Epilepsy - randomised controlled trials and other studies

Randomized, double-blind, placebo-controlled trial
Grade 1- high

Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. New England Journal of Medicine 2017; 376: 2011-20.

120 children and adolescents aged 2-18 with Dravet syndrome and drug-resistant seizures were treated with 20mg/kg/day oral cannabidiol (CBD) (Epidiolex, available at some US sites via an Expanded Access Scheme) or placebo, taken orally for 2 weeks, with a 12-week maintenance period. The cannabidiol formulation under study reduced the frequency of convulsive seizures among children and young adults with Dravet syndrome over a 14-week period but was associated with adverse events including somnolence and elevation of liver-enzyme levels. 3 CBD patients achieved total seizure freedom during the test period; no placebo patients achieved seizure freedom. 43% of CBD patients had a greater than 50% reduction in seizures, compared to 27% of placebo patients. Caregivers of placebo patients were more likely to report an improvement in overall condition. Adverse events included somnolence, diarrhea, decreased appetite, fatigue, pyrexia, vomiting, lethargy, upper respiratory tract infection and convulsion.

Randomized, double-blind, placebo-controlled study
Grade 1- high

French J, Thiele E, Mazurkiewicz-Beldzinska M, Benbadis S, Marsh E, Joshi C, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut syndrome (LGS): results of a multi-center, randomized, double-blind, placebo controlled trial (GWPCARE4). Neurology 2017; 88: s21.

171 patients 2-55 years old with Lennox-Gastaut syndrome were treated with 20mg/kg/day purified oral 100 mg/ml CBD extract (Epidiolex) or placebo. A 2 week test period was followed by 12 weeks maintenance, as an adjunctive treatment. The CBD formulation under study resulted in a significantly greater median percent reduction in monthly drop seizure frequency, versus placebo during the first 4 weeks of the maintenance period. 5 CBD patients were seizure free during the maintenance period. CBD patients/ caregivers were more likely to report an improvement in overall condition. 86% of CBD and 69% of placebo patients had adverse events, most commonly diarrhea, somnolence, pyrexia, decreased appetite, and vomiting. Treatment-related serious adverse events were reported in 9 CBD patients and 1 placebo patient. 12 CBD patients withdrew from the study due to adverse events.

Randomized, double-blind, placebo-controlled trial
Grade 2- moderate

Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 1980; 21: 175-85.

15 adolescent/adult patients aged 14-49 with treatment resistant secondary generalized epilepsy were treated with 200-300 mg CBD isolated from Lebanese hashish supplied by the Israeli police or placebo per day for 8-18 weeks (8 treatment, 7 placebo). Four patients in the cannabidiol group and 1 in the placebo group were seizure-free for the duration of the study; somnolence was a reported side effect. 50% (4) of patients receiving CBD showed considerable improvement in condition. 2 patients showed small improvement, 1 did not improve at all. 1 placebo patient showed complete improvement; the other 7 showed no improvement.

Double-blind, cross-over, placebo controlled add-on trial
Grade 2- moderate

Trembly B, Sherman M. Double-blind clinical study of cannabidiol as a secondary anticonvulsant (abstract only). Paper presented at the Marijuana '90 International Conference on Cannabis and Cannabinoids; 1990 July; Kolympari, Crete.

12 adult patients with incompletely controlled epilepsy were treated with CBD or placebo (300 mg/day). No significant difference was reported between cannabidiol and placebo on seizure pattern, character or frequency; somnolence was a reported side effect.

Case control trial
Grade 3- low

Ames FR, Cridland S. Anticonvulsant effect of cannabidiol (letter to the editor). South African Medical Journal 1986; 69: 14.

12 institutionalized adults with intellectual disability and epilepsy and uncontrolled frequent seizures were treated with isolated oral cannabinoids (cannabidiol) 200-300 mg/day or placebo for 4 weeks (6 treatment, 6 placebo). No statistically significant difference in seizure frequency between the two groups at the end of 4 weeks was reported; a reported side effect was somnolence for some participants. The trial was abandoned when the CBD supply was interrupted.

Parallel RCT
Grade 2- moderate

GW Pharmaceuticals. GW pharmaceuticals announces second positive phase 3 pivotal trial for Epidiolex (cannabidiol) in the treatment of lennox-gastaut syndrome. GW Pharmaceuticals, 2017. https://www.gwpharm.com/ - external site about- us/news/ gwpharmaceuticals-announces- second- positive- phase- 3- pivotal- trial- epidiolex.

Patients aged 2-55 years with a confirmed diagnosis of drug-resistant LGS currently uncontrolled on one or more concomitant anti-epileptic drugs (AEDs) were eligible to participate in this Phase 3, randomized, double-blind placebo-controlled trial. The trial randomized 225 patients into three arms, where Epidiolex 20mg/kg/day (n=76), Epidiolex 10mg/kg/day (n=73) or placebo (n=76) was added to current AED treatment. During the treatment period, patients taking Epidiolex 20mg/kg/day achieved a median reduction in monthly drop seizures of 42 percent compared with a reduction of 17 percent in patients taking placebo (p=0.0047), and patients taking Epidiolex 10mg/kg/day achieved a median reduction in monthly drop seizures of 37 percent compared with a reduction of 17 percent in patients taking placebo (p=0.0016).Epidiolex was generally well tolerated in this trial. The pattern of adverse events was consistent with that reported in the previous two Phase 3 studies. One patient on 10mg/kg Epidiolex discontinued treatment due to an adverse event compared with six patients on 20mg/kg and one patient on placebo. Of the 84 percent of 10mg/kg patients who experienced an adverse event, 89 percent of them deemed it to be mild or moderate. Of the 94 percent of 20mg/kg patients who experienced an adverse event, 88 percent of them reported it to be mild or moderate. 72 percent of patients on placebo experienced an adverse event. Thirteen patients on Epidiolex 10mg/kg experienced a serious adverse event (two of which were deemed treatment-related) compared with thirteen patients on 20mg/kg (five of which were deemed treatment-related) and eight patients on placebo (none of which were deemed treatment-related). Of the patients who completed this trial, 99 percent have opted to continue into an open-label extension trial.

Randomized, double-blind, placebo-controlled trial
Grade 2- moderate

Thiele E, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet 2018. doi: 10.1016/S0140-6736(18)30136-3.[Epub ahead of print 24 Jan 2018].

BACKGROUND: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. METHODS: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (>3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. FINDINGS: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. INTERPRETATION: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. FUNDING: GW Pharmaceuticals.

Randomized, double-blind, placebo-controlled trial
Grade 1- high

Ben-Menachem, E. Gunning, B. Arenas Cabrera, C. M. Van Landingham, K. Crockett, J. Taylor, L. Critchley, D. Tayo, B. Morrison, G. Toledo, M. A phase 2 trial to explore the potential for a pharmacokinetic drug-drug interaction with valproate when in combination with cannabidiol in adult epilepsy patients. Epilepsia 2018; 59 (Supplement 3):S51: http://dx.doi.org/10.1111/epi.14612 - external site.

Purpose: A pharmaceutical formulation of highly purified cannabidiol (CBD) has been shown to be effective in the treatment of Lennox-Gastaut syndrome and Dravet syndrome. Valproate (VPA) is a common therapy in these indications. The primary objective of this randomized, double- blind, placebo-controlled trial in adult epilepsy patients was to investigate the impact of CBD oral solution on the steady-state pharmacokinetics (PK) of VPA and its metabolite 2-propyl-4-pentenoic acid (4-ene-VPA). Safety and tolerability of CBD in combination with VPA were evaluated. Method(s): Plasma concentrations of total VPA and 4-ene- VPA were determined using validated bioanalytical methods. To assess the effect of CBD (10 days of titration followed by 10 mg/kg twice daily for 14 days) on VPA and 4-ene-VPA exposures, a standard 90% confidence interval approach using a linear mixed-effect model was used on the ratios of geometric means of Cmax and AUCtau with and without CBD. Result(s): Twenty-one adult epilepsy patients on stable doses of VPA were enrolled; 20 were treated (CBD [n = 16], placebo [n = 4]. Eighteen (90%) patients completed the trial. Two patients taking CBD withdrew early; 1 due to hypertransaminasemia (>3.0 x upper limit of normal) and 1 because of diarrhea and nausea. Following multiple twice daily dosing of CBD concomitant with VPA (n = 10), there were minor decreases in plasma Cmax and AUCtau of VPA (<=16%) and 4-ene-VPA (<=30%) on Day 26 (VPA+CBD) compared with Day 1 (VPA alone); ratio point estimates were similar for placebo patients (n = 3). CBD PK were consistent with previous clinical trials. Fourteen (87.5%) patients taking CBD and 1 (25.0%) patient taking placebo reported adverse events (AEs); the most common AE was diarrhea (11 [55%] patients). All AEs were mild or moderate. Conclusion(s): There was no evidence for a clinically relevant PK drug-drug interaction of CBD on VPA or its putative hepatotoxic metabolite 4-ene-VPA. The safety profile of CBD was consistent with other clinical trials.

Double-blind, randomised placebo-controlled trial
Grade 1- high

Devinsky, O. Patel, A. D. Cross, J. H. Villanueva, V. Wirrell, E. C. Privitera, M. Greenwood, S. M. Roberts, C. Checketts, D. VanLandingham, K. E. Zuberi, S. M. Effect of cannabidiol on drop seizures in the lennox-gastaut syndrome. New England Journal of Medicine 2018; 378:1888-1897: http://dx.doi.org/10.1056/NEJMoa1714631 - external site.

BACKGROUND Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy. METHODS In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period. RESULTS A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. CONCLUSIONS Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560.). Copyright © 2018 Massachusetts Medical Society.

Double-blind, randomised placebo-controlled trial
Grade 1- high

Devinsky, O. Patel, A. D. Thiele, E. A. Wong, M. H. Appleton, R. Harden, C. L. Greenwood, S. Morrison, G. Sommerville, K. Gwpcare Part A Study Group Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 2018; 90:e1204-e1211: https://dx.doi.org/10.1212/WNL.0000000000005254 - external site.

OBJECTIVE: To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome. METHODS: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality.
RESULTS: Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC_0-t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury, and all recovered. No other clinically relevant safety signals were observed. CONCLUSIONS: Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.

Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study (PROTOCOL)
Grade: N/A

NCT03421496. A Study to Assess the Efficacy, Safety, and Tolerability of Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms. https://clinicaltrials.gov/show/NCT03421496 - external site 2018.

A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy, Safety, and Tolerability of Cannabidiol Oral Solution as Adjunctive Therapy With Vigabatrin as Initial Therapy in Patients With Infantile Spasms. The primary objective of this study is to evaluate the efficacy of Cannabidiol Oral Solution as adjunctive therapy with vigabatrin as initial therapy in treating participants with Infantile Spasms. The secondary objectives for this study are to evaluate the continued efficacy of Cannabidiol Oral Solution after the 14-day treatment with vigabatrin or vigabatrin plus Cannabidiol Oral Solution is complete and to evaluate the safety and tolerability of Cannabidiol Oral Solution as adjunctive therapy with vigabatrin as initial therapy in treating participants with infantile spasms. This is a clinical trials registry record of an ongoing study with an estimated completion date of December 2019. No results posted. https://clinicaltrials.gov/ct2/show/NCT03421496 - external site

Double-blind, Randomized Placebo-controlled Trial (PROTOCOL)
Grade: N/A

NCT02783092. A Double-Blind Trial to Evaluate Efficacy and Safety of Cannabidiol as an add-on Therapy for Treatment in Refractory Epilepsy. https://clinicaltrials.gov/show/NCT02783092 - external site 2016

A Double-blind, Randomized Placebo-controlled Trial to Evaluate Efficacy and Safety of Cannabidiol as an add-on Therapy for Treatment in Refractory Epileptic Crisis in Children and Adolescents. The purpose of this study is to assess the efficacy of the adjuvant use of cannabidiol administered twice daily in doses of 5-25 mg/kg/day among men and women (aged 2-18 years) with treatment-resistant epilepsy. Efficacy will be assessed through the proportion of responsive patients; that is, participants with at least 50% decrease in the frequency of epileptic seizures in the last month of the trial relative to baseline (pretreatment with AEDs only). Recruitment is ongoing. Estimated study completion is December 2020.

Open-label intervention trial
Grade 2- moderate

Abati E, Hess EJ, Morgan A, Bruno PL, Thiele E. Cannabidiol treatment of refractory epileptic spasms: an open-label study (abstract only). Paper presented at the American Epilepsy Society annual meeting; 2015; Philadelphia.

9 patients aged 2-16 years with refractory epilepsy and a diagnosis of infantile or epileptic spasms were given purified oral 100 mg/ml CBD extract (Epidiolex) as an adjunctive treatment. The overall response rate to CBD was 37.5, 43, 50, and 30% at 3, 6, 9, and 12 months. Three patients were seizure free after 2 months of treatment. Patients reported improvement in alertness, verbal capacity/ communications, and cognitive abilities. 3 of 9 patients became spasm free after 2 months of treatment, and remained so for the remainder of the trial. Adverse events included drowsiness, ataxia, appetite loss, diarrhoea, and agitation.

Open-label intervention trial
Grade 2- moderate

Chez MG. Cannabadiol in genetic refractive epilepsy in Dravet and non-Dravet cases (abstract only). Paper presented at the American Epilepsy Society annual meeting; 2015; Philadelphia.

3 patients aged 3.5, 12, and 21 years with genetic refractive epilepsy (SCN1A, GABR3, and SCN2A) were treated with purified oral 100 mg/ml CBD extract (Epidiolex) for 8-12 weeks as an adjunctive treatment; all 3 patients responded dramatically to CBD. Maximal dose was tolerated in all cases with noted seizure reductions. All patients reported improved moods, improved social or cognitive skills, and all tolerated initial dose reductions of some of their concurrent chronic antiepileptic drugs. There were no serious adverse events. Patients' results are at 8 weeks post initiation to CBD. Post-CBD seizure reduction ranged between 75% and 90%. Mild adverse events included ataxia and diarrhoea.

Open-label interventional trial
Grade 2- moderate

Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurology 2016; 15: 270-8.

214 patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy at 11 sites were treated with purified oral 100 mg/ml CBD extract (Epidiolex) for 12 weeks as an adjunctive treatment. The add-on treatment with pure cannabidiol led to a clinically meaningful reduction in seizure frequency in many patients, and had an adequate safety profile in a population with highly treatment-resistant epilepsies. Median monthly frequency of motor seizures decreased from 30.0 at baseline to 15.8 over 12 weeks. Median reduction of monthly motor seizures was 36.5%. The 20% rate of serious adverse events including somnolence, diarrhea, decreased appetite, fatigue, convulsion, and status epilepticus was higher than expected. Adverse events were reported by 79% of patients in the safety assessment group. Adverse events experienced by more than 10% of patients were somnolence, decreased appetite, diarrhoea, fatigue, and convulsion. Few who experienced adverse events stopped treatment, possibly because of parental beliefs, media attention, reduced seizure frequency outweighing the serious adverse event, or occurrence of similar events such as status epilepticus before cannabidiol treatment.

