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The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: From behavior and mechanisms to clinical insights
Abstract
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.
... Epidiolex, a highly purified CBD solution, was approved by the FDA in the USA and has been used to control seizures in patients with refractory epilepsies [9,10]. In preclinical studies, anti-seizure effects of CBD have been shown in a wide range of rodent models, including pilocarpine-induced Status Epilepticus, maximal electroshock, and amygdala electrical kindling, among others; however, CBD effects in genetic models of epilepsies are still limited [11][12][13]. ...
... CBD antiseizure effects have already been shown in several chemical and electrical models of epilepsies, such as the pilocarpine-induced Status Epilepticus, pentylenetetrazol-induced seizures, maximal electroshock, and cocaineinduced seizures, among others [12,[35][36][37]. However, it is worth noting that the present study has some advantages due to the use of a genetic strain in comparison to other models: GEPR-3 s present genetic background associated with seizure susceptibility; there is no need for previous administration of chemical compounds or invasive procedures to induce seizures, which makes possible the assessment of antiseizure medications without any pharmacological interactions; GEPR-3 s can mimic both generalized tonic-clonic and limbic seizures with the possibility to control the exact time of seizure onset based on the acoustic trigger. ...
... CBD presents several mechanisms of action, such as the endocannabinoid system modulation, calcium, and GABA signaling, GPR55, TRPV1, and 5-H1A receptors, among others [6,12,37]. However, the mechanisms of CBD action in genetic models of epilepsies remain understudied. ...
Background
Cannabidiol (CBD) has been of rapidly growing interest in the epilepsy research field due to its antiseizure properties in preclinical models and patients with pharmacoresistant epilepsy. However, little is known about CBD effects in genetic models of epilepsies. Here we assessed CBD dose–response effects in the Genetically Epilepsy Prone Rats (GEPR-3) strain, which exhibits two types of epileptic seizures, brainstem-dependent generalized tonic–clonic seizures and limbic seizures.MethodsGEPR-3 s were submitted to the audiogenic seizure (AGS) protocol. Acute AGS are brainstem-dependent generalized tonic–clonic, while repeated AGS (or audiogenic kindling, AK), an epileptogenic process, leads to increased AGS severity and limbic seizure expression. Therefore, two different dose–response studies were performed, one for generalized tonic–clonic seizures and the other for limbic seizures. CBD time-course effects were assessed 2, 4, and 6 h after drug injection. GEPR-3 s were submitted to within-subject tests, receiving intraperitoneal injections of CBD (1, 10, 50, 100 mg/kg/ml) and vehicle.ResultsCBD dose-dependently attenuated generalized tonic–clonic seizures in GEPR-3 s; CBD 50 and 100 mg/kg reduced brainstem-dependent seizure severity and duration. In fully kindled GEPR-3 s, CBD 10 mg/kg reduced limbic seizure severity and suppressed limbic seizure expression in 75% of animals.ConclusionsCBD was effective against brainstem and limbic seizures in the GEPR-3 s. These results support the use of CBD treatment for epilepsies by adding new information about the pharmacological efficacy of CBD in suppressing inherited seizure susceptibility in the GEPR-3 s.
... Cannabidiol (CBD), a phytocannabinoid present in Cannabis, has been pointed as a prominent drug for the treatment of epilepsies, especially in humans with pharmacoresistant epilepsies [27][28][29]. Additionally, CBD presents anticonvulsant effects in a great variety of experimental models of seizures, but the massive amount of studies investigated CBD effects in acute models of seizures, including acute models of audiogenic seizures [30,31]. However, little is known about CBD effects during chronic protocols of seizures, especially regarding its potential antiepileptogenic effects. ...
... However, little is known about CBD effects during chronic protocols of seizures, especially regarding its potential antiepileptogenic effects. CBD presents several mechanisms of action related to its anticonvulsant effects [31][32][33], and although its direct effects at cannabinoid receptors type 1 (CB1R) are limited, CBD may modulate the activity of this receptor by indirect mechanisms [31,33]. In that context, besides morphological and physiological alterations associated with epilepsy [7,34], we recently described increased CB1R expression in the hippocampus and amygdala of WARs after chronic audiogenic seizures, suggesting that CB1R could be involved with chronic seizures in WARs [35]. ...
... However, little is known about CBD effects during chronic protocols of seizures, especially regarding its potential antiepileptogenic effects. CBD presents several mechanisms of action related to its anticonvulsant effects [31][32][33], and although its direct effects at cannabinoid receptors type 1 (CB1R) are limited, CBD may modulate the activity of this receptor by indirect mechanisms [31,33]. In that context, besides morphological and physiological alterations associated with epilepsy [7,34], we recently described increased CB1R expression in the hippocampus and amygdala of WARs after chronic audiogenic seizures, suggesting that CB1R could be involved with chronic seizures in WARs [35]. ...
Cannabidiol (CBD) is a marijuana compound implicated in epilepsy treatment in animal models and pharmacoresistant patients. However, little is known about chronic CBD administration’s effects in chronic models of seizures, especially regarding its potential antiepileptogenic effects. In the present study, we combined a genetic model of epilepsy (the Wistar Audiogenic Rat strain - WARs), a chronic protocol of seizures (the audiogenic kindling - AuK), quantitative and sequential behavioral analysis (neuroethology), and microscopy imaging to analyze the effects of chronic CBD administration in a genetic model of epilepsy. The acute audiogenic seizure is characterized by tonic-clonic seizures and intense brainstem activity. However, during the AuK WARs can develop limbic seizures associated with the recruitment of forebrain and limbic structures. Here, chronic CBD administration, twice a day, attenuated brainstem, tonic-clonic seizures, prevented limbic recruitment, and suppressed limbic (kindled) seizures, suggesting CBD antiepileptogenic effects. Additionally, CBD prevented chronic neuronal hyperactivity, suppressing FosB immunostaining in the brainstem (inferior colliculus and periaqueductal gray matter) and forebrain (basolateral amygdala nucleus and piriform cortex), structures associated with tonic-clonic and limbic seizures, respectively. Chronic seizures increased cannabinoid receptors type 1 (CB1R) immunostaining in the hippocampus and the BLA, while CBD administration prevented changes in CB1R expression induced by the AuK. The neuroethological analysis provided details about CBD’s protective effects against brainstem and limbic seizures associated with FosB expression. Our results strongly suggest chronic CBD anticonvulsant and antiepileptogenic effects associated with reduced chronic neuronal activity and modulation of CB1R expression. We also support the chronic use of CBD for epilepsies treatments.
... CB1R has been receiving especial attention in epilepsy due to seizure control in several preclinical models and can also be modulated by phytocannabinoids (Wallace et al., 2003;Lutz, 2004;Blair, 2006;Huizenga et al., 2017;Britch et al., 2020). Moreover, anticonvulsant effects were associated with Cannabis-derived compounds, especially the cannabidiol (CBD), reinforcing the role of cannabinoids in epileptic seizures (Friedman and Devinsky, 2015;Rosenberg et al., 2017;Lazarini-Lopes et al., 2020b). CBD, a phytocannabinoid present in Cannabis sp. ...
... CBD, a phytocannabinoid present in Cannabis sp. (Jacob and Todd, 1940;Mechoulam and Shvo, 1963), has receiving especial attention due to its anticonvulsant properties in animal models of the epilepsies Do Val-da Silva et al., 2017;Lazarini-Lopes et al., 2020b) and also in humans with pharmacoresistant epilepsy (Press et al., 2015;Devinsky et al., 2016Devinsky et al., , 2017. Although CBD anticonvulsant mechanisms of action seem to be related with a great diversity of cellular and molecular targets, which include components of the ES, the possible existence of synergistic effects between CBD and conventional anticonvulsant drugs may not be ignored (Mencher and Wang, 2005;Devinsky et al., 2014;Gaston et al., 2017). ...
... Although cannabinoids induce modulation have already been shown as capable of epileptic seizures in several animal models (Rosenberg et al., 2017;Lazarini-Lopes et al., 2020b), studies evaluating the role of the ES on AS experimental models are still scarce. See Table 1 for main results from the literature. ...
Cannabinoids and Cannabis-derived compounds have been receiving especial attention
in the epilepsy research scenario. Pharmacological modulation of endocannabinoid
system’s components, like cannabinoid type 1 receptors (CB1R) and their bindings,
are associated with seizures in preclinical models. CB1R expression and functionality
were altered in humans and preclinicalmodels of seizures. Additionally, Cannabis-derived
compounds, like cannabidiol (CBD), present anticonvulsant activity in humans and in
a great variety of animal models. Audiogenic seizures (AS) are induced in genetically
susceptible animals by high-intensity sound stimulation. Audiogenic strains, like the
Genetically Epilepsy Prone Rats, Wistar Audiogenic Rats, and Krushinsky-Molodkina,
are useful tools to study epilepsy. In audiogenic susceptible animals, acute acoustic
stimulation induces brainstem-dependent wild running and tonic-clonic seizures.
However, during the chronic protocol of AS, the audiogenic kindling (AuK), limbic and
cortical structures are recruited, and the initially brainstem-dependent seizures give
rise to limbic seizures. The present study reviewed the effects of pharmacological
modulation of the endocannabinoid system in audiogenic seizure susceptibility and
expression. The effects of Cannabis-derived compounds in audiogenic seizures were
also reviewed, with especial attention to CBD. CB1R activation, as well Cannabis-derived
compounds, induced anticonvulsant effects against audiogenic seizures, but the effects
of cannabinoids modulation and Cannabis-derived compounds still need to be verified
in chronic audiogenic seizures. The effects of cannabinoids and Cannabis-derived
compounds should be further investigated not only in audiogenic seizures, but also in
epilepsy related comorbidities present in audiogenic strains, like anxiety, and depression.
... 37 In addition to the aforementioned possible targets, GABAergic modulation, endocannabinoid signaling pathways via CB1 receptors, mitochondrial CB1 receptors, large conductance calcium-activated potassium channels, mechanistic target of rapamycin signaling pathways, and voltage-gated sodium channels have also been considered potential targets for CBD, although the evidence is still scarce. 34,[44][45][46] Overall, CBD's antiseizure effects may be attributable to the interplay of multiple mechanisms that are derived from targets discussed earlier or those still unknown. 46 The antiseizure effects of CBD has been well demonstrated in human clinical trials, as well as rodent studies, which revealed antiseizure effect on treatment-resistant epilepsy and developmental and epileptic encephalopathies, including Dravet syndrome and Lennox-Gastaut syndrome. ...
... 34,[44][45][46] Overall, CBD's antiseizure effects may be attributable to the interplay of multiple mechanisms that are derived from targets discussed earlier or those still unknown. 46 The antiseizure effects of CBD has been well demonstrated in human clinical trials, as well as rodent studies, which revealed antiseizure effect on treatment-resistant epilepsy and developmental and epileptic encephalopathies, including Dravet syndrome and Lennox-Gastaut syndrome. 47,48 In addition, experimental studies with rodents have shown CBD's effect on focal and generalized seizures, including nonconvulsive seizures in acute and chronic seizure mouse models 49 and genetic absence epilepsy rats. ...
The endocannabinoid system (ECS) is an integral neuromodulatory system involved in neuronal development, synaptic plasticity, and homeostasis regarding immunity, as well as brain and other physiological functions such as anxiety, pain, metabolic regulation, and bone growth. Cannabis is a plant that contains exogenous cannabinoids, which have the potential for profound interplay within the ECS as enzymatic inhibitors or receptor-mediated interactions. Activation of cannabinoid receptors leads to various intracellular signaling processes that are involved in cellular functions, but those interactions are diverse due to different affinities of each cannabinoid with relevant receptors. Among the exogenous cannabinoids, cannabidiol (CBD) has drawn attention due to its potential anticancer, antiangiogenic, anti-inflammatory, and antiseizure properties using in vitro and in vivo models. Although scientific evidence is limited in dogs, there appears to be cautious optimism regarding the utilization of CBD in conjunction with other therapeutics for a range of disorders. This review will primarily focus on current scientific research on the efficacy of CBD on seizure, anxiety, osteoarthritis, and atopic dermatitis, following a brief discussion of endo- and exogenous cannabinoids, ECS, their molecular mechanism, and potential side effects in veterinary medicine. Cannabinoid pharmacology and pharmacokinetics will be addressed in the companion Currents in One Health by Schwark and Wakshlag, AJVR , May 2023.
