytopenia and therefore embarked on this study. We conducted a single-center systematic chart review of all pediatric patients (<21 years old) who were prescribed cannabidiol from January to August 2019. We evaluated salient features of the patients' epilepsy syndrome, age, concurrent medications, and surveillance laboratory results before and after cannabidiol initiation. Among 87 patients, nine (10%) developed thrombocytopenia (platelet nadir range = 17 000-108 000) following initiation of cannabidiol. Each of these nine children was on combination therapy of cannabidiol with valproic acid. Whereas no children on cannabidiol without valproic acid (0/57) developed thrombocytopenia, nine of 23 treated with combination valproic acid and cannabidiol developed platelets < 110 000/µL (P < .0001). We report a novel and clinically important side effect of thrombocytopenia in one-third of patients treated concurrently with cannabidiol and valproic acid. If this finding is confirmed, clinicians should perform close monitoring for thrombocytopenia when adding cannabidiol to a regimen that includes valproic acid.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy; Female; Humans; Infant; Lennox Gastaut Syndrome; Male; Thrombocytopenia; Valproic Acid; Young Adult

Cannabidiol (CBD) has gained popularity among parents of children with epilepsy, even before evidence of efficacy and safety was available. The aim of our survey was to gain information about parental attitude to CBD, as well as expectations and knowledge of CBD for treatment of their child's epilepsy.. A survey using an open-access online questionnaire for parents or caregivers of children with epilepsy within German-speaking countries from March to June 2019 was used.. Of 378 complete questionnaires (mean age of children: 11.1 (standard deviation [SD] 7.4) years), 28% (n = 106) reported previous or current CBD treatment over a mean time of 17.31 months (SD: 19.74), whereas 72% had no personal experience with CBD. Treatment was proposed by parents and not by physicians in 83% of cases and was mainly carried out with prescription-only products (71%, n = 67). Nevertheless, 29% used unregulated, artisanal products. Of all parents with previous experience, n = 77 (73%) reported that they expected CBD to be more efficient than the common antiseizure drugs (ASDs) at the beginning. Forty-five percent reported that their expectations were not met during therapy. Consistently, lack of seizure reduction was the most common reason to discontinue CBD (12/26). Of those responders without CBD experience, 93% would consider CBD for their child. However, the self-reported level of information was considered to be poor or very poor regarding efficacy (76%, n = 177), tolerance (83%, n = 191), interaction with other medication (91%, n = 211), and potential long-term effects (87%, n = 212).. There is a huge interest in CBD but includes potentially unrealistic expectations of its efficacy and tolerance combined with a low level of information. Neuropediatricians should address parents of children with epilepsy regarding potential motivation and expectations of CBD. In addition, parental education, especially on interactions and potential side effects, is strongly recommended.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Caregivers; Child; Child, Preschool; Epilepsy; Female; Germany; Health Knowledge, Attitudes, Practice; Humans; Male; Motivation; Surveys and Questionnaires

Resting-state (rs) network dysfunction is a contributing factor to treatment resistance in epilepsy. In treatment-resistant epilepsy (TRE), pharmacological and nonpharmacological therapies have been shown to improve such dysfunction. In this study, our goal was to prospectively evaluate the effect of highly purified plant-derived cannabidiol (CBD; Epidiolex®) on rs functional magnetic resonance imaging (fMRI) functional connectivity (rs-FC). We hypothesized that CBD would change and potentially normalize the rs-FC in TRE.. Twenty-two of 27 participants with TRE completed all study procedures including longitudinal pre-/on-CBD rs-fMRI (8M/14F, mean age = 36.2 ± 15.9 years, TRE duration = 18.3 ± 12.6 years); there were no differences in age (p = 0.99) or sex (p = 0.15) between groups. Assessments collected included seizure frequency (SF), Chalfont Seizure Severity Scale (CSSS), Columbia Suicide Severity Rating Scale (C-SSRS), Adverse Events Profile (AEP), and Profile of Mood States (POMS). Twenty-three healthy controls (HCs) received rs-fMRI and POMS once.. Participants with TRE showed average decrease of 71.7% in SF (p < 0.0001) and improved CSSS, AEP, and POMS confusion, depression, and fatigue subscores (all p < 0.05) on-CBD with POMS scores becoming similar to those of HCs. Paired t-tests showed significant pre-/on-CBD changes in rs-FC in cerebellum, frontal areas, temporal areas, hippocampus, and amygdala with some of them correlating with improvement in behavioral measures. Significant differences in rs-FC between pre-CBD and HCs were found in cerebellum, frontal, and occipital regions. After controlling for changes in SF with CBD, these differences were no longer present when comparing on-CBD to HCs.. This study indicates that highly purified CBD modulates and potentially normalizes rs-FC in the epileptic brain. This effect may underlie its efficacy. This study provides Class III evidence for CBD's normalizing effect on rs-FC in TRE.

