cannabidiol, Epilepsy

Scientific and clinical evidence of cannabidiol (CBD) and seizure control: mechanisms, randomized controlled clinical trials, open label trials and animal models

Virginia Thornley, M.D., Neurologist, Epileptologist 

@VThornleyMD

May 22, 2018

Introduction

There are numerous scientific studies that have studied the effect of cannabidiol by itself on seizure control encompassing animal models, longitudinal observational studies, case series and currently randomized double-blinded placebo-controlled clinical trials. It is difficult to ignore the wealth of information regarding the medical value of cannabidiol with a significant role in the treatment of epilepsy.

The endocannabinoid pathway and cannabinoids

The endocannabinoid pathway is found naturally within our system, comprising of receptors, transporters, and endocannabinoids. It is responsible for the sense of well-being one gets after running referred to as the “runner’s high,” and not endorphins, serotonin or noradrenergic neurotransmitters as their molecular sizes are too large to pass through the blood-brain barrier. There are 2 types of receptors, CB1 and CB2 receptors. CB1 is found predominantly within the nervous system and is the receptor on which tetrahydrocannabinol works and it is through this binding where psychoactive properties arise. There are two metabolites within the endocannabinoid pathway, anandamide for which tetrahydrocannabinol (THC) is a phytomimetic and 2-arachidonoyl-glycerol for which cannabidiol is a phytomimetic. Cannabidiol (CBD) acts as an inverse agonist on the CB1 receptor, with a weak affinity. 100 times of cannabidiol is needed to get the same psychoactive properties as tetrahydrocannabinol. When CBD is combined with THC the side effects of paranoia, hyperactivity and agitation become less because it is an inverse agonist of the CB1 receptor. In many animal studies, cannabidiol has anti-inflammatory, anti-oxidative and neuroprotective actions within the nervous system (8).

Mechanisms by which cannabidiol works 

It is thought to modulate the neurotransmitter system. Endocannabinoids are increased as a result if hyperexcitability in the nervous system. CBD can regulate intracellular calcium during hyperexcitability states in the hippocampus in the temporal lobe. CBD can regulate NMDA (N-methyl-D-aspartate) receptor transmission and increase serotonergic 5HT-1A (5-hydroxytryptamine)receptor transmission and reduces GABA, 5-HT1A, and norepinephrine synaptic uptake (9). Cannabidiol is thought to be neuroprotective through its role in controlling intracellular calcium. Excess calcium can activate a cascade of neurochemical events leading to cell degeneration and death through lipases, endonucleases, and proteases. In one study in rat models, there was a suggestion that treatment of seizures was not just at the neurotransmitter level but also modulates the oscillatory nature, neuronal loss and post-ictal lethargy of the status epilepticus model.

Scientific evidence in animal models

Animal studies show that the effectiveness of cannabis is at the level of the CB1 receptor. With the deletion of the CB1 receptors in the forebrain excitatory neurons in the mice model, Kainate-induced seizures were more prominent. The presence of CB1 receptors in the hippocampal gyrus seems to protect against Kainate-induced seizures. Viral-induced CB1 overexpression resulted in less Kainate-induced seizures, CA pyramidal cell 3 cell death. This demonstrates that the presence of the CB1 receptor can limit seizures and reduces gliosis and apoptosis (4).

 

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In animal studies, the CB1 receptors increased 1 week after pilocarpine-induced seizures in the CA1-3 striatum oriens and the dentate gyrus. Patients with temporal lobe epilepsy had reduced Anandamide and increased CB1 receptors suggesting an up-regulation of the CB1 receptor as a homeostatic mechanism in the presence of seizures which can reduce excitatory neurotransmitters (4). This compensatory mechanism may be impaired with long-standing seizures and hippocampal sclerosis and refractoriness to pharmacologic measures.

Case series report

In a small study on patients with tumors with seizures, in 3 patients who were medically refractory were started on cannabidiol (Epidiolex) to treat seizures. 2 out of the 3 had improvement in seizures while all 3 had improvement in the severity in the University of Alabama (2).