... Furthermore, it is worth noting that direct activation of CB1 receptors, as well as the pharmacological treatment with phytocannabinoids, like the cannabidiol, attenuated seizures and prevented neuronal damage induced by SE (Di Maio et al., 2015;Lazarini-Lopes et al., 2020b). It is particularly important to mention that cannabidiol can modulate CB1 signaling through several direct and indirect mechanisms of action associated with seizure control, such as increased AEA ...
... Male CamK-CB1 and WT mice ↑ CB1 immunostaining the hippocampus, especially in the Cornu Ammonis area (CA1-3). Chen et al. (2003) Hyperthermia availability and modulation of intracellular calcium signaling (Britch et al., 2021;Lazarini-Lopes et al., 2020b). Therefore, such information indicates that some of the long-term epileptogenic processes involved with manifestation of spontaneous recurrent seizures after SE induced by chemoconvulsant drugs are, indeed, associated with CB1-mediated endocannabinoid signaling. ...
Currently, there is an urgent need to better comprehend neuroplastic alterations in cannabinoid receptor type 1 (CB1) and to understand the biological meaning of these alterations in epileptic disorders. The present study reviewed neuroplastic changes in CB1 distribution, expression, and functionality in animal models of epileptic seizures. Neuroplastic alterations in CB1 were consistently observed in chemical, genetic, electrical, and febrile seizure models. Most studies assessed changes in hippocampal and cortical CB1, while thalamic, hypothalamic, and brainstem nuclei were rarely investigated. Additionally, the relationship between CB1 alteration and the control of brain excitability through modulation of specific neuronal networks, such as nigrotectal and thalamocortical pathways and inhibitory projections to hippocampal pyramidal neurons were presented and discussed. Neuroplastic alterations in CB1 detected in animal models of epilepsy may reflect two different scenarios: (1) endogenous adaptations aimed to control neuronal hyperexcitability in epilepsy or (2) pathological alterations which facilitate neuronal hyperexcitability. Additionally, a better comprehension of neuroplastic and functional alterations in CB1 can improve pharmacological therapies for epilepsies.
... Chronic administration of CBD prevents premature mortality and improves several behavioral comorbidities, including impaired cognition and social interaction, associated with the SCN1A+/À mouse DS model. 17,18 Interestingly, plant-derived, highly purified CBD in a sesame oil-based oral solution has antiseizure properties in a broad range of epilepsy syndromes and encephalopathy, including DS, Lennox-Gastaut syndrome, and tuberous sclerosis complex. 19 Recent pre-clinical and clinical evidence suggests that CBD may provide an effective, tolerable alternative to current therapeutics on DS, and CBD has been approved in the treatment of DS and Lennox-Gastaut syndrome in USA, Europe, and Australia in 2018,2019, and 2020, respectively. ...
... An increase in endocannabinoid signaling drive, associated with CBD modulation, is mediated by mechanisms of either an inhibition of its hydrolysis or an increase in calcium signaling, which are related to CBD's anticonvulsant effects. 17,139 There were significant increases in CACNA1H subunit and CB2 gene expression in DS patients by CBD targeting analysis. 140 Cannabinoids are promising neuroprotective compounds; they close Ca 2+ channels and prevent toxic intracellular Ca 2+ buildup and reduce glutamate release. ...
Dravet syndrome (DS) is a channelopathy, neurodevelopmental, epileptic encephalopathy characterized by seizures, developmental delay, and cognitive impairment that includes susceptibility to thermally induced seizures, spontaneous seizures, ataxia, circadian rhythm and sleep disorders, autistic-like behaviors, and premature death. More than 80% of DS cases are linked to mutations in genes which encode voltage-gated sodium channel subunits, SCN1A and SCN1B, which encode the Nav1.1α subunit and Nav1.1β1 subunit, respectively. There are other gene mutations encoding potassium, calcium, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels related to DS. One-third of patients have pharmacoresistance epilepsy. DS is unresponsive to standard therapy. Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been introduced for treating DS because of its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. However, the etiological channelopathiological mechanism of DS and action mechanism of CBD on the channels are unclear. In this review, we summarize evidence of the direct and indirect action mechanism of sodium, potassium, calcium, and HCN channels in DS, especially sodium subunits. Some channels’ loss-of-function or gain-of-function in inhibitory or excitatory neurons determine the balance of excitatory and inhibitory are associated with DS. A great variety of mechanisms of CBD anticonvulsant effects are focused on modulating these channels, especially sodium, calcium, and potassium channels, which will shed light on ionic channelopathy of DS and the precise molecular treatment of DS in the future.
... C. sativa produces organic molecules known as "cannabinoids" or "phytocannabinoids," of which nearly 150 have been identified [1]. These cannabinoids are of specific interest for their demonstrated value in nearly all realms of medicine from the treatment of sleep disorders [2], to epilepsy [3], to cancer [4]. ...
... Accession numbers beginning with "KP" reported from Onofri et al.[15], accession numbers beginning with "AB" are from Kojoma et al.[20], and accession numbers beginning with "KT" are unpublished.2 The base pairs highlighted in gray are putatively responsible for inactivation of the THCAS leading to the accumulation of cannabigerolic acid.3 Amino acid positions and changes are indicated in the rows at the bottom of the table. ...
The regulation of cannabinoid synthesis in Cannabis sativa is of increasing research interest as restrictions around the globe loosen to allow the plant’s legal cultivation. Of the major cannabinoids, the regulation of cannabigerolic acid (CBGA) production is the least understood. The purpose of this study was to elucidate the inheritance of CBGA dominance in C. sativa and describe a marker related to this chemotype. We produced two crossing populations, one between a CBGA dominant cultivar and a tetrahydrocannabinolic acid (THCA) dominant cultivar, and one between a CBGA dominant cultivar and a cannabidiolic acid (CBDA) cultivar. Chemical and genotyping analyses confirmed that CBGA dominance is inherited as a single recessive gene, potentially governed by a non-functioning allelic variant of the THCA synthase. The “null” THCAS synthase contains a single nucleotide polymorphism (SNP) that may render the synthase unable to convert CBGA to THCA leading to the accumulation of CBGA. This SNP can be reliably used as a molecular marker for CBGA dominance in the selection and breeding of C. sativa.
... "Type III" plants produce high levels of CBDA and lower levels of THCA. "Type IV" plants predominantly contain CBGA, the precursor of both CBDA and THCA (Lazarini-Lopes et al. 2020). Lastly, "Type V" plants, referred to as "cannabinoid-free", lack detectable amounts of any of the three previously mentioned cannabinoids (De Meijer and Hammond 2005;De Meijer et al. 2009). ...
... 39,56 Meanwhile, other authors have described that CBD favors glutamate release by interacting with several receptors, such as TRPV1, GPR55, and 5-HT1A. 33,57 Synthetic cannabinoids can also affect the anesthetic requirements of inhalation agents, most probably through their action as full presynaptic CB1-R agonists, inhibiting the release of GABA. 58 Regarding intravenous anesthetics, trials in mouse models had reported that the administration of cannabis avoided the hypnotic effect of propofol. ...
Cannabis has been used for recreation and medical purposes for more than a millennium across the world; however, its use’s consequences remain poorly understood. Although a growing number of surgical patients are regular cannabis consumers, little is known regarding the pharmacological interactions between cannabis and general anesthetics; consequently, there is not a solid consensus among anesthesiologists on the perioperative management of these patients. The existing evidence about the molecular mechanisms underlying pharmacological interactions between cannabinoids and anesthetic agents, both in animal models and in humans, shows divergent results. While some animal studies have demonstrated that phytocannabinoids (tetrahydrocannabinol [THC], cannabidiol [CBD], and cannabinol [CBN]) potentiate the anesthetic effects of inhalation and intravenous anesthetics, while others have found effects comparable with what has been described in humans so far. Clinical studies and case reports have consistently shown increased requirements of GABAergic anesthetic drugs (isoflurane, sevoflurane, propofol, midazolam) to achieve adequate levels of clinical anesthesia. Several potential molecular mechanisms have been proposed to explain the effects of these interactions. However, it is interesting to mention that in humans, it has been observed that the ingestion of THC enhances the hypnotic effect of ketamine. Animal studies have reported that cannabinoids enhance the analgesic effect of opioids due to a synergistic interaction of the endogenous cannabinoid system (ECS) with the endogenous opioid system (EOS) at the spinal cord level and in the central nervous system. However, human data reveals that cannabis users show higher scores of postoperative pain intensity as well as increased requirements of opioid medication for analgesia. This review aims to improve understanding of the molecular mechanisms and pharmacological interactions between cannabis and anesthetic drugs and the clinical outcomes that occur when these substances are used together.
... Estimates of the ages of Brassicaceae are dependent on the date of the duplication of the genome in Arabidopsis, which is estimated to have occurred between 24 and 40 million years ago.a 17 Within the scope of this review paper, the primary emphasis of our research was on the information concerning the pharmacological actions of plants belonging to the Brassicaceae family. [77][78][79][80] ...
Background: White cabbage, scientifically known as Brassica oleracea var. capitata f. alba, is a cruciferous vegetable that has long been valued for its culinary and medicinal uses. For the treatment of numerous illnesses, such as diabetes, cancer, inflammation, hypertension, hypercholesterolemia, bacteria, oxidation, and obesity, various preparations derived from various portions of the plant, including roots, shoots, leaves, and the entire plant, are utilized. Objective: Botany, distribution, traditional applications, phytochemistry, and pharmacological properties of B. oleracea var. capitata are all going to be assessed in this review. In addition, the gaps in knowledge will be filled and new research opportunities in pharmacology will be highlighted by this review. Method: Through an internet search of internationally recognised scientific databases, a variety of resources were gathered to gain a comprehensive understanding of Brassica oleracea var. capitata. These resources included research papers, reviews, books, and reports. Results: Alkaloids, flavonoids, organic acids, glucosinolates, steroids, hydrocarbons, and about forty-nine other phytochemical components of Brassica oleracea var. capitata have been culled from various sources. Bactericidal, antioxidant, anti-inflammatory, antibacterial, anti-obesity, anticoagulant, hepatoprotective, and anticancer are only a few of the pharmacological activities exhibited by crude extracts and phytoconstituents of Brassica oleracea var. capitata. Here you may find a complete inventory of the phytochemical components and pharmacological information pertaining to Brassica oleracea var. capitata. Conclusion: Results showed that Brassica oleracea var. capitata is a significant medicinal plant with multiple pharmacological effects, and the study also looked at its phytochemistry, traditional applications, and pharmacological activity. Our goal in conducting this assessment of this plant was to bridge knowledge gaps in the field and lay the groundwork for future studies and medication development. While researching Brassica oleracea var. capitata, we did find a number of significant traditional applications and pharmacological properties.
... Adverse events of the medications used in the study were assessed once per week during the weeks of pharmacological treatment-week 1 (T0) to week 9 (T2)-using the weekly questionnaire. The list of adverse events was built according to the scientific literature (Chan et al., 2019;Fischer, Kuganesan, et al., 2015;Lazarini-Lopes et al., 2020;Morgan et al., 2013;Rodrigues et al., 2020;Ronsley et al., 2020) and the medications' leaflets, such as headache, diarrhea, nausea, sleepiness, dizziness, and anxiety. Participants were asked if they had experienced any adverse events related to taking the medication in the last 7 days. ...
