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Updated on April 7, 2023
Article Summary
Epilepsy often prevents individuals from living a normal life. Even with advanced interventions like vagus nerve stimulation via implanted medical devices, individuals are still liable to be wracked by unpleasant and frightening seizures at any time. If they occur frequently, then these seizures can preclude patients from driving, working, and living independently. Additionally, individuals with epilepsy are often left suffering under the burden of their therapy’s side effects and some side effects—like somnolence and fatigue—can often be just as debilitating as the seizures they are meant to prevent. Nonetheless, even therapies that fail to resolve symptoms to an adequate degree can provide some limited relief, so they continue to be utilized.
Today, however, a growing number of individuals are turning to a powerful therapy that has been proven effective in the context of treatment-resistant epilepsy: cannabidiol. Cannabidiol (CBD) is a chemical derived from the leaves of the hemp plant, which has a history of human use going back thousands of years. CBD has been the subject of intense scientific research owing to relatively recent discoveries that indicate that CBD has the potential to modulate neuronal activity. Significantly, researchers have found that CBD is not overtly psychoactive, unlike other constituents of the cannabis plant, most notably tetrahydrocannabinol (THC). Because CBD isn’t intoxicating or habit-forming, its ability to modulate neuronal activity makes it appealing to many people struggling with epilepsy.
Scientific investigations into CBD’s antiepileptic potential have quickly borne fruitful findings. With a recent systematic review of clinical trials claiming that 48 percent of participants exhibited a 50-percent reduction in the frequency of their seizures after CBD therapy, there is a strong base of evidence in favor of using CBD as an antiepileptic. If an individual is not experiencing remission of their seizures as a result of their current therapeutic regimen, then there is a very real chance they will benefit from trialing CBD therapy.
CBD’s impact on epilepsy is difficult to understand without being familiar with the neural basis of seizures. When neurons in the brain are activated by an electrochemical signal, the neurons transmit their own electrochemical signal to other neurons. The strength of the outgoing signal is dependent on the strength of the signal the neuron receives. Under normal conditions, neurons experience a brief refractory period after they have been activated. This prevents a neuron from repeatedly activating at full strength; subsequent re-activations will not produce as strong of an activation from the recipient neuron until it has recovered from prior activations. And even if a neuron is being over-activated, it is still regulated by other groups of neurons that will detect the over-activation and, subsequently, inhibit it. As a result, neurons normally do not become activated simultaneously, strongly, and repeatedly, even if they are in the same area of the brain and serve the same function.
Under the conditions of extreme over-activation, however, the normal safeguards are overwhelmed. Seizures are caused by the repeated synchronous strong activation of groups of neurons; when the neurons are activated strongly, simultaneously, and repeatedly, this activation cascades to the rest of the brain, temporarily overwhelming the inhibitory circuits. The wave of synchronized over-activation displaces the normal patterns of activation responsible for maintaining homeostasis, disrupting function. Eventually, this cascade arrives at one of the brain’s areas responsible for the visible signs of seizures, typically in the temporal lobes. The activation in these areas can then cause the motions and muscle clenching associated with seizures.
To control seizures, CBD molecules inhibit neuron activation by binding to two of the cannabinoid receptors, CB1 and CB2. Although the mechanism by which binding of CB1 and CB2 inhibit neuronal activation is still under study, researchers believe CBD enables neurons to control their level of calcium, which is necessary for neuronal activation. Rather than simply decreasing the level of intracellular calcium, researchers found that CBD improves the ability of neurons to sequester excess calcium, as well as also their ability to access stored calcium when deficient. Because neurons can’t activate as strongly or as quickly with a modulated calcium balance, the inhibitory neural circuits remain in control, and normal patterns of activation can persist.
CBD’s mode of action differs in significant ways from other therapies. For example, benzodiazepines also inhibit neuron activation but do so via a different mechanism. With benzodiazepines, the level of inhibition is much higher because the drug molecules bind directly to GABA (gamma-aminobutyric acid) receptors rather than CBD receptors. Binding to CBD receptors causes a moderation of the neuron’s ability to activate, but it does not directly engage inhibitory neural mechanisms in the way GABA does. The difference is akin to taking a foot off of the gas (CBD) versus pumping the brakes (benzodiazepines and other GABA-targeted therapies). The consequences of this higher level of neuronal inhibition are sleepiness, reduced motor coordination, slurred speech, sluggish thought, lowered social inhibitions, and amnesia, all of which can significantly compromise quality of life and even personal safety.
Additionally, benzodiazepines are notorious for building both physical and psychological dependency as a result of their anxiolytic properties. Tolerance can build extremely quickly, meaning that patients will often stop experiencing benefits at the dose they were prescribed, causing them to seek stronger doses, potentially resulting in addiction. Furthermore, benzodiazepine class drugs cause neurons to exhibit a rebound effect, wherein neuronal activation is higher than normal following the drug’s clearance from the brain. This rebound effect most often manifests as anxiety, although secondary seizures caused by cessation of antiepileptic therapy and subsequent rebound activation can also occur. Finally, the addictive nature of benzodiazepines makes them unsuitable for long-term seizure therapy in most cases.