Topics: Adult; Cannabidiol; Drug Resistant Epilepsy; Epilepsy; Humans; Magnetic Resonance Imaging; Middle Aged; Seizures; Young Adult

We aimed to determine changes in working memory and functional connectivity via functional magnetic resonance imaging (fMRI)-modified Sternberg task after treatment with highly purified cannabidiol (CBD, Epidiolex®; 100 mg/mL) in patients with treatment-resistant epilepsy (TRE).. Twenty patients with TRE (mean age: 35.8 years; 7 male) performed fMRI Sternberg task before receiving CBD ("PRE") and after reaching stable dosage of CBD (15-25 mg/kg/day; "ON"). Each patient performed 2 runs of the modified Sternberg task during PRE and ON fMRI. Twenty-three healthy controls (HCs; mean age: 25 years; 11 M) also completed the task. All were presented with a sequence of 2 or 6 letters and instructed to remember them (encoding). After a delay, a single letter was shown, and participants recalled if letter was shown in sequence (retrieval). Paired t-tests were used to analyze accuracy/response times. For each subject, event-related modeling of encoding (2 and 6 letters) and retrieval was performed. Paired t-tests controlling for seizure frequency change and scanner type were performed to assess changes in neural recruitment during encoding and retrieval in key regions of interest.. There was nonsignificant increase in mean modified Sternberg task accuracy from PRE to ON-CBD (28.6 vs. 32.1%). PRE and ON accuracy was worse than HCs (75.5%, p < 0.001). ON-PRE comparison revealed increased activation in the right inferior frontal gyrus (IFG) during 6-letter encoding. ON-HC comparison revealed increased activation in bilateral IFG and insula during 2-letter encoding. PRE-HC comparison revealed decreased activation in the left middle frontal gyrus during 6-letter encoding. None of these activations were associated with working memory performance.. Treatment-resistant epilepsy results in poorer working memory performance and lower neural recruitment compared with HCs. Treatment with CBD results in no significant changes in working memory performance and in significant increases in neural activity in regions important for verbal memory and attention compared with HCs during memory encoding.

Topics: Adult; Cannabidiol; Epilepsy; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term

An intermediate-sized, multicenter, expanded-access study was opened in 2015 through the support of the State of Georgia. This study provided children with treatment-resistant epilepsy (TRE) access to plant-derived highly purified cannabidiol (CBD; Epidiolex® in the US; Epidyolex® in the EU; 100 mg/mL oral solution). These children had failed to achieve seizure freedom with available treatment options and were ineligible to participate in randomized controlled trials that only included patients with Lennox-Gastaut and Dravet syndromes.. Cannabidiol safety, changes in seizure type, frequency, and seizure-free days were evaluated for children aged 1-18 years (at time of consent) as an adjunctive treatment for 36 months. The study consisted of a two-month baseline period, a titration period, treatment period, and optional titration period, which occurred after ≥26 weeks of treatment. Cannabidiol treatment was administered up to a targeted dose of 25 mg/kg/day, with an optional secondary treatment up to 50 mg/kg/day. Daily seizure type, seizure frequency, and seizure-free days were recorded in a Web-based diary, and changes in these outcomes were recorded and analyzed for the duration of the study. The occurrence of adverse events (AEs) was also recorded.. The median percentage change in seizures for 45 patients in Months 3, 6, 12, 18, 24, and 36 showed a statistically significant (p < 0.001) reduction in major seizures (ranging from 54 to 72% at various time points) and all seizures (61-70%) compared with baseline. A mean increase in seizure-free days per 28 days was >5 in all treatment periods after Month 2, and an average increase of 7.52 (p < 0.001) seizure-free days per 28 days was observed at the end of follow-up compared with baseline. All patients experienced ≥1 AE. Children who transitioned to the optional secondary treatment (high-dose group) reported more AEs before increasing their dose to >25.0 mg/kg/day compared with the low-dose group. However, the average rate of AEs was significantly lower after moving to a high-dose regimen (p = 0.004). Twelve children reported 20 serious AEs, none of which were considered related to CBD.. This study supports CBD as an adjunctive treatment for children with TRE. Treatment was well tolerated in doses up to 50 mg/kg/day. Patients who did not achieve desired results at a dose of ≤25.0 mg/kg/day reported more AEs when CBD dose increased to >25.0 mg/kg/day. Decreases in major seizure frequency and an increase in seizure-free days compared with baseline were reported during treatment. This supports the efficacy and tolerability of CBD for mixed seizure etiologies.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Epilepsies, Myoclonic; Epilepsy; Humans; Infant; Seizures