Cannabidiol (CBD) has been studied for substance use disorders treatment due to its anxiolytic effects, for sleep, appetite, reduction of craving, and maintenance of abstinence. The study aims to assess CBD’s feasibility, safety/tolerability, and preliminary efficacy compared to pharmacological treatment as usual for reducing crack use in people with crack use disorder (CUD) and investigate other parameters: adverse events, physical health symptoms, and craving. A double-blind, randomized clinical trial (RCT) with two treatment arms (CBD and control group) was conducted. Ninety participants were randomized and 73 were allocated: 37 control group and 36 CBD group for a 10-week treatment, comparing CBD (600 mg) with three drugs (fluoxetine, valproic acid, and clonazepam). The per-protocol analysis of participants who did not deviate from the study protocol compared the control and CBD treatment groups. Thirty-four completed at least half of the study and 25 finished. Participants attended weekly meetings for the study procedures (e.g., to receive the medication and provide urine for toxicological tests). Inter-group differences were performed with the Mann–Whitney test, the Wilcoxon test for differences intra-group, and Pearson’s Chi-square test or Fisher’s exact test to compare inter-group demographic data. The significance level was 5%. A “veracity index” (VI) was created as counterevidence (questionnaire data vs. the toxicological test result). Medications were considered safe/tolerable. The CBD group presented significantly fewer adverse events compared to the control group [e.g., dizziness (p = 0.001), memory impairment (p = 0.043)], which performed better in the reduction of clinical and psychiatric complaints (p = 0.008). In the intra-group analyses, the CBD group performed better in more parameters than the control group [e.g., reducing crack use (p = 0.016; T0 to T1)]. Data questionnaires were reliable regarding the use/non-use of crack (VI = 0.787). CBD is a safe/tolerable product. The CBD group manifested fewer adverse events than the control group, which had better clinical and psychiatric complaints results. There are some advantages for the CBD group in the intra-group analysis. Drug use self-report methodologies can be reliable. Trial registration details: This study is registered with Universal Trial Number (UTN) code: U1111-1234-0806. Available at https://ensaiosclinicos.gov.br/rg/RBR-4stgs8 (Effect of cannabidiol in the treatment of crack dependents)
... Estimates of the ages of Brassicaceae are dependent on the date of the duplication of the genome in Arabidopsis, which is estimated to have occurred between 24 and 40 million years ago.a 17 Within the scope of this review paper, the primary emphasis of our research was on the information concerning the pharmacological actions of plants belonging to the Brassicaceae family. [77][78][79][80] ...
Background: White cabbage, scientifically known as Brassica oleracea var. capitata f. alba, is a cruciferous vegetable that has long been valued for its culinary and medicinal uses. For the treatment of numerous illnesses, such as diabetes, cancer, inflammation, hypertension, hypercholesterolemia, bacteria, oxidation, and obesity, various preparations derived from various portions of the plant, including roots, shoots, leaves, and the entire plant, are utilized. Objective: Botany, distribution, traditional applications, phytochemistry, and pharmacological properties of B. oleracea var. capitata are all going to be assessed in this review. In addition, the gaps in knowledge will be filled and new research opportunities in pharmacology will be highlighted by this review. Method: Through an internet search of internationally recognised scientific databases, a variety of resources were gathered to gain a comprehensive understanding of Brassica oleracea var. capitata. These resources included research papers, reviews, books, and reports. Results: Alkaloids, flavonoids, organic acids, glucosinolates, steroids, hydrocarbons, and about forty-nine other phytochemical components of Brassica oleracea var. capitata have been culled from various sources. Bactericidal, antioxidant, anti-inflammatory, antibacterial, anti-obesity, anticoagulant, hepatoprotective, and anticancer are only a few of the pharmacological activities exhibited by crude extracts and phytoconstituents of Brassica oleracea var. capitata. Here you may find a complete inventory of the phytochemical components and pharmacological information pertaining to Brassica oleracea var. capitata. Conclusion: Results showed that Brassica oleracea var. capitata is a significant medicinal plant with multiple pharmacological effects, and the study also looked at its phytochemistry, traditional applications, and pharmacological activity. Our goal in conducting this assessment of this plant was to bridge knowledge gaps in the field and lay the groundwork for future studies and medication development. While researching Brassica oleracea var. capitata, we did find a number of significant traditional applications and pharmacological properties.
... 13 The underlying mechanism of epileptic seizure is due to the epileptogenesis process which occurs by imbalance between inhibitory and excitatory neurotransmitters. 14 Reduction of inhibitory gammaaminobutyric acid (GABA) and increase of excitatory glutamate induce the development and progression of epileptogenesis. 15 The reason for such imbalance is greatly unknown, though mutation of voltage-gated Na + , Ca 2+ and K + monovalent ion channels provokes neuronal hyper-excitability and decreases seizure threshold. ...
Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well‐controlled disease by anti‐epileptic agents (AEAs) in about 69%. However, 30%–40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA‐approved drugs that have an anti‐seizure activity to the anti‐epileptic regimen is logical. The anti‐diabetic agent metformin has anti‐seizure activity. Nevertheless, the underlying mechanism of the anti‐seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti‐seizure activity by triggering adenosine monophosphate‐activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain‐derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti‐seizure mechanism of metformin. Also, metformin reduces α‐synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.
... In fact, they have a high content in essential fatty acids, minerals, vitamins, and fibers, as well as essential amino acids embedded in highly digestible proteins (Callaway, 2004;Chen et al., 2010). Moreover, among the more than 100 phytocannabinoids produced by hemp (Hanuš et al., 2016), CBD has been suggested as beneficial for human health because of its antiinflammatory, analgesic, anxiolytic, antipsychotic, spasmolytic, as well as anticonvulsant effects (Ellis et al., 2018;Hobbs et al., 2020;Khan et al., 2020;Lazarini-Lopes et al., 2020;Mechoulam et al., 2002;Wong & Cairns, 2019). Following that, hemp seeds and its by-products, such as hempseed flour and oil, have increasingly been used as food and ingredients for food, beverages, and supplements because of the nutritional properties of hemp but also because of the claimed health benefits of CBD. ...
... Cannabidiol (CBD) [85][86][87][88][89][90][91][92][93][94][95][96][97] Antibiofilm Cannabis sativa L. seeds extract [98] Anticonvulsant Cannabidiol (CBD) [99][100][101][102][103] Cannabidivarin (CBDV) [104] Δ 9 -tetrahydrocannabinol [101,105,106] ∆ 8 -tetrahydrocannabinol [101] (-) and (+) Isomers of Cannabidiol (CBD) [107] Antidepressant Cannabidiol (CBD) [96,97,[108][109][110][111] Ethanol extract [112] Δ 9 -tetrahydrocannabinol [113] Antiemitic Δ 9 -tetrahydrocannabinol [52,63] Antifungal Benzene, acetone, ethyl acetate, methanol, and chloroform extracts of different parts of Cannabis [114] Leaf extract of Cannabis [115] The n-hexane extracted volatile component of high-power ...
Medicinal plants have been one of the most important sources of medicine since the dawn of human civilization. Indigenous communities have used products from this plant in different conditions throughout documented history. Cannabis sativa L. is one of the most widely employed herbaceous medicinal plants for textiles and fibers, in medicine, as a source of food, animal food, animal bedding, and agriculture for seeds. This paper highlights the traditional applications, botany, phytochemistry, and pharmacological properties of Cannabis sativa L. Extensive database retrieval, such as Google Scholar, Semantic Scholar, ResearchGate, Academia.edu, PubMed, SciFinder, ChemSpider, CNKI, PubFacts, etc., was performed by using the keywords "Hemp," "Cannabis," as well as the scientific name of this plant species (Cannabis sativa L). Besides, reviews of relevant textbooks, documents, and patents were also employed to collect sufficient information. This study revealed numerous pharmacological activities of Cannabis sativa L. that could help with several medical diseases. Besides that, more than 565 bioactive constituents have been isolated and identified from diverse parts of Cannabis sativa L. This could help discover potential therapeutic effects and develop new medications to benefit human health.
... Its interaction with TRPV receptors (and in particular TRPV1) has been associated with neuroprotective and anticonvulsant effects [29,30], anti-psychotic effects [31], and immunomodulatory effects [32]. Through its 5-HT1A receptor agonist properties, CBD has shown in vivo panicolytic [33], antidepressant [34], and anti-aggression effects [35], as well as a reduction in autonomic stress responses [36] in rodents. ...
Objectives:
To date, very few cannabis-based specialities are authorised on the French market despite a growing demand from patients and health professionals. The objective of this study is to review the tolerance profile and the French legislative status of the two main cannabinoids used for therapeutic purposes: tetrahydrocannabiol (THC) associated with psychoactive effects and non-psychoactive cannabidiol (CBD).
Methods:
This review is based on relevant articles retrieved by a search in Google Scholar and PubMed databases and on an assessment of the legal texts and summaries of product characteristics available in France.
Results:
Evidence for the tolerability of CBD during chronic use is reassuring, but a significant risk of drug interactions exists. THC use appears to be associated with a higher proportion of serious adverse effects, including neuropsychological and cardiovascular effects. Inhaled cannabis appears to be associated with greater toxicity than the oral route. These data are presented together with the pharmacokinetic and pharmacodynamic data of THC and CBD.
Conclusion:
The literature reports several frequent but rarely serious adverse effects of CBD during chronic use as well as a significant risk of drug interactions. THC use seems to be associated with a higher proportion of serious adverse effects compared to CBD, particularly at the neuropsychological and cardiovascular levels. Health professionals should be up to date on the particularities of therapeutic cannabis in terms of efficacy, safety and drug interactions.
... Thus, the affinity and agonistic activity of the TRPV1 receptor was described [48]. The literature also shows that CBD activates other vanilloid receptor subtypes (TRPV1, TRPV2, TRPV3, and TRPV4), transient receptor potential ankyrin 1 (TRPA1) [49][50][51], but the neuroprotective activity is limited to the TRPV1 receptor [52]. The CBD-induced effects which are not directly related to CB1 and/or CB2 receptors, but with transient receptor potential channels are an important topic to be discussed since it has been demonstrated that the CBD activation of receptors such as TRPV1 and TRPV2 produces several effects. ...
The literature provides scientific evidence for the beneficial effects of cannabidiol (CBD), and these effects extend beyond epilepsy treatment (e.g., Lennox–Gastaut and Dravet syndromes), notably the influence on oxidative status, neurodegeneration, cellular protection, cognitive function, and physical performance. However, products containing CBD are not allowed to be marketed everywhere in the world, which may ultimately have a negative effect on health as a result of the uncontrolled CBD market. After the isolation of CBD follows the discovery of CB1 and CB2 receptors and the main enzymatic components (diacylglycerol lipase (DAG lipase), monoacyl glycerol lipase (MAGL), fatty acid amino hydrolase (FAAH)). At the same time, the antioxidant potential of CBD is due not only to the molecular structure but also to the fact that this compound increases the expression of the main endogenous antioxidant systems, superoxide dismutase (SOD), and glutathione peroxidase (GPx), through the nuclear complex erythroid 2-related factor (Nrf2)/Keep1. Regarding the role in the control of inflammation, this function is exercised by inhibiting (nuclear factor kappa B) NF-κB, and also the genes that encode the expression of molecules with a pro-inflammatory role (cytokines and metalloproteinases). The other effects of CBD on cognitive function and physical performance should not be excluded. In conclusion, the CBD market needs to be regulated more thoroughly, given the previously listed properties, with the mention that the safety profile is a very good one.
... In the search of new therapeutic options, CBD has managed to position itself as a promising molecule to treat seizures [126]. ...
