Cannabidiol: Promise and Pitfalls
Over the past few years, increasing public and political pressure has supported legalization of medical marijuana. One of the main thrusts in this effort has related to the treatment of refractory epilepsy—especially in children with Dravet syndrome—using cannabidiol (CBD). Despite initiatives in numerous states to at least legalize possession of CBD oil for treating epilepsy, little published evidence is available to prove or disprove the efficacy and safety of CBD in patients with epilepsy. This review highlights some of the basic science theory behind the use of CBD, summarizes published data on clinical use of CBD for epilepsy, and highlights issues related to the use of currently available CBD products.
Cannabidiol is the major nonpsychoactive component of Cannabis sativa. Over the centuries, a number of medicinal preparations derived from C. sativa have been employed for a variety of disorders, including gout, rheumatism, malaria, pain, and fever. These preparations were widely employed as analgesics by Western medical practitioners in the 19 th century (1). More recently, there is clinical evidence suggesting efficacy in HIV-associated neuropathic pain, as well as spasms associated with multiple sclerosis (1).
Basic Pharmacological Mechanisms
Cannabidiol pharmacological effects are mediated through G protein coupled receptors, cannabinoid type I (CB1) and cannabinoid type II (CB2), which are highly expressed in the hippocampus and other parts of the central nervous system (2). When activated, CB1 receptors inhibit synaptic transmission through action on voltage-gated calcium and potassium channels, which are known to modulate epileptiform and seizure activity (3). CB2 receptors are primarily expressed in the immune system and have limited expression in the central nervous system. The effects of CBD are CB2 receptor independent (3).
Studies have demonstrated that CBD has a low affinity for the CB1 receptors, but even at low concentrations, CBD decreases G-protein activity (3). CB1 receptors are expressed on many glutamatergic synapses that have been implicated in seizure threshold modulation. CBD may act at CB1 receptors to inhibit glutamate release (4). Studies have shown changes in the expression of CB1 receptors during epileptogenesis and after recurrent seizures (5). CB1 receptor expression is upregulated at GABAergic synapses and shown to be downregulated at glutamatergic synapses in epilepsy, contributing to lowering seizure thresholds.
Other targets for CBD include transient receptor potential (TRP) channels that are involved with the modulation of intracellular calcium (1, 6). Cannabinoids are highly lipophilic, allowing access to intracellular sites of action, resulting in increases in calcium in a variety of cell types including hippocampal neurons. CBD actions on calcium homeostasis may provide a basis for CBD neuroprotective properties.
Evidence in Animal Models
When administered alone, CBD is an effective anticonvulsant in maximal electrical shock (MES), magnesium-free, 4-aminopyridine, and audiogenic models (7, 8). Co-administration with AEDs leads to various effects; anticonvulsant effects of CBD are enhanced with phenytoin or phenobarbital but decreased with chlordiazepoxide, clonazepam, trimethadione, and ethosuximide. In a recent study using an acute pilocarpine model, although CBD administration reduced the number of animals displaying seizure activity, CBD did not appear to have any significant effect on the number of seizures per animal (7).
Clinical Evidence in Epilepsy
While animal experimental data clearly suggest a potential benefit, supportive clinical data are quite sparse. In a case-control study of 308 cases of new onset seizures, Brust and colleagues found that marijuana use was significantly less prevalent among men who had unprovoked seizures compared to case controls (9). This difference was not significant in women. The authors suggest a potential protective effect against seizures with marijuana use; however, this should be considered speculative.
A survey of patients seen in a tertiary epilepsy center found that 21% of patients admitted to using marijuana in the last year, and 24% of patients believed marijuana to be effective for their seizures (10). While interesting, this anecdotal observation does not rise to the level of evidence needed to evaluate a potential new therapeutic modality.
Gloss and Vickrey conducted a Cochrane systematic review of the use of CBD in the treatment of epilepsy (11). Their methodology included only those trials that were randomized and controlled and excluded case series, case reports, and expert opinion. They were able to identify only 4 randomized controlled studies reported in the literature, and they included a letter to the editor and an abstract. The total number of subjects enrolled in these studies was 48 (11–14). While only four studies and a letter to the editor were in the actual analysis, the authors included a complete reference listing of all articles reviewed for inclusion.