For the first time in Korea, we aimed to study the efficacy and safety of cannabidiol (CBD), which is emerging as a new alternative in treating epileptic encephalopathies.. This study was conducted retrospectively with patients between the ages of 2-18 years diagnosed with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) were enrolled from March to October 2019, who visited outpatient unit at 3 and 6 months to evaluate medication efficacy and safety based on caregiver reporting. Additional evaluations, such as electroencephalogram and blood tests, were conducted at each period also. CBD was administered orally at a starting dose of 5 mg/kg/day, and was maintained at 10 mg/kg/day.. We analyzed 34 patients in the LGS group and 10 patients in the DS group between the ages of 1.2-15.8 years. In the 3-month evaluation, the overall reduction of seizure frequency in the LGS group was 52.9% (>50% reduction in 32.3% of the cases), and 29.4% in the 6-month evaluation (more than 50% reduction in 20.6%). In DS group, the reduction of seizure frequency by more than 50% was 30% and 20% in the 3-month and 6-month evaluation, respectively. Good outcomes were defined as the reduction of seizure frequency by more than 50% and similar results were observed in both LGS and DS groups. Adverse events were reported in 36.3% of total patients of which most common adverse events were gastrointestinal problems. However, no life-threatening adverse event was reported in both LGS and DS during the observation period.. In this first Korean study, CBD was safe and tolerable for use and could be expected to potentially reduce the seizure frequency in pediatric patients with LGS or DS.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Caregivers; Child; Child, Preschool; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; Female; Humans; Infant; Lennox Gastaut Syndrome; Male; Patient Safety; Republic of Korea; Retrospective Studies; Treatment Outcome

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans

Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16 weeks.. The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy.. Patients aged 1-17 years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5 mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25 mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3 months, and every 3 months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3 months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3 months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15 days of treatment, at 1 month, at 3 months, and every 3 months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures.. Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53 months (mean 21 months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6 months and more gradually thereafter. At 24 months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained > 50% reduction in motor seizures, including three (11.5%) who remain seizure free.. Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Drug Therapy, Combination; Epilepsy; Female; Humans; Infant; Male; Prospective Studies; Seizures; Status Epilepticus; Treatment Outcome; United States; Valproic Acid

Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol (CBD) in a battery of acute seizure models. Additionally, we defined the disease-modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus-spontaneous recurrent seizures (RISE-SRS) model of temporal lobe epilepsy (TLE).. We evaluated the acute antiseizure effect of CBD in the maximal electroshock seizure, 6-Hz psychomotor seizure, and pentylenetetrazol acute seizure tests, as well as the corneal kindling model of chronic seizures in mice following intraperitoneal administration. Median effective or behavioral toxic dose was determined in both mice and rats. Next, we tested an intravenous preparation of CBD (10 mg/kg single dose) in a rat model of pilocarpine-induced status epilepticus. We defined the effect of chronic CBD administration (200 mg/kg orally) on spontaneous seizures, motor control, gait, and memory function in the rat RISE-SRS model of TLE.. CBD was effective in a battery of acute seizure models in both mice and rats following intraperitoneal administration. In the pilocarpine-induced status epilepticus rat model, CBD attenuated maximum seizure severity following intravenous administration, further demonstrating CBD's acute antiseizure efficacy in this rat model. We established that oral CBD attenuated the time-dependent increase in seizure burden and improved TLE-associated motor comorbidities of epileptic rats in the RISE-SRS model without affecting gait. Chronic administration of CBD after the onset of SRS ameliorated reference memory and working memory errors of epileptic animals in a spatial learning and memory task.. The present study illustrates that CBD is a well-tolerated and effective antiseizure agent and illustrates a potential disease-modifying effect of CBD on reducing both seizure burden and associated comorbidities well after the onset of symptomatic seizures in a model of TLE.