Evidence in longitudinal observational studies

In one study of 57 patients, ages 1-20 years old, CBD:THC was given at a ratio of 20:1 with the CBD component of 11.4 mg/kg/day. The patients were followed longitudinally for 3 months with a follow-up time of 18 months. 56% or 26 patients had <50% reduction of seizures. No difference was noted between the causes of the seizure and the type of cannabis used. Younger ages of 10 years old and below had a statistically better outcome compared to an older age. Those with higher doses of CBD of >11.4mg/kg/day had a statistically better outcome compared to 11.4mg/kg/day and below. There were side effects in about 46% of patients leading to stopping the protocol. These studies suggest that cannabidiol enriched treatment may be beneficial in seizure control particularly in the pediatric population.  (1).

Open-label studies

In an open-label trial, 214 patients were studied between the ages 1-30, with pharmacoresistant epilepsy. There were 162 in the safety follow-up of 12 weeks, 137 were in the efficacy analysis. For the safety group, 33 had Dravet syndrome and 31 had Lennox-Gastaut syndrome. The rest had medically refractory seizures from different causes. Side effects were mild to moderate including diarrhea, lack of appetite, somnolence, fatigue, and convulsion. 5 had a cessation of treatment related to adverse effects. Serious events were reported in 48 patients with 1 death unrelated to cannabidiol. 20 had severe adverse effect including status epilepticus. The median number of seizures at baseline was 30 which was reduced to 15 per month with a 36.5% reduction of motor seizures (7).

Evidence in randomized controlled clinical trials 

In a multi-country study was performed on Dravet syndrome and effect of cannabidiol in a randomized double-blind trial of cannabidiol versus placebo and in young adults between the ages of 2-18. Dravet syndrome is an epileptic syndrome involving myoclonic epilepsy during childhood which may progress attributed to an SCN1A gene abnormality. There was a 4 week baseline period followed by a 14 week treatment period. The dosages of cannabidiol were increased gradually to 20mg/kg/day. Those in the cannabidiol group was matched to a placebo control. The endpoints were the percentage of change and Caregiver Global Impression of Change (CGIC). In 23 center in the U.S. and in Europe, 120 patients underwent randomization, mean age was 9.8 years old. 108 completed treatment. The median number of drugs was 3 and the most commonly taken were clobazam, valproate, stiripentol, levetiracetam, and topiramate. The most common type of seizures was generalized tonic-clonic followed by secondary generalized tonic-clonic seizures. 114/118 children presented with developmental delay. Adverse reactions were mild to moderate including somnolence, diarrhea and loss of appetite. Elevated liver enzymes were found in those taking valproate likely related to drug-drug interactions. The reduction of seizures was considered meaningful while no change in non-convulsive episodes was noted. In the cannabidiol group, convulsive seizures reduced from 12.4 seizures to 5.9 per month while the placebo control group had a reduction of seizures from 14.9 to 14.1 which was not statistically significant. A reduction of more than 50% of seizures occurred in 43% of patients in the cannabidiol group and 27% in the control cohort. 3 patients in the cannabidiol group and no one in the placebo group became free of seizures. 62% of caregivers thought the condition improved in the cannabidiol group as opposed to 34% in the placebo group (5).

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Another randomized placebo-controlled trial in Lennox-Gastaut syndrome was done using cannabidiol versus placebo. Lennox-Gastaut Syndrome is characterized by multiple seizure types with a slow spike and wave of 2.5 Hz or slower on EEG.  This study covered 30 clinical trial centers between the ages 2-55 with 2 or more seizures per week over 28 days. 225 patients were randomized with 76 in the group for cannabidiol at 20mg/kg/day, 73 in the cannabidiol group at 10mg/kg/day and 76 in the placebo cohort. The reduction in median of drop attacks was 41.9% in the 20mg cannabidiol group, 37% in the 10mg cannabidiol group and 17.2% in the placebo group which was statistically significant. Side effects were somnolence, diarrhea and poor appetite which was dose-related. 9% had higher liver function tests. The study concluded that addition of cannabidiol of either 10mg/kg/day or 20mg/kg/day in addition to standard anti-epileptic agents resulted in a significant reduction of seizures(6).

