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 


May 22, 2018


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).



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).


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.




  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.
Autonomic system, Neuroanatomy, Spidey senses

Do your spidey senses tingle, better listen up

Virginia Thornley, M.D., Neurologist, Epileptologist

March 24, 2018

Have you ever walked down a quiet lonely corridor of a building where almost everyone has gone home for the day and your spidey senses started to tingle? Or perhaps, you were caught up at work in a facility and it is now 8pm with not a soul in sight and you have a long desolate walk to the parking lot to your car. Your spidey senses tingle as you place your first step out the door leaving the brightly fluorescent-lit building to go out in the cold darkness. Your heart races, your eyes widen checking out your surroundings in front, on the sides and behind you. That is your fight or flight response kicking in in high gear. This is a common scenario where your senses tell you instinctively that you are not in the best situation and you need to be hyperalert to survive a situation should something adverse were to occur.

How about a less straightforward situation where you waltz into a bank minding your own business, you just needed quarters to do your laundry because you live in an apartment building with no washer or dryer. As the teller is getting you a roll of coins, someone comes in from your peripheral vision. You think how rude, I was here first why is this guy cutting my line? He has sunglasses, a hat and holds up a note to the teller while telling you to be chill, be chill. Then it dawns on you that you are suddenly in the middle of a bank heist. Do you a) scream and ask for assistance from the security guard standing 2 feet away? b) run for your life because the man beside you has his hand in his pocket and you could turn into smithereens in the next few seconds c) stay frozen as your life passes through your mind thinking hmm, what should I do scream for assistance or be chill like the guy reassuringly told me to be. Your mind instinctively tells you it is prudent to do the latter. This is another situation where you are on edge, your systems are overloaded with information and your mind is racing like a marathon on what was the best case scenario to get yourself out of that situation.




Many times in our life we are faced with situations when we feel potential threat or fear of the unknown and lightning speed logic and actions are required. Our bodies are designed to react quickly to situations. The amygdala has an emotional function in our brain that directs our reactions when the unnerving situation is detected. Signals are sent to the hypothalamus in the brain that connects with the adrenal medulla which lies on top of the kidneys and from where epinephrine and norepinephrine are released  The sympathetic nervous system is the system that allows our pupils to dilate, our heart to pump quickly and our palms to sweat. It is part of the autonomic nervous system that controls and regulates the cardiac muscles, muscles, and glands. During fight or flight response to stress, there is an adrenergic rush when epinephrine is released and is available for immediate reuptake by the post-ganglionic nerve endings in order to kick our bodies into high gear to react rapidly if need be. The heart is pumping to ensure the body gets adequate blood flow. In primitive times, you will need your muscles to outrun that cougar. The blood vessels constrict within the organs to make blood flow more available to the muscles necessary for running. Blood flow is shunted to the liver to make energy stores more available. The pupils dilate so they widen allowing more light and you can see your surroundings better in dark light. The breathing becomes heavier because you will need more oxygen when you try to outrun that crouching cheetah in the jungle.

It is a primitive response so engrained in our system that we cannot ignore or control it.  The palms sweat, well, because that’s part of the sympathetic nervous system. Sweating allows you to cool off in hot temperature. If you run hard and fast you become hot, you need sweat to cool down. It is essentially a primitive response entrenched within our systems that help you react towards an untoward situation. By the same token, animals must sometimes freeze in the jungle so they are not seen and eaten by large predators. This is similar to the evolutionary freezing we feel when we are involved in a potentially dangerous situation and suddenly stop and do not know what to do.


However, everything is interrelated. It is not just the fear of the unknown or being in an unusual situation that can trigger this response. Our memories and emotions may trigger the sympathetic nervous system. Say you walk into a business deal that is supposed to be mutually beneficial. You have high hopes for a great outcome. You walk into the conference room, look your interviewer in the eye and shake his hand. This person is unusually cheerful and accommodating.  You are just happy to have someone interview you in the location of your choice. However, as you start to listen to the situation your mind is triggered by statements that harken back to a situation in a previous job from which you suffered burnout. They are way too accommodating but little statements are voiced making you wonder about the real situation and why they are being a little too nice and too happy about an overburdened schedule. This is where the hippocampal cells in the temporal lobe come in to subserve their function with learned memory.  Your amygdala is processing everything emotionally connecting the dots. While logic is saying take the job it is an ideal location, the salary is great, your amygdala is dissecting emotional content in the discourse and on facial features. It picks up on any fallacy when emotions and statements do not coincide. You detect a disconnect between the sunny disposition and the weight of the job. The intuition many people opine about is really the primitive amygdala telling you when something is not quite right. It detects the unsaid component of a situation and ultimately determines your next course of action. While you are about to start the job your amygdala is screaming out to you releasing hormones producing a milder version of the fight or flight response veering you away from a potentially stressful situation and giving you a completely different reaction from what logic would determine. You feel stressed every time you think about your first day at work. The heart beats a little more quickly, it is a milder version of the sympathetic response found in fight or flight but essentially your amygdala is activating your system to respond as you do in an adverse situation.

The same is true when encountering the threatening looking person. You have an idea they are up to no good, looking shiftily away darting their eyes back and forth. Your brain registers something adverse is about to go down. It’s not paranoia, it’s your primitive brain the amygdala picking up on suspicious activities steering you towards a reaction towards a  potentially adverse event.

Therefore, when your spidey senses tingle, it’s not intuition, it’s not a sixth sense or premonition. It is cerebrally mediated with your primitive brain steering your emotional component to wind your body up about to react to a stressful situation. At one end of the spectrum, it is the fight or flight response at the milder end of the spectrum it is the stress you feel when you are about to make a big mistake. The axiom is true, listen to your gut, to be more apt listen to your amygdala masquerading as your spidey senses.

When the hair on the back of your neck tingles, listen to those spidey senses.