The first studies of pure CBD in the anti-seizure activity of CBD relates to a. Keywords: Cannabidiol (CBD), cannabis, epilepsy, medical marijuana, . Thus seizure control and/or toxicity may result from pharmacokinetic interactions as well . Consequently any future studies of cannabinoid therapy in epilepsy, and in. Information about the use of cannabis oil for epilepsy to gain seizure control. The most well known are two cannabinoids: CBD - cannabidiol - and that THC may have an anti-epileptic effect, animal studies suggest it can.
& CBD Research Epilepsy: Scientific For On Seizures
A different substance in the plant, tetrahydrocannabinol, or THC, is responsible for the high associated with cannabis. In June , Gov. Greg Abbott signed into law the Texas Compassionate Use Act after it passed both chambers of the state legislature by wide, bipartisan margins. Meanwhile, doctors have been slow to sign up for the program as they navigate the new law.
As of late June, just 42 physicians across Texas were registered with the state to become CBD oil prescribers, including 12 in Harris County, though not all are prescribing CBD oil at this point. According to the Epilepsy Foundation of Texas, approximately , Texans have been diagnosed with the form of epilepsy that would make them eligible for the program. For many who have used CBD oil, the newly available treatment has provided relief when all else failed.
But once an epilepsy patient has taken two different medicines without relief, the odds that a third medication will work are less than 1 percent, doctors say. That leaves other options, such as special diets, surgeries, device implementation—or CBD oil. He said the stigma associated with taking medicine derived from cannabis is fading. But for some patients, it can help eliminate or reduce their symptoms, and it may allow them to ease off of other drugs that have serious side effects, including anemia, low platelet levels, liver failure, pancreatitis, allergic reactions and suicidal tendencies.
Before the Texas law took effect, many patients were trying CBD oil on their own by visiting other states or ordering it online, which is a legal gray area. For context, recreational marijuana might measure 20 percent THC. Those restrictions ensure Texas CBD oil makers maximize the compounds that provide symptom relief while minimizing those that can cause side effects or a high Trysten Pearson, for his part, said he experiences no side effects from CBD oil. The portions of the female flowering plants known as trichomes provide the highest yield of phytochemicals Because of the high use and abuse of cannabis products, a great deal is already known about the pharmacological properties of these substances 11 , 13 , The cannabinoids all share the heterocyclic terpeno-phenolic structure.
As large heterocyclic structures they are very lipophilic. Thus they cross the blood brain barrier readily and distribute easily to lipid laden tissues including brain parenchyma and neuronal cell membranes specifically. They may remain in such lipid laden tissues presumably including the brain for weeks and from these are released only gradually into the blood stream. CBD and THC, when taken orally, undergo first pass metabolism, thereby affecting bioavailability and dosage Due to this phenomenon, different routes of administration oral vs.
Furthermore, in the cannabis plant these substances naturally occur in the relatively inactive carboxylated state. Smoking and heating decarboxylates the molecules thus conferring greater bioactivity Finally, the cannabinoids and CBD in particular are primarily metabolized by the hepatic cytochrome P enzyme system, and in turn CBD appears to be an inhibitor of several of the microsomal hepatic metabolic enzymes and in particular of CYP2C19 11 , Thus, it is possible that CBD in significant concentrations may increase levels of concomitantly administered drugs metabolized by CYP2C This applies to the benzodiazepines and in particular to clobazam whose major active metabolite N-desmethylclobazam is primarily metabolized by CYP2C19 19 , Whether or not this degree of enzyme inhibition will result in clinically significant drug interactions is nevertheless still uncertain.
The very existence of natural substances the cannabinoids that have such remarkable and broad effects on human behavior and function presupposes a set of target receptors or endogenous physiological processes upon which these chemicals act.
Indeed, the search for the biological targets of THC ultimately lead to the discovery of specific cannabinoid receptors and then to the identification of endogenous ligands for those receptors. This complex physiological system is referred to as the endocannabinoid system 21 , The two most prevalent cannabinoid receptors are both G-protein-coupled receptors that exert their physiological effects through the adenylate cyclase second messenger system.
The CB1 receptor is widely distributed in brain and largely modulates endocannabinoid effects in the CNS 21 - These receptors are primarily situated pre-synaptically on axon terminals, with their highest density being in the perisynaptic region Figure 2 21 , Activation of the CB1 receptor results primarily in the inhibition of neurotransmitter release 21 , While CB1 receptors are known to regulate both GABA and glutamate release, a greater density of these receptors exists on inhibitory versus excitatory synapses in most brain regions 21 , The perisynaptic location of CB1 receptors A is depicted.