Topics: Animals; Anticonvulsants; Behavior, Animal; Cannabidiol; Disease Models, Animal; Epilepsy; Epilepsy, Temporal Lobe; Kindling, Neurologic; Memory, Short-Term; Mice; Pilocarpine; Rats; Seizures; Status Epilepticus

Topics: Amidohydrolases; Animals; Cannabidiol; Endocannabinoids; Epilepsy; Humans; Mice; Phytotherapy; Rats; Receptors, Cannabinoid; Seizures

Topics: Cannabidiol; Drug Development; Epilepsy; Humans; Mental Disorders

Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug-drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3-fold increase in dose-normalized tacrolimus concentrations while receiving 2000-2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA-approved CBD product. Larger studies are needed to better understand the impact of this drug-drug interaction in solid organ transplant recipients.

Topics: Adult; Cannabidiol; Drug Interactions; Epilepsy; Female; Humans; Immunosuppressive Agents; Nephritis, Interstitial; Prognosis; Tacrolimus

Useof cannabidiol oil in children The use of cannabidioloil (CBD oil), a cannabis-derived chemical, is increasing. CBD oil is freely available in the Netherlands, but its composition and quality are not monitored. However, the alternative, pharmacist-prepared oil, is more expensive and difficult to acquire. Common reasons for CBD oil use in children include impulsive behaviour, itch, epilepsy, stress, pain and sleeping problems. However, evidence of its effectiveness is scarce and focuses primarily on the effectiveness of the oil in reducing epileptic seizures. Known side-effects are vomiting, diarrhoea, fever, sleepiness, and abnormal liver function test results. We advise medical professionals who encounter young patients who may potentially be using CBD oil, to discuss its questionable quality and potential side effects and interactions. If a patient presents with poorly-understood fever, diarrhoea, vomiting or drowsiness, then the side effects of CBD oil should be considered. Finally, CBD should be differentiated from delta-THC, a cannabis-derived chemical with a psychoactive effect, the use of which should be discouraged in children.

Topics: Cannabidiol; Child; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Humans; Netherlands; Pain

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.. 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.. This was a single-center, prospective, open-label study. Patients aged from 1 to 18 years with DEE and seizures refractory to appropriate antiepileptic drugs (AEDs) and other alternative treatments (i.e., vagal nerve stimulator and ketogenic diet) were included. Crystalline extract CBD powder (98-99% pure) in an oil artisanal formulation was added to the baseline AED regimen at a dosage of 2-5 mg/kg/day divided for twice-daily administration, then up-titrated until intolerance or a maximum dosage of 25 mg/kg/day was reached. Patients were treated for at least 6 months. Efficacy, safety and tolerability of CBD treatment were assessed through the evaluation of seizure frequency and reports of adverse effects.. 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.. 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.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Drug Resistant Epilepsy; Epilepsy; Female; Humans; Infant; Male; Prospective Studies

The use of cannabidiol (CBD) for treatment of pharmacoresistant epilepsies is increasing. CBD is metabolized via UDP-glucuronosyltransferase (UGT) and cytochrome 450 (CYP) enzymes, but information on interactions with common anticonvulsive drugs is incomplete. We report a case series of five patients receiving adjunctive treatment with CBD who showed increases in brivaracetam (BRV) levels by 95% to 280%. Only two patients reported mild adverse events, leading to a reduction of BRV in one patient. One possible mechanism contributing at least partially to increasing BRV level is the inhibition of CYP2C19 by cannabidiol. Further pharmacokinetic studies are required to understand other possible mechanisms of brivaracetam-cannabidiol interaction.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Drug Interactions; Epilepsy; Female; Humans; Male; Middle Aged; Pyrrolidinones; Young Adult

The expansion of medical and recreational marijuana legalization facilitates patient access to cannabis, and many patients with epilepsy pursue marijuana as a treatment for seizures. We administered a nine-item survey on marijuana use to patients seen in an epilepsy clinic over a 9 month period at a tertiary care center in Oregon where recreational use was legalized in 2015. The majority of respondents (n = 39) reported cannabis use for the purpose of treating epilepsy (87.2%, n = 34), and strongly agreed (53.8%, n = 21) or agreed (28.2%, n = 11) that cannabis use improved seizure control. The most commonly selected cannabis strains were high cannabidiol (CBD) (30.8%, n = 12) or multiple types (30.8%, n = 12), with administration methods of smoking (66.7%, n = 26), edibles (48.7%, n = 19), and concentrates (43.6%, n = 17). More participants reported using marijuana with primarily CBD than primarily tetrahydrocannabinol (THC) or equal CBD:THC content, and very few women reported using marijuana with primarily THC compared with men (10% of female versus 47% of male respondents). Only 2 of 39 participants were able to give an exact dosage used in milligrams. Medical and recreational dispensaries were the most common cannabis sources, followed by homegrown and friends/family members. Although pharmaceutical CBD extract is now Food and Drug Administration (FDA)-approved for certain epilepsy types, access remains limited. Further research is needed to understand recreational cannabis use among patients with epilepsy while clinical research for pharmaceutical cannabis products continues.