Cannabidiol as an add-on adjunct for refractory seizures

In another study in Slovenia, add-on cannabidiol was given to 66 patients who were deemed medically refractory at a dosage of 8mg/kg/day. 32 or 48% of patients experienced fewer seizures of more than 50% reduction. 14 (21%) were seizure free. No patient had to worsen and 15 or 22.7% there was no effect. Patients reported less robust seizures, less recovery time and less time duration of the seizures as positive outcomes. Adverse effects were seen in 5 patients or 0.07% of patients. They concluded that there are some beneficial effects of cannabidiol as an add-on adjunctive treatment in controlling medically refractory epilepsy(3). However, this study focused on cannabidiol as an adjunctive treatment, not as monotherapy.  Regardless, there are some beneficial aspects as evidenced in this study (3).

In summary

There is growing evidence that cannabidiol which is the non-psychoactive component of the Cannabis sativa plant is effective in treating intractable seizures, from the mouse model to randomized controlled clinical trials, which can no longer be ignored. There are mostly mild to moderate side effects involving the gastointestinal and neuropsychiatric system, although severe adverse outcomes include status epilepticus. There were no fatal outcomes associated with the use of cannabidiol. The real question are the long-term side effects and drug-drug interactions which can be studied once the cannabidiol is well-established as a conventional agent in the future.

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References:

  1. Hausman-Kedem, M., et al, “Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – an observational longitudinal study,” Brain Dev., 2018 Apr., pii:S0387-7604 (18)30112-8 doi: 10.1016/j.braindev2018.03.013. (Epub ahead of print)
  2. Warren, et al, “The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy,” Neurocase, 2017, Oct.-Dec., 23 (5-6):287-291.
  3. Neubauer, D., et al, “Cannabidiol for treatment of refractory childhood epilepsies: experience from a single tertiary epilepsy center in Slovenia,” Epilepsy Behav., 2018 Apr., 81:79-85. doi:10.1016/j.yebeh.2018.02.009. (Epub ahead of print)
  4. Rosenberg, et al, “Cannabinoids and epilepsy,” Neurotherapeutics, 2015, Oct., 12 (4):747-768.
  5. Devinsky, O., et al, “Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome,” New England Journal of Medicine, 2017, 376: 2011-2020.
  6. Devinsky, et al, “Effect of cannabidiol on drop seizures in the Lennox-Gastaut Syndrome,” NEJM, 2018, May,  378:1888-1897.
  7. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open label interventional trial,” Lancet Neurology, 2016, Mar., 15 (3):270-8.
  8. Fernandez-Ruiz, et al, “Prospects of cannabinoid therapies in basal ganglia disorder,” British Journal of Pharmacology, 2011, Aug., 163 (7):1365-1378.
  9. Do Val-da-Silva, et al, “Protective effects of cannabidiol against seizures and neuronal death in a rat model of mesial temporal lobe epilepsy,” Front. Pharmacol., 2017, 8:131.
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Anxiety, cannabidiol

Anxiety: the science behind anxiety and effectiveness of cannabidiol and tetrahydrocannabinol in anxious patients

Virginia Thornley, M.D., Neurologist, Epileptologist

March 27, 2018

Introduction

Anxiety is a state of unease, the sense of restlessness you feel when you are out of sorts. It may be due to the simple circumstances of being late for a charity dinner to feeling scared out of your wits when your car is trembling on the highway because your wheels are not balanced. Everybody has experienced it at some point in their life. Some more chronically and severely than others. In primitive times, one must redirect their attention from the task of scavenging for food in the jungle to suddenly be alert to imminent danger from the bear prowling behind you. In modern times, one must react quickly to that bus coming at you as you try to cross the street on 51st Street and 5th Avenue. You suddenly look up startled redirecting your focus to the imminently life-threatening event. For someone with clinical anxiety, this would be akin to being fearful every time you try to walk and cross the street despite no threats just the usual fast-paced taxicabs waiting for that green light. There is a chronic response of fearfulness that is not befitting to the situation. Threats are perceived more frequently harboring frequent fearful responses.