Post synaptic changes induce metabolism of membrane derived phospholipids G leading to formation of endocannabinoid H. The latter diffuses back stimulating the perisynaptic CB1 receptor A.
CB2 receptors on the other hand are particularly prevalent on lymphocytes, neoplastic cells and other systemic target tissues 12 , 21 , 22 , Presumably, many of the systemic effects of cannabinoids result from binding to CB2 receptors 22 , The physiological role of CB2 receptor activation in the periphery is suspected to be similar to the neural modulatory role described above for CB1 receptors though details are not as clearly worked out.
In addition to these two best characterized cannabinoid receptors, it is believed that the endocannabinoids and phytocannabinoids may act at a number of other receptor or target sites including GPR55 receptors and TRPV type 1 channels 11 , 12 , THC appears to act at CB1 and CB2 receptors as a partial agonist 21 - 23 , whereas CBD appears to have a very low affinity for both of the major cannabinoid receptors 23; see below.
This receptor distribution is ideally situated to serve in the capacity of neuromodulation 21 , 22 , Indeed a number of complex neuromodulatory processes have been linked to endocannabinoid processing including presynaptic modulation, retrograde neuromodulation and multiple physiologically defined forms of synaptic plasticity including depolarization-induced suppression of inhibition DISI , depolarization-induced suppression of excitation DSE and long-term depression LTD 21 , 22 , These in turn diffuse back to the presynaptic terminal activating perisynaptic presynaptic CB1 receptors, the activation of which in turn inhibits release of additional neurotransmitter on variable time scales thereby constituting a form of feedback inhibition This feedback process may be important during periods of intense synaptic activity.
The two major endocannabinoids are metabolic products of membrane phospholipid metabolism i. CBD may act by increasing levels of one or more of the endocannabinoids presumably by interfering with their metabolism or by inhibiting re-uptake; In any case, one can conceptualize these two endogenous cannabinoids as another set of second messenger systems derived from phospholipid metabolism all of which play key roles in neuromodulation.
Chemical structures of the two major endocannabinoids: Similarity to arachidonic acid and arachidonic acid metabolites is apparent. Therefore, overall the evidence suggests that endocannabinoid signaling serves to decrease synaptic transmission during periods of intense cellular activity.
The key features of this system include: I neuromodulation; II widespread CNS effects via CB1 receptor stimulation; III widespread systemic effects including anti-inflammatory and immune mediated effects modulated via CB2 receptors; IV neuromodulation via inhibitory presynaptic effects with greater influence over inhibitory than excitatory neurotransmission; V a pivotal role in retrograde neurotransmission and resultant presynaptic neuromodulation; and finally, VI a biphasic effect of the endocannabinoids in numerous physiological systems 21 , 22 , Given the widespread distribution of cannabinoid receptors in brain and body and the key role these receptors play in the modulation of physiological functions, one might anticipate a very broad range of physiological effects resulting from endocannabinoid signaling 12 , Indeed these range from roles in pain and sensory modulation to vegetative functions, endocrine regulation, and neurophysiological and psychological functions ranging from motor control to mood and behavioral regulation Table 1.
Likewise, it is easy to see why the exogenously administered cannabinoids might have far ranging effects and hence potential broadly distributed therapeutic potential Table 2. Consequently, the putative therapeutic benefits of the cannabinoids range from treatment of nausea and vomiting, cancer therapeutics to the modulation of neurological and psychiatric disease 12 Table 2. It is important to recognize, however, that at this stage these extensive putative therapeutic benefits touted by the proponents of medical marijuana are largely unproven 8 , 9.
At present, high quality medical evidence supporting the use of these agents in most of these conditions remains modest at best. Likewise, the widespread physiological effects of the cannabinoids also presuppose the potential for a broad range of toxicities.
Thus enthusiasm for therapeutic benefits needs to be tempered by the realistic appreciation of potential adverse effects Table 3 4 , 28 , The latter could include inhalational injury from smoking, inhalation of associated microorganisms or fungi, inadvertent intake of co-administered pesticides or other byproducts, and so forth.
It is important to recall, again, that the cannabis plant produces a remarkably broad array of phytochemicals. It would be anticipated that these could have varying degrees of efficacy as well as toxicity. Specifically, there is considerable evidence that suggests that of the phytocannabinoids, deltaTHC is likely to be the substance largely responsible for most of the systemic and neurotoxic effects of cannabis preparations 13 , 14 , Meanwhile, there is growing evidence that CBD may actually inhibit, reduce or moderate some of these adverse effects 27 , 31 - Obviously, from a scientific standpoint, it becomes virtually impossible to properly conduct carefully controlled studies with vernacular cannabis preparations given that these products likely contain widely disparate relative quantities of the various constituent cannabinoids.
Finally, among the potential toxicities of the cannabinoids, those of greatest concern to neurologists in particular are neurological and neuropsychiatric toxicities Table 3.
Unfortunately, there is considerable high-quality data coming from various sources that indicates that long-term exposure to THC can have serious deleterious effects on neurological functioning 34 - In particular, there is strong evidence that progressive memory impairment as well as impaired executive functions results 34 , 37 , There is additional concern about a deleterious effect on neural plasticity, particularly with regard to the developing brain 39 - There is strong evidence that cannabis use results in an increased risk of psychosis in predisposed individuals 43 , Acute and chronic cannabis use have also been linked to aggravation of anxiety, mania and depression.
Consequently any future studies of cannabinoid therapy in epilepsy, and in particular in childhood epilepsy, must very carefully assess acute and long-term neurotoxicity. Authors focused on the following neurological conditions: It is enlightening to briefly review the data that supports this therapy and compare it with what exists with respect to the treatment of epilepsy with cannabis products. Controlled trials of various pharmaceutical cannabis products for the treatment of multiple sclerosis specifically the painful spasms of MS began in the early s Initial studies did use a variety of preparations Table 4.
This culminated in a series of high quality placebo-controlled trials with Sativex a These trials demonstrated a statistically significant benefit of Sativex in the management of painful MS spasms, resulting in the marketing of this agent in England and many other countries not including the United States. However, quick perusal of Table 4 demonstrates that well over patients were studied in this fashion.
In addition, published post-marketing data regarding well over 10, patient-years of experience with Sativex demonstrates relatively low toxicity and statistical absence of serious adverse events 46 - Since Sativex is a mixture of THC and CBD, these observations do provide some reassurance that CBD itself may have minimal toxicity and a low propensity to result in dangerous or serious adverse effects.
However contrast this with the published data regarding the use of medical marijuana for the treatment of epilepsy Table 5 50 - Until the last few years, the published data was minimal Table 5 and included less than 70 subjects. Very few of these were children.
However this state of affairs is rapidly changing given the current climate. In , Porter and Jacobson 54 published the self-reported experience of 19 patients whose families had given their children some form of high-CBD medical marijuana product for severe intractable epilepsy. The majority of families reported improvement: Others reported an ability to discontinue previously administered medications Though clearly this data would not be considered high quality medical evidence, the information at the time was tantalizing.
In addition, considerable preclinical evidence regarding the potential efficacy of cannabinoids for the treatment of epilepsy does exist. Some of these studies began as early as the s. Phytocannabinoids particularly CBD have been studied in a wide array of animal models of epilepsy 55 - For the most part, these have demonstrated substantial efficacy.
There is some evidence that THC itself can be pro- convulsant in some animal models More recently, efficacy in animal models of temporal lobe epilepsy and partial seizures has been demonstrated In addition there is some evidence that tolerance to the anticonvulsant effects of CBD is not a prominent feature in animal models of epilepsy Thus based on these preclinical studies, one would be excited about the potential therapeutic potential of the cannabinoids.
However, it is undeniable that the complex regulation that surrounds these schedule I substances has impeded scientific investigation of their therapeutic potential. Spurred by the widespread interest in the therapeutic potential of CBD for the treatment of intractable childhood epilepsies, GW pharmaceuticals the makers of Sativex developed a pure CBD product known as Epidiolex.
Initial reports of the experience with these children again uncontrolled were recently presented Adverse effects were modest somnolence, diarrhea, fatigue and decreased appetite. While the results remain promising, outcome data nevertheless is based on self-reported seizure frequencies, is uncontrolled and may suffer from the same methodological problems to some degree as did the Porter and Jacobson report. However, placebo controlled trials of Epidiolex for Dravet and Lennox-Gastaut syndrome are now in process.
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CBD also interacts with some other seizure medicines. (cannabidiol, CBD) oral solution for the treatment of seizures associated with two epilepsy syndromes. This study also is the first to offer information on cannabidiol dosing for of dangerous seizures in patients with a severe form of epilepsy called. A collection of published research articles, videos, and other educational Therapeutic effects of cannabinoids in animal models of seizures, epilepsy.