The use of Cannabis for medicinal purposes has been documented since ancient times, where one of its principal cannabinoids extracted from Cannabis sativa, cannabidiol (CBD), has emerged over the last few years as a promising molecule with anti-seizure potential. Here, we present an overview of recent literature pointing out CBD’s pharmacological profile (solubility, metabolism, drug-drug interactions, etc.,), CBD’s interactions with multiple molecular targets as well as advances in preclinical research concerning its anti-seizure effect on both acute seizure models and chronic models of epilepsy. We also highlight the recent attention that has been given to other natural cannabinoids and to synthetic derivatives of CBD as possible compounds with therapeutic anti-seizure potential. All the scientific research reviewed here encourages to continue to investigate the probable therapeutic efficacy of CBD and its related compounds not only in epilepsy but also and specially in drug-resistant epilepsy, since there is a dire need for new and effective drugs to treat this disease.
... Results showed that two of the cannabinoids, THC and cannabidiol, had therapeutic potential against seizures. The next goal was to check its activity in chronic seizures; rats were subjected to daily of electric shock to induce chronic seizures, and then given THC 33 . Clinical test performed on humans were rare. ...
... 68 In fact, CBD directly interacts with various receptors, enzymes, and ion channels; however, it has also been shown to interact directly and indirectly with the endocannabinoid system. 69,70 The current state of knowledge suggests that the CBD mechanism of action for antinociceptive effects is distinct from the endocannabinoid system as 246 SILVA-CARDOSO AND LEITE-PANISSI previous studies have shown that the antihyperalgesic effect of CBD is prevented by capsazepine (the vanilloid receptor antagonist) but not by rimonabant or SR144528 (CB1 and CB2 antagonists, respectively). 9,71 CBD also has the high affinity for ionotropic receptors, such as the transient receptor potential (TRP) channels-cationic ion channels located mainly in the plasma membrane of various types of animal cells; among them TRPA1, TRPV1, TRPV2, and TRPV4 are activated by CBD, in addition to acting as an antagonist for TRPM8. ...
The incidence of chronic pain is around 8% in the general population, and its impact on quality of life, mood, and sleep exceeds the burden of its causal pathology. Chronic pain is a complex and multifaceted problem with few effective and safe treatment options. It can be associated with neurological diseases, peripheral injuries or central trauma, or some maladaptation to traumatic or emotional events. In this perspective, animal models are used to assess the manifestations of neuropathy, such as allodynia and hyperalgesia, through nociceptive tests, such as von Frey, Hargreaves, hot plate, tail-flick, Randall & Selitto, and others. Cannabidiol (CBD) has been considered a promising strategy for treating chronic pain and diseases that have pain as a consequence of neuropathy. However, despite the growing body of evidence linking the efficacy of CBD on pain management in clinical and basic research, there is a lack of reviews focusing on chronic pain assessments, especially when considering pre-clinical studies, which assess chronic pain as a disease by itself or as a consequence of trauma or peripheral or central disease. Therefore, this review focused only on studies that fit our inclusion criteria: (1) used treatment with CBD extract; (2) used tests to assess mechanical or thermal nociception in at least one of the following most commonly used tests (von Frey, hot plate, acetone, Hargreaves, tail-flick, Randall & Selitto, and others); and (3) studies that assessed pain sensitivity in chronic pain induction models. The current literature points out that CBD is a well-tolerated and safe natural compound that exerts analgesic effects, decreasing hyperalgesia, and mechanical/thermal allodynia in several animal models of pain and patients. In addition, CBD presents several molecular and cellular mechanisms of action involved in its positive effects on chronic pain. In conclusion, using CBD seems to be a promising strategy to overcome the lack of efficacy of conventional treatment for chronic pain.
... Thereafter, we evaluated the involvement of PI3K in the CBD anticonvulsant effect in PTZ-induced seizures. As expected, CBD showed robust anticonvulsant property, increasing the latency for the first seizure, extending previous results from various groups in which this phytocannabinoid prevented seizures and associated brain alterations [36,37]. For instance, we recently observed that CBD increased latency for seizure onset, decreased the seizure severity according to Racine's scale, as well as prevented neurodegeneration, microgliosis, and astrocytosis induced by intrahippocampal pilocarpine injection [13]. ...
Background
The phytocannabinoid cannabidiol (CBD) has previously shown to have anticonvulsant effects in preclinical and clinical studies. Recently, CBD has been approved to treat certain types of drug-resistant epileptic syndromes. However, the underlying mechanism of action remains unclear. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been proposed to modulate seizures and might be recruited by CBD. Thus, we tested the hypothesis that the anticonvulsant effect of CBD involves PI3K in a seizure model induced by pentylenetetrazole (PTZ).Methods
We employed pharmacological and genetic approaches to inhibit PI3K and quantified its effects on seizure duration, latency, and number.ResultsPI3K genetic ablation increased the duration and number of seizures. CBD inhibited PTZ-induced seizures in mice. Genetic deletion of PI3K or pretreatment with the selective inhibitor LY294002 prevented CBD effects.Conclusion
Our data strengthen the hypothesis that the CBD anticonvulsant effect requires the PI3K signaling pathway.
... CBD is one agent that influences weight and fasting blood sugar in both animals and humans, most likely through its agonist actions at 5-HT 1A receptors, and cannabinoid GPR55 receptors in the islets of Langerhans [9][10][11][12]. It may also act as an antagonist/ inverse agonist at CB1 receptors [13,14]. Further, CBD is a partial agonist at dopamine receptors [15]. ...
Objectives
The duration of administration (e.g., subchronic or chronic) of haloperidol may influence its adverse effects. We studied the effects of duration of administration of haloperidol on body weight and fasting blood sugar (FBS). In addition, we examined whether orally administered cannabidiol (CBD) had any putative mitigating influence on haloperidol-induced body weight changes and FBS elevation.
Methods
Haloperidol (5 mg/kg/day) was administered for 21 days (subchronic administration), via the intraperitoneal (IP) route, or monthly (50 mg/kg monthly) for 3 months (chronic administration), via the intramuscular (IM) route, either alone or before CBD (5 mg/kg/day). Oral CBD (5 mg/kg/day) alone and distilled water alone were administered for 21 days. Weight and FBS were measured before administration of pharmacological agents (distilled water in the control group) and post-administration.
Results
Group differences in average weight across time were significant. Pairwise comparisons showed that mean weight of the subchronic (IP) haloperidol alone group (Group A) and the chronic (IM) haloperidol before CBD group (Group F) increased significantly over time. Post medications, there was a significant increase in mean FBS in the subchronic (IP) haloperidol group compared to the subchronic (IP) haloperidol before CBD group. There was also a significant reduction in mean FBS from the baseline for the control group only.
Conclusion
We demonstrated that the duration of administration of haloperidol influenced weight and FBS in rats, suggesting that metabolic side effects, may be influenced by duration of administration. CBD ameliorated the increase in weight and FBS observed in the subchronic (IP) haloperidol groups.
... 35 Further, CBD behavior as a potent ASM and antiepileptic drug has been confirmed internationally in genetic models, such as the Wistar Audiogenic Rat (WAR) strain, in our and other laboratories. [36][37][38] It is unfortunate for the patients and families, but also for the clinicians/surgeons and the basic scientists that we still depend on a tunnel view that has plagued the last decades of epileptology, with separate concerns and selective solutions, ignoring the fact that we are dealing with phenomena that as mentioned above, if seen as complex challenges, therefore, they will also need complex solutions. 39,40 This is particularly the case when on top of the epilepsies' networks, we find overlapped the neuropsychiatric entities networks, among others, as comorbidities. ...
Drug‐resistant epilepsy remains to this day as a highly prevalent condition affecting around one‐third of patients with epilepsy, despite all the research and the development of several new antiseizure medications (ASMs) over the last decades. Epilepsies are multifactorial complex diseases, commonly associated with psychiatric, neurological, and somatic comorbidities. Thus, to solve the puzzling problem of pharmacoresistance, the diagnosis and modeling of epilepsy and comorbidities need to change toward a complex system approach. In this review, we have summarized the sequence of events for the definition of epilepsies and comorbidities, the search for mechanisms, and the major hypotheses of pharmacoresistance, drawing attention to some of the many converging aspects between the proposed mechanisms, their supporting evidence, and comorbidities‐related alterations. The use of systems biology applied to epileptology may lead to the discovery of new targets and the development of new ASMs, as may advance our understanding of the epilepsies and their comorbidities, providing much deeper insight on multidrug pharmacoresistance.
... Cannabidiol (CBD) oral solution was approved to treat seizures related to DS and Lennox-Gastaut syndrome in patients two years of age or older, when given in addition to standard-of-care medications [3]. This nonpsychoactive phytocannabinoid holds promise to become a novel therapeutic modality to treat seizures and related conditions [4][5][6][7][8]. CBD attenuates seizures and improves social and cognitive deficits in DS mice through the modulation of GABAergic neurotransmission [4]. ...
Dravet Syndrome (DS) is a severe childhood epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene encoding brain type-I voltage-gated sodium channel Nav1.1. DS is a devastating disease that typically begins at six to nine months of age. Symptoms include recurrent intractable seizures and premature death with severe neuropsychiatric comorbidities, including hyperactivity, sleep disorder, anxiety-like behaviors, impaired social interactions, and cognitive deficits. There is an urgent unmet need for therapeutic approaches that control and cure DS, as available therapeutic interventions have poor efficacy, intolerance, or other side effects. Here we investigated the therapeutic potential of combining the benzodiazepine clonazepam (CLZ) with the nonpsychotropic phytocannabinoid cannabidiol (CBD) against thermally induced febrile seizures in a conditional mouse model of DS. Our results show that a low dose of CLZ alone or combined with CBD elevated the threshold temperature for the thermal induction of seizures. Combination of CLZ with CBD significantly reduced seizure duration compared to the vehicle or CLZ alone, but did not affect seizure severity, indicating potential additive actions of CLZ and CBD on the duration of seizures. Our findings provide preclinical evidence supporting combination therapy of CLZ and CBD for treatment of febrile seizures in DS.
... Cannabidiol is a terpenophenol, a non-psychoactive phytocannabinoid, found in a high percentage in the Cannabis plant [16]. It is a promising compound for treating epilepsy due to its anticonvulsant properties, particularly in patients resistant to all conventional anti-epileptic drugs [17,18]. Its antimicrobial activity has also been demonstrated, specifically in Gram-positive bacteria [19]. ...
Background
Some plant seeds and berries have gained increased recognition due to their wide variety of bioactive compounds. Many of these foods are rich in lipids with high nutritional value, of which n-3 and n-6 essential fatty acids stand out. However, knowledge of these foodstuffs’ chemical composition and biological activity and their value as a source of healthy lipids is far from being fully explored.
Objective and Methods
The benefits of the intake of hemp seeds, flaxseed and açaí berries, considered functional foods, have been compiled in this review. Likewise, their general chemical composition will be described to evaluate their relevance in a healthy diet, highlighting their lipid components and nutritional lipid indices.
Results and Conclusion
The fibres and essential fatty acids of hemp seeds and flaxseed and the antioxidant properties of açaí berries provide them protective roles against several chronic non-communicable diseases and represent significant beneficial effects that add value to these healthy natural products. More research is needed to deepen the knowledge on their lipids’ molecular composition and bioactivity.
... CBD is one of several phytocannabinoids that were found in Cannabis sativa L. 1 Although the pharmacologic mechanism of CBD is still a topic of numerous studies, its multipotent action is currently confirmed. [2][3][4] The activity is associated with interaction with cannabinoid receptor 1 (CB1) and 2 (CB2), vanilloid and serotonin receptors, G protein-coupled receptors 55 (GPR55), mitochondrial sodium-calcium exchanger (NCX), and modulation of glutamategamma-aminobutyric acid (GABA) systems and serotonergic signaling. It affects intracellular calcium concentration through CB1 and mitochondrial NCX. ...
