Marijuana Compounds: A Non-Conventional Therapeutic Approach to Epilepsy in Children, Mariana Babayeva et al., 2014

Marijuana Compounds : A Non-Conventional Therapeutic Approach to Epilepsy in Children

Mariana Babayeva, Malka Fuzailov, Paulina Rozenfeld and Paramita Basu

Journal of Addiction and Neuropharmacology, 2014, 1, 1, 002



Epilepsy in children is a complex disease, with a variety of distinct syndromes and many alternative treatment options. Even with a plethora of available treatment options, childhood epilepsies are
commonly associated with seizures that are resistant to existing treatment methods. Treatment of pediatric epilepsy is challenging and requires more effective therapy to avoid short-term and longterm neurological disorders.

Marijuana has been used to treat disease since ancient times. Marijuana ingredients Cannabidiol (CBD) and D9- Tetrahydrocannabinol (THC) have created a significant research interest as potential therapy options in epilepsy treatment. THC is the major psychoactive component of marijuana that aids in reducing epileptic seizures. CBD has proven to have anticonvulsant effect not only in experimental models but also in clinical studies. Research studies have provided strong evidence for safety and
anticonvulsant properties of medical marijuana. Principal concerns regarding the use of medical marijuana in children include lack of standardization and regulation, imprecise dosing, possible adverse side effects and medication interactions.

Keywords : AED; Children; Epilepsy; Medical marijuana

Medical Marijuana

Marijuana is reported to be the most commonly used illicit substance in the United States, despite the drug’s classification as a Schedule 1 Controlled Substance by US Congress in 1970 [1]. The use of marijuana is categorized as such due to its high abuse potential, lack of established safety for use under medical supervision and no current accepted use for medical purpose. In order for the FDA to approve a compound for medical use, the active ingredients must be of measurable units to properly evaluate quality control. Even with stringent federal provisions, the legalization of medical marijuana has been surrounded by much controversy and debate in many states. There continues to be much speculation amongst policy makers regarding the safety, efficacy and potential outcomes of marijuana [2]. Since 1996, there have been 20 states in addition to Washington DC that passed laws, which allow marijuana to be used to treat certain medical conditions. In 2012, the states of Washington and Colorado passed initiatives legalizing the recreational use of marijuana in adults aged 21 and older [3]. Despite the shift of legalization in some states, the US Government highlights the public health consequences of legalizing marijuana [2]. Legalization would lead to a cascade of negative outcomes that threaten the approach to
drug policy. Increasing the availability of the drug would demonstrate a positive correlation in the use of the drug and could result in addiction, respiratory illness, and declines in cognitive processing [3]. Impairments in cognitive function were reported as an 8 point drop in IQ scores between the ages of 18-38 in a New Zealand study [4]. Individuals who began using marijuana during adolescence were unable to have their lost cognitive abilities fully restored in adulthood [5]. At the same time recent research studies have provided strong evidence for therapeutic use of medical marijuana [6-9].

Marijuana is derived from the Cannabis sativa L. plant. The plant species Cannabis sativa L. has two main sub-species, Cannabis indica and Cannabis sativa [10]. Cannabis sativa and Cannabis indica differ
fundamentally in their chemical composition, physiological aesthetic, and medical application. Marijuana contains the active chemicals known as cannabinoids. At least 67 phytocannabinoids can be
regarded as a natural library of unique compounds. The therapeutic potential of many of these ligands still remains largely unexplored prompting a need for further research [11]. The chemicals responsible
for the medicinal effects of marijuana are D9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) [12,13]. Sativa’s cannabinoid profile is dominated by high THC levels and low or no CBD [10,14]. Indica’s
chemical composition shows a more balanced mix, with moderate THC levels and higher levels of CBD [15,16].

Cannabinoids are also found endogenously in the body. These chemicals (endocannabinoids) play a role in the endocannabinoid system and aid in regulation of memory, pleasure, concentration,
thinking, movement and coordination, sensory and time perception, appetite, and pain [17]. For example, the endocannabinoids synthesized from membrane phospholipids in the cardiovascular
tissues can relax coronary and other arteries and decrease cardiac work [18]. Endocannabinoids are largely protective; they decrease tissue damage and arrhythmia in myocardial infarction, and in
addition, may reduce progression of atherosclerosis [18].

The endocannabinoids activate two G-protein-coupled cell membrane receptors, consequently named the Cannabinoid type 1 (CB1) and type 2 (CB2) receptors [18]. CB1 receptors are located primarily in central and peripheral neurons and CB2 receptors predominantly in immune cells [19]. CB1 receptors are important mediators in signaling pathways and have been identified on both glutamatergic and GABAergic neurons [20]. It is believed that one important role of the neuronal CB1 component is to modulate neurotransmitter release in a manner that maintains homeostasis in health and disease by preventing the development of excessive neuronal activity in the central nervous system [19]. Animal models illustrate that activation of CB1 receptor by their endogenous ligands can result in prominent neuroprotective effects and may prevent and are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells [22]. They are also expressed on peripheral nerve terminals where these receptors play a role in antinociception, or the relief of pain [23]. In the brain, they are mainly expressed by microglial cells, where their role remains unclear [24]. While the most likely cellular targets and executors of the CB2 receptor-mediated effects of endocannabinoids or synthetic agonists are the immune and immune-derived cells the number of other potential cellular targets is expanding, now including endothelial and smooth muscle cells, fibroblasts of various origins, cardiomyocytes, and certain neuronal elements of the peripheral or central nervous
systems [25,26].

