This information has been pulled and curated largely from Drs. Campbell, Phillips & Manasco’s 2017 review article
Epilepsy & CBD Full Report
Dating back as far as 2000 BC, hemp plants had been used for various medicinal and industrial purposes. In 1851, the United States Pharmacopeia (USP) classified marijuana as a legitimate medical compound and many physicians supported its use for conditions such as epilepsy, chronic migraines, and pain (Campbell, Phillips, & Manasco, 2017).
Over the past several years, medical marijuana use has become a controversial topic not only within the medical community but also at state and national legislative levels. Many of the misconceptions regarding medical marijuana in the pediatric population stem from negative connotations associated with the term marijuana owing to its psychoactive effects. Therefore, it is important to define the various terms associated with products that are currently being used by the public as well as by pediatric researchers (Campbell et al., 2017).
Cannabinoids are the chemicals found within cannabis that interact with specific receptors, namely, cannabinoid (CB) receptors, within the body. The over 60 types of cannabinoids currently identified differ by the degree to which they are psychoactive (University of Washington Alcohol and Drug Abuse Institute [Internet]. Seattle: University of Washington., 2017). While delta-9-tetrahydrocannabinol (THC), the cannabinoid most commonly associated with marijuana as a drug of abuse, is psychoactive, other cannabinoids including CBD are not (Campbell et al., 2017). CBD has one of the highest safety profiles of all the cannabinoids.
On the other hand, THC can be a contributor to neurodevelopment deficits in adolescents (Borgelt, Franson, Nussbaum, & Wang, 2013; Meier et al., 2012). Different marijuana strains will have varying amounts of both THC and CBD, and thus the concentrations and ratios of these different cannabinoids within a product, especially for pediatric use, has been a subject of interest not only for medical professionals but also for state legislators as well (Campbell et al., 2017).
Despite its controversial nature, the use of medical marijuana and cannabis-derived medicinal products grows more popular with each passing year. As of November 2016, over 40 states have passed legislation regarding the use of either medical marijuana or cannabidiol products. Many providers have started encountering patients experimenting with cannabis products for a wide range of conditions (Campbell et al., 2017).
A human’s central nervous system is naturally impregnated with cannabinoid receptors and endocannabinoids. In the early 1990s, 2 receptors were discovered, cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2). Both CB1 and CB2 are G-coupled protein receptors located pre-synaptically and control the release of neurotransmitters at both inhibitory and excitatory synapses. CB1 is mostly expressed on presynaptic peripheral and central nerve terminals and is believed to be responsible for psychologic effects on pleasure, memory, thought, concentration, sensory and time perceptions, and coordinated movement. CB2 receptors, concentrated in peripheral tissues and immune cells, may play an anti-inflammatory and immunosuppressive role. In addition to directing the release of various neurotransmitters, this receptor regulates the release of certain cytokines. Innervation of both these receptors results in both physiological (tachycardia, hypertension, dry mouth and throat) as well as psychological (elation, euphoria, heightened perception, irritability, poor coordination and balance) effects (Baron, 2015; Borgelt et al., 2013; Campbell et al., 2017). Check out Dr. Orrin Devinsky’s short video on CBD/THC and epilepsy here. Also check out The Child Neurology Foundation’s video on cannabis and epilepsy here.
Additionally, endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, both arachidonic acid derivatives, bind with CB1 and CB2. While the function of these endogenous ligands is not fully understood, their action may be attributed as antiemetic, anti-analgesic, and anti-inflammatory (Campbell et al., 2017).
Endocannabinoids can also play a role in excitation of the neuronal networks, thus having effect on the quality of a seizure. Previous studies have documented deficiencies in endocannabinoids in temporal lobe epilepsy patients as well as a rise in anandamide concentrations post seizures in mice, suggesting an anti-seizure activity profile (Friedman & Devinsky, 2015). The 2 most studied exogenous cannabinoids include THC and CBD. THC is a partial agonist at both CB1 and CB2 receptors and achieves its psychoactive properties likely through modulation of gamma-aminobutyric acid (GABA) and glutamine (Campbell et al., 2017).
THC seems to possess anti-seizure activity but may be a pro-convulsant in certain cases (M R Cilio, Thiele, & Devinsky, 2014). CBD, however, does not appear to bind to either CB1 or CB2 but does possess neuroprotective and anti-inflammatory effects (Baron, 2015). Several possible mechanisms of CBD have been proposed: inhibition of cyclooxygenase and lipoxygenase, inverse agonism at CB1/ CB2 receptors, and enhancement of anandamide (Borgelt et al., 2013; Campbell et al., 2017).
It is proposed that CBD may be effective in epilepsy through modulation of the endocannabinoid system. CBD halts the degradation of the endocannabinoid anandamide, which may have a role in inhibiting seizures. Additionally, research demonstrates that CBD may play a role with the regulation of T-type calcium channels and nuclear peroxisome proliferator-activated receptor-γ, both of which have been implicated in seizure activity (Maria Roberta Cilio, Thiele, & Devinsky, 2014). Because CBD is one of the most abundant cannabinoids within cannabis resin and its mechanism is still unclear, there is peaked interest in the possible clinical indications that it could treat including epilepsy, pain, and inflammatory disorders (Campbell et al., 2017).
Both THC and CBD are highly lipophilic with long half-lives, 30 hours versus 9 to 32 hours, respectively (Borgelt et al., 2013; Hadland, Knight, & Harris, 2015; Whiting et al., 2015). CBD is also highly protein bound and is both metabolized by and a potent inhibitor of the CYP450 enzymes (2C19, 3A4), potentially causing significant medication interactions(Borgelt et al., 2013; Hadland et al., 2015; Seamon, Fass, Maniscaolco-Feichtl, & Abu-Shraie, 2007; Whiting et al., 2015). While CYP inducers such as phenytoin and carbamezapine may decrease CBD concentrations, CBD is known to increase concentrations of clobazam, an antiepileptic drug approved by the FDA in 2011 for the treatment of Lennox-Gastaut syndrome (LGS). CBD inhibits CYP3A4 and CYP2C19, preventing the degradation of clobazam and its active metabolite, N-desmethylclobazam. In an expanded access trial, patients with concomitant clobazam and CBD use had increases in clobazam concentrations of > 60% and N-desmethylclobazam, of 500% (Geffrey, Pollack, Bruno, & Thiele, 2015). At this time it is not clear what other drug interactions may exist and what dosage manipulations may be necessary (Campbell et al., 2017).
Epilepsy Clinical Data
The data in pediatric epilepsy have been surrounding the use of CBD products as well as unregulated THC/CBD products from private dispensaries. A Cochrane review (Gloss & Vickrey, 2014) was conducted in 2012 to assess the safety and efficacy of cannabinoid use in patients with epilepsy. The authors included blinded and unblinded randomized controlled trials. The authors summarized the finding that a CBD dose of 200 mg to 300 mg daily was safely administered over a short period, and the rate of adverse reactions in each of the studies was low over a short period. The American Academy of Neurology conducted a systematic review in 2014 which included 34 studies that used medical marijuana to treat MS, epilepsy, and movement disorders (Koppel, Brust, & Fife, 2014). Two studies were included to assess the role of cannabinoids in decreasing seizure frequency(Ames, Cridland, & Med, 1985; Campbell et al., 2017; Cunha, Carlini, & Pereira, 1980).
Many parents and patients are making the decision to use CBD for 3 reasons according to Cilio et al (Maria Roberta Cilio et al., 2014): 1) prominent Internet and nation media attention; 2) reports of cases of children successfully treated with CBD products; and 3) the belief that treatments derived from natural products are safer or more effective (Campbell et al., 2017; Maria Roberta Cilio et al., 2014).
National attention has been on those patients who have moved to states where CBD use is legal and researchers have sought to gather data from parental observations. The most famous case was presented on a CNN special, “Weed.”29 Charlotte is a little girl from Colorado who was diagnosed with Dravet syndrome at the age of 3 months. She suffered from frequent status epilepticus. Charlotte failed multiple medications, and at 5 years of age, she had significant cognitive delay and required help with all of her activities of daily living (Maa & Figi, 2014). Her parents sought out a group in Colorado that created an oral, liquid, high-concentration CBD-to-THC strain of cannabis. Once her parents started giving her this strain, dubbed “Charlotte’s Web”, within 3 months Charlotte had a 90% reduction in her seizure frequency and by month 20, Charlotte was able to perform most of her daily activities independently with only 2 to 3 nocturnal tonic-clonic seizures per month. Stories like Charlotte’s have prompted parents across the country in similar situations to move their families across the country to gain access to these products. In a retrospective chart review of 75 children and adolescents younger than 18 years who were given oral cannabis extracts for treatment of their epilepsy, 57% of parents reported some improvement in seizure frequency with 33% reporting a 50% reduction in seizures (Press, Knupp, & Chapman, 2015). Dosage information was not reported and parents used various formulations and concentrations of CBD and THC. Parents also described improvements in behavior and alertness (33%), language (11%), and motor skills (11%). Major adverse effects noted were somnolence (12%) and gastrointestinal symptoms (11%) (Campbell et al., 2017; Press et al., 2015).
Investigators at Stanford University administered a survey to 150 parents on Facebook to identify parentally reported effects of CBD on their child’s seizures (Porter & Jacobson, 2013). Of 19 respondents aged 2 to 16 years, 18 had treatment-resistant epilepsy for more than 3 years before CBD use. Based on parental response, 84% reported a reduction in child’s seizure frequency with 50% having a greater than 80% reduction in seizure frequency. Twelve of these 19 patients were also able to be weaned from another antiepileptic drug. In addition, parents reported overall better mood, increased alertness, and better sleep. Parents reported oral CBD dosages of 0.5 mg/kg/ day to 28.6 mg/kg/day and THC of 0 to 0.8 mg/kg/day. In a similar Facebook survey administered by researchers at the University of California, Los Angeles, the authors (Hussain, Zhou, & Jacobson, 2015) similarly reported an 85% reduction in seizure frequency among 117 respondents, with an average age of 6 years. Most patients (86%) conveyed that changes in frequency occurred within 14 days. As with previous surveys, dosage and formulations were varied but based on parental report of formulation used. Overall, most parents (83.5%) reported using an oral CBD product with at least a 15:1 ratio of CBD to THC.
Of the 40% of respondents who provided dosages, the median weight-based dose of CBD was 4.3 mg/kg/day given in 2 to 3 oral doses. As mentioned above, these surveys should be evaluated carefully given the inability to verify dose, formulation, and response. The conclusion that can be made is that there is a rather strong positive parental perception regarding the efficacy of cannabinoids, specifically CBD. Most orphan drug designations for CBD are for pediatric seizure disorders (Table 4) (Washington, 2017). A search of ClinicalTrials.gov in November 2016 identified 4 completed Phase 2 and Phase 3 protocols for pediatric seizure disorders, as well as 14 ongoing treatment trials, includeing intermediate-size expanded access protocols (up to 50 patients each). Published findings from open-label use of CBD for treatment-resistant epilepsy under an expanded-access program at 11 epilepsy centers in the United States suggest that CBD might reduce seizure frequency and might have an adequate safety profile in children and young adults with this condition (Campbell et al., 2017; Devinsky et al., 2016).
Congressional testimony in June 2015 indicated that 20 intermediate-size expanded access Investigational New Drug Applications had been authorized to treat approximately 420 children with 1 CBD product; most of these are not listed on ClinicalTrials.gov (Throckmorton, 2017). After announcing positive results from 2 pivotal randomized, double-blind, Phase 3 trials for the treatment of seizures related to LGS, and a third for sei- zures associated with Dravet syndrome in 2016, GW Pharmaceuticals expects to submit a single New Drug Application for both indications to the FDA in the first half of 2017 for its proprietary pharmaceutical-grade CBD product Epidiolex (2017b). In the second LGS study, patients randomized to the investigational product 20 mg/kg/day (n = 76) or 10 mg/kg/day (n = 73) added to their current antiepileptic treatment, experienced a median reduction in monthly drop seizures of 42% and 37%, compared to 17% in the placebo group (n = 73); a difference that was statistically and clinically significant (p = 0.0047 and p = 0.0016, respectively) (Devinsky et al., 2016). These data confirmed the results of the first LGS trial in which 86 patients receiving Epidiolex 20 mg/kg/day achieved a 44% mean reduction in monthly drop seizures as com- pared to 22% for 85 patients in the placebo group (p = 0.0135) (2017a). Patients with Dravet syndrome receiving the GW Pharmaceuticals’ CBD in addition to their baseline antiepileptic regimen (n = 61 ) achieved the primary end-point of a significant reduction in convulsive seizures (p = 0.01, median reduction of 39%) assessed over the 14-week treatment period as compared with the addition of placebo (n = 59). Insys Therapeutics (Phoenix, AZ) has reported that their synthetic pharmaceutical CBD in a nonalcoholic, medium-chain triglyceride-based formulation was generally well tolerated in a completed Phase 1/Phase 2 safety and pharmacokinetic study in 61 pediatric patients with treatment-resistant epilepsy at total daily doses up to 40 mg/kg (Campbell et al., 2017; Insys Therapeutics, 2017).
Evolving legislation and the increased use of cannabinoid products outside of investigational studies have also impacted our health care delivery and emergency resources. The state of Colorado has been on the forefront of the medicinal and recreational use of cannabis debate. Physicians are also poised to participate in the design and evaluation of current and future research in this area. The importance of drug interactions between CBD and other anti-epileptics remains uncertain both for the efficacy and safety of CBD products, however, CBD has shown exceptional safety profiles on its own (Gable, 2004; Lachenmeier & Rehm, 2015). The difference in concentrations, dosages, and formulations of various products sold at private dispensaries are not commonly standardized or regulated, and it is important to be an educated consumer when seeking CBD sources to treat epilepsy. Differences in state legislation on allowable concentrations and amounts can be confusing for patients and their families, and physicians can help to provide that information (Campbell et al., 2017).
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