Background: Beside others, neuroinhibitory and sedative effects of CBD were documented. Aim and Methods: The aim of the study was to assess the dose-related effects of CBD premedication on the course of isoflurane anesthesia. Wistar rats were pretreated with different doses of CBD 1 h before isoflurane anesthesia. In the pretreatment, animals were given CBD at doses of 100, 20, 10, or 2 mg kg-1. Before the fifth (control) anesthesia, the animals were given only mid-chain triglyceride oil, which served as a solvent in the CBD formulation. The induction time was determined, and on awakening, the time to appearance of the flexion reflex and the recovery from anesthesia were determined. Results: Statistical analysis showed a significantly shorter induction time if animals were pretreated with 20 mg kg-1 CBD. In addition, pretreatment with 100 mg kg-1 CBD resulted in a prolonged induction time, while on awakening, delayed appearance of reflexes and prolonged recovery from anesthesia compared to pretreatment with 20 mg kg-1 CBD were observed. Conclusions: The results indicate that the influence of CBD on the course of isoflurane anesthesia depends on the dose and can reduce the induction time. Although this study was performed in laboratory rats, in clinical practice, these data should be considered when CBD-treated patients undergo isoflurane anesthesia.
... For this reason, there is still an urgent need to find treatments against drug-resistant epilepsy (DRE) [9,10]. In this view, CBD has received great scientific interest due to its anticonvulsant proprieties, as revealed in experimental animal models of epilepsy [11]. Notably, CBD (Epidiolex), recently reviewed by Abu-Sawwa and Park [12], has been the first cannabis-derived medication approved in 2018 by the FDA for patients ≥2 years of age diagnosed with rare forms of AEDs-refractory epilepsy such as Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). ...
Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.
... In turn, during the GPR55 activation [61], CBD as an antagonist may increase intracellular calcium via inositol 1,4,5-triphosphate (IP3) signaling. Furthermore, CBD can act on the NCX, reducing or elevating cytosolic calcium [59,62]. ...
As the major nonpsychotropic constituent of Cannabis sativa, cannabidiol (CBD) is regarded as one of the most promising therapeutic agents due to its proven effectiveness in clinical trials for many human diseases. Due to the urgent need for more efficient pharmacological treatments for several chronic diseases, in this review, we discuss the potential beneficial effects of CBD for Alzheimer’s disease, epilepsy, multiple sclerosis, and neurological cancers. Due to its wide range of pharmacological activities (e.g., antioxidant, anti-inflammatory, and neuroprotective properties), CBD is considered a multimodal drug for the treatment of a range of neurodegenerative disorders, and various cancer types, including neoplasms of the neural system. The different mechanisms of action of CBD are here disclosed, together with recent progress in the use of this cannabis-derived constituent as a new therapeutic approach.
... Progress in the patients' autonomy, increased motor, and cognitive performances as well as communication and social interaction improvements were also reported. The expected anticonvulsant effect of CBD (Mullard, 2018;Silvestro et al., 2019;Alves et al., 2020;Aran and Cayam-Rand, 2020;Lazarini-Lopes et al., 2020) was confirmed in two studies in which seizures were at least partially or even completely controlled (Bar-Lev Schleider et al., 2019;Fleury-Teixeira et al., 2019). In accordance with these studies, a recent case report about a 15-year-old boy with ASD who was treated with CBD-enriched cannabis extract oil (CBD/ THC ratio of 20:1; 4 mg CBD and 0.2 mg THC twice a day) reported that CBD-based treatment aided in the control of ASDrelated behavioral symptoms, core social communication abilities, anxiety, sleep difficulties, and body weight (Ponton et al., 2020). ...
Schizophrenia and autism spectrum disorders (ASD) are psychiatric neurodevelopmental disorders that cause high levels of functional disabilities. Also, the currently available therapies for these disorders are limited. Therefore, the search for treatments that could be beneficial for the altered course of the neurodevelopment associated with these disorders is paramount. Preclinical and clinical evidence points to cannabidiol (CBD) as a promising strategy. In this review, we discuss clinical and preclinical studies on schizophrenia and ASD investigating the behavioral, molecular, and functional effects of chronic treatment with CBD (and with cannabidivarin for ASD) during neurodevelopment. In summary, the results point to CBD's beneficial potential for the progression of these disorders supporting further investigations to strengthen its use.
Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers. Significance Statement This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.
Alpha-synuclein (α-Syn) is a specific neuronal protein that regulates neurotransmitter release and trafficking of synaptic vesicles. Exosome-associated α-Syn which is specific to the central nervous system (CNS) is involved in the pathogenesis of epilepsy. Therefore, this review aimed to elucidate the possible link between α-Syn and epilepsy, and how it affects the pathophysiology of epilepsy. A neurodegenerative protein such as α-Syn is implicated in the pathogenesis of epilepsy. Evidence from preclinical and clinical studies revealed that upregulation of α-Syn induces progressive neuronal dysfunctions through induction of oxidative stress, neuroinflammation, and inhibition of autophagy in a vicious cycle with subsequent development of severe epilepsy. In addition, accumulation of α-Syn in epilepsy could be secondary to the different cellular alterations including oxidative stress, neuroinflammation, reduction of brain-derived neurotrophic factor (BDNF) and progranulin (PGN), and failure of the autophagy pathway. However, the mechanism of α-Syn-induced-epileptogenesis is not well elucidated. Therefore, α-Syn could be a secondary consequence of epilepsy. Preclinical and clinical studies are warranted to confirm this causal relationship.
Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss‐of‐function mutation in CDKL5 gene, encoding a serine–threonine kinase highly expressed in the brain. CDD manifests with early‐onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5 R59X knock‐in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre‐treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long‐term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild‐type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G‐coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild‐type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.
The intricate relationship between viruses and epilepsy involves a bidirectional interaction. Certain viruses can induce epilepsy by infecting the brain, leading to inflammation, damage, or abnormal electrical activity. Conversely, epilepsy patients may be more susceptible to viral infections due to factors, such as compromised immune systems, anticonvulsant drugs, or surgical interventions. Neuroinflammation, a common factor in both scenarios, exhibits onset, duration, intensity, and consequence variations. It can modulate epileptogenesis, increase seizure susceptibility, and impact anticonvulsant drug pharmacokinetics, immune system function, and brain physiology. Viral infections significantly impact the clinical management of epilepsy patients, necessitating a multidisciplinary approach encompassing diagnosis, prevention, and treatment of both conditions. We delved into the dual dynamics of viruses inducing epilepsy and epilepsy patients acquiring viruses, examining the unique features of each case. For virus-induced epilepsy, we specify virus types, elucidate mechanisms of epilepsy induction, emphasize neuroinflammation’s impact, and analyze its effects on anticonvulsant drug pharmacokinetics. Conversely, in epilepsy patients acquiring viruses, we detail the acquired virus, its interaction with existing epilepsy, neuroinflammation effects, and changes in anticonvulsant drug pharmacokinetics. Understanding this interplay advances precision therapies for epilepsy during viral infections, providing mechanistic insights, identifying biomarkers and therapeutic targets, and supporting optimized dosing regimens. However, further studies are crucial to validate tools, discover new biomarkers and therapeutic targets, and evaluate targeted therapy safety and efficacy in diverse epilepsy and viral infection scenarios.
Citation: Walczyńska-Dragon, K.; Kurek-Górecka, A.; Niemczyk, W.; Nowak, Z.; Baron, S.; Olczyk, P.; Nitecka-Buchta, A.; Kempa, W.M. Cannabidiol Intervention for Muscular Tension, Pain, and Sleep Bruxism Intensity-A Randomized, Double-Blind Clinical Trial.
Background: Cannabidiol (CBD), a substance that belongs to the phytocannabinoids, appears to exert antioxidant, neuroprotective, antipsychotic, anticonvulsant, and anticancer properties. Recent evidence supports the immunoregulatory effect of CBD on autoimmune and/or inflammatory disease. Psoriasis is a chronic skin disease. The main immune cell population involved in the pathogenesis of the disease is the interleukin- (IL-) 17-producing T helper (Th) 17 subset. Other subpopulations, such as interferon-γ (IFNγ) -producing Th1 and T cytotoxic (Tc) 1, IL-17-producing Tc17, as well as natural killer (NK) and natural killer T cells (NKT) have been implicated in psoriasis development. Purpose: The aim of the present study was to evaluate the in vitro effect of CBD on the aforementioned subpopulations isolated from patients with psoriasis using flow cytometry. Methods: Cells were stimulated in the presence or absence of CBD, stained and examined using surface and intracellular markers. Results: CBD decreased IL-17 production within the CD3, Th, and NKT cell compartments and IFNγ production within the CD3 compartment in cells isolated from patients with psoriasis. Interestingly, CBD supplementation did not inhibit production of proinflammatory cytokines in cells isolated from healthy individuals. On the contrary, IFNγ-producing Th, Tc, and NK cells increased after CBD supplementation. Conclusion: CBD provides anti-inflammatory effects in T cells isolated from patients with psoriasis. Our results could be the impetus for future investigations regarding the immunomodulatory properties of CBD and its utilization for development of CBD-containing antipsoriatic agents.
Cannabinoids interact with Cannabinoid Receptors (CBRs) and some related non-cannabinoid transcription factors within neurological and non-neuronal-specific receptors. The current review has covered pharmacological molecular mechanisms during an epileptic attack and provided a beneficial therapeutic approach for the treatment of neurological disorders. CBRs and new targets may be involved in Cannabidiol (CBD) effects. Although it has a low affinity for both CB1 and CB2 receptors, CBD can effectively block CB1 receptors when concentrations are high. The following are numerous potential CBD goals: (A) Blocking GPR55 receptors; (B) Systematic desensitization of TRPV1 channels; (C) Suppressing adenosine re-uptake transporters; (D) Regulating GABA production; and (E) Influencing the Endocannabinoid networks. According to the current review, numerous outstanding cannabis formulations are currently being developed and proven in numerous clinical studies. Nevertheless, more research is urgently needed to determine the best dosage and proportions of cannabinoids for reducing seizure frequency. This study needs to take place in huge, rising randomized clinical trials that really can reveal the rewards and drawbacks of cannabinoids in controlled patients. Furthermore, there is a lot of significant variation in the experimental approaches performed, particularly when it comes to the length of immunosuppressive drugs, dosages, and delivery methods in animal models. So, reproducing the existing results using comparable methods will be one of the biggest challenges in the additional investigation.
OBJETIVO: Apresentar as informações disponíveis sobre o canabidiol na forma de uma revisão bibliográfica narrativa, abordando sua utilização medicinal, mecanismos de ação e questões regulatórias para auxílio e embasamento técnico, a partir de informações publicadas na literatura científica. MÉTODOS: Nesta revisão bibliográfica narrativa (bases de dados, sites e periódicos especializados) foram selecionados estudos sobre a utilização de canabidiol (CBD) na terapêutica, abordando possíveis mecanismos neurobiológicos e legislação pertinente. As bases de dados avaliadas foram MEDLINE, PUBMED, SCIENCE DIRECT, SciELO e LILACS. RESULTADOS: Nos estudos selecionados sobre o tema foram descritos os mecanismos de ação do CBD, aplicações terapêuticas e questões regulatórias, sendo apresentadas as evidências descritas em literatura científica. CONCLUSÃO: A utilização clínica do CBD não se restringe somente à epilepsia pediátrica, havendo evidências consistentes sobre os benefícios de intervenções deste composto não só para doenças neurodegenerativas convencionais, mas também para condições neurodegenerativas secundárias a outras complicações do SNC isoladamente ou como adjuvante terapêutico. As suas aplicações na área de saúde mental e dor apresentam potencial terapêutico significativo, além de perfil terapêutico promissor para crianças e adolescentes com Transtornos do Espectro Autista.
Background:
There is a lack of research on the effects of cannabidiol (CBD) on health-related fitness, physical activity, cognitive health, psychological wellbeing, and concentrations of C-reactive protein (CRP) in healthy individuals. CBD has potential anti-inflammatory and neuroprotective effects.