These reports suffered from a number of design flaws, including incomplete baseline quantification of baseline seizure frequency, indeterminate time periods for outcome determination and, in some cases, inadequate (or missing) statistical analysis—in general, a lack of sufficient detail to adequately evaluate and interpret the findings. Limitations aside, several studies did report that administration of adjunctive CBD did not result in meaningful changes in seizure frequency (11–13).
Cunha et al. reported a 2-phase pilot study of CBD versus placebo in normal volunteers and patients with refractory secondarily generalized epilepsy (14). In the first phase, 8 normal volunteers received CBD or placebo in a doubled-blind fashion, at a dose of 3 mg/kg for 30 days. The second phase was also double-blinded in 15 patients with epilepsy receiving 200 to 300 mg daily of CBD or placebo for 135 days. Patients continued baseline AED. All subjects tolerated CBD well, with no serious adverse events. Four of the epilepsy patients receiving CBD were “almost free of convulsive crisis” for the duration of the study. Three other patients receiving CBD had a partial reduction in seizures, and 1 subject had no response. Of the 7 patients receiving placebo, seizure frequency was unchanged in 6, and 1 had clear improvement in seizure control.
Using rigorous review methodology, Gloss and Vickery conclude that based on the low quality of the reports available, there is insufficient data available to draw any conclusions regarding the efficacy and or long-term safety of CBD in treating epilepsy (11). From the data available, it does appear that daily doses of 200 to 300 mg were safe in this small group of patients for a short period of time (14).
Tolerability and Drug Interactions
CBD is well tolerated in humans with doses up to 600 mg not resulting in psychotic symptoms (15). In the few small placebo-controlled studies performed, no significant CNS effects were noted. Oral CBD undergoes extensive first-pass metabolism via CYP3A4, with a bioavailability of 6%. Following single doses in humans, the half-life of CBD when taken orally is about 1 to 2 days.1 In vitro studies have shown that CBD is a potent inhibitor of multiple CYP isozymes, including CYP 2C and CYP3A (16, 17). Whether these in vitro observations are relevant at plasma concentrations likely to be seen in patients is unclear. In addition, given its metabolism via CYP3A4, clinical trials of CBD in patients receiving enzyme-inducing AEDs, such as carbamazepine or phenytoin, will require detailed pharmacokinetic studies.
A number of difficulties exist in evaluating published data on CBD or marijuana use for epilepsy. The extremely limited published studies were small, poorly described, and not well designed. Contributing to the difficulty of interpreting published studies, CBD products are not produced under the guidance of good manufacturing practices (GMP) and are not subject to regulations governing labeling, purity, and reliability. In other words, currently, there is no guarantee of consistency between products, or even differing lots produced by the same manufacturer. Without independent testing (e.g. USP certification) of CBD products for content and purity, as well as bioavailability testing of specific products, uncertainty surrounds the use of available CBD products in routine clinical settings.
At this time, there does seem to be a growing body of basic pharmacologic data suggesting there may be a role for CBD, especially in the treatment of refractory epilepsy. However, given the lack of well-controlled trials, we must also ask if we are getting ahead of ourselves. Clearly, this is an emotionally and politically charged issue. If this were any other uninvestigated pharmaceutical compound, would we feel as compelled to make the agent widely available before statistically valid class 1 evidence was available for review? Until data from well-designed clinical trials are available and reliable, and standardized CBD products that are produced using GMP are available, caution must be exercised in any consideration of using CBD for the treatment of epilepsy. In the meantime, based upon promising preliminary data, further clinical research should be wholeheartedly pursued.
CBD for Seizures- Use, Effectiveness, Side Effects, and More
If you have seizures or are the parent of a child who has seizures, then you are probably constantly on the lookout for ways to control seizures with as few side effects as possible. CBD oil is one of the latest things to be touted as a miracle cure for seizures. While its effects are not the miracle cure some people suggest, it is a promising treatment that might be right for you.
