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Jose Alexandre De Souza Crippa - One of the best experts on this subject based on the ideXlab platform.
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dissociation between the panicolytic effect of Cannabidiol microinjected into the substantia nigra pars reticulata and fear induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus the role of cb1 canna
European Journal of Pharmacology, 2015Co-Authors: Juliana Almeida Da Silva, Antonio Waldo Zuardi, Audrey Francisco Biagioni, Rafael Carvalho Almada, Jose Alexandre De Souza Crippa, Jaime Eduardo Cecilio Hallak, Norberto Cysne CoimbraAbstract:Many studies suggest that the substantia nigra, pars reticulata (SNpr), a tegmental mesencephalic structure rich in γ-aminobutyric acid (GABA)- and cannabinoid receptor-containing neurons, is involved in the complex control of defensive responses through the neostriatum-nigral disinhibitory and nigro-tectal inhibitory GABAergic pathways during imminently dangerous situations. The aim of the present work was to investigate the role played by CB1-cannabinoid receptor of GABAergic pathways terminal boutons in the SNpr or of SNpr-endocannabinoid receptor-containing interneurons on the effect of intra-nigral microinjections of Cannabidiol in the activity of nigro-tectal inhibitory pathways. GABAA receptor blockade in the deep layers of the superior colliculus (dlSC) elicited vigorous defensive behaviour. This explosive escape behaviour was followed by significant antinociception. Cannabidiol microinjection into the SNpr had a clear anti-aversive effect, decreasing the duration of defensive alertness, the frequency and duration of defensive immobility, and the frequency and duration of explosive escape behaviour, expressed by running and jumps, elicited by transitory GABAergic dysfunction in dlSC. However, the innate fear induced-antinociception was not significantly changed. The blockade of CB1 endocannabinoid receptor in the SNpr decreased the anti-aversive effect of canabidiol based on the frequency and duration of defensive immobility, the frequency of escape expressed by running, and both the frequency and duration of escape expressed by jumps. These findings suggest a CB1 mediated endocannabinoid signalling in Cannabidiol modulation of panic-like defensive behaviour, but not of innate fear-induced antinociception evoked by GABAA receptor blockade with bicuculline microinjection into the superior colliculus, with a putative activity in nigro-collicular GABAergic pathways.
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the role of 5 ht1a receptors in the anti aversive effects of Cannabidiol on panic attack like behaviors evoked in the presence of the wild snake epicrates cenchria crassus reptilia boidae
Journal of Psychopharmacology, 2013Co-Authors: Andre Twardowschy, Audrey Francisco Biagioni, Jose Alexandre De Souza Crippa, M A Castiblancourbina, A Uribemarino, Carlos Jose Salgadorohner, N C CoimbraAbstract:The potential anxiolytic and antipanic properties of Cannabidiol have been shown; however, its mechanism of action seems to recruit other receptors than those involved in the endocannabinoid-mediated system. It was recently shown that the model of panic-like behaviors elicited by the encounters between mice and snakes is a good tool to investigate innate fear-related responses, and Cannabidiol causes a panicolytic-like effect in this model. The aim of the present study was to investigate the 5-hydroxytryptamine (5-HT) co-participation in the panicolytic-like effects of Cannabidiol on the innate fear-related behaviors evoked by a prey versus predator interaction-based paradigm. Male Swiss mice were treated with intraperitoneal (i.p.) administrations of Cannabidiol (3 mg/kg, i.p.) and its vehicle and the effects of the peripheral pre-treatment with increasing doses of the 5-HT1A receptor antagonist WAY-100635 (0.1, 0.3 and 0.9 mg/kg, i.p.) on instinctive fear-induced responses evoked by the presence of a wild snake were evaluated. The present results showed that the panicolytic-like effects of Cannabidiol were blocked by the pre-treatment with WAY-100635 at different doses. These findings demonstrate that Cannabidiol modulates the defensive behaviors evoked by the presence of threatening stimuli, and the effects of Cannabidiol are at least partially dependent on the recruitment of 5-HT1A receptors.
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anti aversive effects of Cannabidiol on innate fear induced behaviors evoked by an ethological model of panic attacks based on a prey vs the wild snake epicrates cenchria crassus confrontation paradigm
Neuropsychopharmacology, 2012Co-Authors: A Uribemarino, Jose Alexandre De Souza Crippa, Jaime Eduardo Cecilio Hallak, Andre Twardowschy, M A Castiblancourbina, Carlos Jose Salgadorohner, Audrey Francisco, Antonio Waldo ZuardiAbstract:Several pharmacological targets have been proposed as modulators of panic-like reactions. However, interest should be given to other potential therapeutic neurochemical agents. Recent attention has been given to the potential anxiolytic properties of Cannabidiol, because of its complex actions on the endocannabinoid system together with its effects on other neurotransmitter systems. The aim of this study was to investigate the effects of Cannabidiol on innate fear-related behaviors evoked by a prey vs predator paradigm. Male Swiss mice were submitted to habituation in an arena containing a burrow and subsequently pre-treated with intraperitoneal administrations of vehicle or Cannabidiol. A constrictor snake was placed inside the arena, and defensive and non-defensive behaviors were recorded. Cannabidiol caused a clear anti-aversive effect, decreasing explosive escape and defensive immobility behaviors outside and inside the burrow. These results show that Cannabidiol modulates defensive behaviors evoked by the presence of threatening stimuli, even in a potentially safe environment following a fear response, suggesting a panicolytic effect.
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performance of schizophrenic patients in the stroop color word test and electrodermal responsiveness after acute administration of Cannabidiol cbd
Revista Brasileira de Psiquiatria, 2010Co-Authors: Jaime Eduardo Cecilio Hallak, Jose Alexandre De Souza Crippa, Joao Paulo Machadodesousa, Rafael Faria Sanches, Clarissa Trzesniak, Cristiano Chaves, Sandra Aparecida Bernardo, Simone Cecilio Hallak Regalo, Antonio Waldo ZuardiAbstract:OBJETIVO: Descobertas relativas a possiveis disfuncoes do sistema canabinoide endogeno na esquizofrenia e sua relacao com o prejuizo cognitivo caracteristico da doenca tem aumentado durante a ultima decada. Estudos com modelos animais, voluntarios saudaveis e pacientes psicoticos sugerem claramente que o canabidiol possui efeitos antipsicoticos. Este estudo investigou os efeitos do canabidiol sobre a atencao seletiva por meio do Stroop Color Word Test e a responsividade eletrodermica a estimulos auditivos em 28 pacientes com esquizofrenia. METODO: Duas sessoes experimentais foram realizadas, a primeira sem a administracao de drogas. Na segunda sessao, os sujeitos foram divididos em tres grupos que receberam dose unica de canabidiol 300mg, canabidiol 600mg ou placebo. RESULTADOS: Os tres grupos nao diferiram significativamente no que se refere as medidas eletrodermicas nas duas sessoes experimentais. Os tres grupos apresentaram melhora da primeira para a segunda avaliacao, com os grupos placebo e canabidiol 300mg superiores ao grupo canabidiol 600mg. CONCLUSAO: A administracao aguda de canabidiol em dose unica parece nao ter efeitos beneficos sobre o desempenho de pacientes com esquizofrenia no Stroop Color Word Test, embora estes dados nao sejam suficientes para refutar a hipotese de que a administracao continuada de canabidiol possa resultar em melhora no funcionamento cognitivo em esquizofrenia.
Elizabeth A Thiele - One of the best experts on this subject based on the ideXlab platform.
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add on Cannabidiol treatment for drug resistant seizures in tuberous sclerosis complex a placebo controlled randomized clinical trial
JAMA Neurology, 2021Co-Authors: Elizabeth A Thiele, Martina E Bebin, Hari Bhathal, Floor E Jansen, Katarzyna Kotulska, John A Lawson, Finbar Ocallaghan, Michael Wong, Farhad Sahebkar, Daniel CheckettsAbstract:Importance: Efficacy of Cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). Objective: To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day Cannabidiol dosages vs placebo against seizures associated with TSC. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication. Interventions: Patients received oral Cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks. Main Outcomes and Measures: The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for Cannabidiol vs placebo during the treatment period. Results: Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with Cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking Cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo. Conclusions and Relevance: Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage. Trial Registration: ClinicalTrials.gov Identifier: NCT02544763.
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Cannabidiol in patients with seizures associated with lennox gastaut syndrome gwpcare4 a randomised double blind placebo controlled phase 3 trial
The Lancet, 2018Co-Authors: Elizabeth A Thiele, Paul D Lyons, Maria Mazurkiewiczbeldzinska, Eric D. Marsh, Charuta Joshi, Selim R. Benbadis, Jacqueline A French, Adam Taylor, Claire Roberts, Kenneth W SommervilleAbstract:Summary 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 ( 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.
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Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
New England Journal of Medicine, 2017Co-Authors: Orrin Devinsky, Eric D. Marsh, Elizabeth A Thiele, Linda Laux, J. Helen Cross, Ian Miller, Ingrid E. Scheffer, Rima Nabbout, Stephen WrightAbstract:BackgroundThe 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. MethodsIn 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. ResultsThe 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 i...
Antonio Waldo Zuardi - One of the best experts on this subject based on the ideXlab platform.
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dissociation between the panicolytic effect of Cannabidiol microinjected into the substantia nigra pars reticulata and fear induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus the role of cb1 canna
European Journal of Pharmacology, 2015Co-Authors: Juliana Almeida Da Silva, Antonio Waldo Zuardi, Audrey Francisco Biagioni, Rafael Carvalho Almada, Jose Alexandre De Souza Crippa, Jaime Eduardo Cecilio Hallak, Norberto Cysne CoimbraAbstract:Many studies suggest that the substantia nigra, pars reticulata (SNpr), a tegmental mesencephalic structure rich in γ-aminobutyric acid (GABA)- and cannabinoid receptor-containing neurons, is involved in the complex control of defensive responses through the neostriatum-nigral disinhibitory and nigro-tectal inhibitory GABAergic pathways during imminently dangerous situations. The aim of the present work was to investigate the role played by CB1-cannabinoid receptor of GABAergic pathways terminal boutons in the SNpr or of SNpr-endocannabinoid receptor-containing interneurons on the effect of intra-nigral microinjections of Cannabidiol in the activity of nigro-tectal inhibitory pathways. GABAA receptor blockade in the deep layers of the superior colliculus (dlSC) elicited vigorous defensive behaviour. This explosive escape behaviour was followed by significant antinociception. Cannabidiol microinjection into the SNpr had a clear anti-aversive effect, decreasing the duration of defensive alertness, the frequency and duration of defensive immobility, and the frequency and duration of explosive escape behaviour, expressed by running and jumps, elicited by transitory GABAergic dysfunction in dlSC. However, the innate fear induced-antinociception was not significantly changed. The blockade of CB1 endocannabinoid receptor in the SNpr decreased the anti-aversive effect of canabidiol based on the frequency and duration of defensive immobility, the frequency of escape expressed by running, and both the frequency and duration of escape expressed by jumps. These findings suggest a CB1 mediated endocannabinoid signalling in Cannabidiol modulation of panic-like defensive behaviour, but not of innate fear-induced antinociception evoked by GABAA receptor blockade with bicuculline microinjection into the superior colliculus, with a putative activity in nigro-collicular GABAergic pathways.
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Cannabidiol reduces host immune response and prevents cognitive impairments in wistar rats submitted to pneumococcal meningitis
European Journal of Pharmacology, 2012Co-Authors: Tatiana Barichello, Joao Quevedo, Renan Antonio Ceretta, Jaqueline S Generoso, Ana Paula Moreira, Lutiana R Simoes, Clarissa M Comim, Marcia Carvalho Vilela, Antonio Waldo ZuardiAbstract:Abstract Pneumococcal meningitis is a life-threatening disease characterized by an acute infection affecting the pia matter, arachnoid and subarachnoid space. The intense inflammatory response is associated with a significant mortality rate and neurologic sequelae, such as, seizures, sensory-motor deficits and impairment of learning and memory. The aim of this study was to evaluate the effects of acute and extended administration of Cannabidiol on pro-inflammatory cytokines and behavioral parameters in adult Wistar rats submitted to pneumococcal meningitis. Male Wistar rats underwent a cisterna magna tap and received either 10 μl of sterile saline as a placebo or an equivalent volume of S. pneumoniae suspension. Rats subjected to meningitis were treated by intraperitoneal injection with Cannabidiol (2.5, 5, or 10 mg/kg once or daily for 9 days after meningitis induction) or a placebo. Six hours after meningitis induction, the rats that received one dose were killed and the hippocampus and frontal cortex were obtained to assess cytokines/chemokine and brain-derived neurotrophic factor levels. On the 10th day, the rats were submitted to the inhibitory avoidance task. After the task, the animals were killed and samples from the hippocampus and frontal cortex were obtained. The extended administration of Cannabidiol at different doses reduced the TNF-α level in frontal cortex. Prolonged treatment with canabidiol, 10 mg/kg, prevented memory impairment in rats with pneumococcal meningitis. Although descriptive, our results demonstrate that Cannabidiol has anti-inflammatory effects in pneumococcal meningitis and prevents cognitive sequel.