Methods:
This study aimed to investigate the effects of 8 weeks of CBD on the above-mentioned measures in healthy individuals. Forty-eight participants were randomized into two groups receiving either oral capsules of 50 mg of CBD or a calorie-matched placebo daily. Participants completed pre- and post-intervention assessments, including blood draws, body composition, fitness, physical activity, and self-reported surveys.
Results:
There were no significant differences between groups regarding body composition, aerobic fitness, muscular strength, physical activity, cognitive health, psychological wellbeing, and resting CRP concentrations. However, the placebo group experienced a decline in mean peak power and relative peak power compared to the CBD group.
Conclusions:
The results suggest that 8 weeks of CBD supplementation may prevent declines in anaerobic fitness over time. However, long-term CBD supplementation may not be beneficial for altering measures of health-related fitness, mental health, and inflammation in healthy individuals.
Cannabidiol (CBD) is a non-psychotropic phytocannabinoid of the plant Cannabis sativa L. CBD is increasingly being explored as an alternative to conventional therapies to treat health disorders in dogs and cats. Mechanisms of action of CBD have been investigated mostly in rodents and in vitro and include modulation of CB1, CB2, 5-HT, GPR, and opioid receptors. In companion animals, CBD appears to have good bioavailability and safety profile with few side effects at physiological doses. Some dog studies have found CBD to improve clinical signs associated with osteoarthritis, pruritus, and epilepsy. However, further studies are needed to conclude a therapeutic action of CBD for each of these conditions, as well as for decreasing anxiety and aggression in dogs and cats. Herein, we summarize the available scientific evidence associated with the mechanisms of action of CBD, including pharmacokinetics, safety, regulation, and efficacy in ameliorating various health conditions in dogs and cats.
According to the 2017 ILAE's official definition, epilepsy is a slow brain disease state characterized by recurrent episodes. Due to information released by ILAE in 2017, it can be divided into four types, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and unknown epilepsy. Since 1989, 24 new antiepileptic drugs have been approved to treat different types of epilepsy. Besides, there are a variety of antiepileptic medications under clinical monitoring. These novel antiepileptic drugs have plenty of advantages. Over the past 33 years, there have been many antiepileptic drugs on the mearket, but no one has been found that can completely cure epilepsy. In this paper, the mentioned drugs were classified according to their targets, and the essential information, and clinical studies of each drug were described. The structure-activity relationship of different chemical structures was summarized. This paper provides help for the follow-up research on epilepsy drugs.
There is currently a growing interest in the use of cannabidiol (CBD) to alleviate the symptoms caused by cancer, including pain, sleep disruption, and anxiety. CBD is often self-administered as an over-the-counter supplement, and patients have reported benefits from its use. However, despite the progress made, the mechanisms underlying CBD’s anti-cancer activity remain divergent and unclear. Herein, we provide a comprehensive review of molecular mechanisms to determine convergent anti-cancer actions of CBD from pre-clinical and clinical studies. In vitro studies have begun to elucidate the molecular targets of CBD and provide evidence of CBD’s anti-tumor properties in cell and mouse models of cancer. Furthermore, several clinical trials have been completed testing CBD’s efficacy in treating cancer-related pain. However, most use a mixture of CBD and the psychoactive, tetrahydrocannabinol (THC), and/or use variable dosing that is not consistent between individual patients. Despite these limitations, significant reductions in pain and opioid use have been reported in cancer patients using CBD or CBD+THC. Additionally, significant improvements in quality-of-life measures and patients’ overall satisfaction with their treatment have been reported. Thus, there is growing evidence suggesting that CBD might be useful to improve the overall quality of life of cancer patients by both alleviating cancer symptoms and by synergizing with cancer therapies to improve their efficacy. However, many questions remain unanswered regarding the use of CBD in cancer treatment, including the optimal dose, effective combinations with other drugs, and which biomarkers/clinical presentation of symptoms may guide its use.
The endocannabinoid system modulates epileptic seizures by regulating neuronal excitability. It has become clear that agonist activation of central type I cannabinoid receptors (CB1R) reduces epileptogenesis in pre-clinical animal models of epilepsy. The audiogenic seizure-prone hamster GASH/Sal is a reliable experimental model of generalized tonic-clonic seizures in response to intense sound stimulation. However, no studies hitherto had investigated CB1R in the GASH/Sal. Although the distribution of CB1R has been extensively studied in mammalian brains, their distribution in the Syrian golden hamster brain also remains unknown. The objective of this research is to determine by immunohistochemistry the differential distribution of CB1R in the brains of GASH/Sal animals under seizure-free conditions, by comparing the results with wild-type Syrian hamsters as controls. CB1R in the GASH/Sal showed a wide distribution in many nuclei of the central nervous system. These patterns of CB1R-immunolabeling are practically identical between the GASH/Sal model and control animals, varying in the intensity of immunostaining in certain regions, being slightly weaker in the GASH/Sal than in the control, mainly in brain regions associated with epileptic networks. The RT-qPCR analysis confirms these results. In summary, our study provides an anatomical basis for further investigating CB1R in acute and kindling audiogenic seizure protocols in the GASH/Sal model as well as exploring CB1R activation via exogenously administered cannabinoid compounds.
Background:
Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016.
Methods:
Children and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex®; 100 mg/mL) in oral solution at 2-10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25-50 mg/kg/day. Patient visits were every 2-4 weeks. The percentage change from baseline in median monthly convulsive (ie, major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had ≥50%, ≥75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks.
Results:
Of the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0-10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1-146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥50%, ≥75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%).
Conclusions:
Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.
Background
Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population.
Objective
The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy.
Methods
In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years).
Results
Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2–6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%).
Conclusions
Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated.
Trial Registration
ClinicalTrials.gov (NCT02324673).
Objective
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).
Methods
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.
Results
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.
Significance
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.
Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer's and Parkinson's, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer. CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke. In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion. These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R-/- mice. Thus, CBD displays antagonist-like activity toward σ1R to reduce the negative effects of NMDAR overactivity in the abovementioned experimental situations.
Background and purpose:
A non-psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. In an attempt to understand the mechanisms by which CBD exerts its anti-seizure effects, we investigated the effects of CBD at synaptic connections, and the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin -expressing (PV) and adapting, cholecystokinin-expressing (CCK) interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.
Experimental approach:
Electrophysiological intracellular whole-cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy (in vivo kainic acid-induced) and in vitro (Mg2+-free-induced) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg kg-1) at zero time and 90 minutes post status epilepticus (SE) induced with kainic acid.
Key results:
Bath-application of CBD (10 μM), dampened excitability at unitary synapses between pyramidal cells, but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK, and pyramidal cells in a cell type-specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction of atrophy and death of PV- and CCK-expressing interneurons after CBD treatment.
Conclusions & implications:
In conclusion, our data suggest CBD restores excitability and morphological impairment in epileptic models to pre-epilepsy control levels through multiple mechanisms to restore normal network function.
Epilepsy is a devastating disease, with cognitive and emotional consequences that are not curable. In recent years, it became apparent that cannabinoids help patients to cope with epilepsy. We have studied the effects of cannabidiol (CBD) on the ability to produce long term potentiation (LTP) in stratum radiatum of CA1 region of the mouse hippocampus. Exposure to seizure-producing pilocarpine reduced the ability to generate LTP in the slice. Pre-exposure to CBD prevented this effect of pilocarpine. Furthermore, CBD caused a marked increase in ability to generate LTP, an effect that was blocked by calcium store antagonists as well as by a reduction in serotonin tone. Serotonin, possibly acting at a 5HT1A receptor, or fenfluramine (FFA), which causes release of serotonin from its native terminals, mimicked the effect of CBD. It is proposed that CBD enhances non-NMDA LTP in the slice by facilitating release of serotonin from terminals, consequently ameliorating the detrimental effects of pilocarpine.
The interest in cannabis-based products for the treatment of refractory epilepsy has skyrocketed in recent years. Marijuana and other cannabis products with high content in Δ(9) - tetrahydrocannabinol (THC), utilized primarily for recreational purposes, are generally unsuitable for this indication, primarily because THC is associated with many undesired effects. Compared with THC, cannabidiol (CBD) shows a better defined anticonvulsant profile in animal models and is largely devoid of adverse psychoactive effects and abuse liability. Over the years, this has led to an increasing use of CBD-enriched extracts in seizure disorders, particularly in children. Although improvement in seizure control and other benefits on sleep and behavior have been often reported, interpretation of the data is made difficult by the uncontrolled nature of these observations. Evidence concerning the potential anti-seizure efficacy of cannabinoids reached a turning point in the last 12 months, with the completion of three high-quality placebo-controlled adjunctive-therapy trials of a purified CBD product in patients with Dravet syndrome and Lennox-Gastaut syndrome. In these studies, CBD was found to be superior to placebo in reducing the frequency of convulsive (tonic-clonic, tonic, clonic, and atonic) seizures in patients with Dravet syndrome, and the frequency of drop seizures in patients with Lennox-Gastaut syndrome. For the first time, there is now class 1 evidence that adjunctive use of CBD improves seizure control in patients with specific epilepsy syndromes. Based on currently available information, however, it is unclear whether the improved seizure control described in these trials was related to a direct action of CBD, or was mediated by drug interactions with concomitant medications, particularly a marked increased in plasma levels of N-desmethylclobazam, the active metabolite of clobazam. Clarification of the relative contribution of CBD to improved seizure outcome requires re-assessment of trial data for the subgroup of patients not comedicated with clobazam, or the conduction of further studies controlling for the confounding effect of this interaction.
Endocannabinoids (eCBs) are amongst the most ubiquitous signaling molecules in the nervous system. Over the past few decades, observations based on a large volume of work, first examining the pharmacological effects of exogenous cannabinoids, and then the physiological functions of eCBs, have directly challenged long-held and dogmatic views about communication, plasticity and behavior in the Central Nervous System (CNS). The eCBs and their cognate cannabinoid receptors exhibit a number of unique properties that distinguish them from the widely studied classical amino acid transmitters, neuropeptides and catecholamines. Although we now have a loose set of mechanistic rules based on experimental findings, new studies continue to reveal that our understanding of the endocannabinoid system (ECS) is continuously evolving and challenging long-held conventions. Here, we will briefly summarize findings on the current canonical view of the ‘endocannabinoid system’ and will address novel aspects that reveal how a nearly ubiquitous system can determine highly specific functions in the brain. In particular, we will focus on findings that push for an expansion of our ideas around long-held beliefs about eCB signaling that, whilst clearly true, may be contributing to an oversimplified perspective on how cannabinoid signaling at the microscopic level impacts behavior at the macroscopic level.
Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED50 164 mg/kg), mouse MES (ED50 83.5 mg/kg) and rat MES (ED50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.
The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.
The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) "partial" becomes "focal"; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.
The present study reports the behavioral, electrophysiological, and neuropathological effects of cannabidiol (CBD), a major non-psychotropic constituent of Cannabis sativa, in the intrahippocampal pilocarpine-induced status epilepticus (SE) rat model. CBD was administered before pilocarpine-induced SE (group SE+CBDp) or before and after SE (group SE+CBDt), and compared to rats submitted only to SE (SE group), CBD, or vehicle (VH group). Groups were evaluated during SE (behavioral and electrophysiological analysis), as well as at days one and three post-SE (exploratory activity, electrophysiological analysis, neuron density, and neuron degeneration). Compared to SE group, SE+CBD groups (SE+CBDp and SE+CBDt) had increased SE latency, diminished SE severity, increased contralateral afterdischarge latency and decreased relative powers in delta (0.5–4 Hz) and theta (4–10 Hz) bands. Only SE+CBDp had increased vertical exploratory activity 1-day post SE and decreased contralateral relative power in delta 3 days after SE, when compared to SE group. SE+CBD groups also showed decreased neurodegeneration in the hilus and CA3, and higher neuron density in granule cell layer, hilus, CA3, and CA1, when compared to SE group. Our findings demonstrate anticonvulsant and neuroprotective effects of CBD preventive treatment in the intrahippocampal pilocarpine epilepsy model, either as single or multiple administrations, reinforcing the potential role of CBD in the treatment of epileptic disorders.