Current approach to anxiety

The current armamentarium of a physician includes prescribing anti-anxiety agents, referring to a therapist, recommending relaxation techniques such as yoga, Tai Chi or meditation, or any physician’s all-time fallback choice which is to refer to a psychiatrist. Many medications take weeks to take effect and after all that, not all of them are effective requiring several trials of medications to get to one that may even partially work. A therapist is beneficial, however, cons include the patient not having enough time or resources. In some patients it may help in others, similar to medications, it does diddly squat. In addition, some patients must cope with anxiety through natural means due to the prohibitive nature of their occupation. Some highly sensitive occupations disallow any use of anti-anxiety agents which might be potentially sedating in a patient’s history which could cost them their jobs.  Medications may be helpful in certain populations but it often takes time to find the right agent and the right dose.

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The science and mechanisms behind anxiety

The mechanism of anxiety and its complexities are studied. At the chemical level, it is thought to be due to the lack of serotonin. Many anti-anxiety agents work at the level of the serotonin receptor.  But the thought processes underlying anxiety are far more complex than at a single chemical level which likely is the reason why many medications do not work given the complexity of the emotional response.

Neuroimaging studies have elucidated that anxiety may be attributed to the involvement of an amygdala to prefrontal cortex circuit. Instead of the normal fear response one has to certain stimuli, the amygdala is overly responsive to the threat. This leads to an abnormal attentional and interpretive response level that is consistently fearful.  For instance, your bakery might be the best in town but if the client is highly anxious, any little mistake on that wedding cake may be perceived as a personal slight giving rise to an extremely anxious response causing them to want their money back. In other words, the level of anxiety is greatly out of proportion to the situation. There is nothing that bakery could have done to ease that person’s anxiety over the cake.

Patients with anxiety are selectively attentive to threat-related situations. Anxious patients perceive neutral events with negative connotations and potentially threat-related. Stimuli with conditioned threat significance may elicit attention and lead to physiologic responses including increased heart rate, sweating, heavier breathing. This may be the reason why in dealing with an anxious person, no matter what has been said that individual has a hyperalert response and has a very low threshold for a fearful response to a threat-perceived situation when the situation is very neutral (1). For example, you could be the most highly skilled neurosurgeon in the world, if your delivery of the prognosis is a 60% chance of recovery, that could be a source of great angst. The clinically anxious person will hear how she or he  will have the 40% chance of not recovering.

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Cannabidiol 

Cannabidiol is the non-intoxicating phytocannabinoid from the Cannabis sativa plant. It has a weak affinity for the CB1 receptor and one needs 100 times the amount to get the same euphoria as tetrahydrocannabinol. Cannabidiol is found to help with anxiety. It works at the level of the 5HT-1 receptor to exert its anxiolytic properties. A combination of cannabidiol and tetrahydrocannabinol often called Indica is often used for anxiety and insomnia. It is often used by patients with anxiety primarily at night due to its calming and sedating properties.

In one study of 24 patients with anxiety who were about to give a presentation, cannabidiol was given at 600mg. The anxiety, cognitive impairment, and alert arousal response were much lower compared to the control group who had a placebo. The placebo group had much higher anxiety, greater discomfort, and alert responses (2).

Although federally illegal in many states despite medical marijuana laws and dispensaries popping up around the nation, medical marijuana is an alternative agent that should be considered in patients who are medically refractory to medications, psychotherapy, and other techniques. It has a valuable place in the physician’s medicine bag in treating anxiety and illnesses related to anxiety-related disorders.

References

  1. Bishop, et al, “Neurocognitive mechanisms of anxiety: an integrative account,” Trends in Cognitive Behavior, article in press.
  2. Bergamaschi, et al, “Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients,” Neuropsychopharmacology, 2011, May, 36 (6): 1219-26.
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