Other antiepileptics include carbamazepine and its analogues, phenytoin, phenobarbital, valproate, gabapentin, and lamotrigine. Most of these drugs operate by increasing the concentration of GABA. The impact and side effects of these drugs vary considerably as a result of their differing mechanisms. Some, like phenobarbital, share many overlapping side effects with the benzodiazepines. Others, like valproate, have a different side effect profile altogether; individuals can experience bleeding, anemia, nausea, and depressed mood.
Not all antiepileptic drugs utilize GABA concentrations as their primary mechanism, however. In contrast to the GABA-enabling drugs, carbamazepine and phenytoin block the sodium channels on neurons. This prevents the neurons from initiating the repetitive activation characteristic of seizures but does not result in systemic inhibition in the way that the GABA-enabling drugs do. Persons taking these drugs can struggle with blurred vision and low blood pressure as a consequence. Gabapentin, on the other hand, operates by tuning the calcium channels on neurons, causing transient dizziness, sleepiness, and unexpectedly aggressive behavior. By altering the calcium channels, neurons are less able to rapidly recover the ability to send a strong signal after activation. Thus, the over-activation seizure state is less likely to occur. As powerful and as diverse as these drugs can be, however, some individuals with epilepsy still have seizures even when taking several different medications.
CBD has a distinct advantage over many other epilepsy therapies not only due to the novel mechanism of action, but as a result of its low side effect profile and lack of dependency risk. This makes CBD appealing for a broad range of individuals struggling with epilepsy, giving them the ability to effectively address symptoms in a way other therapies do not, while optimizing quality of life and minimizing the potential of new dangers.
Although the relative safety and tolerability of CBD make it highly attractive to many, CBD therapy is also exciting because it has been shown to ameliorate epilepsy symptoms even when other interventions have failed. For the 74 patients from a study of five Israeli pediatric epilepsy clinics, CBD therapy might have been life-changing. In the study, the patients selected for analysis experienced daily seizures despite trials of eight or more antiepileptic drugs. If CBD therapy was successful within this cohort, then researchers posited it would make for an effective adjunct therapy that might give patients relief before last resort therapies were necessary. The majority of the patients were under age 12, and all were under age 18. In each of the five clinics, patients received varying doses of CBD over different intervals of time. Because each clinic had its own methods, there was no unified study protocol, but rather a handful of different clinical practices being implemented piecemeal in an attempt to help patients after other interventions had failed.
Nonetheless, CBD succeeded where the other therapies had failed. In fact, 89 percent of patients with treatment-resistant epilepsy experienced a lower frequency of seizures after they began CBD therapy. Of these patients, 18 percent claimed their seizures nearly or totally disappeared as a result of CBD therapy. Another 34 percent experienced a 50 percent reduction in the frequency of their seizures, and an additional 12 percent reported lesser but still significant reductions. These impressive results suggest that most people with epilepsy will experience a substantial improvement in their symptoms with the help of CBD therapy. Although larger clinical trials with adults are needed to characterize the most effective therapeutic regimen, the results of the Israeli study are extremely promising and have been replicated in a slightly older cohort by other researchers.
Of course, CBD—like other therapies—does have the potential for side effects. Patients who take CBD sometimes experience daytime sleepiness, excessive fatigue, or gastrointestinal disturbances, which sometimes make patients discontinue CBD therapy. According to the summary of the Israeli trials, as many as seven percent of the study participants experienced a worsening of their seizures after starting CBD therapy, although no causal relationship was established. For most individuals, however, there will be few side effects of CBD therapy. Nonetheless, experimentation with CBD should be performed with the help of a medical professional and begun gradually.
As a result of the overwhelmingly positive evidence in favor of using CBD therapeutically, the antiepileptic therapy landscape today is drastically more favorable than that in prior years. And there is reason to believe this landscape will continue to improve; scientific interest in CBD therapeutics for epilepsy of all types is growing at a rapid pace, and new studies are increasing the understanding clinicians have regarding what CBD therapy can do. Although there is strong evidence that CBD can be highly beneficial for individuals with treatment-resistant epilepsy, research indicates that CBD has the potential to be an excellent first-line therapy for epilepsy as well. Given the extensive side effect profile of traditional antiepileptics, CBD is likely to soon become a mainstream therapy, helping individuals with epilepsy improve their quality of life and potentially allowing them to replace their current regimen of antiepileptics.
Individuals with epilepsy need not wait for the forthcoming clinical trials regarding CBD therapy to begin to address their symptoms. A plethora of CBD products intended for therapeutic use are already on the market, and more are soon to arrive. Although clinical protocols for CBD therapy are still forming, the abundance of evidence suggests patients can benefit from 10-20 mg/kg of 99 percent CBD oil and 1 percent propylene glycol administered daily. As a result of the recent publications and positive press coverage of CBD therapeutics, individuals struggling with epilepsy will likely find that their health-care providers are amenable to helping them with a trial of CBD therapy.
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