Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy?
Epilepsy is an important disease that affects brain function, particularly in those under 3 years old. Uncontrolled seizures can affect cognitive function and quality of life. For these reasons, many trials have been conducted to investigate treatments for pediatric epilepsy. Currently, many antiepileptic drugs are available for the treatment of epilepsy, but cases of intractable epilepsy continue to exist. In the past, cannabis has been tested as a potential treatment of intractable epilepsy. Since 2013, 10 epilepsy centers in America have conducted research regarding the efficacy of cannabis to treat epilepsy. Cannabis has many components, including cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC). THC has psychoactive properties exerted through its binding of the cannabinoid receptor (CBR) whereas CBD is a CBR antagonist. The inhibition of epilepsy by CBD may therefore be caused by various mechanisms, although the detailed mechanisms of CBD actions have not yet been well defined. In most studies, trial doses of CBD were 2–5 mg/kg/day. Several such studies have shown that CBD does have efficacy for treatment of epilepsy. Reported adverse effects of CBD were mostly mild, including drowsiness, diarrhea, and decreased appetite. Severe adverse reactions requiring treatment, such as status epilepticus, have also been reported but it is not clear that this is related to CBD. Furthermore, many previous studies have been limited by an open-label or survey design. In future, double-blind, controlled trials are required and the use of CBD to treat other neurological problems should also be investigated.
Epilepsy impacts the brain, and is associated with cognitive dysfunction and behavior disorder, which can affect quality of life, especially during the developmental period.1–3 Early onset epilepsy, particularly in those less than 3 years old, and uncontrolled seizures are associated with poor cognitive function later in life.4
Currently, more than 20 different antiepileptic drugs (AED) exist for the treatment of epilepsy. However, 30% of patients with epilepsy continue to have seizures.5–7 Many new medications have been approved in the past two decades, but these have not reduced the proportion of patients with intractable epilepsy.5 Recently, cannabis has attracted attention as a potential treatment of epilepsy.7 Cannabis was used to treat epilepsy in Sumeria as early as 1800 BCE.7,8 In the late 19th century, English neurologists also used cannabis for the treatment of epilepsy.9–11 More recently, some states in America have approved medical marijuana for the treatment of epilepsy. Moreover, since 2013, the effects of cannabidiol (CBD) in the treatment of epilepsy have been studied at 10 epilepsy centers using Epidiolex, a purified cannabis containing 99% CBD and less than 0.10% tetrahydrocannabinol (THC). (GW Pharmaceuticals, Sativex, London, UK).
Cannabis contains more than 545 distinct compounds, the most abundant of which are cannabinoids.12 The most important neuro-active components of cannabis are CBD and Δ 9 -THC. THC binds to G-protein-coupled cell membrane receptors, including the cannabinoid receptor type 1 (CB1R), which is found primarily in the brain, but is also present in peripheral tissues, and the cannabinoid receptor type 2 (CB2R), which is located mainly in immune and hematopoietic cells. THC binds CB1R in inhibitory gamma-aminobutyric acid-ergic and excitatory glutamatergic neurons.13,14 These interactions are the pathways by which cannabis exerts its psychoactive function. However, CBD is an antagonist to CB1R and CB2R.15 Some animal studies show that CB1R antagonists can reduce the threshold of seizures.16 This suggests that CBD has another mechanism by which it can control seizures. Indeed, CBD acts via multiple mechanisms ( Fig. 1 ).7,14,15 These include effects on transient receptor potential ation channels at a low level,17 and antagonistic functions at G-protein-coupled receptor 55, by which it can decrease presynaptic glutamate release.18 However, the mechanisms underlying the anti-epileptic effects of CBD are not well defined.
Cannbidiol mechanism and structure. CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; GPR 55, G-protein-coupled receptor 55; TRPV1–4, transient receptor potential cation channel subfamily V 1–4;TRPVM8, transient receptor potential cation channel subfamily M 8; 5HT3AR, 5-hydroxytryptophan type 3A receptor.
CBD is metabolized by the liver, and it can inhibit cytochrome P (CYP) 450, especially CYP 2C and CYP 3A, which aids metabolism of several AED.19,20 Therefore, if a patient with epilepsy takes CBD with an enzyme-inducing AED, such as carbamazepine or phenytoin, the AED can reduce serum CBD levels. Whereas, if the patient takes clobazam (CLB) with CBD, CBD can raise the serum level of nor-oclobazam, the active metabolite of CLB.21 The half-life of CBD in humans is estimated to be between 18 and 32 hours.22
Here, we review recent trials that have investigated the use of CBD as a treatment for epilepsy and highlight key issues for future research.
Trial dosages of CBD
In many studies, CBD was added to a baseline AED at an initial dose of 2–5 mg/kg/day divided into two doses. CBD was up-titrated by 2–5 mg/kg once a week until intolerance or to reach a maximal dose of 25 mg/kg/day. Some studies increased the does to 50 mg/kg/day, as allowed by the US Food and Drug Administration. The average of dose of CBD was 200–300 mg/day.7
Clinical trials of CBD to treat epilepsy
Some U.S. states now allow the use of cannabis for medical treatment. Many patients with epilepsy have wanted to try cannabis as a treatment even though preclinical and clinical evidence is limited. As mentioned above, several clinical studies have investigated CBD after the late 19th century. Recent studies have shown an effect of CBD in treating epilepsy ( Table 1 ). They suggest that CBD can reduce the frequency of seizures, reducing monthly frequency in most types of seizures. Many studies have included a significant number of patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), and have observed reduced seizures as an effect of CBD.
Study in cannabidiol in the treatment of epilepsy
|Study||Age (year)||Dose||Group (n)||Results||Reference|
|Retrospective, parent survey in pediatric refractory epilepsy||6–13||19||Complete seizer freedom: 2 patients
More than 80% reduction in seizure frequency: 8 patients
25–60% seizure reduction in seizure frequency: 6 patients
|Porter and Jacobson33|
|Retrospective, 12- month trial for refractory epilepsy in tuberous sclerosis complex||3–29||Maximum dose of 50 mg/kg/day||18||The 50% responder rates were 50 % after 12 months.||Hess et al.25|
|Retrospective, open label, 12- week trial in refractory epilepsy||1–22.2||Maximum dose of 25 or 50 mg/kg/day||162||More than 50% reduction in seizure frequency: 51 patients
More than 70% reduction in seizure frequency: 30 patients
More than 90% in seizure frequency: 11 patients.
|Devinsky et al.23|
Between 2014 and 2015, Devinsky et al.23 conducted a prospective, open-label, and expanded trial at 11 epilepsy centers in America. They enrolled 214 patients in the study, of which 137 (64%) were included in an efficacy analysis group and 162 (76%) were included in a safety analysis group. They observed enrolled patients for 12 weeks. This study reported a decrease of 34.6% in the median change of total seizures after 12 weeks’ treatment with CBD. It also showed a decrease of 55% in focal seizures and 54.3% in atonic seizures. They observed a decrease of 36.5% and 16% in tonic seizures and tonic-clonic seizures, respectively. Overall, the median monthly frequency of motor seizures decreased by 47%.
This open-label trial enrolled a large portion of patients with DS (n = 32) or LGS (n = 30). In the case of DS, 16 patients (50%) showed a reduction in motor seizures of more than 50%, and one patient (3%) was free from motor seizures during the 12 weeks of treatment. They reported a median change of −69.2% in monthly tonic seizures (n = 6) and a median change of −46.7% in monthly tonic-clonic seizures (n = 29). Non-motor-focal seizures (n = 10) were observed to show a median reduction of 83.3%. Among patients with LGS (n = 30), 11 (37%) showed a decrease in seizures of more than 50%, but none were seizure free during treatment. The percentage change in monthly seizures for all seizure types was −35.5%. The median change for atonic seizures (n = 14) was −68.8%. In patients with tonic seizures (n = 21), there was a median reduction of 44.0%. However, there was no change in tonic-clonic seizures (n = 16).
Infantile spasm (IS) is another epileptic encephalopathy in need of an effective treatment. In 2014, Hussain et al. conducted a survey about CBD exposure,24 which included patients with IS and LGS. Although this study had several limitations, it supported the possibility that CBD could effectively treat IS and LGS.
Hess et al. studied the efficacy of CBD for refractory epilepsy in tuberous sclerosis complex (TSC).25 They enrolled 18 patients with epilepsy and TSC between 2014 and 2015, and treated them for 6–12 months with CBD. In total, 14 patients (77%) had a mutation, half of whom had a TSC1 mutation and the other half of whom had a TSC2 mutation. At baseline, 72% of patients had shown one or more type of seizure.25 In this study, the median total weekly seizure frequency reduced by 32% after 2 months and 55% after 6 months. At study completion after 12 months of treatment, the seizure frequency was decreased to 63%. Regarding the CBD effect on each type of seizure, epileptic spasms and atonic seizures showed the greatest response. The responder rate of tonic-clonic seizures was 66.7% after 3 months’ treatment. The rates of complex partial seizures and complex partial seizures with secondary generalization were 53.8% and 50% after 3 months’ treatment, respectively. This study was limited by a small sample size, as well as an uncontrolled and unblinded design, but suggests a potential effect of CBD in TSC.
Reported adverse effects
In previous studies, the most common adverse effect of CBD was drowsiness. Most reported adverse effects were mild, for example diarrhea, fatigue, and decreased appetite. Nonetheless, some more serious effects, including status epilepticus, have been reported.
Devinsky et al. reported adverse events in 128 (79%) of 162 recruited patients.23 Most of these adverse effects were mild or moderate, and transient. Critical adverse effects considered to be caused by CBD were observed in 20 patients (12%).23 The most common adverse event was somnolence, while status epilepticus was the most severe and required urgent treatment ( Table 2 ). It is interesting that CBD had this severe adverse effect, status epilepticus, because animal studies have not shown any proconvulsant effects of CBD.9,26 Devinsky et al. also reported thrombocytopenia in 5 patients (3%), but there were no clinical changes in white or red blood cells. CBD also did not affect renal function. Ten patients (6%) showed elevated liver enzymes and this elevation was significant in one patient (< 1%). The authors did not find any relationship between status epilepticus and reduced doses of AED or CBD. Four patients stopped CBD treatment before the end of 12 weeks because of a worsening of seizures or poor efficacy.
CBD is a component of the cannabis plant that is used to relieve stress and anxiety . It is known for its anti-seizure properties. It is not psychoactive, and does not produce a ‘high’ in its users, unlike another popular cannabis component, Tetrahydrocannabinol (THC).
CBD Oil is an effective and legitimate way to treat seizures.
Studies have suggested that teens and children who have epilepsy and were treated with pharmaceutical Cannabidiol (CBD) products, experienced enhanced seizure control than those treated with artisanal CBD.
Pharmaceutical CBD products do not contain THC, while artisanal CBD does.
A CBD drug Epidiolex has been approved by the Food and Drugs Administration (FDA) to treat the two most severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. People who suffer from these disorders often do not respond to convention medications that are used to treat epilepsy.
CBD Derived from Hemp
Hemp is a variety of the Cannabis Sativa plant. Hemp was originally grown for the fibrous materials that are found in its seeds and stalks. It has been traditionally used to manufacture items such as upholstery, clothing fibre, and other household items.
Hemp plant is abundantly rich in CBD , and contains much lower concentrations of THC than the cannabis plant. Cannabinoids that are extracted from hemp plants, including CBD, were up until recently considered as marijuana, and were classified as Schedule I substances.
According to the Drug Enforcement Agency (DEA) , the substances that constitute Schedule I have no accepted medical usage and have high potential for being abused.
After the enactment of the Farm Bill in 2018, hemp and CBD derived from hemp are no longer classified as Schedule I substances. Instead, they are recognized as an agricultural commodity. Thus, CBD derived from hemp is not illegal at the federal level of the USA, however some states still demm it as illegal. So before purchasing any CBD product make sure to check your state laws.
What are Complex Partial Seizures?
A Complex Partial Seizure is a type of seizure that starts out in a single area of our brain. It is also known as a focal onset impaired awareness seizure or a focal impaired awareness seizure. More often than not, the seizure starts in the temporal lobe of the brain.
It most commonly affects people who have epilepsy. A complex partial seizure also affects people with cerebral palsy.
The seizures are characterised by uncontrolled movement of limbs and other parts of the body. The seizures last for a short duration, during which the person experiencing the seizures is unaware of their surroundings.
The person experiencing the seizure may also lose consciousness for a brief duration of time. People who have been diagnosed with epilepsy often experience this type of seizure.
Symptoms of Complex Partial Seizures
A Complex Partial Seizure can have several symptoms associated with it. However, it is not necessary that all symptoms are visible during each and every seizure. Complex Partial Seizures usually only last for a few minutes.
Seizures that begin in the frontal lobe of the brain generally last shorter than the ones that start in the temporal lobe area.
Symptoms often appear abruptly, and they person experiencing them may not even realise that they have just had a seizure. The symptoms include:
- Being unable to recollect the seizure after it ends
- Being unable to respond during the seizure
- Being partially or wholly unaware of their surroundings
- Being confused when the seizure ends
- Say words repetitively
- Scream, laugh, or cry uncontrollably
- Trying to hurt themselves
What Causes Complex Partial Seizures?
While Complex Partial Seizures are usually a consequence of epilepsy, they can be caused by several other factors. Some of these include:
- Anxiety and Depression
- Damage caused prior to birth
- Extreme stress
- Neurologic conditions
- Other medical conditions related to the brain
- Psychological distress or trauma
What Triggers the Complex Partial Seizures?
A Complex Partial Seizure usually occurs without warning, and can happen at any given time. Sometimes the person can first experience an aura, which is a simple partial seizure. It acts as a warning that a bigger seizure is on its way.
Some additional factors that can trigger a seizure include:
- Flashing Lights
- High Fever
- Low Blood Sugar
- Reactions to certain medications
Treatments for Complex Partial Seizures
There are several types of treatments available to manage Complex Partial Seizures. Some of the common ones are:
- Antiepileptic Drugs
- Tiagabine hydrochloride (Gabitril), a new antiepileptic drug that shows significant promise in several trials
- Stimulation of the Vagus nerve
- Responsive Neurostimulation
- Dietary changes
Health Conditions Associated with Complex Partial Seizures
A Complex Partial Seizure can be experienced by anyone. However, people who have certain medical conditions makes them predisposed to these seizures. These conditions include:
- Brain Injury
- Cerebral Palsy
- Infection in the brain
- Some heart conditions
People who are afflicted with these conditions may have higher chances of experiencing Complex Partial Seizures.
Are Antiepileptic Drugs Effective?
Conventionally, the preferred choice of treatment for seizures and epilepsy are antiepileptic drugs. While these drugs are effective, they are also riddled with several side effects. These side effects include:
- Sleep Disorders
Moreover, studies have found that up to thirty percent of people who have epilepsy do not respond to antiepileptic drugs. As the success rate of antiepileptic drugs is not very high, researchers have started to explore more natural and efficient methods of treatment.
CBD to Treat Complex Partial Seizures
A meta-analysis published in the Journal of Neurology, Neurosurgery and Psychiatry studied the effects of CBD in treating epilepsy. It suggested that CBD could aid in reducing and even stopping seizures altogether.
Researchers from various institutions studied the results of the analysis. Most of the studies that were a part of the meta-analysis involved children with the average age of 16 years.
The team observed that CBD reduces seizures along with improving the quality of life of patients suffering from seizures and epilepsy. They also noted a significant drop in the frequency of the seizures in over half of the participants of the studies.
The research team also found that almost forty eight percent of the people who participated in the studies experienced a reduction in the frequency of their seizures by over fifty percent.
The evidence suggests that CBD has tremendous potential to be a natural and effective treatment to manage and reduce seizures.
Epidiolex is a pharmaceutical drug that contains CBD, and has been approved by the FDA to treat two severe forms of childhood epilepsy. However, currently the drug is prescribed to treat only Lennox-Gastaut syndrome and Dravet syndrome.
If you are looking to treat other kinds of seizures, including Complex Partial Seizures, there are several other CBD infused products available in the market like CBDistellery’s CBD oil , that is made with organically grown hemp and can be used to treat your condition.
To sum up, there is sufficient evidence that suggests that CBD products can be beneficial in treating and managing seizures and epilepsy, including Complex Partial Seizures. To choose the best course of treatment for yourself, it is recommended that you consult your doctor and get an accurate diagnosis of your condition. Only after you are diagnosed by a qualified medical practitioner, you should start to look for treatment options.
CBD has proven to be an effective and a natural treatment to several ailments, especially epilepsy. It may successfully aid in relieving the symptoms of Complex Partial Seizures.
Cannabis, Cannabidiol, and Epilepsy
A new frontier brings new questions and old dilemmas.
M. Scott Perry, MD; and Adrian L. Turner, PharmD
As early as 12,000 BCE, texts from central Asia reported human use of cannabis for nonmedical indications including ropes, fibers, and cloth. Ancient Chinese manuscripts from approximately 10,000 years later give the first documented use of cannabis for medical purposes. 1 Other early reports from ancient Mesopotamia, Persia, and India describe cannabis use for indications such as spasticity, depression, anxiety, and epilepsy. 1,2
Cannabis for medicinal purposes was not scientifically studied until the 19th century. In 1840, William O’Shaughnessy documented efficacy of cannabis for treating babies with infantile convulsions and studied cannabis’s effect in patients with epilepsy, spasticity, and arthritis. Cannabis and its various components, namely δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have continued to be researched. 3 In recent years, use of CBD for treating patients with refractory epilepsies has come to the forefront, increasing research and resulting in the first Food and Drug Administration (FDA)-approved CBD-based medication for patients with epilepsy.
With this new frontier in modern medicine, practitioners are faced with new questions and old dilemmas. Use of medical marijuana and CBD are becoming increasingly common, but there is still much to be discerned in the realm of evidence-based medicine. Several recent randomized controlled trials of CBD have shown efficacy in a standardized, controlled manner allowing the data to be adjudicated scientifically and applied practically. With solid data for physicians to justify therapeutic plans that include CBD, the horizons for our patients with epilepsy have expanded. Practitioners, then, must also look to the horizon and expect unforeseen hurdles before the place for CBD is ultimately found. Furthermore, CBD is one cannabinoid amongst more than 100 within the cannabis plant. We can expect subsequent research to broaden the indications and availability of other cannabis-based compounds in the future.
Mechanism of Action
The endocannabinoid system, which may play a role in epileptogenesis, includes 2 G-protein coupled receptors (cannabinoid type 1 [CB1] and cannabinoid type 2 [CB2]) and 2 endogenously synthesized, lipid-signaling endocannabinoids (anandamide [N-arachidonyl ethanolamide] and 2-arachidonoyl glycerol [2-AG]) that bind to CB1 and CB2. A presynaptic receptor, CB1 is highly expressed in the hippocampus, amygdala, cingulate, cerebral cortex, basal ganglia, midbrain, and medulla. Therapeutic effects of CB1 binding are via modulation of neurotransmitter release, including dopamine, GABA, glutamine, serotonin, norepinephrine, and acetylcholine. Concentrated in peripheral immune tissues (i.e. spleen, bone marrow, B-cells, macrophages), CB2 receptors have limited expression in the brainstem and hippocampus. In the context of seizures and epilepsy, although it seems CB1 would be a likely target, that does not appear to be the case.
Cannabis contains more than 100 unique compounds called phytocannabinoids, which are quite similar to lipophilic endocannabinoids—differentiated only by the origin of synthesis (ie, plants). The 2 primary phytocannabinoids are THC and CBD. 3,5 A direct agonist of the CB1 and CB2 receptors, the psychoactive effect of THC is secondary CB1 activation. There are mixed reports of seizure treatment success and seizure exacerbation. 3,5 Unlike THC, CBD does not directly agonize CB1 receptors and subsequently is not psychoactive. Some believe this is a benefit as it may have less potential for abuse. CBD’s mechanism of action is not fully elucidated yet and appears to be related to its effects on serotonergic and GABAergic activity, intracellular calcium modulation, and potential anti-inflammatory effects. CBD is highly lipophilic and becomes distributed in the brain rapidly. 3-6
Much remains to be ascertained regarding cannabis and its precise mechanism(s) of action in epilepsy. Evidence suggests that in addition to THC and CBD other components of cannabis may have anticonvulsant properties (eg, δ-9-tetrahydrocannabivarin [THCV], cannabidivarin [CBDV], δ-8-tetrahydrocannabinol [δ-8-THC], and cannabinol [CBN]. 4 Only time and additional scientific effort will help discern their potential as medications.