Background:
Anxiety and depression are the most frequent comorbidities of different types of convulsive and non-convulsive epilepsies. Increased anxiety and depression-like phenotype have been described in the genetic absence epilepsy models as well as in models of limbic epilepsy and acquired seizure models, suggesting a neurobiological connection. However, whether anxiety and/or depression are comorbid to audiogenic epilepsy remains unclear. The aim of this study was to investigate whether anxiety or depression-like behavior can be found in rat strains with different susceptibility to audiogenic seizures (AS) and whether chronic fluoxetine treatment affects this co-morbidity.
Methods:
Behavior in the elevated plus-maze and the forced swimming test was studied in four strains: Wistar rats non-susceptible to AS; Krushinsky-Molodkina (KM) strain, selectively bred for AS propensity from outbred Wistar rats; and a selection lines bred for maximal AS expression (strain "4") and for a lack of AS (strain "0") from KM×Wistar F2 hybrids. Effects of chronic antidepressant treatment on AS and behavior were also evaluated.
Results:
Anxiety and depression levels were higher in KM rats (with AS) compared with Wistar rats (without AS), indicating the comorbidity with AS. However, in strains "4" and "0" with contrasting AS expression, but with a genetic background close to KM rats, anxiety and depression were not as divergent as in KMs versus Wistars. Fluoxetine treatment exerted an antidepressant effect in all rat strains irrespective of its effect on AS.
Conclusions:
Genetic background contributes substantively to the co-morbidity of anxiety and depression with AS propensity.
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.
Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa, has therapeutic potential for certain psychiatric and neurological disorders. Studies in laboratory animals and limited human trials indicate that CBD has anticonvulsant and neuroprotective properties. Its effects against cocaine neurotoxicity, however, has remained unclear. Thus, the present study tested the hypothesis that CBD protects against cocaine-induced seizures and investigated the underlying mechanisms. CBD (30mg/kg) pre-treatment increased the latency and reduced the duration of cocaine (75mg/kg)-induced seizures in mice. The CB1receptor antagonist, AM251 (1 and 3mg/kg), and the CB2receptor antagonist, AM630 (2 and 4mg/kg), failed to reverse this protective effect, suggesting that alternative mechanisms are involved. Synaptosome studies with the hippocampus of drug-treated animals revealed that cocaine increases glutamate release, whereas CBD induces the opposite effect. Finally, the protective effect of this cannabinoid against cocaine-induced seizure was reversed by rapamycin (1 and 5mg/kg), an inhibitor of the mammalian target of rapamycin (mTOR) intracellular pathway. In conclusion, CBD protects against seizures in a model of cocaine intoxication. These effects possibly occur through activation of mTOR with subsequent reduction in glutamate release. CBD should be further investigated as a strategy for alleviating psychostimulant toxicity.
Copyright © 2015. Published by Elsevier B.V.
Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate. Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD), protects against cocaine toxicity. URB597 (1.0 mg/kg) abolished cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg) reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen) increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics. These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.
Epilepsy is a chronic neurological condition characterized by recurrent seizures that affects millions of people worldwide. Comprehension of the complex mechanisms underlying epileptogenesis and seizure generation in temporal lobe epilepsy and other forms of epilepsy cannot be fully acquired in clinical studies with humans. As a result, the use of appropriate animal models is essential. Some of these models replicate the natural history of symptomatic focal epilepsy with an initial epileptogenic insult, which is followed by an apparent latent period and by a subsequent period of chronic spontaneous seizures. Seizures are a combination of electrical and behavioral events that are able to induce chemical, molecular, and anatomic alterations. In this review, we summarize the most frequently used models of chronic epilepsy and models of acute seizures induced by chemoconvulsants, traumatic brain injury, and electrical or sound stimuli. Genetic models of absence seizures and models of seizures and status epilepticus in the immature brain were also examined. Major uses and limitations were highlighted, and neuropathological, behavioral, and neurophysiological similarities and differences between the model and the human equivalent were considered. The quest for seizure mechanisms can provide insights into overall brain functions and consciousness, and animal models of epilepsy will continue to promote the progress of both epilepsy and neurophysiology research.
Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. Since the two non-psychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in such slices exposed to a Mg(2+)-free solution using multi electrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV anti-epileptiform effects in the Mg2+-free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg(2+)-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy.
Objectives: The objective of the study was to describe electroclinical patterns in habitual seizures with motor se-miology at onset, triggered by diagnostic stimulation, in patients undergoing presurgical evaluation using stereoelectroencephalography (SEEG). Methods: Seizure semiology, stimulation parameters, electroclinical data, and anatomical localization were evaluated in stimulated and spontaneous seizures. Results: From 120 habitual seizures triggered by 50-Hz train bipolar stimulation during SEEG, 20 presented initial motor semiology (elementary motor signs, complex motor behavior, or both). Two patterns occurred: long la-tency onset (7/20), where semiology occurred after the stimulation train, following visible cortical epileptic discharge similarly to spontaneous seizures; and short latency onset (13/20), in which typical semiological expression occurred during the stimulation train, preceding typical cortical discharge. Conclusions: This novel observation shows that in some conditions, seizures with habitual motor semiology could be triggered early during stimulation, before typical cortical epileptic discharge became visible. The earliness of clinical onset with regard to visible cortical discharge, notably in comparison with clinically similar spontaneous seizures, suggests differences in electrophysiological mechanisms that require further investigation. These may involve preferential involvement of descending corticosubcortical connections within the same epileptogenic network for a given patient.
Patients with treatment-resistant epilepsy (TRE) frequently exhibit memory and attention deficits that contribute to their poor personal and societal outcomes. We studied the effects of adjunct treatment with pharmaceutical grade cannabidiol (CBD) oral solution (Epidiolex®; Greenwich Biosciences, Inc.) on attention control processes related to stimulus conflict resolution in patients with TRE. Twenty-two patients with TRE underwent 3 T magnetic resonance imaging (MRI) before receiving (PRE) and after achieving a stable dose of CBD (ON). Functional MRI (fMRI) data were collected while patients performed 2 runs of a flanker task (FT). Patients were instructed to indicate via button press the congruent (CON) and incongruent (INC) conditions. We performed t-tests to examine with FT attention control processes at PRE and ON visits and to compare the 2 visits using derived general linear model (GLM) data (INC - CON). We performed generalized psychophysiological interaction (gPPI) analyses to assess changes in condition-based functional connectivity on FT. Median time between fMRI visits was 10 weeks, and median CBD dose at follow-up was 25 mg/kg/d. From PRE to ON, participants experienced improvements in seizure frequency (SF) (p = 0.0009), seizure severity (Chalfont Seizure Severity Scale (CSSS); p < 0.0001), and mood (Total Mood Disturbance (TMD) score from Profile of Mood States (POMS); p = 0.0026). Repeated measures analysis of variance showed nonsignificant improvements in executive function from 34.6 (23.5)% to 41.9 (22.4)% CON accuracy and from 34.2 (25.7)% to 37.6 (24.4)% INC accuracy (p = 0.199). Change in CON accuracy was associated with change in INC accuracy (rS = 0.81, p = 0.0005). Participants exhibited CBD-induced increases in fMRI activation in the right superior frontal gyrus (SFG) and right insula/middle frontal gyrus (MFG) and decrease in activation for both regions at ON relative to PRE (corrected p = 0.05). The subset of patients who improved in FT accuracy with CBD showed a negative association between change in right insula/MFG activation and change in accuracy for the INC condition (rS = -0.893, p = 0.0068). The gPPI analysis revealed a CBD-induced decrease in condition-based functional connectivity differences for the right SFG seed region (corrected p = 0.05). Whole-brain regression analysis documented a negative association of change in right insula/MFG condition-based connectivity with change in INC accuracy (corrected p = 0.005). Our results suggest that CBD modulates attention control processing in patients with TRE by reducing right SFG and right insula/MFG activation related to stimulus conflict resolution and by dampening differences in condition-based functional connectivity of the right SFG. Our study is the first to provide insight into how CBD affects the neural substrates involved in attention processing and how modulation of the activity and functional connectivity related to attentional control processes in the right insula/MFG may be working to improve cognitive performance in TRE.
Background:
Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients.
Methods:
In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690.
Findings:
Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment.
Interpretation:
Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial.
Funding:
GW Pharmaceuticals.
Significance
Medicinal cannabis use is booming despite limited preclinical evidence and mechanistic insight. Recent clinical trials of cannabidiol (CBD) in Dravet syndrome (DS) support its clinical efficacy for reduction of seizure frequency and invite study of its benefits for additional DS symptoms. We demonstrate here that treatment with CBD is beneficial for seizure frequency, duration, and severity and for autistic-like social deficits in a mouse model of DS. CBD rescue of DS symptoms is associated with increased inhibitory neurotransmission, potentially mediated by antagonism of the lipid-activated G protein-coupled receptor GPR55. These studies lend critical support for treatment of seizures in DS with CBD, extend the scope of CBD treatment to autistic-like behaviors, and provide initial mechanistic insights into CBD’s therapeutic actions.
Cannabidiol (CBD), the main nonpsychotomimetic compound from Cannabis sativa, inhibits experimental seizures in animal models and alleviates certain types of intractable epilepsies in patients. Its pharmacological profile, however, is still uncertain. Here we tested the hypothesis that CBD anticonvulsant mechanisms are prevented by cannabinoid (CB1 and CB2) and vanilloid (TRPV1) receptor blockers. We also investigated its effects on electroencephalographic (EEG) activity and hippocampal cytokines in the pentylenetetrazole (PTZ) model. Pretreatment with CBD (60mg/kg) attenuated seizures induced by intraperitoneal, subcutaneous, and intravenous PTZ administration in mice. The effects were reversed by CB1, CB2, and TRPV1 selective antagonists (AM251, AM630, and SB366791, respectively). Additionally, CBD delayed seizure sensitization resulting from repeated PTZ administration (kindling). This cannabinoid also prevented PTZ-induced EEG activity and interleukin-6 increase in prefrontal cortex. In conclusion, the robust anticonvulsant effects of CBD may result from multiple pharmacological mechanisms, including facilitation of endocannabinoid signaling and TRPV1 mechanisms. These findings advance our understanding on CBD inhibition of seizures, EEG activity, and cytokine actions, with potential implications for the development of new treatments for certain epileptic syndromes.
Objective:
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.
Methods:
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.
Results:
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).
Significance:
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.
Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100 mg/kg) or vehicle 60 min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1 mg/kg), a 5HT1A antagonist, or saline vehicle injection 80 min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3 mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80 min prior to seizure testing. 85 mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30 min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.
Background
The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.
Methods
In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.
Results
The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.
Conclusions
Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)
In the context of modeling epilepsy and neuropsychiatric comorbidities, we review the Wistar Audiogenic Rat (WAR), first introduced to the neuroscience international community more than 25 years ago. The WAR strain is a genetically selected reflex model susceptible to audiogenic seizures (AS), acutely mimicking brainstem-dependent tonic–clonic seizures and chronically (by audiogenic kindling), temporal lobe epilepsy (TLE).
Seminal neuroethological, electrophysiological, cellular, and molecular protocols support the WAR strain as a suitable and reliable animal model to study the complexity and emergent functions typical of epileptogenic networks. Furthermore, since epilepsy comorbidities have emerged as a hot topic in epilepsy research, we discuss the use of WARs in fields such as neuropsychiatry, memory and learning, neuroplasticity, neuroendocrinology, and cardio-respiratory autonomic regulation. Last, but not least, we propose that this strain be used in “omics” studies, as well as with the most advanced molecular and computational modeling techniques.