Therapeutic Uses of Marijuana

Cannabis has been used to treat disease since ancient times. Out of the two major therapeutically active components of marijuana, THC is the major psychoactive ingredient, acting primarily upon the central nervous system where it affects brain function. CBD is the major non-psychoactive ingredient in cannabis and appears to relieve convulsion, inflammation, anxiety, and nausea. Both compounds have anticonvulsant properties. In addition, CBD produces neuroprotective and anti-inflammatory effects, and it is well tolerated
in humans [27].

Better understanding of cannabinoid pharmacology and the endocannabinoid system has led to the approval of pharmaceutical cannabinoids that target specific patient populations. Since the 90s, a pill form of marijuana has been prescribed to treat wasting syndrome in AIDS patients [28]. Nausea, appetite loss, pain, and anxiety are afflictions of wasting, all of which can be mitigated by marijuana [29]. Moreover, while multiple reviews have concluded immunosuppressive consequences of cannabis use, recent findings suggest marijuana may even help combat the AIDS. The new study has shown that chronic intake of marijuana can protect critical immune tissue from the damaging effects of HIV infection [30]. At present, AIDS and cancer patients utilize various drugs containing synthetic THC such as Dronabinolor Nabilone [31-33]. The drugs are used to decrease marijuana withdrawal symptoms as well as to increase appetite and prevent chemotherapy related nausea and vomiting [28,34,35].

Study data published by GW Pharmaceuticals reported positive results of THC: CBD treatment in patients affected by Multiple Sclerosis (MS), spinal cord injury, neuropathic pain or peripheral neuropathy. This report also confirmed excellent safety profiles for cannabis-based medicines [36]. At present, a combination of both cannabinoids THC and CBD are used therapeutically in Sativex to alleviate pain symptoms in multiple sclerosis [37,38]. Sativex was approved in UK, Spain, Czech Republic, Germany, Denmark, Sweden, Italy and Austria. In Canada Sativex has been approved for the treatment of multiple sclerosis spasticity and also for advanced cancer pain [39].

Clinical trials are currently underway in San Francisco, CA investigating the effects of a pure cannabinoid drug called Epidiolex. The trial will evaluate the safety and tolerability of this drug in the treatment of severe and debilitating seizures in children nonresponsive to traditional anti-epileptic drug regimens [38].

While some studies have found that some percentage of the general population using cannabis for therapeutic purposes may develop a dependence on this substance [40], a growing amount of research on cannabis-related substitution suggests that for many patients cannabis is not only an effective medicine, but also a potential exit drug to problematic substance use. It was reported that subjects frequently use cannabis as a substitute for alcohol, illicit substances, and prescription drugs [41].

Even with promising results promoting the therapeutic applications of marijuana, federal barriers and public health concerns regarding marijuana’s potential risk to cause addiction and dependence, increase co-morbidities, cardiopulmonary effects and overall mental health still exist [42]. Other negative effects may include paranoia and psychosis when consumed in high doses [43,44]. According to studies focused on cannabis dependence, approximately 300,000 patient admissions into substance abuse treatment clinics are predominantly marijuana-related problems, exceeding the rates of heroin and cocaine [35].

Epilepsy and Traditional Therapy

Epilepsy is a neurological disorder characterized by recurrent unprovoked seizures and is recognized as one of the most common nervous system disorders [45]. According to the Epilepsy Foundation of America, approximately 3 million Americans are affected with epilepsy [46], and up to 50,000 Americans die each year from seizures and related causes [47]. 30% of the patients diagnosed with epilepsy are children. Costs of the disease result in significant financial impact of $15.5 billion annually [48]. Despite current pharmacologic and medical treatment, more than one-third of individuals with epilepsy continue to experience seizures [49]. Children epilepsy may result from various etiologies but the majority of epilepsy cases are of idiopathic nature [50]. Numerous medical conditions can cause epilepsy, in addition to genetic mutations and traumatic injury to the brain. Certain patient populations that are at greater risk for developing seizures and epilepsy include those with mental retardation, cerebral palsy, head injuries, or strokes [51]. Seizures are triggered when electrical patterns in the cerebral cortex are simultaneously activated, leading to hyperexcitbaility of neuronal activity and disruptions in homeostatic mechanisms [52,53]. The outcome of a seizure depends largely on the location in the brain where the electrical imbalance occurred. Epileptic seizures can be divided into two broad categories of generalized seizures, which include absence, atonic, tonic-clonic, myoclonic seizures, as well as partial seizures.