Open-label intervention trial
Grade 2- moderate

Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia 2016; 57: 1617-24.

18 pediatric and adult patients aged 2-31 with epilepsy and tuberous sclerosis complex enrolled in investigators' expanded access study were given purified oral 100 mg/ml CBD extract (Epidiolex) for 6-12 months as an adjunctive treatment. Median weekly seizure rate decreased from 22 (IQR 14.8-57.4) to 13.3 (IQR 5.1-22.1) after 3 months of treatment. Median reduction in seizure frequency of 49% and >50% reduction in seizures in around half of patients was maintained during the 12-month follow-up. Treatment responder rate ranged from 38.9%-50% over the 12 months of treatment. Those taking clobazam and CBD had a higher responder rate. Side effects including drowsiness, ataxia, diarrhea, and agitation, were reported in 66.7% of patients; none considered serious.

Retrospective chart review
Grade 3- low

Ladino LD, Hernandez-Ronquillo L, Tellez-Zenteno JF. Medicinal marijuana for epilepsy: a case series study. Canadian Journal of Neurological Sciences 2014; 41: 753-8.

18 adult outpatients authorized to use cannabis for medical purposes were identified at a Canadian adult epilepsy clinic during May-November 2013. Ten patients reported withdrawal seizure exacerbation when they stopped the marijuana. Only two patients reported side effects, and all patients found medicinal marijuana helped control seizures and improved mood disorders. The effect was complicated to estimate because of concurrent use of other antiseizure medications.

Retrospective chart review; parent report
Grade 3- low

Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy & Behavior 2015; 45: 49-52.

Parents of 75 children known to the neurology service at the Children's Hospital Colorado who had given their children oral cannabis extracts of varying concentrations not always known and usually untested reported on treatment response. 57% reported improved seizure duration and frequency; with reduction of >50% in frequency of seizures in 25 patients. 15% discontinued use – 7 had an adverse event, and 10 did not respond. Side effects reported included somnolence, fatigue, and increased seizures; rarely, developmental regression, and status epilepticus. Investigators found a striking difference in responder rate for families who had moved to Colorado for oral cannabis extracts treatment. 56% reported additional improvements including increased alertness/behaviour, language, motor skills, and sleep.

Retrospective study
Grade 3- low

Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience. Seizure 2016; 35: 41-4.

74 patients (aged 1–18 years) with refractory epilepsy were given CBD-enriched medical cannabis taken orally for 6 months on average; 66 reported a reduction in seizure frequency; 13 reported 75–100% reduction; 25 reported 50–75% reduction; 9 reported 25–50% reduction; and 19 less than 25% reduction. Side effects included somnolence, fatigue, gastrointestinal disturbances, and irritability. 7% of patients reported aggravation of seizures which led to CBD withdrawal. 5 patients experienced adverse effects.

Retrospective chart study
Grade 3- low

Sulak D, Saneto R, Goldstein B. The current status of artisanal cannabis for the treatment of epilepsy in the United States. Epilepsy & Behavior 2017; 70: 328-33.

272 patients aged 2-46 with medically refractory epilepsy with mixed etiologies in Washington State and California, plus 4 case reports from Maine reported on the use of various artisanal preparations. 86% of patients experienced some clinical benefit, and 10% experienced a complete clinical response. Adverse effects were mild, though 4% of patients experienced an exacerbation of seizures in response to cannabis; beneficial side effects such as improved cognition were reported. Investigators concluded patients and families should not rely on product labels, but test every batch for cannabinoid potencies and potential contaminants at industry-standard laboratories.

Case study
Grade 4- very low

Lorenz R. On the application of cannabis in paediatrics and epileptology. Neuroendocrinology Letters 2004; 25: 40-4.

8 children aged 3-14 with neurodegenerative disease, mitochondriopathy, post-hypoxic state, epilepsy (4), or "posttraumatic reaction" were treated with dronabinol (THC) taken orally. Of 4epilepsy cases, in 1 an effect could not be assessed, in 1 there was no effect on seizures, in 2 seizure frequency decreased; an explicit decrease measure was lacking.

Case study
Grade 4- very low

Crippa JA, Crippa AC, Hallak JE, Martin-Santos R, Zuardi AW. Delta9-THC intoxication by cannabidiol-enriched cannabis extract in two children with refractory epilepsy: full remission after switching to purified cannabidiol. Frontiers in Pharmacology 2016; 7: 359.

Two children with treatment-resistant epilepsy (left frontal dysplasia and Dravet Syndrome) were treated with CBD-enriched extract initially, followed by a change to purified CBD supplied by UK STI Pharm and European partners to Brazilian investigators. Follow up assessments at 1 year (Case A) and 1 year and 10 months (Case B) showed remission of seizures and clear progressive improvement of the remaining general symptoms with the use of pure CBD. The other medications remained stable before and during the time of transition from the cannabinoid extract to the purified CBD in both cases. Likewise, there were no changes in the dose or frequency of administration of the purified CBD oil. No side-effects were reported for any dose of CBD used.

Case study
Grade 4- very low

Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia 2014; 55: 783-6.

A 5 year old girl with severe Dravet syndrome was treated with oral cannabis extracts of a medical cannabis product produced in Colorado with a high ratio of cannabidiol to delta9-THC (16:1) known as Realm Oil or "Charlotte's Web". Reduction of >90% in frequency of generalized tonic–clonic seizures was reported, which allowed for reduction of other drugs taken for epilepsy. Side effects reported were somnolence and fatigue.

Case study
Grade 4- very low

Mortati K, Dworetzky B, Devinsky O. Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature. Reviews in Neurological Diseases 2007; 4: 103-6.

A 45-year-old man with cerebral palsy and refractory focal epilepsy used smoked marijuana at bedtime and was reported to achieve a 90% reduction in nocturnal seizures and tonic-clonic seizures without adverse events.

Case study
Grade 4- very low

Saade D, Joshi C. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report. Pediatric Neurology 2015; 52: 544-7.

A boy with malignant migrating partial seizures in infancy at 4 and 10 months was treated with purified oral 100 mg/ml CBD extract (Epidiolex) obtained by emergency application to the Expanded Access Scheme by an Iowa physician. Six months after initiation of CBD, the patient was still on levetiracetam and daily clonazepam, with a reported reduced seizure frequency from 10-20 per day to 5 per week with up to 9 days of clinical seizure freedom. Other reported improvements were improved alertness and no subclinical seizures.

Self-report survey
Grade 4- very low

Gedde M, Maa E. Whole cannabis extract of high concentration cannabidiol may calm seizures in highly refractory pediatric epilepsies 9abstract only). Paper presented at the American Epilepsy Society annual meeting; 2013; Seattle, Washington.

Eleven parents of pediatric patients with Doose, Dravet, Lennox-Gastaut, and other refractory epilepsies were treated with Realm Oil, oral cannabis extracts of a medical cannabis product produced in Colorado with a high ratio of cannabidiol to delta9-THC (16:1) also known as "Charlotte's Web". After an average dose of 4–12 mg/kg per day for at least 3 months, parents reported on reduction in weekly frequency of motor type seizures. Nine reported over 75% reduction in seizures, and 2 reported 20-45% relative to baseline. Seven children achieved this reduction in the first month of treatment. At three months, 5 were seizure-free. Side effects included sedation and unsteadiness.

Self-report telephone survey
Grade 4- very low

Gross DW, Hamm J, Ashworth NL, Quigley D. Marijuana use and epilepsy: prevalence in patients of a tertiary care epilepsy center. Neurology 2004; 62: 2095-7.

Twenty-eight past year users of smoked cannabis were identified among 136 epilepsy patients who participated in a survey. Reduction in severity of seizures was reported by 19 patients; 15 patients reported reduction in frequency of seizures. Almost a quarter of all respondents believed that marijuana was an effective treatment for epilepsy. Cannabis use among patients was higher than the general population without the usual pattern of higher use by male sex, younger ages and unemployment. At least weekly use was associated with greater seizure frequency and disease duration, possibly related to failure of conventional treatment.

Self-report online survey
Grade 4- very low

Hussain SA, Zhou R, Jacobson C, Weng J, Cheng E, Lay J, et al. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: a potential role for infantile spasms and Lennox-Gastaut syndrome. Epilepsy á Behavior 2015; 47: 138-41.

117 parents of children with epilepsy (infantile spasms and Lennox–Gastaut syndrome) who gave their children CBD-enriched cannabis extracts of varying or unknown concentration ("CBD content even when reported could not be verified") for a median exposure of around 6 months responded to the survey. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Limitations of the study included participation bias and lack of blinded outcome ascertainment.

Parent online self-report survey
Grade 4- very low

Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior 2013; 29: 574-7.

Nineteen parents of children aged 2-16 with treatment-resistant epilepsy belonging to a Facebook group of 150 parents who reported they gave cannabidiol-enriched cannabis treatments to their children responded to the survey. Parents gave artisanal preparations of cannabidiol-enriched oral cannabis extracts of varying or unknown composition/dose (CBD up to 28 mg/kg/day and THC up to 0.8 mg/kg/day) taken from 2-3 months to a year or more. Sixteen parents reported a reduction in seizure frequency; others reported beneficial effects like improved sleep and mood. Drowsiness, fatigue, and decreased appetite were reported by some parents.

Retrospecti-ve study
Grade 2- moderate

Kramer U. Cannabis for treatment of children with severe epilepsy –promising results; (11-13 September), Tel Aviv, Israel: The International Medical Cannabis Conference. 2016.

130 participants with refactory epilepsy of mixed etiologies were treated with CBD-enriched medicinal cannabis at a dose of 2-27mg/kg/day for >4 months. Of the 130 enroled, 39 (30%) reported 0% reducion in seizures, 34 (26%) reported a 0-50% reduction, 44% reported a >50% reduction, 20 (15.5%) reported a >75% reduction and 7 patients (5.5%) reported being seizure free. Additional benefits reported by patients included shorter and milder seizures, increased alertness and reduced muscular spasticity. The most common adverse events were somnolence (18%), aggressiveness/irritability (11%), exacerbation (6%) and vomiting (4.6%). A total of 38 participants withdrew from the trial, predominantly due to lack of efficacy (n=22).

Self-report survey
Grade 4- very low

Aguirre-Velázquez CG. Report from a survey of parents regarding the use of cannabidiol (medicinal cannabis) in Mexican children with refractory epilepsy. Neurol Res Int 2017;2017:1–5.

Structured online surveys were used to explore the experiences of the parents of children with refractory epilepsy using medicinal cannabis in Mexico during September 2016. The surveys, which were completed in full, were reviewed, and 53 cases of children aged between 9 months and 18 years were identified. Of these, 43 cases (82%) were from Mexico and 10 (18%) were from Latin American countries. Of the 43 Mexican cases, the diagnoses were as follows: 20 cases (47%) had Lennox-Gastaut syndrome (LGS); 13 cases (30%) had unspecified refractory epilepsy (URE); 8 cases (19%) had West syndrome (WS); 1 case (2%) had Doose syndrome (DS); and 1 case (2%) had Ohtahara syndrome (OS). In total, 47.1% of cases had previously been treated with 9 or more anticonvulsant therapies. The parents reported a decrease in convulsions when cannabidiol was used in 81.3% of the cases; a moderate to significant decrease occurred in 51% of cases, and 16% of cases were free from seizure. The number of antiepileptic drugs being used was reduced in 9/43 (20.9%) cases. No serious adverse effects were reported, with only some mild adverse effects, such as increased appetite or changes in sleep patterns, reported in 42% of cases.

Case report
Grade 4- very low

Ellison JM, Gelwan E, Ogletree J. Complex partial seizure symptoms affected by marijuana abuse. J Clin Psychiatry 1990;51:439–40.

Case study of a 29-year-old male with complex partial seizures, who reported suppression of seizures following several years of using smoked cannabis sativa and sudden reemergance of seizures after withdrawal of the substance.

Open-label case series
Grade 4- very low

Gofshteyn JS, Wilfong A, Devinsky O, et al. Cannabidiol as a Potential Treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the acute and chronic phases. J Child Neurol 2017;32:35–40.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy affecting normal children after a febrile illness. FIRES presents with an acute phase with super-refractory status epilepticus and all patients progress to a chronic phase with persistent refractory epilepsy. The typical outcome is severe encephalopathy or death. The authors present 7 children from 5 centers with FIRES who had not responded to antiepileptic drugs or other therapies who were given cannabadiol (Epidiolex, GW Pharma) on emergency or expanded investigational protocols in either the acute or chronic phase of illness. After starting cannabidiol, 6 of 7 patients' seizures improved in frequency and duration. One patient died due to multiorgan failure secondary to isoflourane. An average of 4 antiepileptic drugs were weaned. Currently 5 subjects are ambulatory, 1 walks with assistance, and 4 are verbal. While this is an open-label case series, the authors add cannabidiol as a possible treatment for FIRES.

Self-report survey
Grade 4- very low

Hamerle M, Ghaeni L, Kowski A, et al. Cannabis and other illicit drug use in epilepsy patients. Eur J Neurol 2014;21:167–70.

BACKGROUND AND PURPOSE: This study aimed to assess the prevalence of illicit drug use among epilepsy patients and its effects on the disease. METHODS: We systematically interviewed epilepsy outpatients at a tertiary epilepsy clinic. Predictors for active cannabis use were analysed with a logistic regression model. RESULTS: Overall, 310 subjects were enrolled; 63 (20.3%) reported consuming cannabis after epilepsy was diagnosed, and 16 (5.2%) used other illicit drugs. Active cannabis use was predicted by sex (male) [odds ratio (OR) 5.342, 95% confidence interval (95% CI) 1.416-20.153] and age (OR 0.956, 95% CI 0.919-0.994). Cannabis consumption mostly did not affect epilepsy (84.1%). Seizure worsening was observed with frequent illicit (non-cannabis) drug use in 80% of cases. CONCLUSIONS: Cannabis use does not seem to affect epilepsy; however, frequent use of other drugs increases seizure risk.

Self-report survey
Grade 4- very low

Massot-Tarrús A, McLachlan RS. Marijuana use in adults admitted to a Canadian epilepsy monitoring unit. Epilepsy Behav 2016;63:73–8.

