How Marijuana can help with Epilepsy

For thousands of years cannabis sativa and its extracts have been used to treat a variety of illnesses ranging from epilepsy to gastrointestinal issues. Unfortunately, during the early 20th century cannabis came under the attack of yellow journalism, and was renamed marijuana by the media. Through a series of smear campaigns driven by racism, fear, and politics, slogans such as “smoke one joint and you will want to kill your brother” and movies like Reefer Madness marijuana was made illegal. Eventually it reached the status of a schedule I drug, which according to the FDA means that it has a high potential for abuse, no currently accepted medical, value and a lack of safety. This scheduling has been highly controversial, and due to its legal status research has been difficult. Little research has been done and very few clinical trials have ever been conducted on humans in the United States. The focus of this paper is to evaluate the efficacy of cannabinoid receptor agonists on their ability to prevent or treat epileptic seizures.

In order to understand how a cannabinoid receptor agonist can have an effect on epilepsy it is important to be familiar with the basics of the endocannabinoid system in the brain. The endocannabinoid system is a recently discovered signaling system. Cannabinoid receptors in the brain were discovered in 1990[1]. These are G-coupled receptors with seven transmembrane regions. There are two known cannabinoid receptors: CB1 and CB2. CB1 is heavily concentrated in the central nervous system and is coupled with ion channels[2]. It is also the most ample G-coupled protein receptor in the mammalian brain although this receptor is also found in other tissues. CB2 on the other hand is more localized, found to be associated with immune cells, the pancreas and the lymphoid system. The two endogenous ligands to which these receptors are agonized were not discovered until 1992. Anandamide was the first endocannabinoid to be classified, followed by 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid and both endocannabinoids appear to bind to CB1 and CB2.

The activation of the endocannabinoid system is similar to other G coupled protein receptors in the way it produces a cascade involving protein kinase A, and cyclic AMP[3]. During high levels of neural activity calcium ion concentrations increase in the cytoplasm which promote N-acyltransferase to produce N-arachidonoyl phosphatidyl ethanolamine from phosphatidyl ethanolamine. This intermediate is further processed by phospholipase D to form anandamide. Anandamide, which is now free in the synapse, is subject to degradation by the enzyme fatty acid amide hydrolase (FAAH). However, if it is not degraded anandamide will bind to and activate CB1 . The G-protein dissociates from the receptor and inhibits adenylyl cyclase. Because of this, cytoplasmic concentrations of cAMP decrease, which in turn decrease the levels of PKA. PKA can stimulate the ryanodine, which mediate the release of Ca2+ from the endoplasmic reticulum. Therefore reducing the amount of PKA will reduce the amount of calcium leaking from the ER into the cytoplasm, which will reduce the neurons ability to become depolarized. The bound CB1 receptor activates the extra cellular signal regulated kinase pathway (ERK) which stimulates the transcription of genes encoding transcription factors c-fos, zif268, and BDNF. These transcription factors are known to help ameliorate the effects of excitotoxic damage caused by excessive neural activity[4]. This sequence has the effect of decreasing the likelihood of further neural excitation and putting in motion the creation of gene products that can dampen the effects of excitotoxic events. Furthermore, CB1 receptor stimulation has also been shown to reduce inflammation and promote neurogenesis[5]. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation.

Epilepsy is a disorder which is characterized by excessive synchronized neuronal activity particularly in the cortical, hippocampal, and thalamocortical networks. Certain pathways in a person with epilepsy are prone to becoming repeatedly activated and can cause excitotoxic damage. In total over seventy genes have been identified as epilepsy susceptibility genes. Interestingly, none of the genes coding for the CB receptors have been found to be mutated in people with epilepsy. Several genes that encode for subunits of voltage gated ion channels have been found to be correlated with epilepsy[6]. This would make sense because if the voltage gated ion channels are not working properly, the state of polarization, or depolarization, could be effected dramatically. The progression of the disease is fairly simple. Epileptic seizures can be triggered by reading, sleeping, flickering lights, or often times, without a known trigger. Once an individual has one seizure, it becomes much more likely that they will experience more within their lifetime. This has been attributed to the hotly debated kindling theory of seizure progression [7]. Additionally, excessive neural activity can trigger molecular pathways that lead to neuronal death. This is called an excitotoxic event. If a cure is to be found, research into what causes seizures and what can stop them is necessary. However, using humans as research subjects can be unethical, therefore animal models are needed.

In order to study epilepsy in greater detail, animal models have been used to simulate epileptic seizures. Three in particular provide good insight into epilepsy: the maximal electroshock model, the pilocarpine model, and the kainic acid model. The maximal electroshock model is exactly what it sounds like: an electric shock is applied so that a maximal amount of test subjects, mice in this scenario, are sent into seizure. This model is most useful in determining seizure threshold, that is, how much electric shock is needed in order to induce seizure. During this procedure, an electric shock is admistered via corneal electrodes to mice who have either received a dose of anandamide or nothing (placebo), in order to determine how anandamide affects the seizure threshold. In the pilocarpine model, a special type of seizure is emulated called “status epilepticus” which is a seizure that lasts for at least thirty minutes before the subject regains consciousness. In this model, prolonged seizing is induced by intraperitoneal injection of pilocarpine, which is a muscarinic acetylcholine receptor agonist. This causes prolonged seizure, only to be stopped after thirty minutes when the mice are injected several times with diazepam. This model is useful for seeing the effects of prolonged seizing on neural tissue. The third model of importance is the kainic acid model, which is simply an injection of kainic acid. Kainic acid induces activation of excitatory pathways which lead to seizure. This model was used in order to specifically see if the CB1 receptors were important in the neuroprotective effects of endocannabinoids. All three of these models are also used to determine the relative efficacy of currently prescribed drugs for epilepsy versus the efficacy of cannabinoids, either endogenous or exogenous.

The most commonly prescribed drugs for epilepsy are the benzodiazepines, such as diazepam and lorazepam[8]. These drugs act by binding to the calcium ion channels and block them from allowing calcium ion entry[9]. This protects the neurons from further depolarization and therefore inhibits seizures[10]. Unfortunately derivatives of benzodiazepines have little to no beneficial effect on approximately one third of the epileptic population. In addition to this, a tolerance can result and the beneficial effects are eventually overcome by the negative effects of increasing the dosage, such as extreme prolonged drowsiness, suppression of REM sleep, and depression. As a result of these shortcomings, development of better anticonvulsants are warranted.

A popular alternative medication for epilepsy is Δ9- Tetrahydrocannabinol(THC).
THC acts as a cannabinoid receptor agonist binding to both CB1 and CB2. This binding produces a cascade of events leading to a decrease in cytoplasmic Ca2+ concentration which reduces a neurons ability to become excited. This could prevent or treat seizures by reducing the probability a neuron will come into over excessive stimulation leading to an excitotoxic event. In addition THC being a CB1 receptor agonist could reduce inflammation caused by over stimulation, thereby providing a neuroprotective effect[11]. However, evidence is more important than what seems to make sense.

There is a body of evidence suggesting that both endogenous and exogenous cannabinoids can regulate epilepsy. For instance, in the maximal electroshock model, a 300mg/kg dose of anandamide reduced the amount of convulsions by 12.5%. More impressive however is that a 300mg/kg dose mixed with a fatty acid amide hydrolase inhibitor, phenylmethylsulfonyl fluoride (PMSF), reduced the amount of convulsions by 100%. This would appear to indicate that much of the anandamide is broken down before it can activate the CB1 receptors. This is confirmed when using a synthetic cannabinoid dubbed O-1812. This compound, which is not hydrolyzed by FAAH, produces 100% reduction in convulsions without any PMSF. This would suggest that other exogenous compounds that activate the CB1 receptor and are not susceptible to hydrolysis by FAAH would produce similar results given that binding affinities are similar. In addition, when using a CB1 antagonist like SR141716A, the amount of electric current necessary to produce convulsions in 50% of test animals drops significantly, from 17.57mA to 14.27mA in test mice. Basically, this means that if the cannabinoid receptors are not working, or if there is an insufficient concentration of cannabinoids, the possibility of seizure increases. In the pilocarpine model it was found that treating the rats with CB1 receptor agonists strongly reduced seizure frequency, and that CB1 agonists were more efficient in their ability to reduce the seizures than phenobarbital and phenytoin, which are two prescribed anti-convulsants. The CB1 receptor agonist in this model was 10mg/kg THC. The kainic acid model confirmed that it is through the CB1 receptor mechanism that cannabinoids direct their anti-convulsant properties. To do this, the researchers engineered mice without CB1 receptors and then injected them and their wild-type litter mates with kainic acid. The results showed that the mice without CB1 receptors were much more prone to convulsions due to kainic acid injection versus the wild-type mice. In cell cultures of hippocampal neurons with low Mg2+ treatment, which induces seizure, it was found that treating the cultures with concentrations of anandamide as low as 1μM was able to completely stop seizures, whereas phenobarbital was not able to stop seizures until a concentration of 100μM was applied.

It is clear that the endocannabinoid system is involved in the regulation of neural stimulation through the CB1 receptor cascade. The evidence shows that manipulation of the endocannabinoid system can stop seizures. The evidence also seems to warrant further investigation into the ability of synthetic or natural exogenous cannabinoids to prevent or treat seizures. However as the evidence stands, it appears that there is some validity in the use of THC as an anti-convulsant but should not be recommended because of the lack of clinical trials with humans. Also it has been postulated that prolonged activation of the endocannabinoid system could actually contribute to epilepsy[12]. Further research using double blind clinical trials with humans are necessary in order to determine the efficacy of CB1 receptor agonists on reducing epileptic seizures within humans, specifically using THC as the receptor agonist.








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