“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 D9-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.”
“Seizure frequency in treatment-resistant epilepsies seems to be decreased by cannabidiol (CBD), but contrasting data are available on its effect on sleep, behavior, and quality of life (QoL), and no data is reported on its effect on parental stress in patients with epilepsy (PWE). Thus, we conducted a retrospective study on a cohort of children and adults with drug-resistant epilepsy (DRE) who had been treated with highly purified, pharmaceutical-grade CBD to evaluate its effects on seizure frequency, QoL, behavior, parental stress, and sleep. Eighteen patients (12 adults and 6 children) were included in the cohort and followed for a median of 9 months. At the last follow-up (Tn), nine patients (50%) were considered CBD responders with at least a 50% decrease in seizure frequency. No serious adverse effects were found. No statistically significant differences were found concerning sleep, including daytime sleepiness, and no statistically significant effect was found on parental stress at Tn. An improvement was found for social interaction in quality of life (p < 0.05) for all patients.
Our results demonstrate that CBD is a safe and effective antiseizure medication (ASM).
CBD doesn’t seem to affect sleep measures in adults and children or worsen daytime sleepiness. However, CBD improves specific QoL measures, which could indicate a possible use of CBD for other childhood disabilities. No impact of CBD was seen on parental stress, which could possibly be due to the limited follow-up or could mean that parental stress is not dependent on seizure frequency.”
“Cannabidiol (CBD) is a safe and effective antiseizure medication (ASM).”
“Cannabidiol (CBD) has been recently approved as an antiseizure agent in Dravet Syndrome (DS), a pediatric epileptic encephalopathy, but CBD could also be active against associated comorbidities. Such associated comorbidities were also attenuated by the sesquiterpene β-caryophyllene (BCP). Here, we have compared the efficacy of both compounds and further initiated the analysis of a possible additive effect between both compounds in relation with these comorbidities using two experimental approaches. The first experiment was aimed at comparing the benefits of CBD and BCP, including their combination in conditional knock-in Scn1a-A1783V mice, an experimental model of DS, treated since the postnatal day 10th to 24th. As expected, DS mice showed impairment in limb clasping, delay in the appearance of hindlimb grasp reflex and additional behavioural disturbances (e.g., hyperactivity, cognitive deterioration, social interaction deficits). This behavioural impairment was associated with marked astroglial and microglial reactivities in the prefrontal cortex and the hippocampal dentate gyrus. BCP and CBD administered alone were both able to partially attenuate the behavioural disturbances and the glial reactivities, with apparently greater efficacy against glial reactivities obtained with BCP, whereas superior effects in a few specific parameters were obtained when both compounds were combined. In the second experiment, we investigated this additive effect in cultured BV2 cells treated with BCP and/or CBD and stimulated with LPS. As expected, addition of LPS induced a marked increase in several inflammation-related markers (e.g., TLR4, COX-2, iNOS, catalase, TNF-α, IL-1β), as well as elevated Iba-1 immunostaining. Treatment with BCP or CBD attenuated these elevations, but, again and in general, superior results were obtained when both cannabinoids were combined. In conclusion, our results support the interest to continue investigating the combination of BCP and CBD to improve the therapeutic management of DS in relation with their disease-modifying properties.”
“The use of cannabidiol (CBD) for therapeutic purposes is receiving considerable attention, with speculation that CBD can be useful in a wide range of conditions. Only one product, a purified form of plant-derived CBD in solution (Epidiolex), is approved for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Appraisal of the therapeutic evidence base for CBD is complicated by the fact that CBD products sometimes have additional phytochemicals (like tetrahydrocannabinol (THC)) present, which can make the identification of the active pharmaceutical ingredient (API) in positive studies difficult. The aim of the present review is to critically review clinical studies using purified CBD products only, in order to establish the upcoming indications for which purified CBD might be beneficial.
The areas in which there is the most clinical evidence to support the use of CBD are in the treatment of anxiety (positive data in 7 uncontrolled studies and 17 randomised controlled trials (RCTs)), psychosis and schizophrenia (positive data in 1 uncontrolled study and 8 RCTs), PTSD (positive data in 2 uncontrolled studies and 4 RCTs) and substance abuse (positive data in 2 uncontrolled studies and 3 RCTs). Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT. Limited evidence supports the use of CBD for the treatment of Parkinson’s (3 positive uncontrolled studies and 2 positive RCTs), autism (3 positive RCTs), smoking cessation (2 positive RCTs), graft-versus-host disease and intestinal permeability (1 positive RCT each). Current RCT evidence does not support the use of purified oral CBD in pain (at least as an acute analgesic) or for the treatment of COVID symptoms, cancer, Huntington’s or type 2 diabetes.
In conclusion, published clinical evidence does support the use of purified CBD in multiple indications beyond epilepsy. However, the evidence base is limited by the number of trials only investigating the acute effects of CBD, testing CBD in healthy volunteers, or in very small patient numbers. Large confirmatory phase 3 trials are required in all indications.”
“Cannabidiol oil (CBD) has been approved as an anti-seizure medication for the treatment of uncommon types of epilepsy, occurring in children: Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. There are few publications in relation to use the CBD in adult patients with focal drug-resistant epilepsy. The objective of this study was to evaluate the efficacy, tolerability, safety, and quality of life, of adjuvant treatment with CBD, in adult patients with drug-resistant focal epilepsy for at least 6 months. An open, observational, prospective cohort study was conducted using a before-after design (time series) in adult patients undergoing outpatient follow-up in a public hospital in Buenos Aires, Argentina. From a total of 44 patients, 5% of patients were seizure-free, 32% of patients reduced more than 80% of their seizures and 87% of patients reduced 50% of their monthly seizures. Eleven percent presented a decrease of less than 50% in seizure frequency. The average final dose was 335 mg/d orally administered. Thirty-four percent of patients reported mild adverse events and no patient reported severe adverse effects. At the end of the study, we found in most patients a significant improvement in the quality of life, in all the items evaluated. Adjuvant treatment with CBD in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated, and associated with a significant improvement in their quality of life.”
“Most patients have a significant improvement in their quality of life.”
“Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARγ2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI’s pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI’s synaptic effects and dampening hyperexcitability.”
“Objective: Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest anti-seizure effects also beyond these three epilepsy syndromes.
Methods: In a retrospective multi-center study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers.
Results: The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0-72) years (235 children and adolescents, 76 adults). Therapy with CBD was off-label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co-medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%).
Significance: Our study highlights that CBD has an anti-seizure effect comparable to other anti-seizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children < 2 years of age.”
“Background There is a paucity of high-quality evidence of the efficacy and safety of cannabis-based medicinal products in treatment of treatment-resistant epilepsy (TRE) in children.
Methods A case series of children(<18 years old) with TRE from the UK Medical Cannabis Registry was analysed. Primary outcomes were ≥50% reduction in seizure frequency, changes in the Impact of Paediatric Epilepsy Score(IPES) and incidence of adverse events.
Results Thirty-five patients were included in the analysis. Patients were prescribed during their treatment with the following-CBD isolate oils(n=19), CBD broad-spectrum oils(n=17), and CBD/Δ9-THC combination therapy(n=17). Twenty-three(65.7%) patients achieved a ≥50% reduction in seizure frequency. 94.1%(n=16) of patients treated with CBD and Δ9-THC observed a ≥50% reduction in seizure frequency compared to 31.6%(n=6) and 17.6%(n=3) of patients treated with CBD isolates and broad-spectrum CBD products respectively(p<0.001). Twenty-six(74.3%) adverse events were reported by 16 patients(45.7%). The majority of these were mild(n=12; 34.2%) and moderate(n=10; 28.6%).
Conclusions The results of this study demonstrate a positive signal of improved seizure frequency in children treated with CBMPs for TRE. Moreover, the results suggest that CBMPs are well-tolerated in the short term. The limitations mean causation cannot be determined in this open-label, case series.”
“Objective: Cannabidiol (CBD) expanded access program (EAP), initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsy (TRE) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019.
Methods: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/mL oral solution), increasing from 2-10 mg/kg/d to tolerance or maximum 25-50 mg/kg/d dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit.
Results: Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (0-74.5), and patients were taking a median (range) 3 (0-10) antiseizure medications (ASMs) at baseline; most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/d; median exposure duration was 694 days. Median percentage reduction from baseline ranged from 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) ranged from 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. Most common AEs (≥20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%).
Significance: Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of TREs.”
“Objective: The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures.
Methods: This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses.
Results: Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%.
Conclusions: This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.”