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Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex
Epilepsia
Abstract
Objective:
Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC.
Methods:
Eighteen of the 56 patients who have enrolled in our current expanded-access study of cannabidiol for patients with treatment-resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1 month, patients began treatment with CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD.
Results:
The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8-57.4), which decreased to 13.3 (IQR 5.1-22.1) after 3 months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was -48.8% (IQR -69.1% to -11.1%) after 3 months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12 months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n = 12), the responder rate after 3 months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n = 6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n = 8, 44.4%), ataxia (n = 5, 27.8%), and diarrhea (n = 4, 22.2%).
Significance:
Although double-blind, placebo-controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well-tolerated treatment option for patients with refractory seizures in TSC.
... The therapeutic use of CBD is more attractive than THC due to its non-psychoactive properties [2]. This has led to an increasing interest in using CBD to treat brain disorders, such as epilepsy, pain, depression, anxiety, and psychosis [3][4][5][6][7][8][9][10]. This is reflected in the approval of Epidi-olex® (a CBD oral solution) by the United States Food and Drug Administration in June 2018 for treating refractory epileptic seizures in patients with Dravet and Lennox-Gastaut syndromes, as well as in July 2020 for seizures associated with tuberous sclerosis complex [11]. ...
... The use of CBD in refractory seizures associated with TSC was studied by Hess et al. [4]. Patients with TSC associated with drug-resistant epilepsy were given a maximum of 50 mg/kg/day CBD for 3 months. ...
... Patients with TSC associated with drug-resistant epilepsy were given a maximum of 50 mg/kg/day CBD for 3 months. A significant reduction by nearly half (48.8%) in weekly seizure frequency was recorded when compared to baseline [4]. Thiele et al. conducted a similar clinical trial in patients with TSC showed that 16-week CBD administration (25 or 50 mg/kg/day) reduced seizure frequency by 47-49%, which was about 20% more reduction than the placebo group (26.5%) [67]. ...
The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.
... We implemented several inclusion and exclusion criteria to identify relevant papers (Table 1). We found two primary types of studies: openlabel studies from the expanded access programs (12 months follow-up, 5-year follow-up, efficacy and safety of CBD therapy with or without clobazam, the efficacy of CBD against epileptic spasms) and one pivotal RCT (16 weeks efficacy and safety, efficacy in patients with or without a history of spasms, and multiple interim analysis of open-label extension) [14][15][16][17][18][19][20][21][22][23]. Many of these studies are still available in abstract form only [15,[20][21][22]. ...
... Clinical efficacy of 99% pure CBD extract in DRE with TSC was first reported in 2016 from an open-label, expanded-access program (EAP) in 18 patients [18]. In that study, weekly median seizure frequency decreased by half after three months of treatment, and 38.9-50% of patients had !50% seizure reduction throughout the treatment course over one year. ...
... CBD's role in the serotonergic/dopaminergic pathway leads to further hope in mitigating cognitive and behavioral challenges [40,41]. Hess et al. reported that 12 (85.7%) of 14 patients had improved cognitive function (improved alertness, verbal communication, vocalizations, cognitive ability, and initiation of emotional and physical connections), and in 6 (66.7%) patients had behavioral improvements during treatment with CBD [18]. These changes were independent of seizure control. ...
Cannabidiol (CBD) has recently been approved as an add-on therapy by various regulatory agencies for tuberous sclerosis complex (TSC)-associated seizures based on its short-term efficacy and safety in a pivotal randomized controlled trial. However, critical information about which patients with TSC and seizure types respond best to CBD (clinical, electrophysiological, and genetic predictors of responsiveness), when to use CBD in the treatment algorithm, and how CBD can be combined with other antiseizure medications (ASMs) in the form of a rational polypharmacy therapy is still lacking. In general, there is a limited in-depth critical review of CBD for the treatment of TSC to facilitate its optimal use in a clinical context. Here, we utilized a scoping review approach to report the current evidence of efficacy and safety of pharmaceutical-grade CBD in patients with TSC, including relevant mechanism of action and drug–drug interactions with other ASMs. We also discussed emerging information about CBD’s long-term efficacy and safety data in patients with TSC. Finally, we discussed some critical unanswered questions in several domains related to effective clinical management of TSC using CBD, including barriers to early and aggressive treatment in infants, difficulty with universal access to CBD, a lack of studies to understand CBD’s impact on seizure severity and specific seizure types, insufficient exploration of CBD in TSC-related cognitive and behavioral issues, and the need for more research into CBD’s effects on various biomarkers.
... Although most studies support our findings, a 2018 review that included non-RCT articles reported no significant change in withdrawal rates after monitoring patients for 883 weeks (Stockings et al. 2018). Yet, several clinical trials involving various types of epileptic patients have indicated a significantly higher withdrawal rate among those in the CBD arm due to adverse effects (Devinsky et al. 2018;Hess et al. 2016;Miller et al. 2020). ...
... In contrast, a clinical trial indicated significant increased risk of vomiting as a side effect for CBD use in patients with TSC (Thiele et al. 2021). However, these findings are against other large trials reporting significant risk of diarrhea, somnolence, changes in appetite and fatigue as main adverse effects following the consumption of CBD (Devinsky et al. 2018;Hess et al. 2016;Miller et al. 2020). Likewise, recent reviews have confirmed our findings regarding the risk of pyrexia, vomiting, and upper respiratory infection, identifying diarrhea, somnolence, and changes in appetite as the primary side effects of CBD use (Franco et al. 2021;Solmi et al. 2023). ...
Background
Epilepsy ranks among the most prevalent neurological conditions worldwide. Cannabidiol (CBD) has received authorization for epilepsy treatment, yet utilizing CBD is linked to a variety of adverse events (AEs). This umbrella review aims to explore risk and frequency of AEs in epilepsy patients undergoing treatment with CBD.
Methods
International electronic databases comprising Scopus, PubMed, and Web of Science were extensively searched from the most ancient data accessible until May 2024. In line with fundamental principle of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA), this umbrella review was executed. RStudio software version 2023.03.1 along with R software 4.3.2 was used for our statistical analyses.
Results
Thirteen meta-analyses and systematic reviews were included. CBD use in epileptic patients compared to controls can be meaningfully linked with 10.87% becoming seizure-free (RD: 10.87%, 95%CI: 2.39%, 19.34%; I² = 80%). Compared to controls, a meaningful 73% increase in 50% or greater reduction in seizure frequency was observed (RR: 1.73, 95%CI: 1.47, 2.03; I² = 0%). In epileptic individuals who using CBD with the dosage of 20 mg/kg/d, a higher incidence of treatment withdrawal was detected (RR: 4.39, 95%CI: 2.46, 7.83; I² = 0%).
Conclusion
In this umbrella review of meta-analyses and systematic reviews, CBD use in epileptic patients was linked to an increased risk of ample AEs. Further research, specifically targeting various epilepsy categories, is essential to fully understand the effectiveness and potential side effects of CBD across different epilepsy forms.
... [15][16][17][18] An interim analysis of patients with TSC at a single EAP site showed a reduction in seizure frequency (all types) after 3 months of CBD treatment. 1 In this analysis of the pooled data from patients with TSC in the EAP, we report the long-term efficacy (up to 144 weeks) and safety (through 233 weeks) of add-on CBD treatment. ...
... These patients were also included in our previous EAP reports. 1,18,19 In the TSC cohort, overall, eight (24%) patients withdrew, primarily because of lack of efficacy (4 [12%]). Five patients withdrew within 1 year of starting treatment, and three patients withdrew after 1 year of treatment (Table S1). ...
Objective
The cannabidiol (CBD) Expanded Access Program provided compassionate access to CBD for patients with treatment‐resistant epilepsy, including tuberous sclerosis complex (TSC), at 35 US epilepsy centers. Here, we present the long‐term efficacy and safety outcomes for add‐on CBD treatment in patients with TSC.
Methods
Patients received plant‐derived, highly purified CBD (Epidiolex® 100 mg/mL, oral solution), increasing from 2 to 10 mg/kg/d to tolerance or maximum of 25–50 mg/kg/d. Efficacy endpoints were percentage change from baseline in median monthly convulsive, focal, and total seizure frequency and ≥ 50%, ≥75%, and 100% responder rates across 12‐week visit windows through 144 weeks. Adverse events (AEs) are reported through 233 weeks.
Results
Thirty‐four patients with confirmed TSC were included. Mean age was 12.4 years (range, 1.8–31.2), and patients were receiving a median of 3 (range, 1–7) antiseizure medications (ASMs) at baseline. Median CBD dose was 25–28 mg/kg/d for 36 weeks and then 20–50 mg/kg/d through 228 weeks. Dose reduction from baseline occurred for most ASMs, except topiramate. Median reduction in the frequency of convulsive, focal, and total seizures was 44%–81%, 51%–87%, and 44%–87%, respectively, through 144 weeks. Responder rates (≥50%, ≥75%, and 100% reduction) were 43%–71%, 14%–58%, and 0%–25% for convulsive seizures; 52%–75%, 35%–60%, and 7%–32% for focal seizures; and 46%–79%, 26%–65%, and 0%–13% for total seizures. A total of 94% of patients experienced ≥1 AE; 47% had serious AEs, considered treatment unrelated by the investigator. Treatment‐related AEs (TRAEs) occurred in 71% of patients. The most frequently reported TRAEs were somnolence, diarrhea, and ataxia. Two patients experienced AEs leading to discontinuation. There were no deaths.
Significance
Long‐term add‐on CBD use was associated with reduced seizure frequency through 144 weeks. The safety profile was consistent with previous reports.
Plain Language Summary
In this study, we evaluated efficacy and safety of cannabidiol (CBD) treatment in patients with tuberous sclerosis complex receiving CBD in addition to other antiseizure treatments in an Expanded Access Program. After starting CBD, 46%–79% of patients had at least 50% reduction and 26%–65% had at least 75% reduction in the number of seizures per month; up to 13% had no seizures through 144 weeks. Safety results were similar to prior studies; sleepiness and diarrhea were common treatment‐related side effects. These results show that long‐term CBD treatment was associated with fewer seizures and mild/moderate side effects.
... Sonuç olarak, nöbetler üzerindeki etkiyi araştıran bu çalışmalar arasında 13 çalışma bir iyileşme gösterdi (209,(210)(211)(212)(213)(214)(215)(216)(217)(218)(219)(220)(221), 4 çalışma değişiklik göstermedi (220, 222-224) ve 2 çalışma sonuçsuz kaldı (225,226)]. Birincil sonuç olarak sağlıkla ilgili yaşam kalitesini veya yaşam kalitesini araştıran çalışmalarda, her iki çalışma da bir iyileşme gösterdi (220,222) ve bir çalışma değişiklik olmadığını gösterdi (222). ...
... 218, 221, 227-230) , 1'i karışık bulguları(231), 5'i değişiklik olmadığını gösterdi( 211,217,220,232) ve 2 sonuçsuzdu (225,226). 1 kesitsel çalışma dahil olmak üzere üç uygun çalışma, diğer sonuçları araştırdı. ...
... There is low-to moderate-quality evidence that Sativex® oromucosal spray can alleviate spasticity, jerking movements, tremors, chorea, neuropathic pain and improve the quality of sleep, in patients with parkinsonism, multiple sclerosis, Huntington's disease, and PTSD (Akinyemi et al., 2020;Longoria et al., 2022). Numerous studies have demonstrated that oral and sublingual CBD has antiseizure effects, providing improvement in patients with treatment-resistant epilepsies of various etiologies, including generalized epilepsy, focal epilepsy, DEE, and postinfectious brain damage or febrile infection-related epilepsy syndrome (FIRES) (Tzadok et al., 2016;Hess et al., 2016;Gofshteyn et al., 2017;Thiele et al., 2018;Devinsky et al., 2017Devinsky et al., , 2018aNeubauer et al., 2018;Porcari et al. 2018;Pietrafusa et al., 2019;Klotz et al., 2019;Laux et al. 2019;Miller et al. 2020;Hussain et al. 2020;Poisson et al. 2020;Patel et al. 2021;Marchese et al. 2022). Cannabis whole plant extracts that contain combinations of CBD and THC have also been prescribed in the UK to relieve intractable seizures including Bedrolite® (<1% THC and 9% CBD), Bedica® (14% THC and <1% CBD), Sweet Pink CBD (<1% THC and 10.6% CBD) and Althea 100 (<1% THC and 10% CBD) (Zafar et al. 2021). ...
... Drug interactions are relevant for orally administered CBD in epilepsy since ingested CBD is metabolized into its active metabolite (7-OH-CBD) primarily in the liver by cytochrome P450 CYP2C19, and into its inactive metabolite (7-COOH-CBD) by CYP3A4, both isoforms inducible by concomitant phenytoin, topiramate and carbamazepine, and inhibited by valproate and other AED (Lazaridis et al., 2019;Abu-Sawwa et al., 2020). Drug interactions between CBD and clobazam cause adverse effects associated with clobazam because CBD inhibits the CYP2C19 and CYP3A4 enzymes that catalyze its active metabolite N-desmethylclobazam (Hess et al., 2016). CBD is also metabolized in the gut by UGT1A7, UGT1A9, and UGT2B7. ...
Seizures in 20-30% of epileptics are resistant to treatment with anti-epileptic drugs (AED). This chapter evaluates studies on the efficacy of cannabinoids as adjunctive therapy for control of intractable seizures, with a focus on developmental epileptic encephalopathies (DEE). A systematic review conducted by literature search through PubMed, EBSCO, and ProQuest electronic databases identified 16 studies in the last seven years. Moderate- to low-certainty of evidence supports the benefits of cannabinoids in reducing seizure frequency, intensity, duration, and epileptics' overall condition in many types of intractable seizures. Studies used either synthetic cannabidiol (CBD), highly purified plant-derived CBD (Epidiolex®), or less pure cannabis plant-based CBD oils, and extended over months to two years. Drug interactions of ingested CBD with concomitant valproate and clobazam could be avoided with sublingual CBD. Five percent of patients became seizure free. Future studies are warranted to optimize the anti-seizure effects of emerging cannabinoid treatment strategies.
... Evidence of CBD treatment for patients with TSC has also been widely reported. Hess et al. [15] studied CBD for drug-resistant TSC and proved that the median weekly seizure frequency decreased from 22.0 (IQR, 14.8 to 57.4) to 13.3 (IQR, 5.1 to 22.1) after 3 months of treatment with CBD. In a randomized controlled trial conducted in 2019, there was a significant monthly seizure fre-quency reduction from baseline to 48.6% (95% CI, 40.4% to 55.8%) for the CBD25 (25 mg/kg/day) group and 47.5% (95% CI, 39.0% to 54.8%) for the CBD50 (50 mg/kg/day) group [7]. ...
... Positive effects on neuro-cognition were observed in six (20%) patients treated with CBD. There is growing evidence for the improvement of neurocognition and sleep architecture after treatment with CBD [10,15,[19][20][21]. Due to the nature of real-world study data with a small population and the nature of LGS, which is usually accompanied by intellectual disabilities, the neuro-cognitive improvements in our study could not be objectively evaluated using a neuropsychiatric assessment tool, and the main resources for the cognitive and behavioral improvements were caregivers' subjective documentation. ...
Purpose: This study evaluated the efficacy and tolerability of cannabidiol (CBD) as an add-on therapy for childhood-onset Lennox-Gastaut syndrome (LGS).Methods: This retrospective study enrolled patients who visited the Department of Pediatric Neurology at Asan Medical Center from March 2019 to February 2022 and were treated with CBD. Electronic medical records and clinically relevant factors (including the type of epilepsy and seizures, etiology, and the number of concomitantly used anti-epileptic drugs) were reviewed. The outcome was clinical response to CBD (≥50% or <50% seizure reduction at 1, 3, and 6 months after CBD introduction and the last follow-up visit). Relevant adverse events were monitored.Results: Thirty patients were included. The median age of epilepsy onset was 5.5 years (interquartile range [IQR], 3.3 to 25.3), with a median treatment duration of CBD of 6 months (IQR, 3.3 to 7.0). Sixteen patients (53.3%) showed ≥50% seizure reduction at the last follow-up. In a univariate analysis, patients whose epilepsy commenced after 3 years of age were more likely to respond to CBD (odds ratio, 10.11; 95% confidence interval, 1.05 to 97.00; P=0.04). Adverse events were observed in 11 patients (36.6%); the most common adverse event was somnolence. Conclusion: CBD could be a treatment option for children and young adults with drug-resistant LGS with a tolerable safety profile. Age at epilepsy onset (>3 years) was associated with a favorable response to CBD treatment. Further prospective studies with larger populations are needed to evaluate the tolerability and efficacy of CBD in patients with drug-resistant epilepsy of various etiologies.
... Sonuç olarak, nöbetler üzerindeki etkiyi araştıran bu çalışmalar arasında 13 çalışma bir iyileşme gösterdi (209,(210)(211)(212)(213)(214)(215)(216)(217)(218)(219)(220)(221), 4 çalışma değişiklik göstermedi (220, 222-224) ve 2 çalışma sonuçsuz kaldı (225,226)]. Birincil sonuç olarak sağlıkla ilgili yaşam kalitesini veya yaşam kalitesini araştıran çalışmalarda, her iki çalışma da bir iyileşme gösterdi (220,222) ve bir çalışma değişiklik olmadığını gösterdi (222). ...
... 218, 221, 227-230) , 1'i karışık bulguları(231), 5'i değişiklik olmadığını gösterdi( 211,217,220,232) ve 2 sonuçsuzdu (225,226). 1 kesitsel çalışma dahil olmak üzere üç uygun çalışma, diğer sonuçları araştırdı. ...
... The AG-2 effects were mediated by the CB2 receptor [128]. Study [129] 2012 Treatment of TMEV-infected SJL/J mice with CB1/CB2 agonist WIN-55,212-2 for 10 days restored self-tolerance, decreased delayed-type hypersensitivity responses to myelin PLP [139][140][141][142][143][144][145][146][147][148][149][150][151] peptide~60 days after infection (dpi) (p < 0.001), induced long-lasting motor function recovery on rotarod, and vertical and horizontal activity measures (p < 0.001), decreased the activation of CD4 + CD25 + Foxp3 − T cells (p < 0.05), and increased regulatory CD4 + CD25 + Foxp3 + T cells (p < 0.01) in the CNS. Treatment reduced expression of IL-6 and CXCL1 in the CNS (p < 0.01) and upregulated production of IL-5, MCP-1, and IFN-γ (p < 0.05), and IL-9 and VEGF (p < 0.01) at 110 dpi as compared to vehicle-treated controls. ...
... Promising benefits of cannabis use and medical marijuana have also been observed for relief of neurologic symptoms in patients with movement disorders, including Parkinson disease and Huntington disease [145]. Furthermore, oral CBD has been used for the treatment of drug-resistant seizures in children with tuberous sclerosis (TSC) [146], and Epidiolex ® (pure CBD) has been approved for the treatment of intractable epilepsy in patients with developmental epileptic encephalopathies [147] including Dravet syndrome and Lennox-Gastaut syndrome (LGS). Multiple mechanisms are implicated in the ability of CBD to modulate seizures that include antagonism of CB1, CB2, GPR18, GPR55, and voltage-gated sodium channel (VGSC) receptors; agonism of GABA A receptors; activation and desensitization of TRPV1/2 receptors; and allosteric modulation of opioid receptor types µ and δ, leading to inhibition of glutaminergic N-methyl-D-aspartate (NMDA) receptors [148]. ...
Despite current therapeutic strategies for immunomodulation and relief of symptoms in multiple sclerosis (MS), remyelination falls short due to dynamic neuropathologic deterioration and relapses, leading to accrual of disability and associated patient dissatisfaction. The potential of cannabinoids includes add-on immunosuppressive, analgesic, neuroprotective, and remyelinative effects. This study evaluates the efficacy of medical marijuana in MS and its experimental animal models. A systematic review was conducted by a literature search through PubMed, ProQuest, and EBSCO electronic databases for studies reported since 2007 on the use of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) in MS and in experimental autoimmune encephalomyelitis (EAE), Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), and toxin-induced demyelination models. Study selection and data extraction were performed by 3 reviewers, and 28 studies were selected for inclusion. The certainty of evidence was appraised using the Cochrane GRADE approach. In clinical studies, there was low- and moderate-quality evidence that treatment with ~1:1 CBD/THC mixtures as a nabiximols (Sativex®) oromucosal spray reduced numerical rating scale (NRS) scores for spasticity, pain, and sleep disturbance, diminished bladder overactivity, and decreased proinflammatory cytokine and transcription factor expression levels. Preclinical studies demonstrated decreases in disease severity, hindlimb stiffness, motor function, neuroinflammation, and demyelination. Other experimental systems showed the capacity of cannabinoids to promote remyelination in vitro and by electron microscopy. Modest short-term benefits were realized in MS responders to adjunctive therapy with CBD/THC mixtures. Future studies are recommended to investigate the cellular and molecular mechanisms of cannabinoid effects on MS lesions and to evaluate whether medical marijuana can accelerate remyelination and retard the accrual of disability over the long term.
... This phenomenon is attributed to increased levels of clobazam and its active metabolite, N-desmethylclobazam, due to their shared metabolic pathway via CYP. 17 While there is evidence suggesting that combined CBD and clobazam treatment may enhance anticonvulsant effects compared to ASMs alone, this relationship appears complex. A lower subthreshold dose of CBD did not promote greater antiseizure effects despite increasing plasma clobazam concentrations, indicating that CBD may possess independent anticonvulsant activity. ...
Background
Highly purified cannabidiol (CBD), recently approved for various neurological disorders, is explored as a potential therapeutic avenue for drug-resistant epilepsy (DRE) among adult people with epilepsy (PWE) in this systematic review and meta-analysis.
Objectives
To conduct an extensive literature review and meta-analysis of CBD use for DRE in adult PWE.
Design
Systematic review and meta-analysis.
Data sources and methods
We conducted a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and two electronic resources; we searched Ovid MEDLINE and Scopus using appropriate keywords until August 2023. Data were presented as standardized mean difference (SMD) and odds ratio with confidence interval (CI) via random effect. We appraised the risk of bias of the included studies using the Joanna Briggs Institute critical appraisal tool while their strength of evidence with the Oxford Centre for Evidence-Based Medicine (OCEBM) and Grading of Recommendations Assessment Development and Education (GRADE) Levels of Evidence.
Results
We identified 16 studies, 3 of which were randomized controlled trials and 3 prospective cohort studies, while the rest were expanded access programs, deriving a total of 668 participants receiving CBD for seizure control. CBD was used concomitantly with antiseizure medications in all studies. There was a statistically significant seizure reduction in the group receiving CBD therapy compared to the placebo group (SMD: −1.50, 95% CI (−3.47, 0.47), p < 0.01).
Conclusion
The evidence on CBD use in adult patients with DRE demonstrates a moderate level of certainty according to GRADE level and OCEBM level 2. Further prospective studies involving multiple centers are encouraged to study both the efficacy and safety of CBD in adult patients with DRE.
Trial registration
International Prospective Register of Systematic Reviews (PROSPERO) 2023 CRD42023449955.
... Cannabidiol (CBD) is a highly lipophilic Biopharmaceutics Classification System (BCS) Class II phytocannabinoid originally isolated from the Cannabis sativa plant. According to previous reports, CBD has substantial immunomodulatory effects at high concentrations, suggesting its potential in treatment of autoimmune diseases (Hess et al., 2016;Hoffenberg et al., 2019;Nichols and Kaplan, 2019;Zgair et al., 2017). Efficient delivery of CBD to the intestinal lymphatic system can lead to sufficient exposure of the immune cells to the drug, potentially resulting in more efficient treatment of autoimmune diseases (Zgair et al., 2017). ...
... By inhibiting GPR55 activation, CBD may re-establish GABA A R to the postsynaptic membrane, reopening the pathway to benzodiazepines. Both observational trials and the DS mouse model support this notion, where CBD in combination with benzodiazepines attenuated seizures more than benzodiazepines alone [84][85][86]. It would be interesting to see data regarding benzodiazepines-CBD efficacy in CDD patients and if CBD can rectify CDKL5-mediated GABA A R localization disruption. ...
Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers. The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBD’s antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids’ pharmacodynamics. This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid’s potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid’s therapeutic potential for CDD.
... 15,16 Second, the same drugs were approved by the FDA in 2020 for the treatment of tuberous sclerosis complex (TSC)-related seizures. 17,18 While the potential is increasing, little research has been conducted to investigate the potential therapeutic effects of CBD on COVID-19 or the clinical symptoms caused by SARS-CoV-2. ...
The aim of this study was to determine the antiviral activity of cannabidiol (CBD) against SARS‐CoV‐2 infection. CBD is the second most studied cannabinoid obtained from Cannabis plants. We investigated the potential use of CBD, which has so far proven to have a positive effect on different diseases, in the SARS‐CoV‐2 infection. To test this, in vivo studies were carried out using K18‐hACE2 transgenic mice. To reveal the potential therapeutic effect of the CBD at the histopathological and molecular level challenge experiments were performed. The study was designed with two groups (n = 10) and in the treatment group animals were infected with SARS‐CoV‐2 virus strain B.1.1.7 alpha before the administration of CBD. While the disease progressed and resulted in death in the control group that was infected by the virus alone, it was observed that the infection slowed down and the survival rate increased in the mice treated with CBD along with the virus. In this study, K18‐hACE2 transgenic mice infected with the wild SARS‐CoV‐2 virus were used to investigate and prove the antiviral activity of CBD.
... Epidiolex, the formulation of CBD employed in the current study, is an FDA-approved prescription drug indicated for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients 1 y of age and older (US Food and Drug Administration 2018). It is pharmaceutical-grade CBD that has been extensively tested for efficacy, safety, and purity in patients with these rare seizure disorders (Hess et al. 2016;Devinsky et al. 2018;Miller et al. 2020). This is in contrast to the numerous CBD products available over-the-counter for which clinical research is sparse, claims are not closely scrutinized by the FDA, and product purity is often not accurately labeled Spindle et al. 2022). ...
... Hess E. J. ir kt. (2016) at lik ta me ty ri me pa ste bë jo, kad po 3 më ne siø CBD var to ji mo epi lep si jos prie puo liø su ma þë jo apie 48,8 %, ta èiau 3 më ne sius gre ta CBD pri dë jus klo baza mà bu vo dar ge res në prie puo liø kon tro lë [43]. ...
Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the presence of benign tumors in many organs. The pathogenic mutation is found in either the TSC1 or TSC2 tumor suppressor genes. The presence of cortical or subcortical tubers is associated with focal epileptiform discharges on the electroencephalogram and subclinical seizures prior to the onset of clinical seizures. It is known that epileptic seizures in tuberous sclerosis are very resistant to the treatment, therefore, developmental delay usually occurs. In the last decade, more attention has been paid to early recognition and control of seizures (with vigabatrin or everolimus) in tuberous sclerosis complex, as this is highly correlated with improved developmental and neurological outcomes.The article reviews epilepsy and preventive antiepileptic treatment for tuberous sclerosis complex.
... Inversely, CBD is a multi-target molecule that does not elicit psychoactive activity and acts not only on the eCB system, but also on other targets, such as the agonist for the serotoninergic 5-HT1A receptor and the transient receptor potential vanilloid subtype 1 (TRPV1), the inhibitor of the enzyme fatty acid amide hydrolase (FAAH) and the antagonist of the G protein-coupled receptor 55 (GPR55) [5], in addition to other pharmacodynamic actions. Furthermore, CBD is more frequently associated to anti-inflammatory properties and antiepileptic activity [6][7][8]. The main target of phytocannabinoids is the endocannabinoid (eCB) system, which is highly conserved among vertebrates and is composed of cannabinoid receptors, bioactive lipids called endocannabinoids and the enzymes responsible for their synthesis and degradation on demand [9,10]. ...
The endocannabinoid system (eCS) is widely distributed in mammalian tissues and it is classically formed by cannabinoid receptors, endogenous bioactive lipids and its synthesis and degradation enzymes. Due to the modulatory role of eCS in synaptic activity in the Central Nervous System (CNS), phytocannabinoids have been increasingly used for the treatment of neurological disorders, even though little is known in terms of the long-term effect of these treatments on CNS development, mainly in the timeframe that comprises childhood and adolescence. Furthermore, an increased number of clinical trials using full-spectrum Cannabis extracts has been seen, rather than the isolated form of phytocannabinoids, when exploring the therapeutical benefits of the Cannabis plant. Thus, this study aims to evaluate the effect of cannabidiol (CBD)-enriched Cannabis extract on synaptic components in the hippocampus of rats from adolescence to early adulthood (postnatal day 45 to 60). Oral treatment of healthy male Wistar rats with a CBD-enriched Cannabis extract (3 mg/kg/day CBD) during 15 days did not affect food intake and water balance. There was also no negative impact on locomotor behaviour and cognitive performance. However, the hippocampal protein levels of GluA1 and GFAP were reduced in animals treated with the extract, whilst PSD95 levels were increased, which suggests rearrangement of glutamatergic synapses and modulation of astrocytic features. Microglial complexity was reduced in CA1 and CA3 regions, but no alterations in their phagocytic activity have been identified by Iba-1 and LAMP2 co-localization. Collectively, our data suggest that CBD-enriched Cannabis treatment may be safe and well-tolerated in healthy subjects, besides acting as a neuroprotective agent against hippocampal alterations related to the pathogenesis of excitatory and astrogliosis-mediated disorders in CNS.
... It is commonly used as antimicrobial, anti-bacterial, anti-oxidant, analgesic [9] , antiinflammatory [10] , . In the open study it was seen that the daily cannabis use lowers the plasma HIV viral load [11] It is recommended in the effective treatment of epilepsy [12] , and in Parkinson's disease as it reduces pain and improves movement [13] Treatment with dronabinol in the majority of pediatric palliative patients showed the promising effect in treating resistant spasticity. [14] Phytocannabinoids are been recognized as the key substance which is improves sleep disorder concerned in analgesia anti-inflammatory effects. ...
In recent years, the growing demand for Indian weeds has led to a new way in the field of plant materials traded
within and across the countries. The medicinal properties of these plants have been investigated in the light of
recent scientific developments, due to their potent pharmacological activities, less toxicity, and economic viability.
Many of patients use medicinal weeds or seek the advice of their physician regarding their use. By the help of this
review, we have explored the various pharmacological properties of weeds which will serve mankind and also the
common people will be able to explore their knowledge regarding weeds and can also utilize them as their home
remedy.
KEYWORDS: Weed, Pharmacological activity, Medicinal Property.
... The neurotoxicity studies on CBD would be particularly informative and beneficial in the healthcare sector, considering much interest in CBD against neurological diseases, [6] as well as recent U.S. Food and Drug Administration (FDA) approval of CBD as a treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients 1 year of age or older. [7][8][9] However, fundamental studies on the cytotoxicity of CBD in neurons, a major cell type that executes main functional roles in the nervous system, still have been limited. Our group has reported that CBD shows neurotoxicity with half maximal lethal concentration (LC 50 ) of 9.85 μm in the in-vitro culture of primary hippocampal neurons with morphological characteristics of detachment-induced cell death. ...
Cannabidiol (CBD), a main nonpsychoactive phytocannabinoid in the Cannabis genus, has been in the limelight for its potential health benefits in various neurological diseases. However, the safety issue of CBD in the nervous system has not been settled fully, while CBD has been reported to have mild side effects including dizziness and somnolence. In this work, a platform of neuron‐astrocyte sandwich coculture to investigate the neurotoxicity of CBD, as well as the neuronal responses to CBD, in a more in vivo relevant mode is constructed. CBD (15 and 30 µm) causes the viability decrease, along with morphological damage, in the neuron‐alone culture, whereas its neurotoxic effects are significantly attenuated by the supports of astrocytes in the neuron‐astrocyte coculture. In addition, it is found that CBD‐induced increase of intracellular Ca²⁺ concentration and depolarization of mitochondrial membrane potential, via activation of transient receptor potential vanilloid 1, are noticeably ameliorated by coculturing neurons with astrocytes. This work provides crucial information in the development of CBD as therapeutics for neurological disorders, as well as in a fundamental understanding of how CBD works in the nervous system.
... [89][90][91] Although Barnett et al showed that therapeutic doses of epidiolex did not reduce the volume of TSCassociated SEGAs or renal angiomyolipomas, in contrast to mTOR inhibitors, 92 recent studies have shown that cannabidiol decreases seizure frequency. 93,94 In 2020, Thiele et al published the findings of the GWPCARE6 study (NCT02544763), a randomized, placebo-controlled study that showed the efficacy of cannabidiol as an adjunctive treatment in TSC, as well as providing guidance with regard to optimal dosing (25 mg/kg/day), leading to FDA approval for TSC for patients >1 years of age and >2 years of age by the European Medicinal Agency. 94 Additionally, longer-term adjunctive cannabidiol treatment was studied in an open-label extension to the GWPCARE6 trial and demonstrated maintenance of seizure reduction through 48 weeks, as well as 87% of patients and caregivers reporting subjective global improvement in quality of life and epilepsy control. ...
Tuberous sclerosis complex (TSC) is a neurogenetic disorder that affects multiple organ systems, including the heart, kidneys, eyes, skin, and central nervous system. The neurologic manifestations have the highest morbidity and mortality, in particular in children. Clinically, patients with TSC often present with new-onset seizures within the first year of life. TSC-associated epilepsy is often difficult to treat and refractory to multiple antiseizure medications. Refractory TSC-associated epilepsy is associated with increased risk of neurodevelopmental comorbidities, including developmental delay, intellectual disability, autism spectrum disorder, and attention hyperactivity disorder. An increasing body of research suggests that early, effective treatment of TSC-associated epilepsy during critical neurodevelopmental periods can potentially improve cognitive outcomes. Therefore, it is important to treat TSC-associated epilepsy aggressively, whether it be with pharmacological therapy, surgical intervention, and/or neuromodulation. This review discusses current and future pharmacological treatments for TSC-associated epilepsy, as well as the importance of early surgical evaluation for refractory epilepsy in children with TSC and consideration of neuromodulatory interventions in young adults.
... Regarding neurological disorders, most pieces of evidence support the use of CBD in epilepsy, which is why the only existing product in CBD-based therapy, Epidiolex ® , was approved [75][76][77]. Beyond this condition, CBD's effects on Parkinson's and Huntington's disease have been intensively researched. ...
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.
... Since then, diverse clinical trials have been conducted to evaluate the safety, tolerability, and efficacy of CBD in humans, mainly in patients with severe epilepsy syndromes and TSC, diseases associated with drug resistant seizures in children and young adults [32,34,211,[213][214][215][216][217][218][219]. ...
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.
... 42 Diabetes type 2 and THCV administration were studied in 1 RCT (n = 62) as an adjuvant therapy at 10 mg/d (0.2 mg/kg/d). The results revealed significant improvement in fasting glycemic control, pancreatic function, adiponectin, and apolipoprotein A. 46 The most studied medical disorder was epilepsy, with all 9 studies describing significant effects of CBD in reducing frequency or severity of seizures, 47-51 , 53 , 57 , 58 , 83 which included Dravet syndrome, 47 , 48 Lennox Gastaut syndrome, 57 , 58 treatment-resistant syndrome, 83 febrile infectionrelated conditions, 49 brain tumor, 53 complex, 50 and drug resistance. 51 Within the 4 conducted RCTs (n = 715), mean dosing of 1085 mg/d (17.5 mg/kg/d) was used in which CBD was given as an add-on therapy against epilepsy episodes. ...
Purpose
This systemic review assesses currently available clinical information on which cannabinoids and what range of doses have been used to achieve positive effects in a diversity of medical context.
Methods
The data were collected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol guidelines. Inclusion criteria were articles that assessed administration of any cannabinoid to any clinical population, reported in the ClinicalTrials.gov or PubMed databases, that involved a comparison with other treatment or placebo and a result measurement to assess the effectiveness or ineffectiveness of the cannabinoid. Exclusion criteria were review or letter; articles not in the English language; not full-text articles; not a clinical trial, case report, case series, open-label trial, or pilot study; administration in animals, in vitro, or in healthy participants; cannabinoids administered in combination with other cannabinoids (except for cannabidiol [CBD] or tetrahydrocannabinol [THC]) or as whole cannabis extracts; no stated concentration; inhalation or smoke as a route of administration; and no results described. The articles were assessed by the risk of bias.
Finding
In total, 1668 articles were recovered, of which 55 studies met the inclusion criteria for 21 diseases. Positive effects were reported in clinical studies: 52% with THC (range, 0.01–0.5 mg/kg/d [0.62–31 mg/d]), 74% with CBD (range, 1–50 mg/kg/d [62–3100 mg/d]), 64% with THC-CBD (mean, 1:1.3 mg/kg/d [ratio, 1:1]), and 100% with tetrahydrocannabivarin (THCV) (0.2 mg/kg/d).
Implications
THC, CBD, and THCV can regulate activity in several pathologies. New studies of cannabinoids are highly encouraged because each patient is unique and requires a unique cannabinoid medication.
... CBD significantly reduces motor seizures by 35% in patients with severe, intractable, childhood onset, treatment-resistant epilepsy (Devinsky et al. 2016). Epidiolex, an oral solution mostly containing CBD, is also effective for the treatment of seizures (Stockings et al. 2018;Hess et al. 2016). There is therefore sufficient evidence for the efficacy of CBD against epilepsy, and this CBD could be extracted from hemp. ...
Background
Interest in industrial hemp is increasing steadily, as can be seen by the growing number of countries that have either decriminalized industrial hemp or are contemplating its decriminalization. In line with this trend, Ghana recently decriminalized the cultivation of industrial hemp (the cannabis variety with low Δ9-tetrahydrocannabinol (THC) and high cannabidiol (CBD) content), resulting in the need for research into its benefits to Ghanaians. This article examines cannabis (including industrial hemp) production, facilities for industrial hemp exploitation, and the potential benefits of industrial hemp in Ghana.
Main body
Indigenous cannabis strains in Ghana have high THC to CBD ratios suggesting the need for the government to purchase foreign hemp seeds, considering that the alternative will require significant research into decreasing the THC to CBD ratio of indigenous cannabis strains. Furthermore, there are several facilities within the country that could be leveraged for the production of medicinal hemp-based drugs, as well as the existence of a number of possible regulatory bodies in the country, suggesting the need for less capital. Research has also shown the potential for treatment of some medical conditions prevalent among Ghanaians using medicinal hemp-based products. These reasons suggest that the most feasible option may be for the government to invest in medicinal hemp.
Conclusion
Considering the challenges associated with the development of other hemp-based products, the availability of resources in the country for exploitation of medicinal hemp, and the potential benefits of hemp-based drugs to Ghanaians, investing in medicinal hemp may be the best option for the government of Ghana.
Paediatric epilepsies are especially concerning as they can be resistant to standard antiepileptic drugs and have high mortality rates. Moreover, young children are naturally at an increased risk of developing epilepsy. In early life, the depolarizing effect of γ-aminobutyric acid (GABA) renders immature neurons incapable of adequate inhibition which predisposes them to becoming hyperexcitable. Until recently, the search has been ongoing for a suitable therapy that would work more effectively in severe childhood epilepsies. Fortunately, cannabidiol (CBD), the non-psychoactive part of cannabis, has recently surfaced as a successful anticonvulsant in rare and severe paediatric epilepsy disorders. CBD circumvents normal endocannabinoid signalling in which endogenous cannabinoids are released by a postsynaptic
neuron to silence the activity of a presynaptic neuron at a synapse. Instead, CBD exerts its anticonvulsant effects by acting on a number of non-cannabinoid targets, namely the transient receptor potential vanilloid 1 channel, G protein-coupled receptor 55, and equilibrative nucleoside transporter 1. In clinical trials, CBD lowered seizure frequency in paediatric patients who had Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), tuberous sclerosis complex (TSC),
and other epilepsy syndromes. For the past few decades, the illegalization of cannabis has halted research into cannabinoids, and we are only now starting to study cannabis further despite knowing for centuries that it relieves a variety of conditions. The Food and Drug Administration and European Medicines Agency have recently approved CBD as an additive treatment option for DS, LGS, and TSC patients. Our society is becoming more open to the prospect of cannabis’ therapeutic potential. This is particularly promising for children suffering from severe forms of epilepsy in which most of our current antiepileptic drugs are often ineffective.
Cannabidiol (CBD) has arisen as a promising therapeutic option for children with drug-resistant epilepsy (DRE). CBD has received regulatory nod from different regulatory authorities in the United States, Europe, and India for children with DRE particularly, Dravet syndrome (DS), Lennox Gastaut syndrome (LGS), and Tuberous sclerosis complex (TSC). Recent clinical trials and observational studies highlight the potential of CBD to lower seizure frequency and provide better quality of life in children affected by these disorders. The safety profile is generally favorable with minor common adverse events such as somnolence, diarrhea, and gastrointestinal issues. Furthermore, the expense associated with CBD remains a notable concern, especially in low- and middle-income countries such as India, where access to this promising treatment may be constrained. This draws attention to the cost-effective perspective of CBD. This review aims to explore the pharmacological properties of CBD, its mechanisms of action, and the clinical evidence supporting its use in various pediatric epilepsies, including LGS, DS, and TSC. Additionally, this review sheds light on the current regulatory landscape in India where CBD use is still in its nascent stages, and discusses the challenges and opportunities for integrating CBD into clinical practice.
Tuberous sclerosis Complex (TSC) is a genetic disorder characterized by multisystem involvement, with epilepsy
affecting 80–90% of patients, often beginning in infancy. Early-life seizures in TSC are associated with poor
neurodevelopmental outcomes, underscoring the importance of timely and effective management. This review
explores the evolving treatment landscape for TSC-associated seizures in young children, focusing on three
recently approved or license-expanded therapies: vigabatrin, everolimus, and cannabidiol. The efficacy and
safety profiles of these treatments are examined based on clinical trials and real-world evidence, with a focus on
their use in treating seizures in young children. The preemptive use of vigabatrin in clinical studies has also been
carefully reviewed. A treatment algorithm is proposed, emphasizing early diagnosis, prompt initiation of
appropriate therapy, and a stepwise approach to managing both infantile spasms and focal seizures. The algorithm
incorporates these newer therapies alongside traditional antiseizure medications and non-pharmacological
approaches. Challenges in optimizing treatment strategies, minimizing side effects, and improving long-term
outcomes are discussed. This review aims to guide clinicians in navigating the complex landscape of early-life
seizures associated with TSC, ultimately striving for improved seizure control and better developmental outcomes
in this vulnerable population.
Introduction:
The landscape of epilepsy treatment has undergone a significant transformation with the emergence of cannabidiol as a potential therapeutic agent. Epidiolex, a pharmaceutical formulation of highly purified CBD, garnered significant attention not just for its therapeutic potential but also for being the first cannabis-derived medication to obtain approval from regulatory bodies.
Area covered:
In this narrative review the authors explore the intricate landscape of CBD as an antiseizure medication, deepening into its pharmacological mechanisms and clinical trials involving various epileptic encephalopathies. This exploration serves as a comprehensive guide, shedding light on a compound that holds promise for individuals contending with the significant challenges of drug-resistant epilepsy.
Expert opinion:
Rigorous studies highlight cannabidiol's efficacy, safety profile, and potential cognitive benefits, warranting further exploration for its approval in various drug-resistant epilepsy forms. As a promising therapeutic option, cannabidiol not only demonstrates efficacy in seizure control but also holds the potential for broader enhancements in the quality of life, especially for patients with epileptic encephalopathies.
Concomitant use of cannabinoids with other drugs may result in pharmacokinetic drug-drug interactions, mainly due to the mechanism involving Phase I and Phase II enzymes and/or efflux transporters. Cannabinoids are not only substrates but also inhibitors or inducers of some of these enzymes and/or transporters. This narrative review aims to provide the available information reported in the literature regarding human data on the pharmacokinetic interactions of cannabinoids with other medications. A search on Pubmed/Medline, Google Scholar, and Cochrane Library was performed. Some studies were identified with Google search. Additional articles of interest were obtained through cross-referencing of published literature. All original research papers discussing interactions between cannabinoids, used for medical or recreational/adult-use purposes, and other medications in humans were included. Thirty-two studies with medicinal or recreational/adult-use cannabis were identified (seventeen case reports/series, thirteen clinical trials, and two retrospective analyses). In three of these studies, a bidirectional pharmacokinetic drug-drug interaction was reported. In the rest of the studies, cannabinoids were the perpetrators, as in most of them, concentrations of cannabinoids were not measured. In light of the widespread use of prescribed and non-prescribed cannabinoids with other medications, pharmacokinetic interactions are likely to occur. Physicians should be aware of these potential interactions and closely monitor drug levels and/or responses. The existing literature regarding pharmacokinetic interactions is limited, and for some drugs, studies have relatively small cohorts or are only case reports. Therefore, there is a need for high-quality pharmacological studies on cannabinoid-drug interactions.
Cannabis was used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including D ⁹ -THC, cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized-controlled clinical trials that led to FDA approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.
A Cannabis sativa, popularmente conhecida como "Cânhamo da Índia", possui um notável potencial terapêutico apesar de suas propriedades psicoativas. Com uma longa história de uso para nutrição, rituais religiosos, práticas médicas e recreação, a cannabis medicinal é permitida em alguns estados dos EUA e países como Portugal, Holanda e Israel para mitigar sintomas de câncer, AIDS, esclerose múltipla, síndrome de Tourette e convulsões epiléticas. No Brasil, sua utilização é obtida por meio de pedidos judiciais para importação, especialmente no tratamento de epilepsia e convulsões. Este estudo visa fundamentar a discussão sobre a descriminalização da cannabis medicinal por meio de evidências científicas, através de uma pesquisa baseada em artigos científicos obtidos em bases de dados como PubMed, Web of Science, Scientific Eletronic Library Online (Scielo) e Google Scholar. Focado na Cannabis sativa, nas leis de drogas, na legalização global da cannabis e em pesquisas sobre seu uso médico, o estudo identificou doenças específicas para as quais a cannabis tem sido estudada, visando fornecer apoio científico ao tópico em questão. O processo de criminalização da cannabis no Brasil seguiu padrões internacionais, em consonância com a abordagem de outras substâncias psicotrópicas. A pesquisa concluiu que há evidências de eficácia e segurança no uso terapêutico da cannabis, especialmente no tratamento da epilepsia, onde observou-se uma redução nas convulsões, notadamente em pacientes com epilepsia refratária. Além disso, estudos indicam seu potencial contra várias doenças. Embora ações legais tenham viabilizado a importação de medicamentos à base de canabidiol no Brasil, barreiras burocráticas e altos custos de importação dificultam o acesso. A criação de uma legislação que regule o uso e aplicação da cannabis poderia estimular mais pesquisas sobre suas ações medicinais e ampliar o acesso aos necessitados. Países como Portugal e Israel oferecem exemplos de uso medicinal sem necessariamente descriminalizar completamente.
Purpose:
To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting.
Methods:
In this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety.
Results:
Forty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were "responders" and 12 (29%) were "super-responders". Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively.
Conclusions:
In this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications.
In clinical trials of cannabidiol (CBD) for the treatment of seizures in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, elevations in serum alanine aminotransferase (ALT) >3× the upper limit of normal (ULN) were observed in some patents, but the incidence was much greater in patients who were receiving treatment with valproate (VPA) before starting CBD. To explore potential mechanisms underlying this interaction, we used DILIsym®, a quantitative systems toxicology (QST) model, to predict ALT elevations in a simulated human population treated with CBD alone, VPA alone, and when CBD dosing was starting during treatment with VPA. We gathered in vitro data assessing the potential for CBD, the two major CBD metabolites, and VPA to cause hepatotoxicity via inhibition of bile acid transporters, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Physiologically-based pharmacokinetic (PBPK) models for CBD and VPA were used to predict liver exposure. DILIsym simulations predicted dose-dependent ALT elevations from CBD treatment and this was predominantly driven by ROS production from the parent molecule. DILIsym also predicted VPA treatment to cause ALT elevations which were transient when mitochondrial biogenesis was incorporated into the model. Contrary to the clinical experience, simulation of two weeks treatment with VPA prior to introduction of CBD treatment did not predict an increase the incidence of ALT elevations relative to CBD treatment alone. We conclude that the marked increased incidence of CBD-associated ALT elevations in patients already receiving VPA is unlikely to involve the three major mechanisms of direct hepatotoxicity.
People with epilepsy may experience episodes of frequent seizure activity (seizure clusters, acute repetitive seizures), and benzodiazepines are the cornerstone of rescue treatment. Cannabidiol (CBD) can be used as an adjunctive treatment for epilepsy, and it may interact with other antiseizure drugs, such as benzodiazepines. Here, we examined the safety and effectiveness of intermittent use of diazepam nasal spray in patients with seizure clusters who also received CBD treatment. This analysis included data from patients aged 6 to 65 years enrolled in a phase 3, long-term safety study of diazepam nasal spray. Age- and weight-based dosing of diazepam nasal spray were administered during a 12-month treatment period. Concomitant CBD use was recorded, and treatment-emergent adverse events (TEAEs) were collected. Of 163 treated patients, 119 (73.0%) did not receive CBD, 23 (14.1%) received the US Food and Drug Administration-approved highly purified CBD and 21 (12.9%) received another form of CBD. On average, patients receiving highly purified CBD were younger and more likely to have epileptic encephalopathies, including Dravet syndrome or Lennox-Gastaut syndrome, than patients who received another CBD preparation or no CBD. Rates of TEAEs and serious TEAEs were greater in patients who received any form of CBD (90.9% and 45.5%, respectively) compared with no CBD (79.0% and 26.1%, respectively). However, the lowest rates of TEAEs attributed to diazepam nasal spray were reported in patients who received highly purified CBD (13.0%), and this result was maintained in those who received concomitant clobazam. Use of second doses of diazepam nasal spray, a proxy for effectiveness, was lowest in the highly purified-CBD group (8.2%) compared with the no-CBD (11.6%) and other-CBD groups (20.3%). These results suggest that CBD does not alter the safety and effectiveness of diazepam nasal spray and supports concomitant use in appropriate patients.
Despite the wide range of compounds currently available to treat epilepsy, there is still no drug that directly tackles the physiopathological mechanisms underlying its development. Indeed, antiseizure medications attempt to prevent seizures but are inefficacious in counteracting or rescuing the physiopathological phenomena that underlie their onset and recurrence, and hence do not cure epilepsy. Classically, the altered excitation/inhibition balance is postulated as the mechanism underlying epileptogenesis and seizure generation. This oversimplification, however, does not account for deficits in homeostatic plasticity resulting from either insufficient or excessive compensatory mechanisms in response to a change in network activity. In this respect, both neurodevelopmental epilepsies and those associated with neurodegeneration may share common underlying mechanisms that still need to be fully elucidated. The understanding of these molecular mechanisms shed light on the identification of new classes of drugs able not only to suppress seizures, but also to present potential antiepileptogenic effects or "disease-modifying" properties.
Importance:
Epilepsy is one of the most common neurologic disorders globally. Cannabidiol (CBD) has been approved for the treatment of epilepsy, but its use has been associated with several different adverse events (AEs).
Objective:
To investigate the frequency and risk of AEs developing in patients with epilepsy who are using CBD.
Data sources:
PubMed, Scopus, Web of Science, and Google Scholar were searched for relevant studies published from database inception up to August 4, 2022. The search strategy included a combination of the following keywords: (cannabidiol OR epidiolex) AND (epilepsy OR seizures).
Study selection:
The review included all randomized clinical trials that investigated at least 1 AE from the use of CBD in patients with epilepsy.
Data extraction and synthesis:
Basic information about each study was extracted. I2 statistics were calculated using Q statistics to assess the statistical heterogeneity among the included studies. A random-effects model was used in cases of substantial heterogeneity, and a fixed-effects model was used if the I2 statistic for the AEs was lower than 40%. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.
Main outcomes and measures:
Frequency of each AE and risk of developing each AE in patients with epilepsy using CBD.
Results:
Nine studies were included. Overall incidences of 9.7% in the CBD group and 4.0% in the control group were found for any grade AEs. The overall risk ratios (RRs) for any grade and severe grade AEs were 1.12 (95% CI, 1.02-1.23) and 3.39 (95% CI, 1.42-8.09), respectively, for the CBD group compared with the control group. Compared with the control group, the CBD group had a greater risk for incidence of serious AEs (RR, 2.67; 95% CI, 1.83-3.88), AEs resulting in discontinuation (RR, 3.95; 95% CI, 1.86-8.37), and AEs resulting in dose reduction (RR, 9.87; 95% CI, 5.34-14.40). Because most of the included studies had some risk of bias (3 raised some concerns and 3 were at high risk of bias), these findings should be interpreted with some caution.
Conclusions and relevance:
In this systematic review and meta-analysis of clinical trials, the use of CBD to treat patients with epilepsy was associated with an increased risk of several AEs. Additional studies are needed to determine the safe and effective CBD dosage for treating epilepsy.
Cannabidiol (CBD) is an easily accessible and affordable Marijuana (Cannabis sativa L.) plant derivative with an extensive history of medical use spanning thousands of years. Interest in the therapeutic potential of CBD has increased in recent years, including its anti-tumour properties in various cancer models. In addition to the direct anticancer effects of CBD, preclinical research on numerous cannabinoids, including CBD, has highlighted their potential use in: (i) attenuating chemotherapy-induced adverse effects and (ii) enhancing the efficacy of some anticancer drugs. Therefore, CBD is gaining popularity as a supportive therapy during cancer treatment, often in combination with standard-of-care cancer chemotherapeutics. However, CBD is a biologically active substance that modulates various cellular targets, thereby possibly resulting in unpredictable outcomes, especially in combinations with other medications and therapeutic modalities. In this review, we summarize the current knowledge of CBD interactions with selected anticancer chemotherapeutics, discuss the emerging mechanistic basis for the observed biological effects, and highlight both the potential benefits and risks of such combined treatments. Apart from the experimental and preclinical results, we also indicate the planned or ongoing clinical trials aiming to evaluate the impact of CBD combinations in oncology. The results of these and future trials are essential to provide better guidance for oncologists to judge the benefit-versus-risk ratio of these exciting treatment strategies. We hope that our present overview of this rapidly advancing field of biomedicine will inspire more preclinical and clinical studies to further our understanding of the underlying biology and optimize the benefits for cancer patients.
Cannabis is one of the oldest crops grown, traditionally held religious attachments in various cultures for its medicinal use much before its introduction to Western medicine. Multiple preclinical and clinical investigations have explored the beneficial effects of cannabis in various neurocognitive and neurodegenerative diseases affecting the cognitive domains. Tetrahydrocannabinol (THC), the major psychoactive component, is responsible for cognition-related deficits, while cannabidiol (CBD), a non-psychoactive phytocannabinoid, has been shown to elicit neuroprotective activity. In the present integrative review, the authors focus on the effects of cannabis on the different cognitive domains, including learning, consolidation, and retrieval. The present study is the first attempt in which significant focus has been imparted on all three aspects of cognition, thus linking to its usage. Furthermore, the investigators have also depicted the current legal position of cannabis in India and the requirement for reforms.
Background
A prior drug trial of cannabidiol for treatment- resistant epilepsy in patients with Sturge-Weber syndrome, a rare neurovascular condition, implicated improvements in neurologic, quality of life, neuropsychological, psychiatric, and motor outcomes.
Methods
Ten subjects with SWS brain involvement, controlled seizures, and cognitive impairments received study drug in this Johns Hopkins IRB approved, open-label, prospective drug trial. Oral cannabidiol was taken for six months (dose ranged from 5 mg/kg/day to 20 mg/kg/day). SWS neuroscore, port-wine birthmark score, quality of life, and adverse events were recorded every 4-12 weeks. Neuropsychological, psychiatric, and motor assessments were administered at baseline and six months follow-up. Most evaluations were conducted virtually due to the COVID-19 pandemic.
Results
Cannabidiol was generally well tolerated. Six subjects reported mild to moderate side effects related to study drug and continued on drug; one subject withdrew early due to moderate side effects. No seizures were reported. Significant improvements in SWS neuroscore, patient- reported quality of life (QOL), anxiety and emotional regulation, and report of bimanual ability use, were noted. Migraine QOL scores were high at baseline in these subjects, and remained high. Neuropsychological, other quality of life and motor outcomes remained stable, with some within subject improvements noted.
Conclusions
Further studies are needed to determine whether Epidiolex can improve quality of life and be beneficial for neurologic, anxiety, and motor impairments in SWS independent of seizure control. Large multi-centered studies are needed to extend these preliminary findings.
Background
Drug-resistance is a significant clinical issue in persons with epilepsy. In the past few years, many studies have been published investigating the management of drug-resistant epilepsy (DRE); however, no systematic and quantitative evaluation of this research has been performed. Therefore, a bibliometric analysis was conducted to demonstrate the current status of DRE research and to reflect the trends and hotspots within the field.
Methods
We retrieved publications on DRE published between 2011 and 2021 from the Science Citation Index Expanded of the Web of Science Core Collection. All articles related to DRE were included in this study. VOSviewer, R software, and CiteSpace were used to perform bibliometric research.
Results
A total of 3,088 original articles were included in this study. The number of publications on DRE has continued to increase over the past 11 years. The USA published the most papers with the highest number of citations and H-index. The National Institutes of Health and the University of Toronto were the most prolific funding agency and affiliation, respectively. Epilepsy & Behavior and Epilepsia ranked first as the most prolific and co-cited journals, respectively. The keywords “cannabidiol”, “neuromodulation”, “seeg” and “perampanel” revealed recent research hotspots. The top 100 most cited papers were classified into eight main topics, of which pharmacotherapy, disease mechanisms/pathophysiology, and neuromodulation were the three most important topics.
Conclusions
This analysis of bibliometric data demonstrated that DRE has always been a topical area of research. The mechanisms of epilepsy and therapies have been the focus of DRE research, and innovative antiseizure medications and surgical approaches are fast-developing research trends.
Novel and effective antiseizure medications are needed to treat refractory and rare forms of epilepsy. Cannabinoids, which are obtained from the cannabis plant, have a long history of medical use, including for neurologic conditions. In 2018, the US Food and Drug Administration approved the first phytocannabinoid, cannabidiol (CBD, Epidiolex®), which is now indicated for severe seizures associated with three rare forms of developmental and epileptic encephalopathy: Dravet syndrome, Lennox–Gastaut syndrome, and tuberous sclerosis complex. Compelling evidence supports the efficacy of CBD in experimental models and patients with epilepsy. In randomized clinical trials, highly-purified CBD has demonstrated efficacy with an acceptable safety profile in children and adults with difficult-to-treat seizures. Although the underlying antiseizure mechanisms of CBD in humans have not yet been elucidated, the identification of novel antiseizure targets of CBD preclinically indicates multimodal mechanisms that include non-cannabinoid pathways. In addition to antiseizure effects, CBD possesses strong anti-inflammatory and neuroprotective activities, which might contribute to protective effects in epilepsy and other conditions. This article provides a succinct overview of therapeutic approaches and clinical foundations of CBD, emphasizing the clinical utility of CBD for the treatment of seizures associated with refractory and rare epilepsies. CBD has shown to be a safe and effective antiseizure medicine, demonstrating a broad spectrum of efficacy across multiple seizure types, including those associated with severe epilepsies with childhood onset. Despite such promise, there are many perils with CBD that hampers its widespread use, including limited understanding of pharmacodynamics, limited exposure-response relationship, limited information for seizure freedom with continued use, complex pharmacokinetics with drug interactions, risk of adverse effects, and lack of expert therapeutic guidelines. These scientific issues need to be resolved by further investigations, which would decide the unique role of CBD in the management of refractory epilepsy.
Introduction
Epilepsy is one of the most common and serious neurological conditions, affecting over 70 million individuals worldwide and despite advances in treatment, the proportion of drug-resistant patients has remained largely unchanged.
Areas covered
The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies.
Expert opinion
Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.
Objetivo: O presente artigo de revisão sistemática tem como objetivo discutir as evidências científicas a respeito do uso do canabidiol (CBD) para tratamento da epilepsia, esclerose múltipla, doença de Alzheimer e doença de Parkinson. Materiais e Métodos: Foram selecionadas 33 publicações entre os anos de 2010 e 2021, em português, inglês e espanhol, das plataformas: Capes, Scielo e PubMed, utizando os seguintes termos de pesquisa: Canabidiol, Epilepsia, Esclerose múltipla, Doença de Alzheimer e Doença de Parkinson. Resultados: Inferiu-se que o canabidiol oferece benefícios terapêuticos e são, geralmente, bem tolerados pelos pacientes portadores de epilepsia e esclerose múltipla. No caso da doença de Parkinson ainda há muitos pontos a serem elucidados a respeito do mecanismo de ação do fármaco sobre a doença. Já para o mal de Alzheimer ainda não há perspectiva de tratamento com o composto, pois os estudos ainda estão na fase pré-clinica. Conclusões: Destaca-se a necessidade de novos estudos que visem elucidar os pontos ainda não esclarecidos a respeito do canabidiol. Desta forma, as aplicações terapêuticas do composto poderão ser ampliadas.
Purpose
Pharmaceutical grade cannabidiol (CBD) is one of the newest anti-seizure medications for refractory epilepsy, and the effects of CBD on EEG have not been fully described.
Methods
Patients enrolled in a CBD expanded access study had EEGs prior to and 12 weeks after initiation of CBD treatment for their refractory epilepsy. In addition to evaluating the clinical EEG reports, a nonbiased quantitative EEG (qEEG) analysis of background EEG was performed to determine whether consistent changes occur in the EEG in response to administration of CBD.
Results
No significant qualitative changes were seen, nor changes in quantitative markers of EEG amplitude (RMS amplitude, standard deviation of the amplitude, skewness, or kurtosis), frequency (relative delta, theta, or alpha power), Spearman correlation, or coherence between brain regions. However, relative beta power and 1/f slope, a measure of signal noise increased with the addition of CBD. When patients were separated into responders and nonresponders based on seizure reduction with CBD, responders also had decreased Spearman correlation between the frontopolar and occipital regions after addition of CBD, suggesting that responders may have quantitatively improved EEG background organization after CBD initiation. The differences in beta and 1/f slope were also seen more robustly in CBD responders compared with nonresponders after CBD initiation. These differences disappeared when analyzing only patients not taking benzodiazepines, suggesting that the effect of CBD on seizures was related to the ability of the brain to further increase beta in response to CBD in patients already taking benzodiazepines.
We noted that even before initiation of CBD, 1/f slope was also significantly different in responders compared to nonresponders. Therefore, to explore the baseline EEG in responders and nonresponders, we utilized a variable selection procedure to identify baseline EEG features that could predict whether a patient’s seizures would improve with CBD. In the optimal multivariable logistic model, baseline coherence, Spearman correlation, and patient sex jointly predicted whether a patient in this cohort would respond to CBD (defined as a seizure reduction of 40% or greater) with 74% accuracy. This model performed less well on a data set of reduced duration and variability, highlighting the importance of real-world testing of any clinically relevant model.
Conclusion
These results suggest that there are subtle changes in certain metrics detected by qEEG even at baseline that may not be perceived during qualitative EEG analysis and that could be used in the future as a biomarker to predict a patient’s clinical response to CBD administration. Development of such a predictive EEG biomarker, especially before the initiation of a medication trial, could reduce unnecessary ASM exposure and improve outcomes for patients with epilepsy facing new medication selection.
Exosomes, which are membrane-enclosed extracellular vesicles (30 - 200 nm) secreted by cells, may be
responsible for the therapeutic benefits associated with the implantation of mesenchymal stem cells. Currently,
ultracentrifugation is commonly used to isolate extracellular vesicles and characterize the exosome fraction. In some
studies, a second ultracentrifugation step for “washing” is included in the isolation process to increase purity by removing
contaminating proteins. This study attempted to investigate the validity of using an additional step to increase the purity
of samples as well as examine the effect on recovery by comparing a single ultracentrifugation step to when a second
ultracentrifugation step is added to the isolation procedure. The results obtained indicated that the additional step
increased the purity of the isolated exosomes by removing contaminating proteins, however, the total yield was lower.
The reduced yield is likely the result of misplacing exosomes during the extra step because it is difficult to ensure all
exosomes are pelleted and re-suspended after ultracentrifugation. Therefore, the inclusion of an additional
ultracentrifugation step in research is dependent on the application. For example, higher purity is a priority in therapeutic
applications, while a higher yield is often preferred in diagnostic applications.
A epilepsia é uma doença neurológica, caracterizada por atividade neuronal excessiva, as crises convulsivas. Estudos comprovam que a incidência dos sintomas é maior no primeiro ano de vida, e o número aproximado de pacientes acometidos no mundo é de 70 milhões de pessoas. Objetivo: O objetivo desse presente trabalho é investigar o uso medicinal da cannabis, assim como analisar sua segurança e eficácia no tratamento da epilepsia. Metodologia: Para que isso fosse possível, foi realizada uma revisão sistemática, em tais bases de dados: ScienceDirect, Biblioteca Virtual de Saúde – BVS e Pubmed, utilizando os descritores cannabis e epilepsia, cannabis e farmacologia. Resultados: Os fármacos que são utilizados como forma de tratamento têm eficácia em cerca de 70% dos casos, onde os 30% restantes apresentam uma forma refratária ao tratamento. Estas circunstâncias geram fervor no desenvolvimento de efetivas soluções terapêuticas no tratamento desses casos refratários, dessa forma, a cannabis chega a ganhar espaço, quando apresenta várias funções terapêuticas, como a diminuição da frequência das convulsões, que é de grande valia para tais pacientes. Conclusão: A partir do recolhimento de dados, a conclusão é que o uso da cannabis tem efeito promissor no tratamento da epilepsia, quando comparado à convencional farmacoterapia, mesmo acompanhando alguns efeitos colaterais que são de certa forma aceitáveis. É de considerável importância ressaltar que por se tratar de um extrato que possui origem de uma planta vista como droga psicoativa, seu rótulo torna-se valioso para o avanço científico, necessitando de mais análises e estudos futuros.
Cannabis sativa has been associated with contradictory effects upon seizure states despite its medicinal use by numerous people with epilepsy. We have recently shown that the phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the well-established in vivo model of pentylenetetrazole-induced generalised seizures, suggesting that earlier, small-scale clinical trials examining CBD effects in people with epilepsy warrant renewed attention. Here, we report the effects of pure CBD (1, 10 and 100mg/kg) in two other established rodent seizure models, the acute pilocarpine model of temporal lobe seizure and the penicillin model of partial seizure. Seizure activity was video recorded and scored offline using model-specific seizure severity scales. In the pilocarpine model CBD (all doses) significantly reduced the percentage of animals experiencing the most severe seizures. In the penicillin model, CBD (≥ 10 mg/kg) significantly decreased the percentage mortality as a result of seizures; CBD (all doses) also decreased the percentage of animals experiencing the most severe tonic-clonic seizures. These results extend the anti-convulsant profile of CBD; when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies.
Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in [(35)S]guanosine 5'-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.
Epilepsy is a common chronic disorder that requires long-term antiepileptic drug therapy. Approximately one half of patients fail the initial antiepileptic drug and about 35% are refractory to medical therapy, highlighting the continued need for more effective and better tolerated drugs. Levetiracetam is an antiepileptic drug marketed since 2000. Its novel mechanism of action is modulation of synaptic neurotransmitter release through binding to the synaptic vesicle protein SV2A in the brain. Its pharmacokinetic advantages include rapid and almost complete absorption, minimal insignificant binding to plasma protein, absence of enzyme induction, absence of interactions with other drugs, and partial metabolism outside the liver. The availability of an intravenous preparation is yet another advantage. It has been demonstrated effective as adjunctive therapy for refractory partial-onset seizures, primary generalized tonic-clonic seizures, and myoclonic seizures of juvenile myoclonic epilepsy. In addition, it was found equivalent to controlled release carbamazepine as first-line therapy for partial-onset seizures, both in efficacy and tolerability. Its main adverse effects in randomized adjunctive trials in adults have been somnolence, asthenia, infection, and dizziness. In children, the behavioral adverse effects of hostility and nervousness were also noted. Levetiracetam is an important addition to the treatment of epilepsy.
In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8 health human volunteers. Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting. Neurological and physical examinations, blood and urine analysis, ECG and EEG were performed at weekly intervals. In phase 2 of the study, 15 patients suffering from secondary generalized epilepsy with temporal focus were randomly divided into two groups. Each patient received, in a double-blind procedure, 200-300 mg daily of CBD or placebo. The drugs were administered for along as 4 1/2 months. Clinical and laboratory examinations, EEG and ECG were performed at 15- or 30-day intervals. Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment, although these drugs no longer controlled the signs of the disease. All patients and volunteers tolerated CBD very well and no signs of toxicity or serious side effects were detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved. The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed.
Background: Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it is effective in patients with epilepsy. Some states in the United States of America have explicitly approved its use for epilepsy. Objectives: To assess the efficacy and safety of cannabinoids when used as monotherapy or add-on treatment for people with epilepsy. Search methods: We searched the Cochrane Epilepsy Group Specialized Register (9 September 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 8), MEDLINE (Ovid) (9 September 2013), ISI Web of Knowledge (9 September 2013), CINAHL (EBSCOhost) (9 September 2013), and ClinicalTrials.gov (9 September 2013). In addition, we included studies we personally knew about that were not found by the searches, as well as searched the references in the identified studies. Selection criteria: Randomized controlled trials (RCTs) whether blinded or not. Data collection and analysis: Two authors independently selected trials for inclusion and extracted the data. The primary outcome investigated was seizure freedom at one year or more, or three times the longest interseizure interval. Secondary outcomes included responder rate at six months or more, objective quality of life data, and adverse events. Main results: We found four randomized trial reports that included a total of 48 patients, each of which used cannabidiol as the treatment agent. One report was an abstract and another was a letter to the editor. Anti-epileptic drugs were continued in all studies. Details of randomisation were not included in any study report. There was no investigation of whether the control and treatment participant groups were the same or different. All the reports were low quality. The four reports only answered the secondary outcome about adverse effects. None of the patients in the treatment groups suffered adverse effects. Authors' conclusions: No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to small numbers of patients generally for short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure.
Public interest in the use of "medical marijuana" for the treatment of childhood epilepsy has burgeoned in the last few years. This has occurred in parallel with a growing interest in "medical marijuana" in general. Physicians and pediatricians must balance their patients' desire for immediate access to these products with the tenets of evidence-based medicine. This review discusses the biochemistry of cannabis products (the phytocannabinoids) setting this in the context of the endogenous endocannabinoid system. The differing and potentially modulating effects of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are reviewed. The evidence-base supporting or not the use of cannabis products for the treatment of neurological disease and specifically epilepsy is explored. The potential for adverse effects and particularly of neurotoxicity is addressed. Finally, public health and sociocultural implications are touched upon. Specific recommendations for interested physicians are provided including advocacy for patients and for a change in the "scheduling" of cannabis in order to better foster much-needed high-quality scientific research in this important area.
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.
The pharmacologic and biochemical features of cannabinoids make them candidates for antiseizure medications. At this time, anecdotes have outstripped controlled clinical trials as sources of support for their clinical value.
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.
Tuberous sclerosis (also known as tuberous sclerosis complex [TSC]) is a multisystem genetic disorder that affects almost every organ in the body. Mutations in the TSC1 or TSC2 genes lead to disruption of the TSC1-TSC2 intracellular protein complex, causing overactivation of the mammalian target of rapamycin (mTOR) protein complex. The surveillance and management guidelines and clinical criteria for tuberous sclerosis were revised in 2012, and mTOR inhibitors are now recommended as treatment options for subependymal giant cell astrocytomas and renal angiomyolipomas-two common features of the disease. However, most morbidity and mortality caused by tuberous sclerosis is associated with neurological and neuropsychiatric manifestations. Treatment of epilepsy associated with tuberous sclerosis remains a major challenge, with more than 60% of patients having ongoing seizures. Tuberous-sclerosis-associated neuropsychiatric disorders (TAND) are multilevel and occur in most individuals with the disorder, but are rarely assessed and treated. Clinical trials of mTOR inhibitors to treat seizures and TAND are underway. Management of the neurological and neuropsychiatric manifestations of the disorder should be coordinated with treatment of other organ systems. In view of the age-related expression of manifestations from infancy to adulthood, continuity of clinical care and ongoing monitoring is paramount, and particular attention is needed to plan transition of patient care from childhood to adult services.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Over the past few years, increasing public and political pressure has supported legalization of medical marijuana. One of the main thrusts in this effort has related to the treatment of refractory epilepsy—especially in children with Dravet syndrome—using cannabidiol (CBD). Despite initiatives in numerous states to at least legalize possession of CBD oil for treating epilepsy, little published evidence is available to prove or disprove the efficacy and safety of CBD in patients with epilepsy. This review highlights some of the basic science theory behind the use of CBD, summarizes published data on clinical use of CBD for epilepsy, and highlights issues related to the use of currently available CBD products.
Cannabidiol is the major nonpsychoactive component of Cannabis sativa. Over the centuries, a number of medicinal preparations derived from C. sativa have been employed for a variety of disorders, including gout, rheumatism, malaria, pain, and fever. These preparations were widely employed as analgesics by Western medical practitioners in the 19 th century ( 1 ). More recently, there is clinical evidence suggesting efficacy in HIV-associated neuropathic pain, as well as spasms associated with multiple sclerosis ( 1 ).
Intractable epilepsies have an extraordinary impact on cognitive and behavioral function and quality of life, and the treatment of seizures represents a challenge and a unique opportunity. Over the past few years, considerable attention has focused on cannabidiol ( CBD ), the major nonpsychotropic compound of Cannabis sativa . Basic research studies have provided strong evidence for safety and anticonvulsant properties of CBD . However, the lack of pure, pharmacologically active compounds and legal restrictions have prevented clinical research and confined data on efficacy and safety to anecdotal reports. Pure CBD appears to be an ideal candidate among phytocannabinoids as a therapy for treatment‐resistant epilepsy. A first step in this direction is to systematically investigate the safety, pharmacokinetics, and interactions of CBD with other antiepileptic drugs and obtain an initial signal regarding efficacy at different dosages. These data can then be used to plan double‐blinded placebo‐controlled efficacy trials.
A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .
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.
Background:
Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it is effective in patients with epilepsy. Some states in the United States of America have explicitly approved its use for epilepsy.
Objectives:
To assess the efficacy of marijuana, or one of marijuana's constituents in the treatment of people with epilepsy.
Search methods:
We searched the Cochrane Epilepsy Group Specialized Register (May 15, 2012), the Cochrane Central Register of Controlled Trials (CENTRAL issue 4 of 12, The Cochrane Library 2012),MEDLINE (PubMed, searched on May 15, 2012), ISI Web of Knowledge (May 15, 2012), CINAHL (EBSCOhost, May 15, 2012), and ClinicalTrials.gov (May 15, 2012). In addition, we included studies we personally knew about that were not found by the searches, as well as references in the identified studies.
Selection criteria:
Randomized controlled trials (RCTs), whether blinded or not.
Data collection and analysis:
Two authors independently selected trials for inclusion and extracted data. The primary outcome investigated was seizure freedom at one year or more, or three times the longest interseizure interval. Secondary outcomes included: responder rate at six months or more, objective quality of life data, and adverse events.
Main results:
We found four randomized reports which included a total of 48 patients, each of which used cannabidiol as the treatment agent. One report was an abstract, and another was a letter to the editor. Anti-epileptic drugs were continued in all. Details of randomisation were not included in any study. There was no investigation of whether control and treatment groups were the same or different. All the reports were low quality.The four reports only answered the secondary outcome about adverse effects. None of the patients in the treatment groups suffered adverse effects.
Authors' conclusions:
No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to small numbers of patients, for generally short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.
Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease.
A retrospective chart review of all patients with TSC seen between January 2002 and October 2008. Charts were reviewed for a history of infantile spasms (IS), seizure other than IS, refractory epilepsy, Lennox-Gastaut syndrome (LGS), anticonvulsant medication use, ages of seizure onset, last seizure, last clinic visit, clinical seizure phenotype(s), cognitive impairment, and genetic mutation.
Two hundred ninety-one patients were included. Among these patients, 37.8% had a history of IS; 85.2% had a history of seizure; 54.1% developed multiple seizure types, not including IS; 63.2% had seizure onset in the first year of life; and 12.1% of adults without a seizure history developed epilepsy. Of epilepsy patients, 62.5% developed refractory epilepsy and 33.5% achieved epilepsy remission; 37.5% of these patients achieved medication freedom. IS was a risk factor for refractory epilepsy (p<0.0001) and LGS (p<0.0001). History of seizure, IS, age at seizure onset, and refractory epilepsy each correlated with poor cognitive outcome (p<0.0001). Epilepsy remission correlated with better cognitive outcome (p<0.0001). TSC2 was a risk factor for IS and epilepsy; patients without an identified mutation were more likely to achieve remission.
Most patients with TSC develop epilepsy and most develop multiple seizure types. Onset typically occurs in the first year of life; however, adults remain at risk. Although refractory epilepsy is common, many patients achieve seizure control. Many features of seizure history are predictive of cognitive and epilepsy outcome.
The effects of cannabidiol (CBD) on electrically evoked kindled seizures were studied in conscious, unrestrained rats with chronically implanted cortical and limbic electrodes, and the results were compared with those of Δ ⁹ ‐tetrahydrocannabinol (Δ ⁹ ‐THC), phenytoin (PHT), and ethosuximide (ESM). All drugs were anticonvulsant, but there were marked differences in their effects on afterdischarge (AD) threshold, duration, and amplitude. CBD, like PHT and Δ ⁹ ‐THC, elevated the AD threshold; in contrast, ESM decreased the threshold but suppressed AD spread. CBD, however, also resembled ESM inasmuch as both drugs decreased AD duration and amplitude. Electrophysiologically, the antiseizure effects of CBD were a combination of those of PHT and ESM. The combination of effects may account for the observation that CBD was the most efficacious of the drugs tested against limbic ADs and convulsions. Other properties of CBD were also noted: For example, compared with Δ ⁹ ‐THC, it is a much more selective anticonvulsant vis‐à‐vis motor toxicity. CBD also lacks the CNS excitatory effects produced by Δ ⁹ ‐THC, PHT, and ESM. These characteristics, combined with its apparently unique set of electrophysiological properties, support the suggestion that CBD has therapeutic potential as an antiepileptic.
RÉSUMÉ
Les effets du cannabidiol (CBD) sur les crises Ďembrasement provoquées par stimulation électrique ont éstéétudiés chez des rats conscients, non mainte‐nus, avec électrodes corticales et limbiques implantées. Les résultats ont été compareés à ceux obtenus avec le Δ ⁹ ‐teatrahydrocannabinol (Δ ⁹ ‐THC), la phénytoi'ne (PHT), et Ľéthosuccimide (ESM). Toutes ces drogues sont anticonvulsivantes, mais leurs effets se sont montrés très différents sur le seuil, la durée et Ľ amplitude des post‐décharges (PD). Le CBD élève le seuil des PD comme le PHT et le Δ ⁹ ‐THC. Au contraire, ĽESM décroit le seuil mais supprime la propagation des PD. Toutefois, le CBD, comme ĽESM, diminue Ľ amplitude et la durée des PD. Ďun point de vue électrophysiologique, le CBD présente done un effet antiépileptique comparable à une combinaison Ďeffets du PHT et de ĽESM. Cette combinaison Ďeffets peut expliquer pourquoi le CBD est le plus efficace des produits testés contre les PD et les crises limbiques. Ďautres propriétés du CBD ont également été observées: par exemple, par comparaison avec le Δ ⁹ ‐THC, il s'agit Ďun produit ayant des propnétés anticonvulsivantes beaucoup plus sélectives vis‐à‐vis des phénomenes moteurs. Le CBD n'entraine pas non plus les effets excitateurs du système nerveux central que produisent le Δ ⁹ ‐THC, la PHT, ou ĽESM. Ces caractéristiques, ainsi que ses propriétés électrophysiologiques apparemment uniques, permettent de suggérer que le CBD a un potentiel thérapeutique en tant qu'antiépileptique.
RESUMEN
Los efectos del cannabidiol (CBD) sobre los ataques condicionados evocados electricamente han sido es‐tudiados en ratas conscientes y libres con electrodos cnonicos implantados en la corteza y en el sistema límbico. Los resultados han sido comparados con los del Δ ⁹ ‐tetrahydrocannabinol (Δ ⁹ ‐THC), de la fenitoina (PHT) y de la etosuximida (ESM). Todas las drogas eran anticonvulsivas pero existían claras diferencias en sus efectos sobre el umbral, la duración y la amplitud de la post‐descarga (AD). El CBD, al igual que la PHT y el Δ ⁹ ‐THC, elevaron el umbral de la AD; por el contrario la ESM redujo el umbral pero suprimio la propagación de la AD. Sin embargo el CBD fue algo semejante a la ESM ya que ambas drogas redujeron la duración y amplitud de la AD. Electro‐fisiológicamente, los efectos anti‐ataque del CBD fueron una combinación de los de la PHT y los de la ESM. Esta combinación de efectos puede explicar la observación de que el CBD fue, de las drogas analizadas, la más eficaz contra la AD límbica y los ataques limbicos. Otras propiedades del CBD han sido también observadas: por ejemplo, compareándolo con el Δ ⁹ ‐THC, es mejor anticonvulsive en relación con su toxicidad motora. El CBD tampoco presenta los efectos excitadores producidos por el Δ ⁹ ‐THC, la PHT y la ESM. Estas characterísticas, combinadas con sus específicas propiedades electrofisiologicas, apoyan la sugerencia de que el CBD tiene potencial terapeútico como antiepiléptico.
ZUSAMMENFASSUNG
Die Wirkung des Cannabidiols (CBD) auf elek‐trisch evozierte Kindling‐Anfälle wurde bei “be‐wußtseinsklaren,” frei sich bewegenden Ratten mit chronisch implantierten kortikalen und limbischen Elektroden untersucht. Die Ergebnisse wurden mit denen verglichen, die durch Delta‐9‐Tet‐rahydrocannabiol (Delta‐9‐THC), Phenytoin (PHT), und Ethosuximid (ESM) erzielt wurden. Alle Drogen wirkten antikonvulsiv, aber es bestanden deutliche Unterschiede in ihren Wirkungen auf Schwelle, Dauer und Amplitude, der Nachentladung (AD). CBD, ebenso wie PHT und Delta‐9‐THC, erhohten den AD‐Schwellenwert. Im Gegensatz hierzu verminderte ESM den Schwellenwert aber unter‐driickte die Ausbreitung. CBD hingegen ähnelte dem ESM insofern, als beide Drogen die AD‐Dauer und Amplitude verminderten. Die antikonvulsiven Wirkungen des CBD bestanden physiologisch in einer Kombination der Wirkungen von PHT und ESM. Die Wirkungskombination mag verantwortlich sein fur die Beobachtung, daß CBD die Substanz war unter den getesteten, die am wirkungsvollsten gegen limbische AD und limbische Anfälle war. Andere Eígenschaften des CBD wurden festgestellt: Z.B. ist es verglichen mit Delta‐9‐THC viel selektiver antikonvulsiv wirksam im Verhältnis zu seiner toxischen Wirkung auf die Motorik. Dem CBD fehlt die excitatorische Wirkung auf das ZNS, die durch Delta‐9‐THC, PHT, und ESM erzielt wird. Diese Charaktaristika zusammen mit offenbar einzigartigen elektrophysiologischen Eigenschaften unterstiltzen die Vermutung, daB CBD therapeutische Möglichkeiten als Antiepileptikum besitzt.
Cannabidiol appears to be a potent diphenylhydantoin like anticonvulsant agent; it also seems to lack hallucinogenic and other neurotoxic properties typical of other marihuana compounds either in man or in laboratory animals.
The anticonvulsant activity of orally administered δ
9-tetrahydrocannabinol (δ
9-THC), δ
8-THC, cannabidiol (CBD) and cannabinol (CBN) was tested in mice utilizing electroshock and chemoshock methods. In doses tested δ
9-THC afforded no protection to mice from chemoshock seizures and was effective against electroshock only in high doses (160–200 mg/kg). CBD and CBN (150–200 mg/kg) were without effect in both tests.
An interaction between cannbinoids was apparent when all three were administered simultaneously (each at 50 mg/kg) because this combination produced a significant reduction in the duration of the hind-limb extensor phase of the electroshock seizures.
The administration of δ
9-THC significantly potentiated the anticonvulsant effectiveness of phenytoin against electroshock seizures and this effect was further potentiated by the concurrent administration of CBD. Whilst the potentiation of phenytoin by δ
9-THC (50 mg/kg) was of the order of 1.5 times, the combination of δ-9THC and CBD (each 50 mg/kg) produced a four-fold potentiation.
Neither within-cannabinoid interaction nor cannabinoid potentiation of phenobarbitone effectiveness could be demonstrated in chemoshock tests.
The mechanism of the cannabinoid facilitation of phenytoin is unknown but it possibly involves activity at central nervous system level rather than being a metabolic interaction. This drug interaction may have potential clinical significance.
In mice, running, clonic and tonic convulsions and lethality were assessed following transcorneal (electroshock) current or convulsant drugs, each administered alone and after cannabidiol (CBD) pretreatment. CBD prevented tonic convulsions caused by a convulsant current (CC) 99.99, and by the convulsant dose (CD) 99.99 values of gamma-aminobutyric acid (GABA) inhibitors, 3-mercaptoproprionic acid (3MPA), picrotoxin (PIC), isonicotinic acid hydrazine (INH), pentylenetetrazol (PTZ) and bicuculline (BIC). Rankorder potencies, based on the antitonic ED50 of CBD, were: 3MPA greater than PIC = current = PTZ = BIC. Further, CBD prevented 3MPA-induced lethality, but failed to prevent the occurrence of the other behavioral endpoints of the above treatments. CBD also failed to prevent convulsions and lethality caused by the CD 99.99 of strychnine, a glycine antagonist. The differential effects of CBD suggest that the cannabinoid acts to inhibit seizure spread in the CNS by an action on GABA, but not glycine, mechanisms.
To evaluate the efficacy and tolerability of levetiracetam (LEV) as adjunctive therapy in children (4 to 16 years) with treatment-resistant partial-onset seizures.
This multicenter, randomized, placebo-controlled trial consisted of an 8-week baseline period followed by a 14-week double-blind treatment period. During the treatment period, patients received either placebo or LEV add-on therapy and were up-titrated to a target dose of 60 mg/kg/day.
One hundred ninety-eight patients (intent-to-treat population) provided evaluable data. The reduction in partial-onset seizure frequency per week for LEV adjunctive therapy over placebo adjunctive therapy was significant (26.8%; p = 0.0002; 95% CI 14.0% to 37.6%). A 50% or greater reduction of partial seizure frequency per week was attained in 44.6% of the LEV group (45/101 patients), compared with 19.6% (19/97 patients) receiving placebo (p = 0.0002). Seven (6.9%) LEV-treated patients were seizure-free during the entire double-blind treatment period, compared with one (1.0%) placebo-treated patient. One or more adverse events were reported by 88.1% of LEV-treated patients and 91.8% of placebo patients. The most common treatment-emergent adverse events were somnolence, accidental injury, vomiting, anorexia, hostility, nervousness, rhinitis, cough, and pharyngitis. A similar number of patients in each group required a dose reduction or withdrew from the study as a result of an adverse event.
Levetiracetam adjunctive therapy administered at 60 mg/kg/day is efficacious and well tolerated in children with treatment-resistant partial seizures.
- Gloss D
- Vickrey B