Collectively, pioneering and recent findings reinforce the complexity associated with WAR alterations, consequent to the combination of their genetically-dependent background and seizure profile. To add to previous studies, we are currently developing more powerful behavioral, EEG, and molecular methods, combined with computational neuroscience/network modeling tools, to further increase the WAR strain's contributions to contemporary neuroscience in addition to increasing knowledge in a wide array of neuropsychiatric and other comorbidities, given shared neural networks.
During the many years that the WAR strain has been studied, a constantly expanding network of multidisciplinary collaborators has generated a growing research and knowledge network. Our current and major wish is to make the WARs available internationally to share our knowledge and to facilitate the planning and execution of multi-institutional projects, eagerly needed to contribute to paradigm shifts in epileptology.
This article is part of a Special Issue entitled Genetic Models–Epilepsy
The new definition of epilepsy establishes that epilepsy is not only a disorder presenting with epileptic seizures but it can be often associated with cognitive and psychiatric comorbidities. In fact, the prevalence of psychiatric comorbidities is relatively high in patients with epilepsy (PWE), as one in three patients will have experienced a psychiatric disorder in the course of their life, with mood and anxiety disorders being the most frequent.
Psychiatric comorbidities often precede the onset of the seizure disorder, and affect the life of these patients and the course of the seizure disorder at several levels, including a worse tolerance of pharmacotherapy with antiepileptic drugs (AEDs), in particular the development of iatrogenic psychiatric symptoms from pharmacologic and surgical treatments, an increased mortality risk, a worse quality of life and higher economic burdens of the patient, family and society as a hole. Accordingly, psychiatric comorbidities should be recognized at the time of the initial evaluation of every PWE and their treatment needs to be incorporated within the overall therapeutic plan. This question is addressed in this article.
There are ever more compelling tools available for neuroscience research, ranging from selective genetic targeting to optogenetic circuit control to mapping whole connectomes. These approaches are coupled with a deep-seated, often tacit, belief in the reductionist program for understanding the link between the brain and behavior. The aim of this program is causal explanation through neural manipulations that allow testing of necessity and sufficiency claims. We argue, however, that another equally important approach seeks an alternative form of understanding through careful theoretical and experimental decomposition of behavior. Specifically, the detailed analysis of tasks and of the behavior they elicit is best suited for discovering component processes and their underlying algorithms. In most cases, we argue that study of the neural implementation of behavior is best investigated after such behavioral work. Thus, we advocate a more pluralistic notion of neuroscience when it comes to the brain-behavior relationship: behavioral work provides understanding, whereas neural interventions test causality.
Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS).
The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100 mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day.
This article is part of a Special Issue titled "Cannabinoids and Epilepsy".
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.
Objective:
To review population-based studies of the prevalence and incidence of epilepsy worldwide and use meta-analytic techniques to explore factors that may explain heterogeneity between estimates.
Methods:
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed. We searched MEDLINE and EMBASE for articles published on the prevalence or incidence of epilepsy since 1985. Abstract, full-text review, and data abstraction were conducted in duplicate. Meta-analyses and meta-regressions were used to explore the association between prevalence or incidence, age group, sex, country level income, and study quality.
Results:
A total of 222 studies were included (197 on prevalence, 48 on incidence). The point prevalence of active epilepsy was 6.38 per 1,000 persons (95% confidence interval [95% CI] 5.57-7.30), while the lifetime prevalence was 7.60 per 1,000 persons (95% CI 6.17-9.38). The annual cumulative incidence of epilepsy was 67.77 per 100,000 persons (95% CI 56.69-81.03) while the incidence rate was 61.44 per 100,000 person-years (95% CI 50.75-74.38). The prevalence of epilepsy did not differ by age group, sex, or study quality. The active annual period prevalence, lifetime prevalence, and incidence rate of epilepsy were higher in low to middle income countries. Epilepsies of unknown etiology and those with generalized seizures had the highest prevalence.
Conclusions:
This study provides a comprehensive synthesis of the prevalence and incidence of epilepsy from published international studies and offers insight into factors that contribute to heterogeneity between estimates. Significant gaps (e.g., lack of incidence studies, stratification by age groups) were identified. Standardized reporting of future epidemiologic studies of epilepsy is needed.
The treatment of epileptic seizure disorders is not restricted to the achievement of seizure-freedom, but must also include the management of comorbid medical, neurological, psychiatric and cognitive comorbidities. Psychiatric and neurological comorbidities are relatively common and often co-exist in people with epilepsy (PWE). For example, depression and anxiety disorders are the most common psychiatric comorbidities in PWE, and they are particularly common in PWE who also have a neurological comorbidity, such as migraine, stroke, traumatic brain injury or dementia. Moreover, psychiatric and neurological comorbodities often have a more severe impact on the quality of life in patients with treatment-resistant focal epilepsy than do the actual seizures. Epilepsy and psychiatric and neurological comorbidities have a complex relationship, which has a direct bearing on the management of both seizures and the comorbidities: the comorbidities have to be factored into the selection of antiepileptic drugs, and the susceptibility to seizures has to be considered when choosing the drugs to treat comorbidities. The aim of this Review is to highlight the complex relationship between epilepsy and common psychiatric and neurological comorbidities, and provide an overview of how treatment strategies for epilepsy can positively and negatively affect these comorbidities and vice versa.
Background:
Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy.
Methods:
In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test.
Results:
Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0-96·0) at baseline and 15·8 (5·6-57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0-64·7).
Interpretation:
Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.
Funding:
GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.
For thousands of years cannabis has been valued as a versatile herbal medicine. In the twentieth century, prescription gave way to proscription. Might this ancient remedy be about to regain its healing reputation? By Stephanie Pain
The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD (10, 20 and 50 mg/kg) for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits (NR1 and NR2B) was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD (50 mg/kg). The neuronal loss and astrocyte hyperplasia in the hippocampal area were also decreased. CBD treatment did not affect the expression of iNOS in the hippocampus; however, the expression of NR1 was decreased significantly. Thus, CBD administration inhibited the effect of pentylenetetrazole in rats, decreased the astrocytic hyperplasia, decreased neuronal damage in the hippocampus caused by seizures and selectively reduced the expression of the NR1 subunit of NMDA. Therefore, CBD exhibits an anticonvulsive effect in the rats with chronic epilepsy.
The more recent history and main experimental data for the Krushinsky-Molodkina (KM) audiogenic rat strain are presented. The strain selection started in late 1940. Now this strain is inbred, and two new strains are maintained in a laboratory in parallel. These strains originated from KM×Wistar hybrids and were bred (starting from 2000) for no-seizure and intense audiogenic seizure phenotypes, respectively. The experimental evidences of audiogenic seizure physiology were accumulated in parallel with (and usually ahead of) data on other audiogenic-prone strains. The peculiar feature of the KM strain is its vulnerability to brain hemorrhages. Thus, the KM strain is used not only as a genetic model of seizure states, but also as a model of blood flow disturbances in the brain. This article is part of a Special Issue entitled: "Genetic Models-Epilepsy".
Copyright © 2015 Elsevier Inc. All rights reserved.
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.
Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
The definition of reflex epileptic seizures is that specific seizure types can be triggered by certain sensory or cognitive stimuli. Simple triggers are sensory (most often visual, more rarely tactile or proprioceptive; simple audiogenic triggers in humans are practically nonexistent) and act within seconds, whereas complex triggers like praxis, reading and talking, and music are mostly cognitive and work within minutes. The constant relation between a qualitatively, often even quantitatively, well-defined stimulus and a specific epileptic response provides unique possibilities to investigate seizure generation in natural human epilepsies. For several reflex epileptic mechanisms (REMs), this has been done. Reflex epileptic mechanisms have been reported less often in focal lesional epilepsies than in idiopathic "generalized" epilepsies (IGEs) which are primarily genetically determined. The key syndrome of IGE is juvenile myoclonic epilepsy (JME), where more than half of the patients present reflex epileptic traits (photosensitivity, eye closure sensitivity, praxis induction, and language-induced orofacial reflex myocloni). Findings with multimodal investigations of cerebral function concur to indicate that ictogenic mechanisms in IGEs largely (ab)use preexisting functional anatomic networks (CNS subsystems) normally serving highly complex physiological functions (e.g., deliberate complex actions and linguistic communication) which supports the concept of system epilepsy. Whereas REMs in IGEs, thus, are primarily function-related, in focal epilepsies, they are primarily localization-related. This article is part of a Special Issue entitled "Genetic Models-Epilepsy".
Copyright © 2015 Elsevier Inc. All rights reserved.
Oral cannabis extracts (OCEs) have been used in the treatment of epilepsy; however, no studies demonstrate clear efficacy. We report on a cohort of pediatric patients with epilepsy who were given OCE and followed in a single tertiary epilepsy center.
A retrospective chart review of children and adolescents who were given OCE for treatment of their epilepsy was performed.
Seventy-five patients were identified of which 57% reported any improvement in seizure control and 33% reported a >50% reduction in seizures (responders). If the family had moved to CO for OCE treatment, the responder rate was 47% vs. 22% for children who already were in CO. The responder rate varied based on epilepsy syndrome: Dravet 23%, Doose 0%, and Lennox-Gastaut syndrome (LGS) 88.9%. The background EEG of the 8 responders where EEG data were available was not improved. Additional benefits reported included: improved behavior/alertness (33%), improved language (10%), and improved motor skills (10%). Adverse events (AEs) occurred in 44% of patients including increased seizures (13%) and somnolence/fatigue (12%). Rare adverse events included developmental regression, abnormal movements, status epilepticus requiring intubation, and death.
Our retrospective study of OCE use in pediatric patients with epilepsy demonstrates that some families reported patient improvement with treatment; however, we also found a variety of challenges and possible confounding factors in studying OCE retrospectively in an open-labeled fashion. We strongly support the need for controlled, blinded studies to evaluate the efficacy and safety of OCE for treatment of pediatric epilepsies using accurate seizure counts, formal neurocognitive assessments, as well as EEG as a biomarker. This study provides Class III evidence that OCE is well tolerated by children and adolescents with epilepsy.
Copyright © 2015 Elsevier Inc. All rights reserved.
Translation of successful target and compound validation studies into clinically effective therapies is a major challenge, with potential for costly clinical trial failures. This situation holds true for the epilepsies—complex diseases with different causes and symptoms. Although the availability of predictive animal models has led to the development of effective antiseizure therapies that are routinely used in clinical practice, showing that translation can be successful, several important unmet therapeutic needs still exist. Available treatments do not fully control seizures in a third of patients with epilepsy, and produce substantial side-effects. No treatment can prevent the development of epilepsy in at-risk patients or cure patients with epilepsy. And no specific treatment for epilepsy-associated comorbidities exists. To meet these demands, a redesign of translational approaches is urgently needed.
Psychiatric disorders seem to be more frequent in patients with epilepsy (PWE) than the general population. Although researchers have documented a strong association between epilepsy and psychiatric comorbidities, the nature of this relationship is poorly understood. According to this, psychiatric diseases are often underdiagnosed and undertreated in PWE with further decrease of the quality of life of patients. The aim of the review was to examine the most frequent psychiatric comorbidities in adults with epilepsy (AWE) and the main psychiatric comorbidities in children with epilepsy (CWE) in order to better understand the relationship between epilepsy and the development of psychiatric disorders.
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. Δ9-Tetrahydrocannabinol (Δ9-THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ9-THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ9-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:Δ9-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.
Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy ( ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age‐dependent epilepsy syndrome but are now past the applicable age or who have remained seizure‐free for the last 10 years and off antiseizure medicines for at least the last 5 years. “Resolved” is not necessarily identical to the conventional view of “remission or “cure.” Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use.
A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .
