Conclusion (the bottom line)
Cannabidiol has a wide range of biologic effects with multiple potential sites of action in the nervous system. Preclinical evidence for antiseizure properties and a favorable side-effect profile support further development of CBD-based treatments for epilepsy. Activity in models of neuronal injury, neurodegeneration, and psychiatric disease suggest that CBD may also be effective for a wide range of central nervous system disorders that may complicate the lives of individuals with epilepsy; a treatment for both seizures and comorbid conditions is highly desirable. Decades of prohibition have left cannabis-derived therapies in a legal gray area that may pose challenges for the evaluation and clinical development of CBD-based drugs for epilepsy and other disorders. However, a growing acceptance of the potential benefits of cannabis-derived treatments in many countries may ease the regulatory and bureaucratic path for clinicians and scientists to conduct well-designed studies of CBD. Much remains to be learned about CBD even as investigation moves into humans: We do not fully understand the targets through which this pleiotropic compound produces its antiseizure effects. Identifying these targets may also yield important insights into the mechanisms of seizures and epilepsy.
CBD for Dravet and Lennox-Gastaut Syndromes
Several countries and U.S. states have liberalized their laws to allow individuals to access cannabis for medicinal use. Because of the historical and limited preclinical and clinical evidence for the efficacy of cannabinoids in general and CBD specifically, many patients have turned to medical marijuana when traditional AEDs have failed due to lack of efficacy or intolerable side effects. Perhaps most desperate of all for new therapies have been parents of children with severe early life epilepsy. Accounts of dramatic improvements with cannabis-based products with high CBD:Δ9-THC (e.g., >20:1) ratios in the popular press have sparked a serious interest among epilepsy clinicians in pursuing the rigorous, scientific study of CBD. The use of cannabinoid-based therapies for the treatment of spasticity, pain, and anorexia has demonstrated to clinicians and pharmaceutical companies that it is possible to develop and commercialize cannabinoids for human disease. Exploring CBD treatments in populations that are increasingly turning to cannabis-based epilepsy therapies because of a lack of therapeutic alternatives and given that the lack of THC reduces the potential for adverse effects, this a promising avenue for clinical development. Preclinical testing in recently developed murine models of Dravet syndrome could provide further support for the efficacy of CBD in this condition.
Planned trials for CBD in Dravet and Lennox–Gastaut syndromes
Among children with treatment-resistant epilepsy, those with early onset and severe epilepsies such as Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) have the greatest neurodevelopmental problems, including intellectual disability and autism. In DS, which most often results from mutations in the SCN1A gene, healthy, developmentally normal children present in the first year of life, usually around 6 months, with convulsive status epilepticus (SE) frequently triggered by fever. Further episodes of SE, hemiclonic or generalized, tend to recur and, after the first year of life, other seizure types develop, including focal dyscognitive seizures, absences, and myoclonic seizures. Seizures in DS are usually refractory to standard AEDs and, from the second year of life, affected children develop an epileptic encephalopathy resulting in cognitive, behavioral, and motor impairment. Outcome is generally poor, with intellectual disabilities and ongoing seizures in most patients.
Thus early and effective therapy for DS is crucial. More effective early control of epilepsy is associated with better developmental outcomes in children today than those who were treated 20–30 years ago. Currently, doctors know to avoid drugs that can worsen seizures (e.g., carbamazepine and lamotrigine) and to prescribe effective drugs (e.g., valproic acid, clobazam, topiramate, stiripentol) or dietary therapies (ketogenic or modified Atkins diet) earlier in the disease course. Stiripentol (STP) is the only compound for which a controlled trial has been performed in DS, and it has showed a high rate of responders (71% responders on STP versus 5% on placebo). Stiripentol was awarded Orphan Drug Designation for the treatment of DS by the European Medicine Agency (EMA) in 2001 and by the U.S. Food and Drug Administration (FDA) in 2008.
LGS is a rare but devastating childhood epilepsy syndrome that can result from diverse etiologies, including structural, metabolic, and many genetic disorders; in many cases the cause is unknown. LGS presents in children ages 1 to 8 years; in most cases, onset is between the ages of 3 and 5 years. Most patients with LGS experience multiple refractory seizures every day despite multiple AEDs and nonpharmacologic treatment including ketogenic diet, vagus nerve stimulation, and epilepsy surgery. The prognosis remains poor with current therapies. Morbidity is significant: Head injuries are common, so that patients often must wear helmets; some patients have even become wheelchair-bound as a result of violent drop attacks.
Effective treatments for both DS and LGS are needed. A recent U.S. survey of 19 parents, 12 of whom had children with DS, explored the use of CBD-enriched cannabis therapy. Of the 12 DS parental respondents, 5 (42%) reported a >80% reduction in seizure frequency. A single LGS parent responded and reported a >80% reduction in seizure frequency. Overall, parents reported improved alertness and lack of side effects apart from fatigue and drowsiness in some children. This may have been related to clinically significant levels of THC in some cannabis preparations used.
Patients with DS and LGS are potentially good candidates for a CBD trial given the need for more effective and better-tolerated therapies for these epilepsies, the high rate of seizure frequency, and the relative homogeneity of the specific syndromes. Several of the authors are currently initiating a study to determine the tolerability and optimal dose of CBD in children with DS and LGS. Inclusion criteria include a definite epilepsy syndrome diagnosis, ongoing seizures despite having tried two or more appropriate AEDs at therapeutic doses, and at least two seizures per week. To help improve the accuracy of seizure frequency reporting, seizures will be recorded with video–electroencephalography (EEG) to ensure that the seizure types documented by parents are confirmed by epileptologists. This is particularly important, since these syndromes may include some seizure types that are difficult to identify (e.g., atypical absence) or quantify (e.g., eyelid myoclonias); these will not be used as countable seizure types in the planned studies. We will focus attention on the most disabling seizure types: tonic, atonic, and tonic–clonic seizures. Based on the information obtained from these dose tolerability studies, we will then plan subsequent randomized, placebo-controlled, double-blind studies in DS and LGS. The ultimate goal is to determine whether CBD is effective in treating these epilepsies, with the hope of improving seizure control and quality of life. Although initial studies have been planned to focus on these severe childhood-onset epilepsies, there is no reason to believe based on available evidence that CBD would not be effective in other forms of treatment-resistant epilepsy.
Cannabidiol and related compounds
CBD is the only non–∆9-THC phytocannabinoid to have been assessed in preclinical and clinical studies for anticonvulsant effects. In mice, CBD blocked MES-induced seizures in one study but had no effect on pentylenetetrazol (PTZ)–induced or MES-induced seizures in another. However, given the routes of administration used, the lack of efficacy in the latter study may reflect inadequate CBD levels, since several other reports (see subsequent text) have found CBD to be effective against both PTZ-induced and MES-induced seizures.
The anticonvulsant effects of CBD, ∆9-THC, and other cannabinoids were also compared using a variety of standard seizure models by Karler and Turkanis. Significant anticonvulsant effects against the MES test in mice were found for the following cannabinoids (approximate effective dose (ED50) values in parentheses): CBD (120 mg/kg), ∆9-THC (100 mg/kg), 11-OH-∆9-THC (14 mg/kg), 8β- but not 8α-OH-∆9-THC (100 mg/kg), ∆9-THC acid (200–400 mg/kg), ∆8-THC (80 mg/kg), cannabinol (CBN) (230 mg/kg), and ∆9-nor-9α- or ∆9-nor-9β-OH-hexahydro CBN (each 100 mg/kg). More recently, CBD has been shown to have antiepileptiform and anticonvulsant effects in in vitro and in vivo models. In two different models of spontaneous epileptiform local field potentials (LFPs) in vitro, CBD decreased epileptiform LFP burst amplitude and duration. CBD also exerted anticonvulsant effects against PTZ-induced acute generalized seizures, pilocarpine-induced temporal lobe convulsions, and penicillin-induced partial seizures in Wistar-Kyoto rats.[34, 35]
Despite the convincingly anticonvulsant profile of CBD in acute models of seizure, there is less preclinical evidence for CBD’s effects in animal models of chronic epilepsy. CBD exerted no effect on focal seizure with a secondary generalization produced by cobalt implantation, although ∆9-THC had a time-limited (~1 day) anticonvulsant effect. Model-specific effects were evident for CBD, which was effective in the MES and all of the γ-aminobutyric acid (GABA)–inhibition-based models, but was ineffective against strychnine-induced convulsions. CBD has also been shown to increase the afterdischarge threshold and reduce afterdischarge amplitude, duration, and propagation in electrically kindled, limbic seizures in rats.
As mentioned previously, CBDV, the propyl variant of CBD, also has significant anticonvulsant properties. Using the same in vitro models of epileptiform activity described earlier, CBDV attenuated epileptiform LFPs and was anticonvulsant in the MES model in ICR mouse strain mice and the PTZ model in adult Wistar-Kyoto rats. In the PTZ model, CBDV administered with sodium valproate or ethosuximide was well tolerated and retained its own additive anticonvulsant actions. It also retained efficacy when delivered orally. In contrast, although CBDV exerted less dramatic anticonvulsant effects against pilocarpine-induced seizures, it acted synergistically with phenobarbital to reduce seizure activity. CBDV exerts its effects via a CB1-receptor-independent mechanism.
The mechanisms by which CBD and CVDV exert their antiseizure effects are not fully known, although several of the potential targets of cannabidiols described earlier may be involved. Via modulation of intracellular calcium through interactions with targets such as TRP channels, G-coupled protein receptor protein 55 (GPR55), or voltage-dependent anion-selective channel protein 1 (VDAC1), CBD and related compounds may reduce neuronal excitability and neuronal transmission. Alternatively, the antiinflammatory effects of cannabidiol, such as modulation of tumor necrosis factor alpha (TNFα) release, or inhibition of adenosine reuptake may also be involved in antiictogenesis. Careful pharmacologic studies are needed to further delineate mechanisms.
Of the plant cannabinoids that have been identified, few have been investigated beyond early screening for affinity or activity at CB receptors. ∆9-THCV, a propyl analog of ∆9-THC, is a neutral antagonist at CB1 receptors. ∆9-THCV exerts some antiepileptiform effects in vitro and very limited anticonvulsant effects in the PTZ model of generalized seizures. Synthetic CB1-receptor antagonists/inverse agonists have also been investigated in some models of acute seizure and, although partial or full CB1 agonism produces largely anticonvulsant effects, neutral antagonism has very limited effects on seizure, and inverse agonism has either no effect or a limited proconvulsant effect (see Table 2). Finally, CBN exerted no effect upon chemically or electrically induced seizures in mice .
Cannabidiol Pharmacology in Humans
Studies of synthetic CBD and plant extracts, either isolated or in combination with ∆9-THC, have likely provided sufficient human data on the pharmacology of CBD to proceed with dosing and efficacy trials for epilepsy. There are multiple potential routes of administration for CBD. The most common delivery form for CBD the inhaled route as a constituent of smoked cannabis used for recreational or medicinal purposes. This approach is obviously unsuitable for medicinal drug delivery but highlights the fact that the lungs are a very efficient mechanism for drug delivery. Studies that have examined delivery of CBD through aerosolization or vaporization using specialized devices have reported rapid peak plasma concentrations (<10 min) and bioavailability of ~31%, although such an approach is limited by the need for specialized equipment and patient cooperation with administration.
CBD has been delivered orally in an oil-based capsule in some human trials. Because of low water solubility, absorption from the gastrointestinal system is erratic and leads to variable pharmacokinetics. Bioavailability from oral delivery has been estimated at 6% due to significant first-pass metabolism in the liver. Oral-mucosal/sublingual delivery through sprays/lozenges has bioavailability similar to the oral route but less variability. Most of the data for oral-mucosal delivery comes from studies of nabiximols oral spray, which is a mixture of ~1:1 ∆9-THC and CBD. Serial measurement of serum CBD levels in healthy volunteers after a single dose of nabiximols containing 10 mg each of CBD and THC has demonstrated a maximum concentration (Cmax) of 3.0 ± 3.1 μg/L and maximum time (Tmax) of 2.8 ± 1.3 h. Transdermal approaches to CBD delivery have also been investigated, but due to CBD’s high lipophilicity, special ethosomal delivery systems are needed to prevent drug accumulation in the skin, which are impractical and costly at this time.
The distribution of CBD is governed by its high lipophilicity (Koctanol-water ~6-7), and a high volume of distribution (~32 L/kg) has been estimated, with rapid distribution in the brain, adipose tissue, and other organs. CBD is also highly protein bound, and ~10% is bound to circulating red blood cells. Preferential distribution to fat raises the possibility of accumulation of depot in chronic administration, especially in patients with high adiposity.
Metabolism and elimination
Like most cannabinoids, CBD is metabolized extensively by the liver, where it is hydroxylated to 7-OH-CBD by cytochrome P450 (CYP) enzymes, predominantly by the CYP3A (2/4) and CYP2C (8/9/19) families of isozymes. This metabolite then undergoes significant further metabolism in the liver, and the resulting metabolites are excreted in the feces and to a much lesser extent in the urine. The terminal half-life of CBD in humans is estimated at 18–32 h, and following single dose administration in chronic cannabis users, the clearance was 960–1,560 ml/min.
Safety in humans
Multiple small studies of CBD safety in humans in both placebo-controlled and open trials have demonstrated that it is well tolerated across a wide dosage range. No significant central nervous system side effects, or effects on vital signs or mood, have been seen at doses of up to 1,500 mg/day (p.o.) or 30 mg (i.v.) in both acute and chronic administration. Limited safety data exist for long-term use in humans, although there have been many patient-years of exposure to nabiximols following approval in many European countries and Canada. There is some theoretical risk of immunosuppression, as CBD has been shown to suppress interleukin 8 and 10 production and to induce lymphocyte apoptosis in vitro.[51, 52]
It should be noted that the above studies were performed in adults. The pharmacokinetics and toxicity of CBD in children is not well understood.
Few data exist regarding drug interactions with CBD in humans, although there are some theoretical concerns that could have implications for its use in people with epilepsy (PWE). CBD is a potent inhibitor of CYP isozymes, primarily CYP2C and CYP3A classes of isozymes, in vitro and in animal models. This is particularly important because many medications are substrates for CYP3A4. However, inhibition has typically not been observed at concentrations used in human studies.
Repeated administration of CBD may induce CYP2B isozymes (CYP2B1/6) in animal models, which may have implications for PWE, because antiepileptic drugs (AEDs) such as valproate and clobazam are metabolized via these isozymes. Finally, because CBD is metabolized in a large part by CYP3A4, it is likely that common enzyme-inducing AEDs such as carbamazepine and phenytoin could reduce serum CBD levels.
CBD Oil and Epilepsy Studies
- CBD for children with Dravet’s and intractable seizures (Video)
- Hypnotic and antiepileptic effects of CBD
- The cannabinoids as potential antiepileptics
- Cannabidiol–antiepileptic drug comparisons and interactions in experimentally induced seizures in rats
- channels in vitro: potential for the treatment of neuronal hyperexcitability
- Chronic administration of CBD to healthy volunteers and epileptic patients
- Endocannabinoid system protects against cryptogenic seizures
- CBD Post-Treatment Alleviates Rat Epileptic-Related Behaviors
- Pharmacology of cannabinoids in the treatment of epilepsy
- Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection
- Report from a Survey of Parents Regarding the Use of Cannabidiol in Mexican Children with Refractory Epilepsy.
- Protective Effects of Cannabidiol against Seizures and Neuronal Death in a Rat Model of Mesial Temporal Lobe Epilepsy
- CBD Treatment for Refractory Seizures in Sturge-Weber Syndrome
- Report of a parent survey of CBD-enriched cannabis use in pediatric treatment-resistant epilepsy
- Medicinal marijuana stops seizures, brings hope to a little girl
- Cannabinoids for epilepsy
- Cannabis, CBD, and epilepsy – From receptors to clinical response
- The non-psychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1)
- Seizing an opportunity for the endocannabinoid system
- Cannabidiol: promise and pitfalls
- Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatricdisorders
- Report of a parent survey of cannabidiol-enriched cannabis use in pediatrictreatment-resistant epilepsy
- From the Editors: Cannabidiol and medical marijuana for the treatment of epilepsy
- Cannabidivarin (CBDV) suppressespentylenetetrazole (PTZ)-inducedincreases in epilepsy-related gene expression
- CBD exerts anti-convulsant effects in animal models of temporal lobe and partial seizures
- Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo