Did you know that... cannabis could be used to treat epilepsy?

In this third post we want to speak you about the relationship between epilepsy and cannabis, a current issue still in the process of providing a final conclusion which has fascinated us from start to finish. We are going to try to briefly introduce the set of processes that define epilepsy, analyzing their incidence and etiology. Later, we are going to see how the compound called cannabidiol, a non-psychoactive cannabis compound, can influence the course of the disease and the results obtained to date. Finally we are going to discuss some conclusions and future perspectives.

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Epilepsy is a chronic neurological disorder defined as a brain condition that causes spontaneous and recurrent seizures. The term seizure describes brief episodes of involuntary movements that can affect a body part or entirely. In turn, the frequency thereof may vary from less than one in a year to several per day. Often they worsen progressively and are accompanied by cognitive and behavioral disorders. Epilepsy affects people of all ages and about 50 million people suffer around the world (WHO 2016). In Spain, according to the Spanish Society of Neurology, epilepsy cases reach 400000 people. The causes of epilepsy are varied and, without going into too much detail, these causes can include:

• Brain damage due to prenatal or perinatal injury.
• Birth defects or genetic disorders associated with brain malformations.
• Severe traumatic brain injury.
• Brain stroke or ischemia restricting the entry of oxygen to the brain.
• Brain infections such as meningitis and encephalitis, among others.
• Some genetic syndromes.
• Brain tumors.

At pathophysiological level, seizures can be defined as a temporary, excessive and uncontrolled change in the electrical activity of a group of neurons, which constitute the so-called epileptogenic focus. Neuronal electrical activity is given by the membrane potential and this depends on intra- and extracellular concentrations of ions, as well as the flow thereof through the membrane. Epileptic seizures are caused by an imbalance between excitatory and inhibitory processes. In the central nervous system glutamate is the most important excitatory neurotransmitter and GABA (gamma-aminobutyric acid), the inhibitory one. The arrival of each one of them to its specific receptor means the opening or closing of different ion channels that cause an ion exchange between the intra- and extracellular spaces, altering the membrane potential. GABA reduces neuronal excitability hyperpolarizing the cell membrane, while glutamate is potentially excitatory, depolarizing the membrane. Glutamate can be toxic so that its levels have to be highly regulated.

In the membrane of the epileptogenic focus neurons occurs a permanent partial depolarization staying, largely, by the existence of synchronized excitatory synaptic connections without an inhibitor control There are a number of mechanisms possibly involved in the development of seizures such as changes in membrane proteins (mainly receptors), altered levels of both neurotransmitters (GABA, glutamate) and endogenous neuropeptides, changes in the intra- and extracellular ions ratio (for example, an increase in potassium ions in the extracellular space favors constant hyperactivity), and monoaminergic and cholinergic influences over the epileptogenic zone, among others which have been hypothesized in various studies.

In the next picture the hypothetical cases in which a partial and a widespread seizures occur related to the signals that are collected in an electroencephalogram (EEG) are illustrated. The EEG is a graph recording the electrical activity of the brain, so that when brain activity increases, the amplitude and frequency of the waves increases too.

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During the period of latency or epileptogenesis (period between seizures) the cascade of events that switches a non-epileptic brain into one that releases spontaneous seizures takes place. During this period of latency a specific treatment could stop or modify the epileptogenic process and positively influence the quality of life of epileptic subject. Classic antiepileptic drugs (AEDs) basically act on sodium ion channels or voltage-dependent calcium channels, preventing depolarization of the neuronal membrane. New AEDs, however, are designed to favor the action of GABA at different levels (agonists, reuptake and degradation inhibitors, etc.) or by anti-glutamatic effects. Unfortunately, these drugs only have symptomatic effects, not anti-epileptogenic. In other words, they reduce the occurrence of events symptomatically but do not prevent that epileptogenesis occurs. Moreover, many of these compounds exhibit side effects that influence and/or condition both the quality of life for patients and the seizures themselves.

To make matters worse, after more than two decades in which a new AED is marketed almost annually, 30% of patients remain uncontrolled. To date, about 15 million patients worldwide have refractory epilepsy or treatment resistant epilepsy. In these cases, in order to reduce the frequency of seizures, the physician may recommend a special diet and reducing stress as well as alcohol, drugs and stimulants, or even may recommend surgery to remove abnormal brain cells that cause seizures. However, these approaches are still insufficient so that improving current treatments or the development of new therapies remain absolutely necessary.

Here we leave you a shocking video in which a man with epilepsy connected to an EEG apparatus suffers an attack. You can see the increase in brain waves reaching going off the scale of the graph.

For all the above, many research efforts have focused on identifying new therapies able to deal with epileptogenesis, epilepsy and problems related to both phenomena. A great emphasis has been placed on the phytocannabinoids, compounds synthesized by several species of cannabis. Cannabis has been widely used medicinally for centuries in the treatment of various neurological disorders, including epilepsy. Currently its use is limited exclusively to treat pain and spasticity in multiple sclerosis, and to treat nausea during chemotherapy. Cannabis contains more than 80 phytocannabinoids and, although little is known about the therapeutic potential effect of these molecules, the pharmacological interest of this plant (mainly species Cannabis sativa and Cannabis indica) comes after the identification of two major neuroactive components thereof: tetrahydrocannabinol (THC), which is psychotropic and cannabidiol (CBD) non-psychotropic; along with the discovery of an endogenous cannabinoid signaling pathway in our body. The therapeutic use of THC is limited to its psychotropic and side effects. There is also controversy regarding its effect on seizures since it has been shown to have both anti- and pro-convulsant activity in different studies. Furthermore, in recent years research has been conducted on CBD as an alternative to THC, including studies with human patients with refractory epilepsy.

 

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CBD has been shown to have anticonvulsant properties in animal model studies of epileptogenesis and various types of epilepsy, as well as some clinical trials. Compared to currently used AEDs, it demonstrated similar efficacy but a better side effect profile in several of these models. However, further studies to better characterize its pharmacokinetic profile and the molecular mechanisms that give their pharmacological properties in epilepsy and other pathological processes are needed, and their possible molecular targets are not entirely clear. What it has been demonstrated is that CBD, unlike THC, do not active type 1 and 2 cannabinoid receptors (CB1 and CD2), which are located in the membrane of CNS neurons, among other places, and not just so but antagonize ligands of these receptors very potently. That is, despite its structural similarity with THC, CBD anticonvulsant activity is not mediated by interaction with cannabinoid receptors. This explains its lack of psychotropic effects and its no-participation in endocannabinoid signaling pathway of the body.

Related to its anticonvulsant properties, it has been shown that CBD can influence and act on neuronal hyperexcitability in several ways:

1. Reducing synaptic release of glutamate as a result of antagonism in GPR55 cannabinoid receptor.
2. Activating 5-HT1A receptors which induce the release of β-endorphin, an "endogenous opioid" with anxiolytic, antidepressant and analgesic effects.
3. Stimulating and desensitizing TRPA1 channel, a receptor whose activation is involved in pain and stress.
4. Stimulating and desensitizing TRPV1 and TRPV2 channels, which mediate pain transmission.
5. Inhibiting synaptic the reuptake of norepinephrine, GABA, adenosine and dopamine, neurotransmitters with inhibitory, sedative, reinforcement or pleasurable effect on neuronal activity, as appropiate.

It has been hypothesized about other possible action targets but we need more studies to clarify this point and the relationship of these targets with epilepsy. Furthermore, it has been observed that CBD has the ability to interact with other drugs. For instance, its interaction with clobazam can be used to control epilepsy and, in particular, the refractory one. Clobazam is one of the currently used AEDs, a potent benzodiazepine (BDZ) which reduces abnormal electrical activity of neurons by increasing GABA inhibitory activity. Its mechanism of action is detailed in the following figure:

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To date, May 2016, only four articles of clinical studies on the therapeutic application of CBD with other AEDs have been published. All of them show signs of improvement in the treatment of disease and symptoms but is not clarified if CBD is effective per se or by increasing the effects of other AEDs because of their interaction. More clinical studies are needed with a better design, double-blind and randomized, including patients with homogeneous and well-defined epileptic syndromes, since in many cases not all patients had the same type of epilepsy, which makes the interpretation of the results very difficult. This will provide us reliable information on the efficacy and safety of CBD.

Many of these studies are already being carried out today, using natural or synthetic derivatives of CBD, CBD+clobazam and CBD itself. Previous results are promising, including a decrease in seizure frequency and a favorable safety profile, highlighting the case of CBD+clobazam where the best results appear to be reached. Focusing on refractory epilepsy, one of the most current clinical trials (Devinsky 2016) has shown that CBD can reduce seizure frequency and has an adequate safety profile in children and adolescents with treatment resistant epilepsy. It was further demonstrated that 50% of patients treated with CBD at the same time they are taking clobazam had a reduction of more than 50% in seizure frequency, while patients taking only CBD had a lower decrease. Only 3% of patients developed side effects such us sleepiness, decreased appetite and diarrhea. These studies begin to provide evidence, or are in the process of doing it, that CBD can be an effective option to treat epilepsy and more specifically, refractory epilepsy.

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CBD has also shown to possess antioxidant, anti-inflammatory and neuroprotective properties in animal models, which can be useful for treating other neurological disorders, while it has been suggested that may have antipsychotic, antidepressant and anxiolytic effects. In fact, one study showed that prolonged treatment with CBD can prevent memory deficits in mice model of Alzheimer’s disease (see references).

Given the data above, we can say that CBD is presented as a potent therapeutic option not only for epilepsy, but for many other disorders. Although in animal models the conclusions are favorable and promising, clinical trials in human patients are in the process of getting them. Anyway, previous results are very promising. More specifically, it is a great hope for patients with refractory epilepsy, whose quality of life is severely affected and, in some cases, it costs their life.

Another point to consider are the positive effects of CBD on cognitive function and mood. It may be useful given the comorbidities associated to epilepsy, which represent a major problem in the management of these patients.

All these data should be considered when claiming to influence the regulatory laws of many countries in the world, trying to accelerate the clinical legal use of CBD. To date, only a few specialist physicians approve the clinical use of marijuana and, more specifically, of CBD to treat severe epilepsy but 98% of patients who have tried it recommend its use and say it has helped them.

At this point, this post does not imply a defense of the use of cannabis as a therapeutic agent in epilepsy since the direct consumption of cannabis, which is in turn the use of a complex mixture of phytocannabinoids with psychotropics, addictive and neurodegenerative effects, among others, would have a negative effect more severe than beneficial as anticonvulsant agent. However, the latter effect is achieved with other compounds purified and administered individually, among which highlights, as we have seen, CBD.

Thank you for dedicating a few minutes. 

We hope you enjoyed!

REFERENCES

1. OMS: http://www.who.int/es/
2. Sociedad Española de Neurología: http://www.sen.es/
3. www.nlm.nih.gov/medlineplus
4. Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Goldberg EM, Coulter DA. Nat. Rev. Neurosci. 2013, 14:337-349.
5. Cannabis and endocannabinoid signalling in epilepsy. Katona I. Handb. Exp. Pharmacol 2015, 231:285-316.
6. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Lancet Neurol 2016, 15(3):270-8.
7. Cannabidiol and epilepsy: Rationale and therapeutic potential. Leo A, Russo E, Elia M. Pharmacological Research 2016, 107: 85-92.
8. Cannbinoids in the treatment of epilepsy. Friedman D, Devinsky O. N Engl J Med 2016, 374(1):94-5.
9. Antiepilépticos: Aportación de los nuevos fármacos. Saíz RA. Información Terapéutica del Sistema Nacional de Salud 2004, vol 28 nº2.
10. Investigational new drugs for focal epilepsy. Mula M. Expert Opin. Investig. Drugs 2016, 25(1)1-5.