Topics: Adult; Aged; Anticonvulsants; Attitude to Health; Cannabidiol; Dronabinol; Epilepsy; Female; Health Care Surveys; Humans; Longitudinal Studies; Male; Marijuana Use; Medical Marijuana; Middle Aged; Oregon; Self Medication; Tertiary Care Centers; Treatment Outcome

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.

Topics: Adolescent; Anticonvulsants; Attention; Cannabidiol; Cannabis; Child; Child, Preschool; Clobazam; Drug Resistant Epilepsy; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Hospitals; Humans; Longitudinal Studies; Male; Retrospective Studies; Seizures; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Alcoholism; Animals; Biomedical Research; Brazil; Cannabidiol; Cannabis; Dronabinol; Epilepsy; Freedom; Humans; Medical Marijuana; Police; Psychopharmacology; Research Personnel

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Topics: Anticonvulsants; Cannabidiol; Cannabis; Drug Approval; Epilepsy; Europe; Humans; Legislation, Drug; Medical Marijuana; United States; United States Food and Drug Administration

Topics: Anticonvulsants; Cannabidiol; Cannabis; Child; Clinical Trials as Topic; Epilepsy; Health Services Accessibility; Humans; Legislation, Drug; Medical Marijuana; Neurologists; Parents; State Medicine; United Kingdom

Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 ± 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo-controlled, double-blind trials are necessary to confirm this finding.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Epilepsy; Female; Humans; Infant; Male; Prospective Studies; Quality of Life; Retrospective Studies; Young Adult

Topics: Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Seizures; Spasms, Infantile

To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs.. In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate.. Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01).. Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Benzodiazepines; Cannabidiol; Child; Child, Preschool; Clobazam; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Topiramate; Triazoles; Young Adult

Topics: Cannabidiol; Drug Resistant Epilepsy; Epilepsy; Epileptic Syndromes; Humans; Seizures

To date, an increasing number of pet owners, especially in the USA, are using cannabis-derived products containing generally delta 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) to help their animals' health. Unfortunately, studies on the clinical use of cannabinoids in veterinary medicine are still limited, and the application of analytical methodologies for the determination of cannabinoids in animal (especially dog) biological matrices such as plasma, is still missing.. A reliable, fast, accurate, simple gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the quantification of THC and CBD in plasma samples of eight dogs under therapeutic treatment for epilepsy and receiving oral administration of medical cannabis (Bediol).. The method was linear for both the analytes under investigation with coefficients of determination (r2) of at least 0.99. Absolute analytical recovery (mean ± SD) ranged from 80.6 ± 6.2% for THC and 81.7 ± 4.3% for CBD. The matrix effect showed less than 10% analytical suppression due to endogenous substances for both the analytes. The intra-assay and inter-assay precision values ranged from 4.9% to 12.7%, and from 5.2% to 8.7% respectively. The intra-assay and inter-assay accuracy values ranged from 2.3% to 9.6% and from 3.4% to 13.0%, respectively.. The validated method was successfully applied to real samples; moreover, to assess the potential of the method applicability and robustness in future veterinary clinical studies on cannabinoids therapy, we attempted to follow the kinetic of THC and CBD in the plasma of two dogs under therapy at different times after Bediol administration.

Topics: Animals; Biological Assay; Cannabidiol; Dog Diseases; Dogs; Dronabinol; Drug Monitoring; Epilepsy; Gas Chromatography-Mass Spectrometry; Humans; Medical Marijuana

Oral cannabis extracts (OCEs) are being used in the treatment of epilepsy with increasing rates in the United States following product legalization; however, no studies demonstrate clear efficacy. We evaluated the duration of use of OCEs as a measure of perceived benefit in a cohort of patients with pediatric epilepsy.. Retrospective chart review was performed of children and adolescents who were given OCEs for treatment of epilepsy.. Of the 119 patients included in the analysis, 71% terminated use of their OCE product during the study period. The average length of use of OCE was 11.7 months (range 0.3-57 months). Perceived seizure benefit was the only factor associated with longer duration of treatment with OCE (p < 0.01). Relocation to Colorado was associated with perceived benefit of OCEs for seizures (65% vs. 38%, p = 0.01), but was not independently associated with longer OCE use. Factors associated with shorter use included adverse effects (p = 0.03) and a diagnosis of Dravet syndrome (p = 0.02). Twenty-four percent of patients were considered OCE responders, which was defined by a parent's report of a > 50% reduction in seizures while on this therapy. Adverse events (AEs) were reported in 19% of patients, with the most common side effects being somnolence and worsening of seizures.. Parental report of OCE use in refractory pediatric epilepsy suggests that some families perceive benefit from this therapy; however, discontinuation of these products is common. Duration appears to be affected by logical factors, such as perceived benefit and side effect profile. Surprisingly, families of patients with Dravet syndrome terminated use of OCEs more quickly than patients with other epilepsy syndromes. Results from this study highlight the need for rigorous clinical studies to characterize the efficacy and safety of OCEs, which can inform discussions with patients and families.

Topics: Administration, Oral; Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Cohort Studies; Epilepsy; Female; Humans; Infant; Kaplan-Meier Estimate; Male; Plant Extracts; United States

Abnormal and sometimes severe behavioral and molecular symptoms are usually observed in epileptic humans and animals. To address this issue, we examined the behavioral and molecular aspects of seizure evoked by pilocarpine. Autophagy can promote both cell survival and death, but there are controversial reports about the neuroprotective or neurodegenerative effects of autophagy in seizure. Cannabidiol has anticonvulsant properties in some animal models when used as a pretreatment. In this study, we investigated alteration of seizure scores, autophagy pathway proteins, and antioxidant status in hippocampal cells during the chronic phase of pilocarpine-induced epilepsy after treatment with cannabidiol. Cannabidiol (100 ng, intracerebroventricular injection) delayed the chronic phase of epilepsy. Single administration of cannabidiol during the chronic phase of seizure significantly diminished seizure scores such as mouth clonus, head nodding, monolateral and bilateral forelimb clonus and increased the activity of catalase enzyme and reduced glutathione content. Such a protective effect in the behavioral scores of epileptic rats was also observed after repeated administrations of cannabidiol at the onset of the silent phase. Moreover, the amount of Atg7, conjugation of Atg5/12, Atg12, and LC3II/LC3I ratio increased significantly in epileptic rats treated with repeated injections of cannabidiol. In short, our results suggest that post-treatment of Cannabidiol could enhance the induction of autophagy pathway and antioxidant defense in the chronic phase of epilepsy, which could be considered as the protective mechanisms of cannabidiol in a temporal lobe epilepsy model.

Topics: Animals; Anticonvulsants; Antioxidants; Autophagy; Autophagy-Related Proteins; Cannabidiol; Epilepsy; Female; Hippocampus; Male; Microtubule-Associated Proteins; Pilocarpine; Rats; Rats, Wistar

Mutations in brain isoforms of voltage-gated sodium channels have been identified in patients with distinct epileptic phenotypes. Clinically, these patients often do not respond well to classic anti-epileptics and many remain refractory to treatment. Exogenous as well as endogenous cannabinoids have been shown to target voltage-gated sodium channels and cannabidiol has recently received attention for its potential efficacy in the treatment of childhood epilepsies. In this study, we further investigated the ability of cannabinoids to modulate sodium currents from wild-type and epilepsy-associated mutant voltage-gated sodium channels. We first determined the biophysical consequences of epilepsy-associated missense mutations in both Nav1.1 (arginine 1648 to histidine and asparagine 1788 to lysine) and Nav1.6 (asparagine 1768 to aspartic acid and leucine 1331 to valine) by obtaining whole-cell patch clamp recordings in human embryonic kidney 293T cells with 200 μM Navβ4 peptide in the pipette solution to induce resurgent sodium currents. Resurgent sodium current is an atypical near threshold current predicted to increase neuronal excitability and has been implicated in multiple disorders of excitability. We found that both mutations in Nav1.6 dramatically increased resurgent currents while mutations in Nav1.1 did not. We then examined the effects of anandamide and cannabidiol on peak transient and resurgent currents from wild-type and mutant channels. Interestingly, we found that cannabidiol can preferentially target resurgent sodium currents over peak transient currents generated by wild-type Nav1.6 as well as the aberrant resurgent and persistent current generated by Nav1.6 mutant channels. To further validate our findings, we examined the effects of cannabidiol on endogenous sodium currents from striatal neurons, and similarly we found an inhibition of resurgent and persistent current by cannabidiol. Moreover, current clamp recordings show that cannabidiol reduces overall action potential firing of striatal neurons. These findings suggest that cannabidiol could be exerting its anticonvulsant effects, at least in part, through its actions on voltage-gated sodium channels, and resurgent current may be a promising therapeutic target for the treatment of epilepsy syndromes.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Calcium Channel Blockers; Cannabidiol; Endocannabinoids; Epilepsy; Female; HEK293 Cells; Humans; Male; Mice; NAV1.1 Voltage-Gated Sodium Channel; NAV1.6 Voltage-Gated Sodium Channel; Neostriatum; Neurons; Patch-Clamp Techniques; Polyunsaturated Alkamides

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans

From May 20 to September 1 2014, Epilepsia conducted an online survey seeking opinions about the use of medical marijuana and cannabidiol (CBD) for people with epilepsy. This study reports the findings of that poll.. The survey consisted of eight questions. Four questions asked if there were sufficient safety and efficacy data, whether responders would advise trying medical marijuana in cases of severe refractory epilepsy, and if pharmacologic grade compounds containing CBD should be available. Four questions addressed occupation, geographic region of residence, if responders had read the paper, and if they were International League Against Epilepsy/International Bureau for Epilepsy (ILAE/IBE) members.. Of 776 who started or completed the survey, 58% were patients from North America, and 22% were epileptologists and general neurologists from Europe and North America. A minority of epileptologists and general neurologists said that there were sufficient safety (34%) and efficacy (28%) data, and 48% would advise using medical marijuana in severe cases of epilepsy. By comparison, nearly all patients and the public said there were sufficient safety (96%) and efficacy (95%) data, and 98% would recommend medical marijuana in cases of severe epilepsy. General physicians, basic researchers, nurses, and allied health professions sided more with patients, saying that there were sufficient safety (70%) and efficacy (71%) data, and 83% would advise using marijuana in severe cases. A majority (78%) said there should be pharmacologic grade compounds containing CBD, and there were no differences between specialists, general medical personal, and patients and the public.. This survey indicates that there is a wide disparity in opinion on the use of medical marijuana and CBD in the treatment of people with epilepsy, which varied substantially, with fewer medical specialists supporting its use compared with general medical personal, and patients and the public.

Topics: Allied Health Personnel; Attitude of Health Personnel; Attitude to Health; Cannabidiol; Data Collection; Epilepsy; Europe; General Practitioners; Humans; Medical Marijuana; Neurology; North America; Nurses; Public Opinion; Specialization

Topics: Animals; Anticonvulsants; Cannabidiol; Epilepsy; Humans

There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.

Topics: Adolescent; Affect; Age of Onset; Anticonvulsants; Attention; Cannabidiol; Cannabis; Child; Drug Resistant Epilepsy; Epilepsy; Female; Health Care Surveys; Humans; Infant; Lennox Gastaut Syndrome; Male; Plant Extracts; Seizures; Sleep; Spasms, Infantile; Syndrome; Young Adult

Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article.. Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored.. We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction.. Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.

Topics: Adolescent; Benzodiazepines; Cannabidiol; Child; Child, Preschool; Clobazam; Cytochrome P-450 Enzyme System; Drug Interactions; Epilepsy; Female; Humans; Male; Young Adult

Topics: Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Legislation, Drug; Medical Marijuana; United States

Topics: Cannabidiol; Child; Epilepsy; Humans

Charlotte, a little girl with SCN1A-confirmed Dravet syndrome, was recently featured in a special that aired on CNN. Through exhaustive personal research and assistance from a Colorado-based medical marijuana group (Realm of Caring), Charlotte's mother started adjunctive therapy with a high concentration cannabidiol/Δ(9) -tetrahydrocannabinol (CBD:THC) strain of cannabis, now known as Charlotte's Web. This extract, slowly titrated over weeks and given in conjunction with her existing antiepileptic drug regimen, reduced Charlotte's seizure frequency from nearly 50 convulsive seizures per day to now 2-3 nocturnal convulsions per month. This effect has persisted for the last 20 months, and Charlotte has been successfully weaned from her other antiepileptic drugs. We briefly review some of the history, preclinical and clinical data, and controversies surrounding the use of medical marijuana for the treatment of epilepsy, and make a case that the desire to isolate and treat with pharmaceutical grade compounds from cannabis (specifically CBD) may be inferior to therapy with whole plant extracts. Much more needs to be learned about the mechanisms of antiepileptic activity of the phytocannabinoids and other constituents of Cannabis sativa.

Topics: Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Female; Humans; Infant; Medical Marijuana; Treatment Outcome

Intractable epilepsies have an extraordinary impact on cognitive and behavioral function and quality of life, and the treatment of seizures represents a challenge and a unique opportunity. Over the past few years, considerable attention has focused on cannabidiol (CBD), the major nonpsychotropic compound of Cannabis sativa. Basic research studies have provided strong evidence for safety and anticonvulsant properties of CBD. However, the lack of pure, pharmacologically active compounds and legal restrictions have prevented clinical research and confined data on efficacy and safety to anecdotal reports. Pure CBD appears to be an ideal candidate among phytocannabinoids as a therapy for treatment-resistant epilepsy. A first step in this direction is to systematically investigate the safety, pharmacokinetics, and interactions of CBD with other antiepileptic drugs and obtain an initial signal regarding efficacy at different dosages. These data can then be used to plan double-blinded placebo-controlled efficacy trials. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Phytotherapy; Plant Extracts; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Medical Marijuana; Surveys and Questionnaires

Topics: Animals; Cannabidiol; Dronabinol; Epilepsy; Humans; Medical Marijuana; Seizures

Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays, and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments. This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child's seizures. Nineteen responses met the following inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic epilepsy. The average number of antiepileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child's seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction. Other beneficial effects included increased alertness, better mood, and improved sleep. Side effects included drowsiness and fatigue. Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for their children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children are not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated, and efficacious at controlling seizures in this pediatric population with difficult-to-treat seizures.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Epilepsy; Female; Health Surveys; Humans; Male; Parents

Topics: Adolescent; Aerosols; Anticonvulsants; Bipolar Disorder; Cannabidiol; Child; Drug Resistance; Epilepsy; Humans; Models, Biological

Endocannabinoids have paradoxical effects on the mammalian nervous system: Sometimes they block neuronal excitability and other times they augment it. In their Perspective, Mechoulam and Lichtman discuss new work (Marsicano et al.) showing that activation of the cannabinoid receptor CB1 by the endocannabinoid anandamide protects against excitotoxic damage in a mouse model of kainic acid-induced epilepsy.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Brain; Brain Diseases; Cannabidiol; Cannabinoid Receptor Modulators; Cannabinoids; Convulsants; Dronabinol; Endocannabinoids; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Glycerides; Humans; Kainic Acid; Mice; Neurons; Neuroprotective Agents; Polyunsaturated Alkamides; Rats; Receptors, Cannabinoid; Receptors, Drug; Signal Transduction

The effects of delta 9-tetrahydrocannabinol (delta 9-THC), two of its metabolites, 8 beta-hydroxy-delta 9-THC and 11-hydroxy-delta 9-THC, and cannabidiol were comparatively studied by means of an iron-induced cortical focal epilepsy in conscious rats with chronically implanted electrodes. delta 9-Tetrahydrocannabinol produced depression of the spontaneously firing epileptic focus, excitatory behavior, generalized after-discharge-like bursts of epileptiform polyspikes and frank convulsions. The pharmacological profiles of the two metabolites differed from that of the parent compound: 11-Hydroxy-delta 9-THC did not precipitate convulsions, but it did elicit all the other effects of delta 9-THC; the 8 beta-hydroxy derivative, on the other hand, exerted only two delta 9-THC-like effects; that is, it evoked polyspike bursts and convulsions. In contrast, cannabidiol, even in large doses (100 mg/kg) was devoid of all the effects of delta 9-THC. Furthermore, pretreatment with cannabidiol markedly altered the responses to delta 9-THC in the following ways: focal depression was partially blocked, polyspike activity was enhanced and convulsions abolished. Phenytoin pretreatment elicited similar effects, but it failed to block the delta 9-THC-induced convulsions. In general, the cannabinoids exhibit a wide spectrum of CNS effects ranging from focal depression to convulsions; specifically, however, the pharmacological profile of each agent can differ markedly; for example, the convulsant properties of delta 9-THC are not a universal characteristic of this class of drugs.

Topics: Animals; Cannabidiol; Central Nervous System; Dronabinol; Electrophysiology; Epilepsy; Iron; Male; Phenytoin; Rats; Rats, Inbred Strains