OBJECTIVES: Epidemiologic evidence supporting antiseizure properties of cannabis is limited and controversial. We determined the prevalence of marijuana use and its perceived effects in patients with and without epilepsy.
METHODS: Information was collected over 14months from consecutive adult patients admitted to an epilepsy monitoring unit using a 27-item anonymous questionnaire. Patients with cognitive impairment unable to understand the questions or give informed consent and readmissions were not recruited. Subjects were divided into 4 groups, those with epileptic seizures, those with psychogenic nonepileptic seizures (PNES), those with both epileptic and PNES, and those with other nonepileptic events. Patients with exclusively epileptic seizures were compared with those with exclusively PNES. RESULTS: From 310 patients, 18 undiagnosed cases were excluded leaving a cohort of 292 patients with median age 35 (range: 27-49) years; 57.2% female. Epilepsy was documented in 190 (65.1%), PNES in 64 (21.9%), and both types of seizures in 26 (8.9%). Median duration of seizure disorder was longer (2 [1-9] vs. 13 [5.7-25] years; p<0.001) and seizure frequency lower (daily or weekly in 62.3% vs. 44.9%; p=0.03) in patients with epilepsy compared with those in patients with PNES. Overall, 166 (57%) had tried marijuana, and 36.2% used it over the past year. Utilization was 57.1% in sole epilepsy and 64.1% in sole PNES, but daily use was more likely in epilepsy (59% vs. 33.3%). Estimated mean dose was 1g/day. Marijuana use was associated with tobacco smoking (p<0.001) but not alcohol use. Eight patients used other street drugs. Improvement in seizures was perceived by 84% in those with epilepsy and 72.7% in those with PNES. In the 2 groups, stress was decreased in 84.9% and 88%, sleep improved in 77.3% and 88%, and memory/concentration was better in 32% and 28%, respectively. Antiepileptic drug side effects were decreased in 53.2% of marijuana users. Perceived effect on epileptic seizures correlated with effect on stress (r=0.35, p=0.004). Adverse effects of marijuana were mild and reported in 30.7% but included possible seizure precipitation in 5 patients with epilepsy. SIGNIFICANCE: Patients with uncontrolled epilepsy or nonepileptic events had a high rate of marijuana use with associated perceived improvements in seizure control, stress, sleep, and drug side effects. Stress reduction may contribute to the perceived impact of marijuana on seizures and nonepileptic events in adults.

Open-label study
Grade 4- very low

Wheless JW, Dlugos D, Miller I, Oh DA, Parikh N, Phillips S, et al. Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy. CNS Drugs. (2019) 33:593–604. 10.1007/s40263-019-00624-4. NCT02324673, https://clinicaltrials.gov/ct2/show/NCT02324673 - external site.

BACKGROUND: Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy.
METHODS: In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). RESULTS: Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2-6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at >10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). CONCLUSIONS: Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated.
TRIAL REGISTRATION:
ClinicalTrials.gov (NCT02324673).

Open-label study
Grade 4- very low

Pelliccia A, Grssi G, Romano A, et al. Treatment with CBD in oily solutions of drug-resistant pediatric epilepsies, in Congress on Cannabis and the Cannabinoids. Leiden, The Netherlands: International Association for Cannabis as Medicine, 2005.

16 children with symptomatic drug-resistant epilepsy received 2.5mg/kg CBD. Of the 16, none withdrew due to side effects, however only 9 remained on treatment due to high treatment costs (~300 Euro/month), despite parent-reported improvements in seizures, awareness and muscle tone. Other improvements included postural tone and speaking ability (n=1), and attentional-behavioural improvement (n=1).

Case study
Grade 4- very low

Rosemergy I, Adler J, Psirides A. Cannabidiol oil in the treatment of super refractory status epilepticus. A case report. Seizure 2016;35:56–8.

An 18 year old New Zealand male presenting with new-onset refractory status epilepticus (NORSE) syndrome commenced the hemp plant extract Elixinol™ (containing 18% CBD) at his parents' request and following New Zealand government ministerial permission. The recommended dose of Elixinol in the outpatient setting for the treatment of epilepsy is variable with reported ranges between 1 and 40 mg/kg. In this case we commenced treatment at 2.5 mg/kg/day, increasing over the course of two weeks to a maximum of 24 mg/kg/day. The product was administered by the intensive care nursing staff via a nasogastric tube. After two weeks of treatment with the CBD product in conjunction with other agents, an attempt was made to lighten the patient's sedation. The underlying EEG confirmed unchanged, sustained, bilateral electrographic seizures. Clinical focal and generalised seizures again occurred. The CBD product continued to be administered at the family's request. The patient subsequently died following withdrawal of treatment, 88 days after presenting to hospital. While the patient had a poor prognosis, the use of CBD whole plant extract in this patient had no effect upon the underlying seizure illness.

Online survey
Grade 4- very low

Suraev AS, Todd L, Bowen MT, et al. An Australian nationwide survey on medicinal cannabis use for epilepsy: History of antiepileptic drug treatment predicts medicinal cannabis use. Epilepsy Behav 2017;70(Pt B):334–40.

Epilepsy Action Australia conducted an Australian nationwide online survey seeking opinions on and experiences with the use of cannabis-based products for the treatment of epilepsy. The survey was promoted via the Epilepsy Action Australia's main website, on their Facebook page, and by word of mouth. The survey consisted of 39 questions assessing demographics, clinical factors, including diagnosis and seizure types, and experiences with and opinions towards cannabis use in epilepsy. A total of 976 responses met the inclusion criteria. Results show that 15% of adults with epilepsy and 13% of parents/guardians of children with epilepsy were currently using, or had previously used, cannabis products to treat epilepsy. Of those with a history of cannabis product use, 90% of adults and 71% of parents reported success in reducing seizure frequency after commencing cannabis products. The main reasons for medicinal cannabis use were to manage treatment-resistant epilepsy and to obtain a more favorable side-effect profile compared to standard antiepileptic drugs. The number of past antiepileptic drugs tried was a significant predictor of medicinal cannabis use in both adults and children with epilepsy. Fifty-six percent of adults with epilepsy and 62% of parents/guardians of children with epilepsy expressed willingness to participate in clinical trials of cannabinoids. This survey provides insight into the use of cannabis products for epilepsy, in particular some of the likely factors influencing use, as well as novel insights into the experiences of and attitudes towards medicinal cannabis in people with epilepsy in the Australian community. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".

Retrospective chart review
Grade 4- very low

Treat L, Chapman KE, Colborn KL, et al. Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients. Epilepsia 2017;58:123–7.

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

Prospective, open label cohort study
Grade 3- low

Chen, K. A. Farrar, M. Cardamone, M. Gill, D. Smith, R. Cowell, C. T. Truong, L. Lawson, J. A. Cannabidiol for treating drug-resistant epilepsy in children: The New South Wales experience. Medical Journal of Australia 2018; 209:217-221: http://dx.doi.org/10.5694/mja18.00023 - external site.

Objective: To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment. Study design: Prospective, open label cohort study. Setting(s): Three tertiary NSW referral centres with paediatric neurology services. Participant(s): First 40 children enrolled in the NSW Compassionate Access Scheme for children with drug-resistant epilepsy and uncountable daily seizures. Intervention(s): Children received cannabidiol as an adjunct anti-epileptic drug, titrated to a maximum of 25 mg/kg/day, for up to 12 weeks. Outcome measures: Adverse events, withdrawals, and caregiver and physician Global Impression of Change assessments were recorded at 4, 8 and 12 weeks. Seizure frequency could not be reliably recorded because of disease severity. Result(s): Thirty-nine patients reported at least one adverse event; many were deemed unrelated to cannabidiol treatment. The most frequent treatment-related adverse event was somnolence (15 participants), which resolved spontaneously in ten patients; it was particularly frequent in patients taking higher clobazam doses. Gastrointestinal effects (nausea, vomiting, diarrhoea) were each reported by seven to nine participants. Four children were withdrawn from treatment, including one with elevated transaminase levels. The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved. Conclusion(s): Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile. Monitoring changes in liver function and awareness of potential drug interactions is essential. Whether the reported benefit is attributable to cannabidiol cannot be established in an open label study of participants with severe intractable epilepsy. Copyright © 2018 AMPCo Pty Ltd. Produced with Elsevier B.V. All rights reserved.

Retrospective chart review
Grade 3- low

Kuester, G. Gazmuri, A. M. Ahumada, A. Bobadilla, P. Clinical response to oral cannabis extracts in severe refractory epilepsy: Preliminary experience in chilean patients. Epilepsia 2016; 57 (Supplement 2):147-148: http://dx.doi.org/10.1111/epi.13609 - external site.

Purpose: To report our preliminary findings in a series of patients with different types of refractory epilepsy treated with oral cannabis extracts. Method(s): We retrospectively reviewed consecutive patients seen between May 2014 and February 2016, treated with oral cannabis extracts with at least a 6-month follow-up period. We reviewed demographic/ clinical data, type of seizures/epileptic syndrome, etiology, and number of previously used antiepileptic drugs (AEDs). Type of cannabis strain, CBD:THC ratio, dosage, frequency/severity of seizures before and after treatment, adverse events, and AEDs regimen during cannabisexposure were documented. Quality of life (QOL) changes were estimated using CAVE scale, and QOLIE-31-P, WHOQOL-BREF subscales. Informed consent was obtained. Result(s): Nine children and two adult patients were selected. Mean age: 11.5 yo (range: 1-37), six females. Etiologies included brain malformations, perinatal hypoxic-ischemic encephalopathy, autism, and tuberous sclerosis. Mean follow-up was 14 mo. Most patients had significant improvement in seizure frequency and one evolved seizure-free. Three patients did not respond or had seizure aggravation by high-CBD extracts. Adverse events included irritability and insomnia but they were easily solved by changing the strain. Most parents/patients reported improvement in behavior, cognition, sleep, alertness, mood and/or motor function, as well as in QOL with cannabis. Conclusion(s): In this small series of patients with different forms of intractable epilepsy, oral cannabis extracts were dramatically more effective than conventional AEDs previously used and had good tolerability. This has been also shown in previous surveys and case reports. Interestingly, some of our patients did not have good response or were aggravated by high-CBD strains, so the optimal therapeutic cannabinoid ratio could vary among different patients. Large randomized controlled trials are needed to establish efficacy and safety of cannabis extracts in epilepsy. Our Foundation is currently conducting the first medicinal cannabis clinical trial in children with pharmacoresistant epilepsy in Chile.

Open-label study
Grade 3- low

Laux, L. C. Bebin, E. M. Checketts, D. Chez, M. Flamini, R. Marsh, E. D. Miller, I. Nichol, K. Park, Y. Segal, E. Seltzer, L. Szaflarski, J. P. Thiele, E. A. Weinstock, A. Long-term safety and efficacy of cannabidiol in children and adults with treatmentresistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results. Epilepsy Research 2019; 154:13-20: http://dx.doi.org/10.1016/j.eplepsyres.2019.03.015 - external site.

Background: Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016. Method(s): Children and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/mL) in oral solution at 2-10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25-50 mg/kg/day. Patient visits were every 2-4 weeks. The percentage change from baseline in median monthly convulsive (i.e., major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had >=50%, >=75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks. Result(s): Of the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0-10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1-146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with >=50%, >=75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%). Conclusion(s): Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS. Copyright © 2019

Open-label study
Grade 3- low

Park, Y. Flamini, R. Pearlman, E. Philbrook, B. Mathur, S. Gregory, M. Long, S. Starnes, N. Wooldridge, L. J. Diamond, M. Update from the Georgia intermediate expanded access study. Neurology. Conference: 68th American Academy of Neurology Annual Meeting, AAN 2016; 86::

OBJECTIVE To provide access to cannabidiol (CBD) for children with medication resistant epilepsy (MRE) and evaluate CBD as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in seizure frequency. BACKGROUND The State of Georgia desires to provide children with MRE access to CBD and contribute to the scientific literature on CBD. DESIGN/METHODS This multicenter study for MRE patients 1 to 18 years of age at time of enrollment consists of 8 week baseline, titration, and treatment periods with CBD up to a 25 mg/kg/day dosage. Treatment will be provided for 52 weeks. The patient or caregiver records seizure frequency and drug compliance into an innovative electronic diary application. Statistical analyses were calculated for relevant median overall seizure frequency reduction from baseline. RESULTS As of 9/30/2015, total enrollment was 46 patients, of which, 20 [average age 9.6 yrs, range 1 to 17 yrs, male (n=11)], received at least 8-weeks of treatment for the analysis below. The common underlying causes of epilepsy were cryptogenic (n=10; 50[percnt]) and cortical dysplasia (n=5; 26[percnt]). The average number of concomitant AEDs was 3 (range= 25). Four patients had a history of epilepsy surgery (i.e. corpus callosotomy, cortical resection). After eight weeks of treatment, 95[percnt] of patients experienced seizure frequency reduction from baseline. Overall, reduction in total seizure frequency for all patients was 51[percnt] with a 48[percnt] reduction in all types of major seizures (tonic, atonic, and generalized tonic clonic). Adverse events in 10[percnt] of patients (n=2) included somnolence (n=1), ataxia (n=1), and vomiting (n=2). One patient withdrew primarily due to lack of efficacy. No related Serious Adverse Events (SAEs) were reported. CONCLUSIONS These results show that CBD may be a promising treatment for MRE and is generally well-tolerated in doses up to 25mg/kg/day.

Single-centre, prospective, open-label study
Grade 3- low

Pietrafusa, N. Ferretti, A. Trivisano, M. de Palma, L. Calabrese, C. Carfi Pavia, G. Tondo, I. Cappelletti, S. Vigevano, F. Specchio, N. Purified Cannabidiol for Treatment of Refractory Epilepsies in Pediatric Patients with Developmental and Epileptic Encephalopathy. Paediatric Drugs 2019; 21:283-290: https://dx.doi.org/10.1007/s40272-019-00341-x - external site.

BACKGROUND: A pharmaceutical grade formulation of cannabidiol (CBD) has been approved for the treatment of Dravet syndrome and Lennox-Gastaut syndrome; however, this formulation is not yet available to patients outside the USA. In addition, CBD is thought to have broad anti-seizure properties that may be beneficial for other types of intractable epilepsy. OBJECTIVE: The aim of this study was to evaluate the efficacy, safety and tolerability of artisanal medical CBD oil in patients with developmental and epileptic encephalopathy (DEE) at the tertiary epilepsy center of Bambino Gesu Children's Hospital in Rome, Italy. METHODS: This was a single-center, prospective, open-label study. Patients aged from 1 to 18 years with DEE and seizures refractory to appropriate antiepileptic drugs (AEDs) and other alternative treatments (i.e., vagal nerve stimulator and ketogenic diet) were included. Crystalline extract CBD powder (98-99% pure) in an oil artisanal formulation was added to the baseline AED regimen at a dosage of 2-5 mg/kg/day divided for twice-daily administration, then up-titrated until intolerance or a maximum dosage of 25 mg/kg/day was reached. Patients were treated for at least 6 months. Efficacy, safety and tolerability of CBD treatment were assessed through the evaluation of seizure frequency and reports of adverse effects. RESULTS: Twenty-nine patients were enrolled in this study (41.4% male). The mean duration of exposure to artisanal CBD was 11.2 months [range 6-25 months; standard deviation (SD) +/- 4.4 months]. Mean age at study enrollment was 9.3 years (range 1.9-16.3 years; SD +/- 4.7 years). Eleven out of 29 patients (37.9%) had a >= 50% improvement in seizure frequency; one patient became seizure free. None of the patients reported worsening seizure frequency; however, 18 patients (62.1%) experienced no beneficial effect regarding seizure frequency. Adverse effects were reported in seven patients (24.14%), most commonly somnolence, decreased appetite and diarrhea. Adverse events were mild and transient, and no dose modification of CBD or other AEDs was required.
CONCLUSIONS: These data suggest that CBD may have beneficial effects in patients with DEE and an acceptable safety profile. Placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in patients with DEE.

Open-label study
Grade 3- low

Vezyroglou, K. Eltze, C. Varadkar, S. Carr, L. O'Sullivan, C. Ninnis, E. Cross, J. H. Efficacy and safety of cannabidiol as add-on therapy in drugresistant epilepsy, a single center experience. European Journal of Paediatric Neurology 2017; 21 (Supplement 1):e87: http://dx.doi.org/10.1016/j.ejpn.2017.04.699 - external site.

Objective: To assess efficacy and side effects of cannabidiol (CBD) as add-on therapy in children with drug resistant complex epilepsy. Method(s): In an open label add-on compassionate use program oral CBD (Epidiolex, GW Pharma) was given as follows: 2 mg/kg/day in two divided doses, increased to 16 mg/kg/day by 2 mg/kg/week over 8 weeks, further up-titration as tolerated individually. Full blood count, electrolytes, renal and liver function were monitored every two weeks. Seizure frequency, added benefits and tolerability were assessed by weekly telephone calls and a parent questionnaire. Result(s): Between December 2014 and June 2016 24 children aged 2-19 (mean 10) years were enrolled who had previously failed 3-11 antiepileptic drugs. Etiologies were structural (7), genetic (5), metabolic (1), inflammatory (3) and unknown (8). One patient was excluded, who only received 5 days of CBD add-on treatment as part of his acute treatment for ultimately fatal refractory status epilepticus (presumed FIRES). Eleven (47.8%) of the remaining 23 patients reported >50% seizure reduction. Twelve (52.1%) patients reported clinical side effects, namely diarrhea (n = 5, 21.7%), somnolence (n = 5, 21.7%), loss of appetite (n = 2, 8.7%), weight loss (n = 1, 4.3%), behavior deterioration (n = 3, 13%) and respiratory depression due to increased clobazam levels (n = 1, 4.3%). Of 21 patients 14 (67%) reported added benefits in form of increased alertness (n = 11, 52%), better sleep (n = 2, 9.5%) and better mood (n = 6, 28.6%). Transaminases increased in 4 patients (17.4%), transiently in three, but leading to CBD discontinuation in one. One patient died of pneumonia unrelated to the drug. Treatment was discontinued in 11 patients (47.8%) after 1-19 months due to lack of efficacy (n = 6, 26%) and side effects (n = 5, 21.7%). Conclusion(s): 47.8% of patients reported an >50% reduction in seizures on CBD with the medication being reasonably well tolerated in this challenging patient cohort. Study limitations are the open label design and absence of a control cohort.

Open-label study
Grade 3- low

Sharma, A. A. Nenert, R. Allendorfer, J. B. Gaston, T. E. Grayson, L. P. Hernando, K. Szaflarski, J. P. A preliminary study of the effects of cannabidiol (CBD) on brain structure in patients with epilepsy. Epilepsy and Behavior Reports 2019; 12 (no pagination):: http://dx.doi.org/10.1016/j.ebr.2019.100341 - external site.

Cannabis use is associated with changes in brain structure and function; its neurotoxic effects are largely attributed to DELTA⁹-tetrahydrocannabidiol. Whether such effects are present in patients with epilepsy exposed to a highly-purified cannabidiol isolate (CBD; Epidiolex; Greenwich Biosciences, Inc.) has not been investigated to date. This preliminary study examines whether daily CBD dose of 15-25 mg/kg produces cerebral macrostructure changes and, if present, how they relate to changes in seizure frequency. Twenty-seven patients with treatment-resistant epilepsy were recruited from the University of Alabama at Birmingham CBD Program. Participants provided seizure frequency diaries (SF), completed the Chalfont Seizure Severity Scale (CSSS) and Adverse Events Profile (AEP), and underwent MRI before CBD (baseline) and after achieving a stable CBD dosage (on-CBD). We examined T1-weighted structural images for gray matter volume (GMV) and cortical thickness changes from baseline to on-CBD in 18 participants. Repeated measures t-tests confirmed decreases in SF [t(17) = 3.08, p = 0.0069], CSSS [t(17) = 5.77, p < 0.001], and AEP [t(17) = 3.04, p = 0.0074] between the two time-points. Voxel-level paired samples t-tests did not identify significant changes in GMV or cortical thickness between these two time-points. In conclusion, short-term exposure to highly purified CBD may not affect cortical macrostructure. Copyright © 2019 The Authors

Open-label prospective study
Grade 3- low

Sands, T. T. Rahdari, S. Oldham, M. S. Caminha Nunes, E. Tilton, N. Cilio, M. R. Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US. CNS Drugs 2019; 33:47-60: http://dx.doi.org/10.1007/s40263-018-0589-2 - external site.

Background: Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16 weeks. Objective(s): The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy. Method(s): Patients aged 1-17 years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5 mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25 mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3 months, and every 3 months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3 months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3 months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15 days of treatment, at 1 month, at 3 months, and every 3 months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures. Result(s): Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53 months (mean 21 months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6 months and more gradually thereafter. At 24 months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained > 50% reduction in motor seizures, including three (11.5%) who remain seizure free. Conclusion(s): Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment. Copyright © 2018, Springer Nature Switzerland AG.

Phase II, prospective study
Grade 3- low

Mitelpunkt, A. Kramer, U. Hausman Kedem, M. Zilbershot Fink, E. Orbach, R. Chernuha, V. Fattal-Valevski, A. Deutsch, L. Heffetz, D. Sacks, H. The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center study. Epilepsy and Behavior 2019; Part A. 98:233-237: http://dx.doi.org/10.1016/j.yebeh.2019.07.007 - external site.

Introduction: Several works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time. Method(s): This phase II, prospective study was open to pediatric patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced >= 4 seizures within four weeks of enrolment and with a history of >= 4 AEDs failing to provide seizure control. Following a 4-week observation period, patients began a 2-week dose-titration phase (up to <= 25 mg/kg or 450 mg, the lower of the two), followed by a 10-week maintenance treatment period. Caregivers recorded seizure frequency, type, and severity and ranked their global impressions after 7 and 12 weeks of treatment. Responders were those showing a >= 50% reduction from baseline monthly seizure frequency. Safety assessments monitored vital signs, adverse effects, physical and neurological exams, and laboratory tests. Result(s): Sixteen patients (age: 9.1 +/- 3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6 +/- 4.2 mg/kg. Patient adherence to treatment regimens was 96.3 +/- 9.9%. By the end of the treatment period, 81.9% and 73.4 +/- 24.6% (p <0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders' rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved. Conclusion(s): PTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE. Copyright © 2019 The Authors

Open-label study
Grade 3- low

Gaston, T. E. Szaflarski, M. Hansen, B. Bebin, E. M. Szaflarski, J. P. Quality of life in adults enrolled in an open-label study of cannabidiol (CBD) for treatment-resistant epilepsy. Epilepsy and Behavior 2019; 95:43009: http://dx.doi.org/10.1016/j.yebeh.2019.03.035 - external site.

Treatment-resistant epilepsy (TRE) is associated with low quality of life (QOL). Cannabidiol (CBD) may improve QOL, but it is unclear if such improvements are independent of improvements in seizure control. Our aim was to compare QOL at baseline and after 1 year of treatment with CBD. We hypothesized that QOL would improve independent of changes in seizure frequency (SF) or severity, mood, or adverse events. We assessed QOL using Quality of Life in Epilepsy-89 (QOLIE-89) in an open-label study of purified CBD (Epidiolex) for the treatment of TRE. All participants received CBD, starting at 5 mg/kg/day and titrated to 50 mg/kg/day in increments of 5 mg/kg/day. We collected QOLIE-89 in adult participants at enrollment and after 1 year of treatment, or at study exit if earlier. We analyzed if the change in QOLIE-89 total score could be explained by the change in SF, seizure severity (Chalfont Seizure Severity Scale, CSSS), mood (Profile of Moods States, POMS), or adverse events (Adverse Event Profile, AEP). Associations among the variables were assessed using bivariate tests and multiple regression. Fifty-three participants completed enrollment and follow-up testing, seven at study termination. Mean QOLIE-89 total score improved from enrollment (49.4 +/- 19) to follow-up (57 +/- 21.3; p =.004). We also saw improvements in SF, POMS, AEP, and CSSS (all p <=.01). Multivariable regression results showed QOLIE-89 at follow-up associated with improvements in POMS at follow-up (p =.020), but not with AEP, CSSS, or SF (p >=.135). Improvement in QOL after treatment with CBD is associated with better mood but not with changes in SF, seizure severity, or AEP. Cannabidiol may have beneficial effects on QOL and mood that are independent of treatment response. Copyright © 2019 Elsevier Inc.

Prospective, open label cohort study
Grade 3- low

Gaston, T. E. Bebin, E. M. Cutter, G. R. Ampah, S. B. Liu, Y. Grayson, L. P. Szaflarski, J. P. Drug-drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program. Epilepsy and Behavior 2019; Part A. 98:201-206: http://dx.doi.org/10.1016/j.yebeh.2019.07.008 - external site.

Objective: We have previously shown that cannabidiol (CBD; Epidiolex) significantly affects levels of clobazam/N-desmethylclobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine. In the present study, we tested whether the presence of concomitant clobazam affected seizure frequency and severity (treatment response) 12 weeks after initiation of therapy with CBD in patients with treatment-resistant epilepsy (TRE). The secondary questions were whether the presence of any of the other antiepileptic drugs (AEDs) had an effect on seizure frequency or severity at 12, 24, or 48 weeks after therapy initiation. Method(s): One hundred and thirty-two adults and children with TRE receiving CBD were studied prospectively. Participants were separated into two groups - either taking (CBD + clobazam) or not taking concomitant clobazam (CBD - clobazam). In the secondary analyses, participants were divided into groups depending on whether they were taking at least 1/4 of the other AEDs shown to interact with CBD (iAED). Seizure counts and Chalfont Seizure Severity Scale (CSSS) were obtained at baseline, 12, 24, and 48 weeks. Groups were compared at each respective time point in the study using generalized estimating equations (GEE) analyses. Result(s): All groups demonstrated statistically significant reductions in seizure frequency and severity from baseline (all P < 0.05). When participants on CBD + clobazam were compared with CBD - clobazam, there were no significant differences in seizure frequency and severity reduction between the groups at 12 weeks (both P > 0.05). When comparing groups with iAEDs vs. group without iAEDs, independent of coadministration of clobazam, no differences in treatment response were observed (all P > 0.05). Longitudinal analyses up to 48 weeks after therapy initiation did not reveal any differences in treatment response between groups. Conclusion(s): These analyses suggest that concomitant to CBD, AEDs may not have an effect on reducing seizure frequency and severity in patients with TRE. Copyright © 2019 Elsevier Inc.

Prospective, open label cohort study
Grade 3- low

Mitelpunkt, A. Kramer, U. Hausman Kedem, M. Zilbershot Fink, E. Orbach, R. Chernuha, V. Fattal-Valevski, A. Deutsch, L. Heffetz, D. Sacks, H. The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center study. Epilepsy and Behavior 2019; Part A. 98:233-237: http://dx.doi.org/10.1016/j.yebeh.2019.07.007 - external site.

Under The Australian Government Therapeutic Goods Administration Special Access Scheme, Category B, paediatric patients with severe refractory epilepsy have been able to access state-sponsored cannabidiol (CBD Max [Tilray]: 98% cannabidiol in grapeseed oil, 100mg/ml). Twenty children aged 2–17 years (median, 10 years) were treated for 9–40 weeks (median, 23 weeks) between February and November 2017; 15 were girls. Cannabidiol was added to the child's usual medication as a twice‐daily dose, titrated in weekly steps from 5 to 20 mg/kg/day. Clinical review and blood tests were repeated monthly for 3 months and then every 3 months. Thirteen achieved the target dose; seven achieved doses of 10–17.5 mg/kg/day. Sixteen children experienced treatment‐emergent adverse events, including somnolence, nausea or vomiting, anorexia, and appetite increase. Eight of ten children taking clobazam and three of ten children not taking clobazam experienced somnolence; this was managed by reducing the clobazam dose if applicable. There were 11 serious adverse events in five children leading to hospitalisation, of which two (somnolence with dehydration; status epilepticus) were attributed to cannabidiol treatment. New abnormal liver function was measured in five children; three with transient alanine aminotransferase level elevation were taking valproate. Measured anti‐epileptic medication levels were unchanged; one child had markedly elevated sirolimus levels. One child discontinued treatment after a serious adverse event (somnolence and anorexia); eight children discontinued (after 9–23 weeks) because of lack of effectiveness. Eleven continued treatment beyond 17–40 weeks, with the parents of nine reporting clinically significant seizure reduction (greater than 50%).

Open-label prospective study
Grade 3- low

Devinsky, O. Verducci, C. Thiele, E. A. Laux, L. C. Patel, A. D. Filloux, F. Szaflarski, J. P. Wilfong, A. Clark, G. D. Park, Y. D. Seltzer, L. E. Bebin, E. M. Flamini, R. Wechsler, R. T. Friedman, D. Open-label use of highly purified CBD (Epidiolex) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy & Behavior 2018; 86:131-137: https://dx.doi.org/10.1016/j.yebeh.2018.05.013 - external site.

OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.
METHODS: We included patients aged 1-30years with severe childhood-onset epilepsy who received CBD for >=10weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n=20), Aicardi syndrome (n=19), Dup15q syndrome (n=8), and Doose syndrome (n=8). These patients were treated at 11 institutions from January 2014 to December 2016. RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n=46] to week 12 (51.4% [n=35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n=27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, chi²(2)=22.9, p=0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up.
SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12weeks to 48weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Open-label prospective study
Grade 3- low

Szaflarski, J. P. Bebin, E. M. Comi, A. M. Patel, A. D. Joshi, C. Checketts, D. Beal, J. C. Laux, L. C. De Boer, L. M. Wong, M. H. Lopez, M. Devinsky, O. Lyons, P. D. Zentil, P. P. Wechsler, R. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia 2018; 59:1540-1548: https://dx.doi.org/10.1111/epi.14477 - external site.

OBJECTIVE: Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. METHODS: Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with >=50%, >=75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit. RESULTS: Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with >=50%, >=75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). SIGNIFICANCE: Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.

Open-label prospective study
Grade 3- low

Thiele, E. Marsh, E. Mazurkiewicz-Beldzinska, M. Halford, J. J. Gunning, B. Devinsky, O. Checketts, D. Roberts, C. Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study. Epilepsia 2019; 60:419-428: http://dx.doi.org/10.1111/epi.14670 - external site.

Objective: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial. Method(s): Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. Result(s): This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. Significance: In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures. Copyright © 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy

Open-label prospective study
Grade 3- low

Upadhyay, R. Ouyang, B. McNulty, M. Majority of Epileptic Marijuana Users Perceive Decreased Seizure Frequency. Neurology. Conference: 69th American Academy of Neurology Annual Meeting, AAN 2017; 88

Objective: To assess the prevalence of marijuana usage in a tertiary care center's epilepsy clinic and identify factors potentially associated with its use. Background(s): Marijuana is the most widely used illicit drug in the world and has been used to treat various conditions for five millenia. Discovery of the endogenous cannabinoid system in the 1990s sparked interest in the use of cannabis derived therapies for nervous system disorders like epilepsy. A majority of patients and minority of neurology providers view marijuana as a safe/efficacious treatment for epilepsy. Design/Methods: This was an IRB approved prospective study conducted from 2/10/16 to 4/27/16 at the Rush Epilepsy Center. Patients 18/older, English speaking, and without significant cognitive deficits were eligible. The anonymous survey questioned demographics, seizure frequency, anti-seizure drugs (ASD), current marijuana usage and its perceived effects on seizures. The provider completed a form indicating epilepsy diagnosis. Patients' characteristics were compared between current users and nonusers with t test, Mann-Whitney U or chi-square test. Result(s): 457 completed surveys were obtained of which 53% were female, 47% were students/employed, and 67% had college education or higher. 18% reported current marijuana usage. Younger age (35.7 +/- 12.8 vs. 41.4 +/-13.8, p=0.001), male gender (26% vs. 12%, p<0.0001), and below college level education (27% vs. 15%, p=0.002) were the only factors statistically significantly associated with current marijuana usage. Of current users, 68% reported decreased seizure frequency with marijuana use while 29% reported no change. Compared to nonusers, there was no difference in seizure frequency/intractability or current number of ASD used. Version:1.0StartHTML:0000000167EndHTML:0000000547StartFragment:0000000457EndFragment:0000000531 (35.7+/-12.8 vs. 41.4+/-13.8 Conclusion(s): This study reinforces patients' positive perception of marijuana use relating to improvement in their seizures; however, the available objective data including seizure frequency and intractability did not differ between users and nonusers.

Open-label prospective study
Grade 3- low

Messenheimer, J. A. O'Brien, T. Berkovic, S. French, J. Bonn-Miller, M. Gutterman, D. Transdermal cannabidiol (CBD) gel for the treatment of focal epilepsy in adults. Neurology 2018; 90 (24):e2188.

Objective To evaluate the safety and efficacy of ZYN002 (transdermal cannabidiol [CBD] gel) as adjunctive therapy for the treatment of adult focal seizures. Background CBD can reduce seizures in pediatric patients, but data in adults are limited. Design/methods STAR 1 was a phase 2A, randomized, double-blind, placebo-controlled study of ZYN002 administered BID for 12 weeks to adults with focal seizures. Patients were initially randomized 1:1:1 to 195 mg or 390 mg CBD daily, or placebo. STAR 2 is the open-label extension study for completers of STAR 1. In STAR 2, all patients started on 390 mg CBD daily. Results A total of 188 patients were initially randomized into STAR 1. After 12 weeks, the median reduction in focal seizures was 18.4% (195 mg CBD/ d; n = 63), 14.0% (390 mg CBD/d; n = 62), and 8.7% (placebo; n = 63). There were no statistically significant differences in efficacy between ZYN002 and placebo. A total of 174 patients completed STAR 1 and 171 patients rolled into STAR 2. Seizure control was evaluated as a function of duration on ZYN002, regardless of initial randomization group or dose. Longer exposure to ZYN002 resulted in greater improvements in seizure frequency, with median percent change in seizures from -16.3% at 3 months (n = 170) to -27.3% at 6 months (n = 148), -50.2% at 9 months (n = 98), and -58.0% at 12 months (n = 70). ZYN002 was well-tolerated, with excellent skin tolerability. The most common adverse events were upper respiratory tract infection (viral and bacterial; 16%), headache (11%), fatigue (7%), and laceration (5%). Conclusions While change in seizure frequency was not significantly different between active and placebo during STAR 1, continued treatment with ZYN002 in STAR 2 appeared to result in improvements in seizure control, with clinically meaningful reductions observed by 6 months of treatment and maintained through 12 months. ZYN002 (administered BID) was well tolerated, with excellent patient compliance and acceptance.

Open-label prospective study
Grade 3- low

Neubauer, D. Perkovic Benedik, M. Osredkar, D. Cannabidiol for treatment of refractory childhood epilepsies: Experience from a single tertiary epilepsy center in Slovenia. Epilepsy & Behavior 2018; 81:79-85: https://dx.doi.org/10.1016/j.yebeh.201 - external site8.02.009.

PURPOSE: Refractory epilepsies in children present a major burden for patients and their families. Cannabidiol (CBD) has been suggested as a potential treatment for refractory epilepsies. The aim of this study was to evaluate the effectiveness of add-on therapy with CBD for the treatment of refractory childhood epilepsies. METHOD: Patients with childhood-onset refractory epilepsy, treated at the tertiary epilepsy center of the University Children's Hospital Ljubljana, Slovenia, were included in the study. Add-on therapy with CBD was initiated once the child's epilepsy was categorized as pharmacoresistant to other antiepileptic drugs/therapies. The dosage of CBD was gradually increased to at least 8mg/kg/day. The effect of CBD treatment was evaluated by the reduction in seizure burden and presence of side effects (positive and negative). Serial electroencephalography was performed in some children. RESULTS: Sixty-six patients were included in the analysis. Thirty-two (48.5%) patients had a more than 50% improvement regarding seizure burden, 14 of whom (21.2%) became seizure-free. None of the patients reported worsening of seizure frequency, but CBD had no effect in 15 (22.7%) patients. Some patients reported less vigorous seizures, shorter duration of seizures, shorter time to recovery, and other positive side effects of CBD treatment. Adverse effects were reported in 5/66 children. CONCLUSIONS: In our cohort of patients, CBD was found to have potential benefits as add-on therapy for refractory childhood epilepsies, mainly by reducing seizure burden.

Case study
Grade 4- very low

Bravo, G. A. Izquierdo, A. Y. Monteiro, G. C. Cristobal, J. H. Adult phenotype of Dravet syndrome associated with STXBP1 (syntaxin binding protein 1) mutation and good response to cannabidiol treatment. European Journal of Neurology 2017; 24 (Supplement 1):159: http://dx.doi.org/10.1111/ene.13367 - external site.

Background and aims: We present a case of Dravet syndrome: adult phenotype with a STXBP1 mutation and its good response to cannabidiol treatment. Method(s): A 19-year-old woman with history of epilepsy since infancy and poor response to various anticonvulsant therapies. She presented a good psychomotor development until the two years of life, although to the six months had a first crisis which coincided with fever and was followed by motor deficit. Two years later she performed episodes of loss of head tone. From the age of 6, she has generalized seizures more than 10 times a day and from the age of 13 she associates reflexive crises after sound and tactile stimuli. Various genetic-metabolic tests were negative, including the mutation for the SCN1A gene (sodium voltage-gated channel alpha subunit 1). In the last year she has presented marked bradykinesia which impedes walking (FAC 1 according to the gait rating scale-Functional Ambulatory Classifier), mood swings, impulsivity associated with heteroaggressive behavior and visual hallucinosis. Result(s): We required whole exome sequencing, finding mutation in the STXBP1 gene. We also suggested to initiate treatment with cannabidiol, achieving a considerable reduction in the number of crises in the day and an improvement in the ability to walk (FAC 4). Conclusion(s): The mutation of STXBP1 gene proved to cause Dravet's syndrome in patients with negativity for the mutation of SCN1A. Our case is special because it presents the recent description of the adult phenotype of Dravet's syndrome moreover it is associated to good response to cannabidiol treatment.

Case study
Grade 4- very low

Deacon, H. Why I campaign for children like my son Alfie Dingley to be able to get medical cannabis. BMJ (Online) 2019; 365 (no pagination): http://dx.doi.org/10.1136/bmj.l1921 - external site.

Case study of a pediatric male patient with PCDH19 epilepsy who received Bedrolite, a full extract CBD oil, and achieved significant reduction in seizure frequency after 3 months' treatment. Addition of THC oil resulted in complete seizure frequency for 40 days, paired with improved cognitive development.

Self-report survey (caregiver)
Grade 4- very low

Pesantez Rios, G. Armijos-Acurio, L. Jimbo-Sotomayor, R. Pascual-Pascual, S. I. Pesantez-Cuesta, G. Cannabidiol: Its use in refractory epilepsies. [Spanish]. Revista de Neurologia 2017; 65:157-160.

Introduction. Some epileptic syndromes are characterised by seizures that are difficult to control and are associated to delayed neuropsychomotor development, which results in a deterioration in the patient's quality of life as well as in that of his or her family. Aim. To evaluate the use of cannabidiol as adjuvant therapy in patients with refractory epilepsies. Patients and methods. An observational study was conducted by means of a survey addressed to the patient's caregiver. Data collected included information about the patient and the caregiver, changes observed in the seizures, neuropsychological effects, side effects and the family's overall perception following the use of cannabidiol. Results. The evaluation examined 15 patients with refractory epilepsies, who received cannabidiol over a period ranging from one month to one year. The frequency of seizures decreased in 40% of the patients, 60% of the patients were seen to have control over 50% of their seizures and in 27% of them the seizures disappeared completely. Neurocognitive changes were also reported: behaviour improved in 73%; 60% reported an improvement in language; in 50% sleep improved; 43% reported improvements in eating habits; and 100% said their mood had improved. The overall perception of the illness was that there had been improvements in 73% of respondents. The most common side effects were drowsiness and fatigue. Conclusions. These results suggest a possible beneficial effect of cannabidiol on the control of seizures and on the improvement of certain neurocognitive aspects in patients with refractory epilepsies. Copyright © 2017 Revista de Neurologia.

Case study
Grade 4- very low

Poisson, K. Wong, M. Lee, C. Cilio, M. Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with kcnt1 mutations. Annals of Neurology 2016; 80 (Supplement 20):S324: http://dx.doi.org/10.1002/pon.4272 - external site.

Objective: Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is an early-onset severe epileptic encephalopathy with polymorphous, migrating focal seizures that are highly treatment resistant. Mutations in KCNT1 appear to be the most frequent cause. We investigated whether treatment with cannabidiol (CBD) would decrease seizure frequency in two patients with EIMFS and KCNT1 mutations. Method(s): Both patients (47 and 21 months old) received CBD through the GW Pharma expanded access program. Treatment regimens included ketogenic diet (patient 1) and ketogenic diet, phenobarbital, and potassium bromide (patient 2). Seizure frequency was documented at baseline (4-week pre-treatment period) and over a 12-week treatment period. CBD was titrated to a maximum dose of 25mg/kg/ d. Patient 2 also had prolonged EEG monitoring before and after 6 months of treatment to accurately quantify response. Result(s): Both patients had no significant improvement in seizure frequency from baseline during the 12-week treatment period. During the 12-week period after CBD reached maximum dose, patient 1 had a modest reduction (-12%) in overall seizure frequency, with a marked reduction (-93%) in the most severe seizures with desaturation noted. Patient 2 did not respond to CBD during 6 months of treatment. Conclusion(s): In two patients with EIMFS associated with a KCNT1 mutation, there was no significant improvement in overall seizure frequency when treated with CBD. However, Patient 1 showed a decrease in seizure intensity at the maximum dose. Further research is needed to determine whether CBD may have an impact on seizures in patients with EIMFS due to mutations in KCNT1.

Retrospective chart review
Grade 4- very low

Porcari, G. S. Fu, C. Doll, E. D. Carter, E. G. Carson, R. P. Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center. Epilepsy & Behavior 2018; 80:240-246: https://dx.doi.org/10.1016/j.yebeh.2018.01.026 - external site.

Medically refractory epilepsy continues to be a challenge worldwide, and despite an increasing number of medical therapies, approximately 1 in 3 patients continues to have seizures. Cannabidiol (CBD), one of many constituents of the Cannabis sativa or marijuana plant, has received renewed interest in the treatment of epilepsy. While highly purified CBD awaits Food and Drug Administration (FDA) approval, artisanal formulations of CBD are readily available and are seeing increased use in our patient population. Although randomized controlled trials of CBD are ongoing and promising, data regarding artisanal formulations of CBD are minimal and largely anecdotal. Here, we report a retrospective study to define the efficacy of artisanal CBD preparations in children with epilepsy. Given the known interaction between CBD and clobazam, we also conducted a subgroup comparison to determine if clobazam use was related to any beneficial effects of CBD. Additionally, we compared response rates with CBD and with clobazam alone within an overlapping patient cohort. A pediatric cohort with epilepsy of 108 patients was identified through a medical record search for patients using CBD oil. The addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The responder rate for clobazam was similar. No patients achieved CBD monotherapy, although the weaning of other antiepileptic drugs (AEDs) became possible in 22% of patients. A comparable proportion had AED additions during CBD therapy. With concomitant use of clobazam, 44% of patients had a 50% reduction in seizures upon addition of CBD compared with 33% in the population not taking clobazam; this difference was not statistically significant. The most common reported side effect of CBD was sedation in less than 4% of patients, all of whom were also taking clobazam. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. Benefits were more marked in the CBD alone group, in contrast to the CBD and clobazam group, but this difference was not statistically significant. In summary, these findings support efficacy of artisanal CBD preparations in seizure reduction with few significant side effects. The response to CBD was independent of concurrent clobazam use, although clobazam may contribute to the sedation seen with concurrent CBD use.

Prospective, open label cohort study
Grade 4- very low

Preto Mimura, P. M. Lima, M. T. A. D. Picoli, R. L. Moller, P. D. D. S. Seguti Ferreira, L. Follow-up of patients with refractory epilepsy treated with cannabidiol. Journal of the Neurological Sciences 2017; 381 (Supplement 1):683: http://dx.doi.org/10.1016/j.jns.2017.08.1921 - external site.

Background: Cannabidiol (CBD)-enriched cannabis, which presents a low delta9-tetrahydrocannabinol content, has become an alternative treatment indicated for refractory epilepsy (RE). Objective(s): We aim to describe the clinical features and outcomes of patients with RE that used CBD as treatment. Patients and Methods/Material and Methods: We selected ten patients diagnosed with RE that had been using CBD as treatment. They were followed up for at least two months. We obtained the patients' and their parents' approval for this study. Result(s): Patients' age at the onset of epilepsy ranged from one month to four years old (average: 12.2 months). Identified etiologies in the seven patients were: neurofibromatosis type 1; SCN1A gene mutation (two patients); multicystic encephalomalacia; hippocampal atrophy and delayed myelination; Snyder-Robinson Syndrome; frontal and temporal cortical dysplasia. All patients used to have daily multiform seizures and had been treated with seven to 11 different antiepileptic drugs (AEDs) at their maximum dose. Treatment with CBD was initiated when the patients were four to 23 years of age (average: 12.3). CBD dose ranged from 1.2 mg to 10 mg/kg/day. Follow-up time ranged from two to 24 months (average: 13.4). Nine of the 10 patients showed an average decrease of 63% in the number of seizures (ranging from a 30% to a 90% decrease). No significant adverse effects were observed, except for sleepiness and fatigability. Conclusion(s): Most patients showed significant decrease in the number of seizures. The use of CBD has been shown to represent a good alternative of treatment for patients with refractory epilepsy.

Open-label study
Grade 4- very low

Warren, Paula Province Bebin, E. Nabors, L. Szaflarski, Jerzy P. The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy. Neurocase 2017; 23:287-291: http://dx.doi.org/10.1080/13554794.2017.1391294.

Epilepsy, commonly encountered by patients with brain tumors, is often refractory to standard therapies. Our aim was to examine the safety and efficacy of pharmaceutical grade cannabidiol (CBD; Epidiolex; Greenwich Biosciences) in those patients with epilepsy with concomitant tumors enrolled in The University of Alabama at Birmingham CBD Program (NCT02700412 and NCT02695537). Of the three patients with refractory seizures and a history of a primary brain tumor, two had improvement in seizure frequency and all three had improvement in seizure severity. These pilot results suggest that CBD should be further studied for the treatment of brain tumor-related epilepsy. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

Case study
Grade 4- very low

Wiemer-Kruel, A. Stiller, B. Bast, T. Cannabidiol Interacts Significantly with Everolimus-Report of a Patient with Tuberous Sclerosis Complex. Neuropediatrics 2019; 50:400-403: http://dx.doi.org/10.1055/s-0039-1695786 - external site.

A 6.5-year-old female patient with a TSC2 mutation had been given everolimus (EVE) for 3 years for pharmacoresistant focal epilepsy and for life-threatening, severe ventricular dysrhythmia. EVE had been started with daily dose of 0.15 mg/kg/day and was increased up to 0.6 mg/kg/day. Target blood trough levels of around 9 mug/L had been documented. Although EVE therapy revealed no effect on seizure activity, cardiac rhythm normalized completely. Thus, EVE was reduced to a dose of 0.3 mg/kg/day leading to stable blood trough levels of 4 to 5 mug/L. Due to refractory tonic seizures with a frequency of 1 to 4 per day, we initiated cannabidiol (CBD) treatment, raising it to a daily dose of 200 mg. After 6 weeks, the EVE blood trough levels rose to 12.0 mug/L. Although we halved the EVE dose, her EVE blood trough level continued increasing up to 16.0 mug/L. The CBD dose was increased to 500 mg/day (20.4 g/kg/day), but EEG parameters and seizures failed to respond. Serum concentrations of EVE were unstable under the co-medication with CBD. Depending on the CBD dose, they varied between 1.7 and 12.3 mug/L, while EVE was always administered at the same dose. Although never before reported, CBD and EVE appear to interact, due to the metabolic pathway through CYP 450 3A4. Although we detected no side effects in our patient, we strongly recommend drug monitoring using the combination of CBD with EVE to prevent harmful overdosing. Copyright © 2019 Georg Thieme Verlag. All rights reserved.

Case study
Grade 4- very low

Rajaraman, R. R. Sankar, R. Hussain, S. A. Successful use of pure cannabidiol for the treatment of super-refractory status epilepticus. Epilepsy and Behavior Case Reports 2018; 10:141-144: http://dx.doi.org/10.1016/j.ebcr.2018.07.004 - external site.

We present the case of a child with long-standing, super-refractory status epilepticus (SRSE) who manifested prompt and complete resolution of SRSE upon exposure to pure cannabidiol. SRSE emerged in the context of remote suspected encephalitis with previously well-controlled epilepsy. We discuss the extent to which response may be specifically attributed to cannabidiol, with consideration and discussion of multiple potential drug-drug interactions. Based on this case, we propose that adjunctive cannabidiol be considered in the treatment of SRSE. Copyright © 2018 The Authors

Case series
Grade 4- very low

Garza Morales, S. J. Benavides Aguilar, O. Bastida Mercado, E. Use of cannabidiol (RSHO) in the treatment of refractory epilepsy (Lennox-Gastaut Syndrome), experience of 38 cases. Epilepsia 2017; 58 (Supplement 5):S53: http://dx.doi.org/10.1111/epi.13944 - external site.

Introduction: The LGS remains as one of the most severe childhood encephalopathies with high seizure frequency (sudden falls, myoclonic and tonic), progressive cognitive impairment and antiepileptic drugs (AED) resistance. Method(s): Between January 2016 and February 2017 we included in the study 45 patients with Lennox-Gastaut Syndrome (According to the criteria of the ILAE) with persistence of various seizures per day despite taking at least three anti-epileptic drugs. Seven patients were excluded from the study (one having started with a THC-containing compound and six who decided not to start the treatment). Result(s): The remaining 38 cases took cannabidiol 100 pure (RSHO 5000) in progressive doses of up to 5-7 mg/kg for at least 6 months of follow-up. All patients had imaging studies (CT or MRI) and at least two EEG studies. 50% presented hypoxic-ischemic encephalopathy or cortical malformations. All patients continued to take basal AED (3.7 per patient). The age was of 10.9 +/- 6 years (23/38 patients are male). All patients had various types of seizures (3.5/patient), dominating the atonic (73%) and focal (86%). 4 patients were callotomized for refractory epilepsy. A significant reduction in the frequency of seizures (>= 50%) was obtained in 86% of the cases (33/38) and 55% of the cases achieved an overall reduction of over 75% (21/38). A complete control of the events for at least 4 months was achieved in 5 cases (13%), an outstanding result for this type of patient. The seizures that achieved better results were atonic, absent and generalized tonic (30-100%), while focal seizures responded less to treatment (0-70%). Other benefits were observed in 89% of patients: alertness (43%), social interaction (40%), attention (30%), etc. Conclusion(s): Addition treatment with 100% Cannabidiol is a good alternative for patients with LGS and reduces the use and potential effects of tetrahidrocanabinol (THC).

Open-label prospective study
Grade 4- very low

Fleury-Teixeira, P. Caixeta, F. V. da Silva, L. C. R. Brasil-Neto, J. P. Malcher-Lopes, R. Effects of cbd-enriched cannabis sativa extract on autism spectrum disorder symptoms: An observational study of 18 participants undergoing compassionate use. Frontiers in Neurology 2019; 10 (OCT) (no pagination):: http://dx.doi.org/10.3389/fneur.2019.01145 - external site.

Autism Spectrum Disorders comprise conditions that may affect cognitive development, motor skills, social interaction, communication, and behavior. This set of functional deficits often results in lack of independence for the diagnosed individuals, and severe distress for patients, families, and caregivers. There is a mounting body of evidence indicating the effectiveness of pure cannabidiol (CBD) and CBD-enriched Cannabis sativa extract (CE) for the treatment of autistic symptoms in refractory epilepsy patients. There is also increasing data support for the hypothesis that non-epileptic autism shares underlying etiological mechanisms with epilepsy. Here we report an observational study with a cohort of 18 autistic patients undergoing treatment with compassionate use of standardized CBD-enriched CE (with a CBD to THC ratio of 75/1). Among the 15 patients who adhered to the treatment (10 non-epileptic and five epileptic) only one patient showed lack of improvement in autistic symptoms. Due to adverse effects, three patients discontinued CE use before 1 month. After 6-9 months of treatment, most patients, including epileptic and non-epileptic, showed some level of improvement in more than one of the eight symptom categories evaluated: Attention Deficit/Hyperactivity Disorder; Behavioral Disorders; Motor Deficits; Autonomy Deficits; Communication and Social Interaction Deficits; Cognitive Deficits; Sleep Disorders and Seizures, with very infrequent and mild adverse effects. The strongest improvements were reported for Seizures, Attention Deficit/Hyperactivity Disorder, Sleep Disorders, and Communication and Social Interaction Deficits. This was especially true for the 10 non-epileptic patients, nine of which presented improvement equal to or above 30% in at least one of the eight categories, six presented improvement of 30% or more in at least two categories and four presented improvement equal to or above 30% in at least four symptom categories. Ten out of the 15 patients were using other medicines, and nine of these were able to keep the improvements even after reducing or withdrawing other medications. The results reported here are very promising and indicate that CBD-enriched CE may ameliorate multiple ASD symptoms even in non-epileptic patients, with substantial increase in life quality for both ASD patients and caretakers. Copyright © 2019 Fleury-Teixeira, Caixeta, Ramires da Silva, Brasil-Neto and Malcher-Lopes.

Open-label prospective study
Grade 4- very low

Hausman-Kedem, M. Menascu, S. Kramer, U. Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents - An observational, longitudinal study. Brain & Development 2018; 40:544-551: https://dx.doi.org/10.1016/j.braindev.2018.03.013 - external site.

The objective of this observational study was to evaluate the efficacy of medical cannabis for the treatment of refractory epilepsy. Fifty-seven patients (age 1-20years) with epilepsy of various etiologies were treated with Cannabis oil extract (CBD/THC ratio of 20:1) for at least 3months (Median follow up time-18months). Forty-Six Patients were included in the efficacy analysis. Average CBD dose was11.4mg/kg/d. Twenty-six patients (56%) had <=50% reduction in mean monthly seizure frequency. There was no statistically significant difference in response rate among various epilepsy etiologies, and cannabis strain used. Younger age at treatment onset (<10years) and higher CBD dose (>11mg/kg/d) were associated with better response to treatment. Adverse reactions were reported in 46% of patients and were the main reason for treatment cessation. Our results suggest that adding CBD-enriched cannabis extract to the treatment regimen of patients with refractory epilepsy may result in a significant reduction in seizure frequency according to parental reports. Randomized controlled trials are necessary to assess its true efficacy.

Open-label prospective study
Grade 4- very low

Sianati, B. Schramke, C. Valeriano, J. Medical Marijuana and its use in treatment-refractory seizures: The Pittsburgh experience. Neurology. Conference: 71st Annual Meeting of the American Academy of Neurology, AAN 2019; 92

Objective: To present interim results of our experience with cannabis-based therapies for various types of refractory seizures and to document its feasibility as an adjunctive treatment. Background(s): Epidiolex, a Cannabidiol (CBD) product, was recently approved by FDA as an adjunctive medication for the treatment-refractory patients of 2 years and older, diagnosed with Lennox-Gastaut and Dravet syndrome. Medical marijuana is now legal in the state of Pennsylvania for patients with intractable epilepsy. Design/Methods: Eligible patients were enrolled in the Medical Marijuana Program between January and October of 2018. Data was collected via both phone interviews and review of medical records and is ongoing. Reported frequency, type, and intensity of seizures were assessed before and 3 months after the start-date and on each follow up visit. Other factors such as behavior, mood, and energy level were assessed based on QOLIE-10-P. Result(s): From January 2018, 22 (30% male, 70% female) patients were enrolled. When contacted by phone, 2 patients had not yet begun treatment and 3 did not respond. Preliminary analysis of the 17 patients with post-transition follow-up longer than 3 months revealed: mean age of 36.8 years (range 18-65), minimum AED of 2 with a reported decrease in seizure frequency by at least 50% in 12 patients, increase by 50% in 2, and indeterminate in 3 due to a late start. Various CBD preparations were used: 6 patients with 1:1 CBD- DELTA(9) - tetrahydrocannabinol (THC), 5 with 10:1 CBD-THC, 2 with 1:5 CBD-THC and 4 were uncertain about their preparation. Patients, on average, reported lower levels of fear and anxiety with improved energy post-transition. Conclusion(s): Preliminary data documents the feasibility of utilizing CBD for treatment refractory seizures. Although data collection is ongoing, preliminary data support optimism in multiple areas including decrease in seizure frequency and improved metrics for patient satisfaction.

Case study
Grade 4- very low

Silveira, L. P. Bayer, D. L. Crippa, A. C. S. Crippa, J. A. S. Patient diagnosed with epilepsy due to mutation in the cdkl5 gene treated with cannabidiol therapy. Developmental Medicine and Child Neurology 2017; 59 (Supplement 1):98-99: http://dx.doi.org/10.1111/dmcn.13347 - external site.

Objective: To describe a rare case of a Brazilian patient with a mutation in the CDKL5 gene who achieved clinical control and electroencephalographic response after the administration of cannabidiol (CBD) as a therapeutic approach. Method(s): Description of a case report. Result(s): Female, 5 years old, started to develop seizures at 45 days of life. Her clinical history included delayed psychomotor development, axial hypotonia and global hyporeflexia. There were no relevant findings in her encephalic magnetic resonance imaging, but her electroencephalogram (EEG) demonstrated alterations consistent with the three stages of epilepsy caused by the CDKL5 gene mutation. Due to the early onset epilepsy of difficult control, a genetic testing was performed, which elucidated the diagnosis of mutation in the CDKL5 gene. After being prescribed several antiepileptic drugs, her seizures were still uncontrolled. At last, after having started cannabidiol therapy as treatment, the latest electroencephalographic results showed no abnormalities and the crisis ceased. Conclusion(s): Early-onset epileptic encephalopathies have been related to genetic mutations in the CDKL5 gene, whose expression can be correlated with neuronal maturation. Most of the patients display partial-onset seizures, which are difficult to control, and infantile spasms (IS). Firstly, in order to consider CDKL5 molecular screening through genetic testing, it is essential that the patient is diagnosed with specific clinical manifestations, which are: early onset epilepsy with very frequent episodes of seizures (in most cases associated with IS), abnormalities in the EEG, severe hypotonia, poor eye contact and a Rett syndrome-like phenotype. Even with diagnostic confirmation, nowadays, there is no specific treatment to subside completely a patient from all the symptoms. Consequently, the application of an alternative therapy (CBD) was capable of controlling these clinical manifestations.

Case study
Grade 4- very low

Sivakumar, S. Zutshi, D. Seraji-Bozorgzad, N. Shah, A. Electroencephalographic observations of medical marijuana for idiopathic generalized epilepsy: A case report. Neurology. Conference: 68th American Academy of Neurology Annual Meeting, AAN 2016; 86.

Objective: To analyze the effect of marijuana on electroencephalography (EEG) in a patient with medically intractable idiopathic generalized epilepsy (IGE). Background(s): Following reports of seizure control with marijuana use among patients with intractable epilepsy, marijuana-based treatment for epilepsy has gained attention. There is limited literature marijuana efficacy for treatment of epilepsy and no literature on their EEG effects. Design/Methods: We performed a retrospective review of three EEGs in a 24-year-old woman with intractable IGE. The first study was a 24-hour video EEG performed while patient was only on antiepileptic drugs (AEDs). The second study was a 72-hour EEG with mixed Cannabis sativa and indica use on days one and three in addition to traditional AEDs. The third study was a 48-hour EEG with higher concentration C. indica use on day two in addition to her AEDs. Generalized spike-wave discharges (GSW) were categorized as interictal and ictal, based on duration of less than 10 seconds or greater respectively. Data from these studies were concatenated to form a contiguous time series with a period of one hour. Regression analysis was used as initial test of correlation between cannabis use (time dependent independent variable) and EEG activity (dependent variables), which was followed by time series analysis. Result(s): Regression analysis showed significant negative correlation between marijuana use and interictal events (p=0.01) but not for rate of ictal events (p=0.075). Time series analysis showed significant inverse correlation for marijuana use with interictal (p<0.004) and ictal (p=0.007) events. Upon auto-regression, ictal events were not statistically significant (p=0.7). Conclusion(s): In this single patient study with intractable IGE, marijuana appears to have significant effect in reducing interictal discharges and possibly ictal events in IGE. Although a novel report, studies involving large number of patients with standardized strains of cannabis will be needed to further validate our findings.

Self-report survey
Grade 4- very low

Suraev, A. Lintzeris, N. Stuart, J. Kevin, R. C. Blackburn, R. Richards, E. Arnold, J. C. Ireland, C. Todd, L. Allsop, D. J. McGregor, I. S. Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community. Scientific reports 2018; 8:10154: https://dx.doi.org/10.1038/s41598-018-28127-0 - external site.

Recent surveys suggest that many parents are using illicit cannabis extracts in the hope of managing seizures in their children with epilepsy. In the current Australian study we conducted semi-structured interviews with families of children with diverse forms of epilepsy to explore their attitudes towards and experiences with using cannabis extracts. This included current or previous users of cannabis extracts to treat their child's seizures (n = 41 families), and families who had never used (n = 24 families). For those using cannabis, extracts were analysed for cannabinoid content, with specific comparison of samples rated by families as "effective" versus those rated "ineffective".

Open-label prospective study
Grade 4- very low

Szaflarski, J. P. Bebin, E. M. Cutter, G. DeWolfe, J. Dure, L. S. Gaston, T. E. Kankirawatana, P. Liu, Y. Singh, R. Standaert, D. G. Thomas, A. E. Ver Hoef, L. W. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy and Behavior 2018; 87:131-136: http://dx.doi.org/10.1016/j.yebeh.2018.07.020 - external site.

The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p >= 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p >= 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p >= 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment. Copyright © 2018 The Authors

Open-label prospective study
Grade 4- very low

Szaflarski, J. P. Hernando, K. Bebin, E. M. Gaston, T. E. Grayson, L. E. Ampah, S. B. Moreadith, R. Higher cannabidiol plasma levels are associated with better seizure response following treatment with a pharmaceutical grade cannabidiol. Epilepsy and Behavior 2019; 95:131-136: http://dx.doi.org/10.1016/j.yebeh.2019.03.042 - external site.

Objective: The objective of this study was to determine the relationship between cannabidiol (CBD)dose, CBD plasma level, and seizure control in a large open-label single-center study. Method(s): All participants with treatment-refractory epilepsy participating in our expanded access program (EAP)were approached for participation. Highly purified grade CBD (Epidiolex)dosing was weight-based and could be increased every 2 weeks by 5 mg/kg/day up to a maximum dosage of 50 mg/kg/day depending on tolerance and seizure control. Seizure counts were obtained at each visit with frequency calculated per 2-week periods. Cross-sectional plasma peak levels of CBD were obtained ~ 4 h after dosing in consecutively presenting patients. Result(s): We evaluated 56 adults and 44 children (100 total; 54 female) at two time points - one before initiating CBD and one at the time of CBD plasma level testing. There was a positive linear correlation between CBD dosage (range from 5 to 50 mg/kg/day) and level (range from 7.1-1200 ng/mL) in all participants (r = 0.640; p < 0.001). The quantile regression model supported the notion of increased CBD levels being associated with improvement in seizure frequency after adjusting for age - specifically, a 100 ng/mL increase in CBD level was associated with approximately two counts reduction in seizure frequency per time period (1.87 96% confidence interval [CI]0.34-3.39; p = 0.018). In participants with the same CBD level, differences in seizure improvement did not depend on age (p = 0.318). Conclusion(s): In this open-label study, we found evidence of a linear correlation between CBD dosage and plasma levels, and that higher dose/levels are associated with a higher response rate for seizure improvement. Children and adults responded to CBD similarly. However, seizure control response rates suggest children may respond to lower dosages/plasma levels than adults. Findings reported in this study are specific to Epidiolex and should not be extrapolated to other CBD products. Copyright © 2019 Elsevier Inc.

Self-report survey
Grade 4- very low

Todd, L. Burford, J. Vithanage, A. Ireland, C. Suraev, A. Lintzeris, N. Attitudes and experiences of medicinal cannabis use in epilepsy. Epilepsia 2017; 58 (Supplement 5):S20: http://dx.doi.org/10.1111/epi.13944 - external site.

Purpose: To measure the Australian experience and attitudes of cannabis use in epilepsy of adults and parents/guardians of children living with epilepsy. Method(s): Online distribution of a forty-one-item survey measuring demographic and clinical factors plus attitudes and opinions of cannabis use in epilepsy. IP address capture was deactivated. Inclusion criteria required a response to question seventeen "Have you or the person with epilepsy tried any form of medicinal cannabis for seizures?" Results: 1,277 responses received over a ten-day period. 983 responses met analysis criteria with a distribution of 45% adults and 55% parents of children with epilepsy. 62% of children and 50% of adults identified as having medical conditions in addition to epilepsy. Overall, 14% of survey respondents have previously used, or currently use medicinal cannabis for epilepsy. Of these people, 86% reported a positive response to cannabis use in managing seizures. 66% of survey respondents would be willing to participate in a medicinal cannabis research trial with 68% of the parents/guardians made comments themed as "willing to try anything". Conclusion(s): This survey provides an insight into the attitudes, experiences and opinions of adults and parents of children living with epilepsy in Australia seeking cannabis as a viable treatment option for epilepsy. Findings support the need for information and education about the cannabis plant, the endocannabinoid system, medicinal uses of cannabinoids and current state of legislation and clinical trials.

Retrospective cohort study
Grade 4- very low

Tzadok, M. Linder, I. Kramer, U. Menascu, S. Lerman-Sagie, T. Dor, M. Ben, Z. B. CBD-Enriched medical cannabis for intractable pediatric epilepsy. Epilepsia 2016; 57 (Supplement 2):169: http://dx.doi.org/10.1111/epi.13609 - external site.

Purpose: There is accumulating information in the basic science and clinical field literature regarding medical cannabis as an add-on anticonvulsant in intractable epilepsy. In addition, there is increasing medical and popular interest in the field. We summarize our preliminary results of CBD-enriched medical cannabis treatment in a cohort of patients. Method(s): 129 patients (age range 1-25 years) suffering from intractable epilepsy were treated with cannabis oil in three Israeli epilepsy centers from 02/2014 for a period of at least 1 month. The formula chosen contained CBD (cannabidiol) and THC (tetrahydrocannabinol) in a ratio of 20:1 dissolved in olive oil. The CBD dose ranged from 1 to 20 mg/kg/ day. short-Term outcome (average of 6 months), side effects and additional effects of the treatment are presented. Result(s): Significant positive effect on seizure load was found. Adverse reactions were minimal and included: somnolence, fatigue, vomiting, irritability and aggravation of seizures. Conclusion(s): These results are promising and suggest that further prospective, well-designed clinical trials using enriched CBD medical cannabis should be conducted.

Case study
Grade 4- very low

Hsu, K. Whitham, E. Kichenadasse, G. Potential role of cannabidiol for seizure control in a patient with recurrent glioma. Journal of Clinical Neuroscience. 2019; :: http://dx.doi.org/10.1016/j.jocn.2019.11.024 - external site.

Glioma-related epilepsy significantly impact on patients' quality of life and can often be difficult to treat. Seizures cause significant morbidity for example neurocognitive deterioration, which may result from seizures themselves or due to adverse effects from antiepileptic drugs. Management of tumour with surgery, radiotherapy and chemotherapy may contribute to seizure control, but tumour related epilepsy is often refractory despite adequate treatment with standard anti-epileptic medications. Given the increasing interest in medicinal cannabis (or cannabidiol or CBD) as an anti-epileptic drug, CBD may help with seizure control in glioma patients with treatment-refractory seizures. Here we present a case of a young lady with recurrent glioma who had refractory seizures despite multiple anti-epileptic agents, who had significant benefit with CBD. Copyright © 2019

Open-label, prospective, dose-escalation trial
Grade 4- very low

Huntsman, R. J. Tang-Wai, R. Alcorn, J. Vuong, S. Acton, B. Corley, S. Laprairie, R. Lyon, A. W. Meier, S. Mousseau, D. D. Newmeyer, D. Prosser-Loose, E. Seifert, B. Tellez-Zenteno, J. Huh, L. Leung, E. Major, P. Dosage related efficacy and tolerability of cannabidiol in children with treatment-resistant epileptic encephalopathy: Preliminary results of the CARE-E study. Frontiers in Neurology 2019; 10 (JUL) (no pagination):: http://dx.doi.org/10.3389/fneur.2019.00716 - external site.

Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Method(s): The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 DELTA9-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified. Result(s): All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS, Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion(s): The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible nonlinear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day. Copyright © 2019 Huntsman, Tang-Wai, Alcorn, Vuong, Acton, Corley, Laprairie, Lyon, Meier, Mousseau, Newmeyer, Prosser-Loose, Seifert, Tellez-Zenteno, Huh, Leung and Major. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Open-label prospective study
Grade 4- very low

Hussain, S. A. Dlugos, D. J. Cilio, M. R. Parikh, N. Oh, A. Sankar, R. Synthetic pharmaceutical grade cannabidiol for treatment of refractory infantile spasms: A multicenter phase-2 study. Epilepsy and Behavior 2020; 102 (no pagination):: http://dx.doi.org/10.1016/j.yebeh.2019.106826 - external site.

Purpose: Limited data suggest that cannabidiol (CBD) may be effective for treatment of refractory infantile spasms (IS). This study was designed to more rigorously evaluate the efficacy and safety of synthetic CBD in the treatment of IS. Method(s): Children six to 36 months of age with IS that failed treatment with both adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) were eligible for enrollment. Children receiving clobazam were excluded. After baseline overnight video-electroencephalography (vEEG) to confirm diagnosis and ascertain hypsarrhythmia, patients were treated with synthetic CBD oral solution (20 mg/kg/day). Overnight video-EEG was repeated after 14 days, and both baseline and repeat video-EEGs were completely de-identified and reviewed in a pairwise fashion by an independent, blinded pediatric electroencephalographer. The primary efficacy endpoint was freedom from spasms and hypsarrhythmia on day 14. Result(s): Nine patients were enrolled, comprising an older (median age = 23 months) cohort with long-standing IS (median duration = 13 months) and numerous prior treatment failures (median = 6). One patient responded to therapy and eight patients exhibited neither clinical nor electrographic response. Conclusion(s): The immediate but temporary response in a single patient suggests that CBD oral solution is not particularly effective in highly refractory cases, but may, nevertheless, be effective in younger patients with shorter durations of IS. Further study, examining both short- and long-term outcomes, is warranted to further evaluate the efficacy and safety of CBD oral solution in the treatment of IS. Copyright © 2019

Open-label prospective study
Grade 4- very low

Kaplan, E. H. Offermann, E. A. Sievers, J. W. Comi, A. M. Cannabidiol Treatment for Refractory Seizures in Sturge-Weber Syndrome. Pediatric Neurology 2017; 71:18-23.e2: https://dx.doi.org/10.1016/j.pediatrneurol.2017.02.009 - external site.

BACKGROUND: Sturge-Weber syndrome results in leptomeningeal vascular malformations, medically refractory epilepsy, stroke(s), and cognitive impairments. Cannabidiol, a cannabinoid without psychoactive properties, has been demonstrated in preclinical models to possibly have anticonvulsant, antioxidant, and neuroprotective actions.
METHODS: Five subjects with Sturge-Weber syndrome brain involvement and treatment-resistant epilepsy were enrolled. Motor seizure frequency, quality of life, and adverse events were recorded from the eighth week of the pretreatment period, eight weeks after starting maintenance dose (week 14), and the most recent visit.
RESULTS: Four subjects had data through week 14, one of whom initially withdrew for lack of efficacy but because of other benefits re-enrolled with a lower dose. Two subjects at week 14 and three subjects with bilateral brain involvement had at the last visit a greater than 50% seizure reduction, reported an improved quality of life, and remained on cannabidiol 63-80 weeks after starting the drug. Three subjects reported mild side effects considered related to cannabidiol.
CONCLUSION: This study suggests that cannabidiol may be well tolerated as adjunctive medication for seizure management and provides initial data supporting further study of cannabidiol in individuals with Sturge-Weber syndrome.

Self-report survey
Grade 4- very low

Kerr, Alysse Walston, Victoria Wong, Victoria S. Kellogg, Marissa Ernst, Lia Marijuana use among patients with epilepsy at a tertiary care center. Epilepsy & Behavior 2019; 97:144-148: http://dx.doi.org/10.1016/j.yebeh.2019.05.037 - external site.

The expansion of medical and recreational marijuana legalization facilitates patient access to cannabis, and many patients with epilepsy pursue marijuana as a treatment for seizures. We administered a nine-item survey on marijuana use to patients seen in an epilepsy clinic over a 9-month period at a tertiary care center in Oregon where recreational use was legalized in 2015. The majority of respondents (n = 39) reported cannabis use for the purpose of treating epilepsy (87.2%, n = 34), and strongly agreed (53.8%, n = 21) or agreed (28.2%, n = 11) that cannabis use improved seizure control. The most commonly selected cannabis strains were high cannabidiol (CBD) (30.8%, n = 12) or multiple types (30.8%, n = 12), with administration methods of smoking (66.7%, n = 26), edibles (48.7%, n = 19), and concentrates (43.6%, n = 17). More participants reported using marijuana with primarily CBD than primarily tetrahydrocannabinol (THC) or equal CBD:THC content, and very few women reported using marijuana with primarily THC compared with men (10% of female versus 47% of male respondents). Only 2 of 39 participants were able to give an exact dosage used in milligrams. Medical and recreational dispensaries were the most common cannabis sources, followed by homegrown and friends/family members. Although pharmaceutical CBD extract is now Food and Drug Administration (FDA)-approved for certain epilepsy types, access remains limited. Further research is needed to understand recreational cannabis use among patients with epilepsy while clinical research for pharmaceutical cannabis products continues. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Case study
Grade 4- very low

Khalid, M. M. Waring, E. D. Vearrier, D. McKeever, R. Greenberg, M. I. Symptomatic elevation of antiepileptic drug concentrations after addition of hemp oil extract to a therapeutic regimen. Clinical Toxicology 2017; 55 (5):467-468: http://dx.doi.org/10.1080/15563650.2017.1309792 - external site.

Objective: We describe a patient with symptomatic elevations of clobazam, valproic acid and lamotrigine concentrations following addition of hemp oil extract to her antiepileptic drug (AED) regimen. Case report: A 7-year-old female with a past medical history of epilepsy, West Syndrome, ring chromosome 14, scoliosis, and constipation presented to the emergency department complaining of unsteady gait, sleepiness, and intermittent seizures over the past 2 weeks. Her medications included clobazam 15 mg oral twice daily, clonazepam 0.5 mg oral once daily, valproate 250 mg oral twice daily and lamotrigine 100 mg oral twice daily for seizures. One month prior to admission, the patient was started on hemp oil extract by her neurologist as an adjunctive treatment for seizures. On presentation, the vital signs were: temperature 36.9degreeC, blood pressure 98/62 mmHg, oxygen saturation 100% (room air), heart rate 82 beats/minute, and respiratory rate 18/minute. On physical examination, she required assistance to stand from a seated position, had an unsteady gait, but was able to walk without assistance. The neurological examination revealed no focal findings. The toxicology service was consulted and discontinuation of the hemp oil extract was recommended due to the possibility of adverse interactions with her antiepileptic medication regimen. The patient remained seizure-free during her hospital stay with resolution of her unsteady gait and somnolence prior to discharge. Initial serum concentrations of the patient's AEDs were noted to be supratherapeutic with lamotrigine 37.8 mug/mL (normal range 2-20 mug/mL), valproate 122 mug/mL (normal range 50-100 mug/mL) from a previous baseline of 66 mug/mL, and clobazam 367 ng/mL (normal range 30-300 ng/mL). Conclusion(s): Cannabidiol contained in hemp oil extract inhibits CYP3A4 and CYP2C19, the primary isoenzymes involved in the metabolism of clobazam, and inhibits UDP-glucuronyl transferase, which is involved in the metabolism of lamotrigine and valproic acid. Symptomatic elevations in valproic acid and clobazam have been reported following the addition of cannabidiol to antiepileptic therapeutic regimens. Several studies have reported the efficacy of cannabidiol as an adjuvant therapy for refractory epilepsy, however evidence suggests that hemp extract may cause elevations of serum concentrations of various AEDs. Clinicians should be aware that the use of hemp extract in combination with AEDs requires caution and careful monitoring of serum AED concentrations.

Case series
Grade 4- very low

Klotz, K. A. Hirsch, M. Heers, M. Schulze-Bonhage, A. Jacobs, J. Effects of cannabidiol on brivaracetam plasma levels. Epilepsia 2019; 60:e74-e77: http://dx.doi.org/10.1111/epi.16071 - external site.

The use of cannabidiol (CBD) for treatment of pharmacoresistant epilepsies is increasing. CBD is metabolized via UDP-glucuronosyltransferase (UGT) and cytochrome 450 (CYP) enzymes, but information on interactions with common anticonvulsive drugs is incomplete. We report a case series of five patients receiving adjunctive treatment with CBD who showed increases in brivaracetam (BRV) levels by 95% to 280%. Only two patients reported mild adverse events, leading to a reduction of BRV in one patient. One possible mechanism contributing at least partially to increasing BRV level is the inhibition of CYP2C19 by cannabidiol. Further pharmacokinetic studies are required to understand other possible mechanisms of brivaracetam-cannabidiol interaction. Copyright Wiley Periodicals, Inc. © 2019 International League Against Epilepsy

Open-label prospective study
Grade 4- very low

Knupp, K. G. Rice, J. D. Helmkamp, L. J. Galinkin, J. Sempio, C. Jost, K. Chapman, K. E. Prospective evaluation of oral cannabis extracts in children with epilepsy. Seizure 2019; 72:23-27: http://dx.doi.org/10.1016/j.seizure.2019.09.007 - external site.

Purpose: Interest in the use of artisanal cannabinoids in pediatric epilepsy has increased but safety and utility data are lacking. Our aim was to prospectively characterize the use of oral cannabis extracts (OCE) in a refractory pediatric epilepsy population. Method(s): Families considering the use of an OCE were enrolled in a prospective observational study. Baseline seizure frequency was assessed over a period of 4 weeks. Seizure frequency, CBD and THC-COOH levels were assessed every 4 weeks during a 12-week treatment period. Response was defined as at least a 50% reduction in seizure frequency over the final 8 weeks of the study relative to baseline. Result(s): Consent was obtained in 32 children; 11 were excluded from analysis (3 failed to complete baseline data, 3 started OCE before completing baseline period and 5 did not start OCE) leaving 21 to be included in subsequent analyses. Median age was 10.3 years (IQR 6.8-12.6), 13 (62%) were male and median seizure frequency was 2.7 seizures/day during the baseline period. The median of the high dose of CBD that was administered during the observation period was of 0.9 (0.6-2.2) mg/kg/day. Of the 21 subjects who were included in the analysis, 5 (24%) were responders. OCE was stopped early in 3 subjects (14%) due to a perceived increase in seizures. THC-COOH and CBD blood levels did not have a significant association with response status (p = 0.95 CBD, p = 0.53 THC-COOH, N = 14). Conclusion(s): The observed response rate in this study is similar to placebo rates in prospective randomized trials of pharmaceutical grade products and the withdrawal rate is greater than rates obtained with retrospective methods. Doses of OCE administered were lower than doses used in randomized trials. Copyright © 2019 British Epilepsy Association

Retrospective chart review
Grade 4- very low

Linder, I. Tzadok, M. Menascu, S. Ben-Zeev, B. Lerman, S. T. Kramer, U. Treatment of pediatric intractable epilepsy with vaporized cannabidiol (CBD) and DELTA9-Tetrahydrocannabinol (THC)- Preliminary findings of the israeli pediatric medical cannabis (MC) cohort. Epilepsia 2016; 57 (Supplement 2):108: http://dx.doi.org/10.1111/epi.13609 - external site.

Purpose: Description of the clinical characteristics of twenty four Israeli pediatric patients with intractable epilepsy treated with vaporized Medical Cannabis. Method(s): CBD & THC treatment by mobile & immobile vaporizers was administered to epileptic patients fulfilling inclusion criteria. All patients were initially treated with 1:20 CBD:THC oil extract with a uniform gradual dosage increase. Patients eligible for vaporization either failed to respond to the target MC dosage, exhibited tolerance to it, presented with cluster seizures or with intense and abrupt seizures. Contra-indications (CI) were divided to absolute CI -Any respiratory disease or hypersensitivity reaction to the oil extract of MC or relative CI such as a known cardio- vascular disease or family history of mental illness. Patients were considered responders if the seizure cluster abated or if the seizure burden decreased according to parental report. Result(s): Twenty four epileptic patients (16 male 8 female) with a diverse range of etiologies were treated with MC vaporization. Sixteen responded (two substantially, eight mildly and six shortened seizure clusters) while six had no response whatsoever. two patients had low compliance to treatment. Conclusion(s): Our preliminary findings regarding MC vaporization treatment for pediatric epileptic patients suggest a new and promising MC treatment modality, expanding the MC treatment options. Lack of uniformity in the treatment protocol, due to scarcity of relevant data, especially the immediate and long term effects of THC on the developing brain, render MC vaporization a promising -yet to be better defined option before implementing it as a routine treatment option for intractable epilepsy in the pediatric population.

Retrospective chart review
Grade 4- very low

Moreno, M. Vaillancourt, R. Pouliot, A. Sell, E. Hevenor, B. Viracoumarane, K. A survey of the use of cannabis in children at a tertiary teaching hospital. Canadian Journal of Hospital Pharmacy 2018; 71 (1):72.

Background: There has recently been an increase use of cannabis for medical purposes in the pediatric population. However, limited data on the efficacy and safety of cannabis in children has been published. A comprehensive characterization of cannabis use in this population can further contribute to a better understanding under which circumstances cannabis is being used and the observed outcomes. Objective(s): To perform a retrospective drug use evaluation to describe all inpatient and outpatient medical uses of cannabis in a tertiary teaching hospital over the last 3 years. Method(s): A retrospective medical record review was completed of inpatients and outpatients <18 years of age prescribed medical cannabis between May 1st, 2014 and May 1st, 2017. Patients using cannabis recreationally were excluded. Result(s): There were a total of 300 unique patients identified and 37 children were included in this study. Of these, 30 patients were using medical cannabis, and most were using it for seizures (93%) where 82% were described as having intractable/ refractory seizures. Among these, 78% reported a decrease in seizures and of those 76% had a transient effect where a decrease was noted for 130.38 days (+/-99.14), but then seizures increased once again. Additionally, a subgroup of 7 patients were self-medicating with cannabis. They obtained cannabis without proper authorization as a dried flower and were using it for chronic pain (71%) and/or anxiety (71%). Conclusion(s): Cannabis use is reported more often for childhood refractory epilepsy compared to other chronic conditions. The use of cannabis in children with medication-refractory epilepsy may be warranted after trying first line anticonvulsant medications and after discussing non-pharmacological options. Based on our data, decrease in seizures may only be transient.

Open-label prospective study
Grade 4- very low

Nickels, K. Cannabidiol in patients with intractable epilepsy due to TSC: A possible medication but not a miracle. Epilepsy Currents 2017; 17:91-92: http://dx.doi.org/10.5698/1535-7511.17.2.91 - external site.

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 non-psychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC. METHOD(S): 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. RESULT(S): 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. Copyright © American Epilepsy Society.

Case series
Grade 4- very low

Pane, C. Sacca, F. The use of medical grade cannabis in Italy for drug-resistant epilepsy: a case series. Neurological Sciences. 2019: http://dx.doi.org/10.1007/s10072-019-04162-1 - external site.

In Italy, medical grade cannabis (MGC) can be prescribed for different medical conditions, including drug-resistant epilepsy (DRE), once standard and approved therapies have failed, or caused non-tolerable side effects. Here, we present a retrospective case series report of five patients with DRE who started therapy with MGC. Authorized ISO 9001:2008 pharmacies prepared MGC according to Italian laws. Olive oil extracts (OOEs) were prepared following standard extraction protocols, and cannabinoids were measured on each OOE to check for successful extraction. After treatment with MGC, all patients reported a reduction in seizure frequency and severity, and some reported improved mood, sleep quality, and general well-being without relevant side effects. Despite the small sample size and open-label nature of the data, we show that MGC may be successfully used to treat DRE. This is especially true when considering that no valid therapeutic option exists for these patients and that MGC was extremely well tolerated. Copyright © 2019, Fondazione Societa Italiana di Neurologia.

Open-label, dose-escalation phase 1 trial (PROTOCOL)
N/A

Reithmeier, D. Tang-Wai, R. Seifert, B. Lyon, A. W. Alcorn, J. Acton, B. Corley, S. Prosser-Loose, E. Mousseau, D. D. Lim, H. J. Tellez-Zenteno, J. Huh, L. Leung, E. Carmant, L. Huntsman, R. J. The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study. BMC Pediatrics 2018; 18:221: https://dx.doi.org/10.1186/s12887-018-1191-y - external site.

BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high-quality safety data especially regarding the potential for harm caused by other cannabinoids, such as DELTA⁹-tetrahydrocannabinol (DELTA⁹-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life.
METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects.
DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids. TRIAL REGISTRATION: http://clinicaltrials.gov - external site [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827 - external site.

Open-label prospective study
Grade 3- low

McCoy, B., Wang, L., Zak, M., Al‐Mehmadi, S., Kabir, N., Alhadid, K., McDonald, K., Zhang, G., Sharma, R., Whitney, R., Sinopoli, K. and Snead, O.C., III (2018), A prospective open‐label trial of a CBD/THC cannabis oil in dravet syndrome. Ann Clin Transl Neurol, 5: 1077-1088. doi:10.1002/acn3.621

INTRODUCTION: Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 - a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life.
METHODS: Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives.
RESULTS: Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%.
CONCLUSIONS: TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.

Open-label prospective study
Grade 3 - low

Wilson CA, Spigarelli M, Sweney M, et al. Efficacy, adverse effects, and additional benefits of epidiolex in children and young adults with treatment resistant epilepsy. Ann Neurol 2015;78:S180. https://onlinelibrary.wiley.com/doi/pdf/10.1002/ana.24477 - external site

Objective: Epidiolex is an investigational drug containing pure Cannabidiol (CBD), a substance shown to have anticonvulsant properties. We describe the efficacy, adverse effects, and other beneficial effects of Epidiolex in an open label trial approved by the FDA and DEA for children and young adults with treatment resistant epilepsy. Methods: 25 subjects received Epidiolex 2 to 25 mg/kg/ day. Eligibility criteria included drug resistant epilepsy, stable medication doses, and not taking another cannabis product. Patient demographics, CBC, CMP, and adverse or beneficial effects reported. Seizure burden (type/frequency/ severity) recorded daily by caregivers. Data at 3 months of Epidiolex use were compared with baseline. Results: Outcome data are reported in Table. Total number of seizures were reduced by a median of 38% at 3 months. Eighteen patients (72% of participants) experienced fewer seizures with an average frequency reduction of 50%. While many patients experienced adverse effects, the vast majority were mild and transient. Seven serious adverse events were reported, none deemed to be directly related to study medication. Seven patients reduced dose due to side effects; one discontinued due to diarrhea and lack of efficacy, another for persistent nausea/vomiting. The additional beneficial effects reported (> 12%) were more sustained throughout treatment. Conclusions: Caretakers reported decreased seizures in the majority of patients treated with Epidiolex. Common side effects included fatigue and diarrhea, but the drug was generally well tolerated. Caretakers reported several other benefits during treatment. The results support future controlled trials of Epidiolex (CBD) in various pediatric epilepsies.