Reports of Therapeutic Efficacy
There are a handful of notoriously refractory epilepsy syndromes for which CBD has reported efficacy; most frequently cited are Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), with the most scientifically rigorous data coming from studies of pharmaceutical-grade CBD (Epidiolex, Greenwich Biosciences, Carlsbad, CA) (Table 1).
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In clinical trials, pharmaceutical-grade CBD treatment (20 mg/kg/day) of pediatric patients with DS had a statistically significant reduction in the number of convulsive seizures per month (-38.9%, 12.4 seizures/month to 5.9 seizures/month) compared to those treated with placebo (-13.3%-14.9
seizures/month to 14.1 seizures/month, P = .01). 7 Notably, 8 patients dropped out of the treatment arm due to side effects compared to only 1 patient in the placebo group. Overall, most side effects were well tolerated. The majority of caregivers (62%) reported an overall improvement for children receiving pharmaceutical-grade CBD compared to that seen by parents of children given placebo (34%) (P = .02). This is significant both clinically and statistically as positive perception may positively affect patient outcomes .7
In a similar study of children and adults with LGS, patients were treated with pharmaceutical-grade cannabidiol at doses of 10 mg/kg/day or 20 mg/kg/day. Both groups of patients treated had larger reductions in drop seizures (37.2% fewer [P = .002] and 41.9% fewer [P = .05], respectively) compared to patients given placebo (17.2% fewer). 8 These studies served as the basis for submission and ultimate approval by the FDA of pharmaceutical-grade CBD.
A multicenter, open-label, prospective study examined the use of pharmaceutical-grade CBD as an adjunctive treatment for 55 patients with other treatment-resistant epilepsy syndromes (eg, Aicardi’s, Dup15q, and Doose’ syndromes). 9 Pharmaceutical-grade CBD appeared not only to be well tolerated (27% withdrawal rate), but also efficacious. Patients experienced statistically significant decreases in convulsive seizures per month after 12 weeks; this was sustained through week 48 of the study. 9
In an open-label trial without a placebo arm for treatment of patients with refractory seizures in tuberous sclerosis complex (TSC), patients treated with pharmaceutical-grade CBD had a 50% response at the 3-month interval and largely maintained this through month 12. The largest effects were seen for tonic-clonic seizures (-91.4%), spasms (-87.5%), and atonic seizures (-86.5%); complex partial seizures with secondary generalization showed less response (-38.6%). Side effects were similar to previous reports (ie, drowsiness, ataxia, diarrhea). 10 An ongoing double-blind, placebo-controlled trial of pharmaceutical-grade CBD for patients with refractory seizures in TSC has completed enrollment and is in the data collection stage.
A large analysis of expanded access to pharmaceutical-grade CBD included 607 patients and 25 institutions. 11 Of these patients, 76% continued treatment at a mean of 48 weeks. Of those who discontinued therapy, 15% withdrew because of lack of efficacy and 5% withdrew due to adverse effects. With adjunctive CBD therapy, the number of median monthly convulsive seizures was reduced by 51% at 12 weeks and this was largely sustained through 96 weeks. Likewise, the total number of seizures per month was reduced by 48% at 12 weeks and similarly sustained through 96 weeks. 11
Many other studies examining both artisanal and pharmaceutical-grade CBD show efficacy in patients with LGS, DS, and convulsive and atonic type seizures (Table 2). 12-14 Current data strongly support that pharmaceutical-grade CBD is efficacious for seizures classified as convulsive or drop type. Data are lacking for nonconvulsive seizures, which are more difficult to quantify; the studies discussed in this article were not designed to assess this endpoint.
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The majority of studies described in this article involve a single, standardized formulation of CBD created with cannabis grown and CBD extracted under extremely strict conditions, as would be required for any drug approved for human consumption. These processes create a reliable amount of highly concentrated CBD (
99.7%) from batch to batch to ensure purity, safety, and efficacy claims of the product.
There are a number of artisanal CBD products available from dispensaries and online retailers, many touting their efficacy for epilepsy and other conditions. Unlike the recently FDA-approved formulation, artisanal CBD products are considered supplements and do not have the same regulatory oversight. As a result, these products cannot be labeled to state claims of health benefit. The consumer must be aware these products may vary widely in contents and purity. A study examined the accuracy of CBD labeling on artisanal products and found that of 84 different CBD extracts reviewed. 26 (
31%) were accurate, 36 (
42%) were underlabeled (exceeded value by more than 10%) and 23 (
25%) were overlabeled (actual content at least 10% below reported value). 15
This is not to say that artisanal cannabis products may not be efficacious for epilepsy. Practitioners simply need to be aware of the differences. Although there is good evidence for safety and efficacy of CBD, many artisanal products may contain high amounts of other cannabinoids for which research is lacking. Consequently, patient response and potential adverse effects are unknown and should be taken into consideration when discussing the risks and benefits of this type of therapy.
Dosing and Monitoring Considerations
The recommended starting dose of pharmaceutical-grade CBD is 2.5 mg per kg twice daily to be titrated up weekly intervals to a maintenance dose of 10 mg/kg/day and a maximum of 20 mg/kg/day. 16 Research supports this, and some even suggests doses of up to 50 mg/kg/day, 11,17 while acknowledging that with increased dosing there is an increased risk of side effects. In a study of patients with DS who were randomized to receive 5, 10, or 20 mg/kg/day of pharmaceutical-grade CBD, or placebo, 32 of 34 patients tolerated the drug and completed treatment, although higher doses were associated with a proportional increase in side effects. 17 Based on this report and other trials, doses of 5 to 20 mg/kg/day appear to balance efficacy with risks for potential side effects.
In the study that included 607 patients at 25 centers, 88% experienced some sort of side effect. 11 Severe side effects were reported in 33% of patients, the most common being convulsion (9%), status epilepticus (7%), pneumonia (5%), and vomiting (3%). Milder side effects included somnolence, fatigue, diarrhea, and reduced appetite. 11 Other reports validate these findings and report statistically significant instances of somnolence, decreased appetite, fatigue, and diarrhea in patients receiving pharmaceutical-grade CBD. More specifically, somnolence occurred in 22% to 36% of patients, diarrhea in 29% to 31%, decreased appetite in 20% to 28%, and fatigue in 20% to 22%. 7-9 Other notable side effects include convulsion, respiratory tract infections, weight loss, status epilepticus, irritability, and pyrexia, which appear to be dose-related and can be therapy-limiting. 7-9,11
Hepatotoxicity has emerged as an adverse effect of CBD treatment of particular concern. Many antiepileptic drugs (AEDs) carry some risk of hepatotoxicity, but with a clear monitoring plan, this concern could be reduced. The manufacturer of pharmaceutical-grade CBD recommends discontinuation if liver function test (LFT) levels rise to 3 times the upper limit of normal (ULN) and bilirubin levels are twice or more the ULN. 16 If patients experience sustained LFT elevation more than 5 times the ULN, CBD treatment should be discontinued. Elevation of LFTs appears to be most common in the first 2 months of treatment but has also been observed in later stages of treatment. Liver monitoring is recommended at months 1, 3, and 6 after initiating treatment with pharmaceutical-grade CBD or monthly after dose changes or addition of another AED that interacts with CBD. 16
The hepatotoxicity risk of pharmaceutical-grade CBD appears to be more common if there is polypharmacy with valproic acid products or clobazam, although LFT elevation has also been shown to occur without these concomitant drugs. 17-19 Some have postulated that interaction with liver enzymes may contribute to the positive therapeutic effects seen in clinical trials of pharmaceutical-grade CBD. 13,20,21 There are several other pertinent interactions to consider when implementing CBD treatment for patients with epilepsy. Varying reports of alterations in serum concentration of rufinamide, topiramate, zonisamide, and eslicarbazepine have also been noted. 17,18 Topiramate and rufinamide both appear to have dose-related increases in serum concentrations in the presence of CBD whereas the serum increases of zonisamide and eslicarbazepine were present to a lesser extent. 17,18, 20
It is likely many of the discussed interactions are related to the effect of CBD on CYP enzyme activity. Strong CYP3A4 or CYP2C19 inhibitors and inducers appear to increase and decrease CBD serum concentrations, respectively. 16 It is wise for practitioners to be especially careful when initiating CBD in patients with epilepsy on concomitant valproic acid or clobazam because these combinations could put patients at a higher risk for hepatotoxicity, drug interactions, and secondary side effects related to subsequent toxicity (eg, sedation, decreased efficacy, and breakthrough seizures). Close monitoring may be encouraged or even required.
Legal and Financial Considerations
In the context of CBD and its role in medicine in the US, approval of pharmaceutical-grade CBD represents a paradigm shift. Alone, CBD has no schedule designation, but as a component of marijuana, it has been listed as a schedule I drug—defined by the Drug Enforcement Administration (DEA) as a substance having high potential for abuse with no medical efficacy. 3 Now that the FDA has approved a CBD product for medicinal use, it is inherently assumed CBD does, indeed, have medical efficacy and requires rescheduling. This will occur imminently in the US prior to expected release of pharmaceutical-grade CBD in late 2018. How this will affect the legality of artisanal CBD products is less clear, as many may contain unacceptable amounts of THC and other cannabinoids which are likely to remain schedule I until there is more evidence for safety and efficacy. Cannabis law varies widely across the US from state to state, further complicating procurement for patients choosing not to use the FDA-approved product.
CBD and marijuana laws vary internationally as well. Several countries allow utilization of cannabis for medical purposes, but the cultivation and possession of marijuana for recreational use remains largely illegal. In the United Kingdom, once pharmaceutical-grade CBD is approved, lawmakers plan to re-examine current laws to allow for legal utilization of this CBD product. 22 Similar to patients in the United States, those in the United Kingdom and Europe will likely gain increased access to CBD as a legitimate treatment option in the near future.
The cost of treatment is another factor that warrants discussion. Currently, CBD oils procured from dispensaries are not covered by health insurance as they lack accepted evidence of efficacy. These oils may place a burden of $100-$600 per month depending on the patient’s dose which often is lower than that shown effective in the placebo-controlled trials. 23 If doses are titrated similarly to those trials, costs often approach $1,500-$3,000 per month for an average-sized adult. Pharmaceutical-grade CBD will likely be covered by insurance for indicated patients based on FDA approval with the average estimated cost of $32,000 per year without insurance. 24
Cannabis and CBD have a long history of use for medical purposes throughout human history. Until recently, standardized studies with large datasets have been lacking. Now, with the change in social climate and attitude towards the potential of cannabis and CBD, data are amassing to provide much-needed insight into the practical application of CBD in patients with seizures and epilepsy.
In patients with refractory epilepsy syndromes—especially in those characterized by convulsive and “drop attack” seizures—CBD is a promising adjunctive alternative treatment. More studies are needed to determine the exact mechanism of therapeutic efficacy (ie direct antiepileptic target vs. optimization of concomitant medications), but in the meantime appears to be reasonably safe and efficacious.
Practitioners still must be cognizant of individual patient factors because CBD is not a benign entity. Vigilance for concomitant hepatotoxic antiepileptics, potential interactions, and side-effects must be maintained and cost and variability between different formulations considered. New options are on the horizon and expanding potential medical treatment with CBD. Governmental acceptance of a CBD-based product is helping to open doors for many families and patients with previously limited options. The CBD safety and efficacy profiles combined with the great need for better treatment options in refractory epilepsy make this a promising therapy for patients and practitioners alike. We are likely experiencing the first among many therapies to be derived from the cannabis plant in the coming years.
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MSP has received honorarium for consulting from Compassionate Cultivation and serves as the site PI for several phase III studies of cannibidiol sponsored by Greenwich Biosciences. The authors have no other financial or other relationships or conflicts to disclose.
M. Scott Perry, MD
Jane and John Justin Neurosciences Center
Cook Children’s Medical Center
Fort Worth, TX