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anti aversive effects of Cannabidiol on innate fear induced behaviors evoked by an ethological model of panic attacks based on a prey vs the wild snake epicrates cenchria crassus confrontation paradigm
Neuropsychopharmacology, 2012Co-Authors: A Uribemarino, Jose Alexandre De Souza Crippa, Jaime Eduardo Cecilio Hallak, Andre Twardowschy, M A Castiblancourbina, Carlos Jose Salgadorohner, Audrey Francisco, Antonio Waldo ZuardiAbstract:Several pharmacological targets have been proposed as modulators of panic-like reactions. However, interest should be given to other potential therapeutic neurochemical agents. Recent attention has been given to the potential anxiolytic properties of Cannabidiol, because of its complex actions on the endocannabinoid system together with its effects on other neurotransmitter systems. The aim of this study was to investigate the effects of Cannabidiol on innate fear-related behaviors evoked by a prey vs predator paradigm. Male Swiss mice were submitted to habituation in an arena containing a burrow and subsequently pre-treated with intraperitoneal administrations of vehicle or Cannabidiol. A constrictor snake was placed inside the arena, and defensive and non-defensive behaviors were recorded. Cannabidiol caused a clear anti-aversive effect, decreasing explosive escape and defensive immobility behaviors outside and inside the burrow. These results show that Cannabidiol modulates defensive behaviors evoked by the presence of threatening stimuli, even in a potentially safe environment following a fear response, suggesting a panicolytic effect.
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administration of Cannabidiol and imipramine induces antidepressant like effects in the forced swimming test and increases brain derived neurotrophic factor levels in the rat amygdala
Acta Neuropsychiatrica, 2011Co-Authors: Gislaine Z Reus, Jaime Eduardo Cecilio Hallak, Roberto B Stringari, Karine F Ribeiro, Tatiana Luft, Helena M Abelaira, Gabriel Rodrigo Fries, Bianca Wollenhaupt De Aguiar, Flavio Kapczinski, Antonio Waldo ZuardiAbstract:Reus GZ, Stringari RB, Ribeiro KF, Luft T, Abelaira HM, Fries GR, Aguiar BW, Kapczinski F, Hallak JE, Zuardi AW, Crippa JA, Quevedo J. Administration of Cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala. Objective: Cannabidiol is a chemical constituent from Cannabis sativa and it has multiple mechanisms of action, including antidepressant effects. The main objective of the present study was to evaluate behavioural and molecular effects induced by administration of Cannabidiol and imipramine in rats. Methods: In the present study, rats were acutely or chronically treated for 14 days once a day with saline, Cannabidiol (15, 30 and 60 mg/kg) or imipramine (30 mg/kg) and the animals behaviour was assessed in forced swimming and open-field tests. Afterwards, the prefrontal cortex, hippocampus and amygdala brain-derived neurotrophic factor (BDNF) levels were assessed by enzyme-linked immunosorbent sandwich assay. Results: We observed that both acute and chronic treatments with imipramine at the dose of 30 mg/kg and Cannabidiol at the dose of 30 mg/kg reduced immobility time and increased swimming time; climbing time was increased only with imipramine at the dose of 30 mg/kg, without affecting locomotor activity. In addition, chronic treatment with Cannabidiol at the dose of 15 mg/kg and imipramine at the dose of 30 mg/kg increased BDNF levels in the rat amygdala. Conclusion: In conclusion, our results indicate that Cannabidiol has an antidepressant-like profile and could be a new pharmacological target for the treatment of major depression.
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performance of schizophrenic patients in the stroop color word test and electrodermal responsiveness after acute administration of Cannabidiol cbd
Revista Brasileira de Psiquiatria, 2010Co-Authors: Jaime Eduardo Cecilio Hallak, Jose Alexandre De Souza Crippa, Joao Paulo Machadodesousa, Rafael Faria Sanches, Clarissa Trzesniak, Cristiano Chaves, Sandra Aparecida Bernardo, Simone Cecilio Hallak Regalo, Antonio Waldo ZuardiAbstract:OBJETIVO: Descobertas relativas a possiveis disfuncoes do sistema canabinoide endogeno na esquizofrenia e sua relacao com o prejuizo cognitivo caracteristico da doenca tem aumentado durante a ultima decada. Estudos com modelos animais, voluntarios saudaveis e pacientes psicoticos sugerem claramente que o canabidiol possui efeitos antipsicoticos. Este estudo investigou os efeitos do canabidiol sobre a atencao seletiva por meio do Stroop Color Word Test e a responsividade eletrodermica a estimulos auditivos em 28 pacientes com esquizofrenia. METODO: Duas sessoes experimentais foram realizadas, a primeira sem a administracao de drogas. Na segunda sessao, os sujeitos foram divididos em tres grupos que receberam dose unica de canabidiol 300mg, canabidiol 600mg ou placebo. RESULTADOS: Os tres grupos nao diferiram significativamente no que se refere as medidas eletrodermicas nas duas sessoes experimentais. Os tres grupos apresentaram melhora da primeira para a segunda avaliacao, com os grupos placebo e canabidiol 300mg superiores ao grupo canabidiol 600mg. CONCLUSAO: A administracao aguda de canabidiol em dose unica parece nao ter efeitos beneficos sobre o desempenho de pacientes com esquizofrenia no Stroop Color Word Test, embora estes dados nao sejam suficientes para refutar a hipotese de que a administracao continuada de canabidiol possa resultar em melhora no funcionamento cognitivo em esquizofrenia.
Kenneth W Sommerville - One of the best experts on this subject based on the ideXlab platform.
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a phase 1 open label pharmacokinetic trial to investigate possible drug drug interactions between clobazam stiripentol or valproate and Cannabidiol in healthy subjects
Clinical pharmacology in drug development, 2019Co-Authors: Gilmour Morrison, Julie Crockett, Graham Blakey, Kenneth W SommervilleAbstract:GW Pharmaceuticals' formulation of highly purified Cannabidiol oral solution is approved in the United States for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of Cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on Cannabidiol and its major metabolites (7-hydroxy-Cannabidiol [7-OH-CBD] and 7-carboxy-Cannabidiol [7-COOH-CBD]); and Cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant Cannabidiol had little effect on clobazam exposure (maximum concentration [Cmax ] and area under the concentration-time curve [AUC], 1.2-fold), N-desmethylclobazam exposure increased (Cmax and AUC, 3.4-fold), stiripentol exposure increased slightly (Cmax , 1.3-fold; AUC, 1.6-fold), while no clinically relevant effect on valproate exposure was observed. Concomitant clobazam with Cannabidiol increased 7-OH-CBD exposure (Cmax , 1.7-fold; AUC, 1.5-fold), without notable 7-COOH-CBD or Cannabidiol increases. Stiripentol decreased 7-OH-CBD exposure by 29% and 7-COOH-CBD exposure by 13%. There was no effect of valproate on Cannabidiol or its metabolites. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clinically significant safety findings.
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Cannabidiol in patients with seizures associated with lennox gastaut syndrome gwpcare4 a randomised double blind placebo controlled phase 3 trial
The Lancet, 2018Co-Authors: Elizabeth A Thiele, Paul D Lyons, Maria Mazurkiewiczbeldzinska, Eric D. Marsh, Charuta Joshi, Selim R. Benbadis, Jacqueline A French, Adam Taylor, Claire Roberts, Kenneth W SommervilleAbstract:Summary 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 ( 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.
Orrin Devinsky - One of the best experts on this subject based on the ideXlab platform.
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effect of Cannabidiol on drop seizures in the lennox gastaut syndrome
The New England Journal of Medicine, 2018Co-Authors: Orrin Devinsky, Claire Roberts, Anup Patel, Helen J Cross, Vicente Villanueva, Elaine C Wirrell, Michael Privitera, Sam M Greenwood, Daniel Checketts, Kevan E VanlandinghamAbstract:Abstract Background Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of Cannabidiol added to a regime...
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Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
New England Journal of Medicine, 2017Co-Authors: Orrin Devinsky, Eric D. Marsh, Elizabeth A Thiele, Linda Laux, J. Helen Cross, Ian Miller, Ingrid E. Scheffer, Rima Nabbout, Stephen WrightAbstract:BackgroundThe 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. MethodsIn 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. ResultsThe 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 i...
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Cannabidiol as a potential treatment for febrile infection related epilepsy syndrome fires in the acute and chronic phases
Journal of Child Neurology, 2017Co-Authors: Jacqueline S Gofshteyn, Eric D. Marsh, Linda Laux, Orrin Devinsky, Angus Wilfong, Judith Bluvstein, Joshi Charuta, Michael A CilibertoAbstract:Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy affecting normal children after a febrile illness. FIRES presents with an acute phase with super-refractory status epilepticus and all patients progress to a chronic phase with persistent refractory epilepsy. The typical outcome is severe encephalopathy or death. The authors present 7 children from 5 centers with FIRES who had not responded to antiepileptic drugs or other therapies who were given cannabadiol (Epidiolex, GW Pharma) on emergency or expanded investigational protocols in either the acute or chronic phase of illness. After starting Cannabidiol, 6 of 7 patients' seizures improved in frequency and duration. One patient died due to multiorgan failure secondary to isoflourane. An average of 4 antiepileptic drugs were weaned. Currently 5 subjects are ambulatory, 1 walks with assistance, and 4 are verbal. While this is an open-label case series, the authors add Cannabidiol as a possible treatment for FIRES.