What is CBD?
CBD is short for cannabidiol, which is a chemical found in marijuana. It is not the same as tetrahydrocannabinol (THC), the chemical in cannabis that is responsible for the “high” feeling people get from marijuana.
What does CBD do?
Well, people make many claims about what CBD can do. Not all of them have been tested and verified. However, there is support for claims that CBD may help reduce pain and anxiety.
Does CBD help seizures?
The short answer is yes. CBD can help prevent some types of seizures in some people and animals. Clinical trials have demonstrated a significant reduction in seizures for people taking CBD to treat Lennox-Gastaut, Dravet syndrome, or tuberous sclerosis complex. Research in other areas is still in early stages, but there are indications that CBD may help prevent other types of seizure or increase the efficacy of other antiepileptic medications. Early clinical trials suggest that CBD may dramatically reduce seizures in people with CDKL5 deficiency disorder, Aicardi syndrome, Doose syndrome, and Dup15q syndrome. In addition, CBD appeared to retain its efficacy over the length of the clinical trial.
How does CBD help prevent seizures?
That is a wonderful question, but, unfortunately, the research simply is not sufficient to give a definitive answer. What we do know is that bodies contain natural neurotransmitters and receptors known as the endocannabinoid system. CBD is believed to interact with that system, which is believed to influence a range of bodily functions and systems including immune response, appetite, pain, and sleep.
Is CBD approved by the FDA to treat seizures?
Yes, but not all CBD oils and not all types of seizures. Currently, Epidolex, a prescription form of CBD, is approved to treat seizures caused by Lennox-Gastaut, Dravet syndrome, and tuberous sclerosis complex.
Does CBD interact with other seizure medications?
Yes. We know that CBD interacts with brivaracetam, clobazam, eslicarbazepine, stiripentol, rufinamide, topirimate, valproic acid, and zonisamide. It also possible that it interacts with other antiepileptics, and as research continues, we should have a better idea of other possible interactions.
How do I use CBD or CBD oil to treat seizures?
If you have a seizure disorder, you should be seeing a neurologist for treatment. It is very important to discuss whether you should use CBD oil with your neurologist. While it is generally safe to use, there is always a risk of potential drug interactions. In addition, some people actually experience an increase in seizures when they use CBD. Therefore, just like with any antiepileptic drugs, you want to have a professional monitoring your use of CBD.
What is an average clinical use of CBD to treat seizures?
The starting dose for CBD is 2.5 mg/kg of Epidolex, two times a day. A normal maintenance dosage is 5mg/kg twice daily, and the maximum dosage is 10mg/kg twice daily. As with other antiseizure medications, it should be introduced or stopped gradually, as sudden changes can increase seizure activity.
What are the potential side effects of CBD when used to treat seizures?
Whether used alone or with other seizure medications, there are some potential side effects of using CBD to treat seizures. It can lead to an increase in suicidal thoughts or behaviors, sleepiness, drowsiness, diarrhea, and loss of appetite. While most of these side effects are inconvenient, interactions can also cause liver damage.
Can CBD increase my seizures?
This is a tricky question to answer. Anecdotally, it seems clear that some percentage of people will have an increase in the number of seizures in response to using CBD. However, why is not so clear. Research seems to suggest that people who use commercial CBD products are likely to see an increase in seizures, while people using prescription CBD are likely to see a reduction in seizures. The speculation is that commercial products are not pure CBD, but are tainted with THC, which is known to be a potential seizure trigger.
Can I use over-the-counter CBD to treat epilepsy?
The problem with OTC CBD is that it is not regulated by the FDA. This makes it impossible to know what dose you would be getting, if the product is contaminated with impurities, or if it even is CBD. If you want to explore using CBD to treat seizures, talk with your doctor about adding Epidolex, an FDA regulated product that eliminates the specific risks posed by an OTC product, to your treatment plan.