cbd treatment for seizures

December 15, 2021 By admin Off

LGS is a developmental disorder that begins in early childhood and is characterized by multiple seizure types, as well as physical and cognitive deficits. The seizures of LGS are difficult to control and are managed with a different medication regimen than that which is used for most epilepsy types.

Sometimes, children and adults who have LGS or Dravet syndrome have some difficulties taking oral medication due to difficulty swallowing, behavioral problems, and/or cognitive issues. It may be a challenge to get your child to take any medication, and you might need to develop strategies to help with this process.

Studies using CBD for seizure control are focused on refractory seizures, which are seizures that are not easily controlled with anti-seizure treatments. It's still too soon to tell whether it will be beneficial and tolerable for people with other seizure types. As such, CBD is not approved for other types of seizures or epilepsy itself at this time.

However, LGS and Dravet syndrome may be treated with medications that aren't commonly used for most types of epilepsy. Additionally, they often require two or more anti-seizure drugs for seizures to be under control.

At this time, cannabidiol has been proven effective for only a few medical conditions. Due to the side effects, it is recommended to be used with caution.

Indications.

Epidiolex comes in an oral solution (liquid form), and the recommended dose is initiated based on weight.

There's still much to be learned about how CBD interacts with other anti-seizure drugs.  

In the aforementioned 2019 review of studies on this drug, however, researchers found that while adding Epidiolex to a treatment regimen may increase certain specific side effects, it may actually decrease the overall amount of side effects participants experienced.

CBD itself does not have abuse potential and does not produce the "high" that is typical of marijuana, so you do not need to worry about your child abusing the drug or becoming addicted to it. However, it is possible that others may misunderstand the effects of the drug, particularly because it is new and because it is derived from the same plant that marijuana is derived from.

It is not completely clear why CBD can reduce some types of seizures. It is known to have a range of biochemical effects on nerve cells in the brain, some of which may have an impact on seizures. Medical research on CBD is still in its early stages.

The side effects of CBD that have been reported in the studies when it was added to other antiseizure medications included:

Seizures are caused by erratic electrical activity in the brain that can spread and cause uncontrolled physical movements and/or alterations of consciousness. Most anti-seizure drugs work by slowing down excitatory nerve activity in the brain.

It’s possible that CBD may raise the blood level of certain other anticonvulsants such as Topamax and Onfi (clobazam), and may result in side effects.

When used with other anti-seizure drugs, CBD can cause elevated liver enzymes, which is often a sign of liver injury.

If you have questions regarding whether cannabidiol is an appropriate treatment for you or someone you know, talk to your healthcare provider first. You can use our Doctor Discussion Guide below to help start that conversation about treatment options and more.

Side Effects.

Some other CBD products contained other compounds from the marijuana plant, including tetrahydrocannabinol (THC)—the part that gets you "high."

Get our printable guide for your next doctor's appointment to help you ask the right questions.

A 2017 study published in JAMA found that 26 percent of products purchased online contained less CBD than their labels claimed.  

Dravet syndrome is a developmental disorder that begins in early childhood and is associated with multiple seizure types as well as seizures triggered by fevers. People with Dravet syndrome often have behavioral challenges and learning difficulties.

Meredith Bull, ND, is a licensed naturopathic doctor with a private practice in Los Angeles. She helped co-author the first integrative geriatrics textbook, "Integrative Geriatric Medicine."

A multitude of CBD-containing products are on the market, and some people have chosen to use them for seizure control. This trend is likely to grow, especially since the 2018 Farm Bill made hemp-derived products, including CBD, legal at the federal level.  

Even with treatment, people with LGS or Dravet syndrome may continue to experience persistent seizures.

What About Other Seizure Types?

A 2019 review of studies on Epidiolex showed a sustained seizure frequency reduction of between 30 and 63 percent.   Additionally, seizures were about half as severe and the postictal (after seizure) state was less severe as well.

Cannabidiol is a controversial treatment because it is one of the components of marijuana, a widely known recreational drug. There are strong opinions about the drug, and proponents advocate for its legalization for medical uses, while some advocate for the legalization of recreational use as well.

It is generally started at a dose of 2.5 mg/kg twice per day and increased weekly. It can be increased up to a dose of 20 mg/kg per day if needed, but increased side effects have been found to occur at the higher dose.

Prescription CBD is specifically recommended for control of seizures in LGS and Dravet syndrome.

However, studies have shown that CBD, when taken with other anti-seizure medications, reduces the frequency and severity of seizures in people who have these disorders.  

More severe side effects, which you should contact your healthcare provider about right away, include:

In studies, these were more common in the first two weeks on Epidiolex, after which time they tended to diminish. Additionally, many of the studies on the drug involved at least one other anti-seizure drug as well, so the side effects may not all have been due to Epidiolex.

Cannabidiol (CBD)—a component of the marijuana plant—has gotten a lot of attention for medical use, including the treatment of epilepsy. Epidiolex is the only prescription form of CBD available, and it was approved by the U.S. Food and Drug Administration (FDA) in June 2018 for the treatment of seizures in two hard-to-treat forms epilepsy—Lennox-Gastaut syndrome (LGS) and Dravet syndrome. Epidiolex is approved for adults and children over the age of 2 who have one of these rare disorders.

They found that CBD may reduce the adverse effects associated with anti-seizure medications, and seems to improve other aspects of health and quality of life for patients.

Compared with the control group, artisanal CBD users reported lower epilepsy medication-related adverse effects (13% lower) and had greater psychological health satisfaction (21% greater) at the beginning of the study. They also reported lower anxiety (19% lower) and depression (17% lower).

Epilepsy, one of the most common nervous system disorders affecting people of all ages, is a neurological condition characterized by recurrent seizures. Treatment for epilepsy includes anti-seizure medications and diet therapy, such as forms of the ketogenic diet. Surgery may be an alternative treatment, especially when medications or diet fail to control seizures, or if drug side effects — including dizziness, nausea, headache, fatigue, vertigo and blurred vision — are too difficult for a patient to tolerate.

Artisanal (non-pharmaceutical) cannabidiol (CBD) products have become popular in recent years for their apparent therapeutic effects. CBD — a naturally occurring compound of the cannabis plant legally derived from hemp — is used widely as a naturopathic remedy for a number of health conditions, including epilepsy and seizure disorders. Now, Johns Hopkins Medicine researchers, in collaboration with the Realm of Caring Foundation and other institutions, have conducted an observational study with participant-reported data to better understand the impact these products may have on people with epilepsy.

For their evaluation, the researchers analyzed data gathered between April 2016 and July 2020 from 418 participants — 230 women and 188 men — with 205 (49%) at least age 18 and 213 (51%) age 18 or younger. The participants included 71 adults with epilepsy who used artisanal CBD products for medicinal purposes and 209 who were caregivers of children or dependent adults to whom artisanal CBD products were given. The control group consisted of 29 adults with epilepsy who were considering the use of CBD products and 109 caregivers who were considering it for a dependent child or adult patient.

Both adult and youth (18 years or younger) CBD users reported better quality sleep, compared with their peers in the control groups.

Importantly, 27 patients in the control group at the start of the study started using artisanal CBD products later in the study. After starting CBD, these patients reported significant improvements in physical and psychological health, as well as reductions in anxiety and depression.

Participants also were asked about possible adverse effects related to their CBD use. Among the 280 users, the majority (79%) did not report any adverse effects. The remaining reported negative factors such as drowsiness (11%), high or prohibitive product cost (4%), worsening of epilepsy symptoms (4%), concerns about legal issues (3%) and worries about problematic drug interactions (1%).

Caregivers of patients currently using CBD products reported significantly less burden and stress, compared with caregivers in the control group (13% less).

Johns Hopkins Medicine researchers have shown that CBD may reduce the adverse effects associated with anti-seizure medications, and seems to improve other aspects of health and quality of life for patients with epilepsy. Credit: Public domain image.

Participants completed a web-based survey that included questions regarding quality of life, anxiety and depression, and sleep. They were prompted via email to complete follow-up surveys at three-month intervals for 14 months.

“The potential of CBD products for the treatment of seizure disorders goes beyond seizure control alone,” says Ryan Vandrey, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “In our study, we saw clinically significant improvements in anxiety, depression and sleep when patients with epilepsy initiated therapeutic use of artisanal CBD products.”

Vandrey says further research is needed to understand how these findings can best be applied to helping people with epilepsy. In the interim, he says, patients should consult with their physician before trying CBD products.

Epidiolex, a pharmaceutical formulation of CBD is approved by the FDA to treat three types of rare seizure disorders (Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex), but is not approved for the many other types of epilepsy. As a result, patients with other forms of epilepsy often seek alternative forms of CBD, including those evaluated in the new study.

“Our hope is to do controlled clinical trials to better inform clinical decision making and identify specific formulations that are most beneficial to patients,” he says.

CBD is highly bound to plasma proteins (> 99%)63 and is extensively metabolized by cytochrome P450 (CYP) enzymes, particularly CYP3A4 and CYP2C19,66 and glucuronyltransferases.67 The major metabolic pathway involves hydroxylation and oxidation at C-7, followed by further hydroxylation in the pentyl and propenyl groups.68 The major oxidized metabolite identified is cannabidiol-7-oic acid containing a hydroxyethyl side chain. The elimination of CBD follows a biphasic pattern, with an initial half-life of about 6 hours which partly reflects distributive processes. Because of its very high lipophilic properties, CBD distributes extensively into tissues, from which it is slowly released, resulting in a late-phase terminal half-life of about 24 hours.63 In a safety and pharmacokinetic study in patients with Dravet syndrome, 27 children aged 4 to 10 years received CBD doses of 5, 10 or 20 mg/kg/day in addition to pre-existing antiepileptic drugs (AEDs).69 On treatment day 22, exposures to CBD and its major metabolites were found to increase dose-proportionally.

Smaller uncontrolled studies and case reports have also suggested that CBD could be of value in the treatment of patients with drug resistant seizures associated with tuberous sclerosis complex,119,120 febrile infection-related epilepsy syndrome (FIRES),121 Sturge-Weber syndrome122 and malignant migrating partial seizures in infancy.123.

These are exciting times for research in cannabinoids. After almost four millennia of their documented medical use in the treatment of seizure disorders, we are very close to obtaining conclusive evidence of their efficacy in some severe epilepsy syndromes. The era of evidence-based prescription of a cannabis product is within our sight.

Pharmacokinetics and drug interactions.

Median percent reduction in seizure frequency in the three randomized adjunctive-therapy placebo-controlled efficacy trials of cannabidiol (CBD) reported to date in patients with Dravet syndrome85 and Lennox-Gastaut syndrome.86,124 For patients with Dravet syndrome, seizure frequency refers to convulsive seizures. For patients with Lennox-Gastaut syndrome, seizure frequency refers to drop seizures. P values refer to comparisons between each CBD group and corresponding placebo group. n refers to number of patients randomized into each group. For further details, see text.

As discussed above, the molecular actions involved in CBD anti-seizure activity do not appear to be mediated by a direct effect on cannabinoid receptors, but the precise mechanisms of action have not been ascertained. In various studies, CBD has been reported to exhibit a range of other activities which suggest potential utility in many other conditions, including anxiety, mood disorders, psychosis, fear, trauma-related conditions, tobacco and opioid addition, inflammatory diseases, neurodegenerative disorders, and as a tool to counteract the undesired psychotropic effects of THC.32,51–56.

As discussed in the introductory section of this article, evidence of cannabis being used in the treatment of seizure disorders dates back thousands of years, and cannabis preparations had a role in the treatment of epilepsy by neurologists in the late nineteenth century. Although use of cannabis in epilepsy declined in the twentieth century due to legal restrictions and the gradual introduction of AEDs, observations suggesting anti-seizure activity continued to be reported. In 1975, Consroe et al.88 described a 24-year-old patient with seizures uncontrolled despite therapy with phenobarbital and phenytoin, who became seizure-free after starting to smoke marijuana. A few other reports suggestive of beneficial effects on seizures of marijuana smoking appeared in the subsequent decades,89–92 including an interesting epidemiological study which found a reduced risk of a first seizure among illicit cannabis users.93 There have been however, also reports of marijuana smoking precipitating or aggravating seizures.94,95.

Evidence about the efficacy and safety of oral cannabis preparations is mostly based on surveys and case reports, including the widely publicized story of Charlotte, a little girl with SCN1A-confirmed Dravet syndrome, who experienced a remarkable improvement in her seizures after being switched to a CBD-enriched extract.102 One of the first surveys targeted a Facebook group of approximately 150 parents in the USA supporting the use of CBD-enriched cannabis in their children with drug refractory seizures.103 There were only 19 respondents, with most of the children having a diagnosis of Dravet syndrome and Doose syndrome. Over 80% of parents in this small and possibly biased sample considered their child to have fewer seizures while on CBD-enriched cannabis, at estimated doses up to 25 mg/kg/day for CBD and up to 0.8 mg/kg/day for THC. Two children were free from seizures. Parents also reported other beneficial effects, including improved alertness, and improved mood and sleep. Side effects included drowsiness and fatigue. Another online survey was directed to parents who used CBD-enriched cannabis products for the treatment of their children’s epilepsy.104 There were 117 respondents (including parents of 53 children with infantile spasms and Lennox-Gastaut syndrome), with 85% reporting a reduction in seizure frequency in their children, and 14% reporting complete seizure freedom. The median duration of therapy was 6.8 months, and the median estimated CBD dosage was 4.3 mg/kg/day. Many responders reported that their children showed improved sleep, alertness and mood. In a very recent web-based survey from Australia targeting people with epilepsy nationwide, 137 of the 976 respondents reported to be using, or having previously used, cannabis products for the treatment of their seizures.105 Use of these products increased with increasing number of AEDs used in the past, suggesting that patients with the most drug resistant seizures were more likely to access cannabis therapy. Products were perceived as helpful in managing seizures in 71% of children and 89.5% of adults, and almost one half of respondents reported to have been able to reduce their concomitant AEDs. Interestingly, only 6.5% of responders stated that they used cannabis because it was recommended by their physician, and the majority of the products used were obtained from illegal suppliers, without knowledge of their precise composition. Positive results with cannabis use were also reported in another recent online survey directed to parents of children with refractory epilepsy in Mexico.106.

Recently, the anticonvulsant profile of CBD was re-evaluated using a refocused screening protocol developed by the National Institute of Neurological Disorders and Stroke (NINDS)-funded Epilepsy Therapy Screening Program.41 In this investigation, CBD given intra-peritoneally (i.p.) produced a dose-dependent protection against maximal electroshock-induced seizures in mice (ED 50 83.5 mg/kg) and rats (ED 50 88.9 mg/kg), and was also found to be effective in the 6 Hz 44 mA seizure model (ED 50 164 mg/kg), and in the corneal kindling model (ED 50 119 mg/kg) in mice. These effects were observed at doses that did not cause motor impairment. No protection, however, was attained in the lamotrigine-resistant amygdala kindled rat at doses up to 300 mg/kg.

The pharmacokinetics of CBDV have not been reported in detail. In a recently completed Phase I study, healthy subjects were given single oral doses ranging between 25 and 800 mg, as well as multiple doses of 800 mg once daily over 5 days.36 Peak plasma concentrations and areas under the plasma concentration-time curve were found to be dose proportional. The 7-hydroxy- and 6-hydroxy-metabolites could be detected shortly after dosing.

Overall, review of the available studies suggests that CBD-enriched cannabis may have anti-seizure effects, but the quality of the evidence does not allow to draw firm conclusions. Studies were generally retrospective, and based on patient or parenteral reports without adequately structured data collection. Many of the patients surveyed used unspecified products whose composition and dosage was unknown. Moreover, estimates of apparent efficacy could be affected by patients’ selection bias, reporting bias, and other confounders such as the natural course of the disease, regression to the mean phenomena, and placebo effects.110 In particular, placebo effects are known to be strongly influenced by expectations,111 and the broad media exposure associated with cannabis products is a strong generator of positive expectations. An indication that patient or parental expectations may have a strong impact on the outcome of cannabis treatment is provided by a comparison of perceived improvement among patients included in the Colorado surveys.107,108 Specifically, outcomes of cannabis therapy were significantly better when families moved their residence to Colorado in order to access the medication compared with families already residing in Colorado ( Fig. 3 ). Although there could be alternative explanations for this finding, it is plausible that patients with high expectations/motivations, leading them to relocate to another state, were those who responded best.

Well controlled randomized trials.

Following administration to healthy subjects of a single 400 mg oral dose encapsulated in gelatin capsules, CBD was found to be rapidly absorbed, with mean peak plasma concentrations of 114 to 181 ng/mL being attained at about 1.5 to 3 hours.62 Following oral administration, CBD shows a high interindividual pharmacokinetic variability. Its oral bioavailability is low, in the order of 6%37 or 10%,63 due in part to extensive first-pass metabolism.37 Bioavailability appears to be higher (in the range of 11 to 45%) after inhalation in cannabis smokers.64 In a study conducted with an oromucosal spray of nabiximols (a formulation containing THC and CBD in an approximately 1:1 ratio, which is approved in some countries for the treatment of symptoms of spasticity associated with multiple sclerosis), co-administration with food resulted in a mean 5-fold increase in CBD bioavailability.65 It is unclear whether a similar effect also occurs with oral formulations.

The list is not exhaustive and not all reported actions may be relevant to anti-seizure activity.

One of the reasons for the utilization of cannabis products to have become so popular among patients and their caregivers is that these products are generally regarded as causing fewer adverse effects compared with traditional AEDs, partly out of the misperception that remedies derived from natural products are unlikely to be harmful. In a survey carried out by Epilepsia , 96% of respondents among the general public felt that there was sufficient safety evidence about cannabis products, whereas only 34% of physicians considered this to be the case.135 In fact, in the randomized controlled trials conducted to date the tolerability profile of CDB was relatively benign, with somnolence, decreased appetite and gastrointestinal symptoms being the most common treatment-emergent adverse events. Although these results are encouraging, further studies are required to evaluate the safety profile of CBD and other cannabis products in greater detail, particularly after long-term exposure and whenever these products are used in subpopulations potentially at risk. Elevations of liver enzymes have been frequently observed, especially in patients comedicated with valproate, and although they were generally reversible, close observation for signs suggestive of hepatic toxicity is advisable. Nabiximols, an oromucosal spray formulation containing approximately equal amounts of THC and CBD, has been commercially available in several countries for a number of years and has a relatively extensive safety record.68 However, the maximum approved daily CBD dose in nabiximols is considerably lower than the CBD doses used in epilepsy trials, and experience of nabiximols in pediatric age is limited because the product is not recommended for use ‘below 18 years of age due to lack of safety and efficacy data’.68 As discussed above, prolonged exposure of the immature brain to THC has been shown to cause deleterious effects on brain connectivity, and there is some evidence of prolonged recreational use of marijuana in adolescence being associated with neuropsychological decline and lower academic performance scores.136,137 There are also special concerns for risks to the offspring of mothers who use marijuana during pregnancy.138,139 Although these findings may be specific for THC and other psychoactive cannabinoids, adequate safety data for young children exposed to long-term CBD therapy are not yet available.24 Another area where limited data is available relates to the risk of rebound seizures following abrupt or rapid discontinuation of treatment. Unlike THC, CBD is not associated with the development of tolerance after repeated administration in various seizure models, and there is no evidence of a withdrawal syndrome developing after CBD discontinuation.12.

In the first trial, 171 patients (mean age 15 years) with uncontrolled drop seizures (median baseline monthly frequency 74) were randomized to receive adjunctive treatment with CBD oral solution 20 mg/kg/day or placebo for a period of 14 weeks (2-week titration and 12-week maintenance).86 Fourteen patients (16%) in the CBD group and one patient (1%) in the placebo group withdrew prematurely. Compared with placebo, CBD treatment was associated with a greater median percent reduction in monthly drop seizures (44% vs. 22%; p = 0.0135, Fig. 4 ) and a greater proportion of patients with a ≥ 50% seizure reduction (44% vs. 24%; p = 0.0043). Adverse events were reported in 86% of CBD and 69% of placebo patients, the most common being diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. Treatment-related serious adverse events were reported in nine CBD patients and one placebo patient. Elevations in transaminases occurred mostly in patients on concomitant valproate therapy and all resolved.

Number of articles retrieved in PubMed by using the search terms ‘cannabis and epilepsy’, grouped by year of publication.

Conclusions and future perspectives.

In preclinical studies, CBD has been found to be active in a variety of seizures models, including seizures induced by maximal electro-shock39–41 and by pentylentetrazole in rats and mice,42–44 audiogenic seizures in rats45 and seizures induced by 3-mercaptopropionic acid, bicuculline, picrotoxin, cocaine and isoniazid (but not strychnine) in mice.39,45,46 In addition, CBD shows protective activity in pilocarpine models of temporal lobe seizures and in the penicillin and cobalt models of focal seizures in rats,47–49 and increases the afterdischarge threshold while reducing afterdischarge amplitude and duration in electrically evoked kindled seizures in rats.50 CBD also inhibits epileptiform potentials induced by a Mg 2+ -free medium and 4-amino-pyridine in hippocampal brain slices.42.

In addition to web-based surveys, there have several reports based on chart reviews. In one such report from the USA, use of artisanal cannabis in 272 children and adults with a variety of seizure types was associated with at least 50% seizure reduction in 55% of cases, with 10% achieving seizure freedom, and there was no indication of improvement being preferentially associated with a specific seizure type or syndrome.61 In a retrospective survey of 75 children and adolescents with refractory epilepsy from Colorado, where use marijuana for medical purposes was legalized in 2,000, one third of patients experienced a > 50% seizure reduction after starting therapy with oral cannabis, with the highest apparent benefit being reported in those with Lennox-Gastaut syndrome.107 Adverse events were reported in almost one half of the cases and included increased seizures (13%) and somnolence/fatigue (12%), but there were also reports of improved alertness or behavior in one third of the cases. Comparable findings were reported in a similar report from Colorado, which included data from 119 patients (it is unclear whether this population partly overlapped with that described in the earlier report by the same group).108 In the latter study, the proportion of patients who showed >50% seizure reduction was 24% and, interestingly, one third of those who did not report any seizure improvement continued to take cannabis therapy, presumably because of other perceived benefits. The average duration of cannabis use in this cohort was 11.7 months (range 0.3 to 57 months) and overall 71% of patients discontinued cannabis therapy during the study period. Another report from Israel included 74 patients with highly drug resistant epilepsies secondary to various etiologies (mostly epileptic encephalopathies), treated with a CBD dose of 1 to 20 mg/kg/day using an oil product containing CBD and THC in a 20:1 ratio.109 Almost 90% of the patients were cognitively impaired and one half were less than 10 years of age. Unlike other studies, therapy in the Israeli setting was generally prescribed by a physician, and the fact that 81% of the patients received relatively low doses (less than 10 mg/kg/day) was attributed to the fact that most patients kept the oil drops sublingually for several minutes, which would be expected to result in higher bioavailability.102 About one half of the patients reported at least a 50% reduction of their seizures, but five reported seizure aggravation leading to treatment withdrawal. As in previous reports, many patients reported improvements in behavior, alertness, language, communication, motor skills and sleep. Thirty-four (45%) patients reported adverse events, including somnolence/fatigue (22%), seizure aggravation (18%), gastrointestinal symptoms and irritability (7%).

Many biological actions of cannabinoids are mediated by their interaction with two closely related receptors, cannabinoid receptor type 1 (CB1) and 2 (CB2), although a variety of other receptors and targets are also involved in the effects of these compounds.9–13 Both the CB1 and the CB2 receptors belong to the class of G i/o -coupled metabotropic receptors and are widely distributed throughout the central nervous system (CNS), with CB1 receptors being localized primarily in neurons and CB2 receptors being expressed in microglia and, to a greater extent, in the immune system.9 The discovery of cannabinoid receptors in the CNS led to a search for endogenous substances interacting with these receptors and to the identification of so-called ‘endogenous cannabinoids’, the most important of which are the arachidonic acid derivatives anandamide (2-arachido-noylethanolamide) and 2-arachidonoyl glycerol.9 Extensive evidence has now accumulated that endocannabinoids play an important role in the control in synaptic transmission and the regulation of the rate of neuronal firing.13–17 In the CNS, CB1 receptors are expressed pre-synaptically on both glutamatergic and GABAergic interneurons, and activation of these receptors results in inhibition of synaptic transmission, including glutamate release.9,10,16 An involvement of endo-cannabinoid signaling pathways in the pathophysiology of epilepsy (and the possibility of targeting these pathways for therapeutic purposes) is suggested by a number of experimental and clinical observations. Experimentally, many studies reviewed in recent articles10,14,16,17 have demonstrated that endogenous cannabinoids systems are altered in a variety of models of seizures, epilepsy and epileptogenesis, whereas external modulation of these systems can prevent or modulate seizure activity. Clinically, observations implicating a role of endocannabinoid systems in epilepsy include the finding of reduced anandamide concentrations in the cerebrospinal fluid of individuals with new-onset temporal lobe epilepsy;18 demonstration of downregulation of CB1 receptors and related molecular components in glutamatergic neurons from surgical samples of epileptic human hippocampus;19 demonstration of sprouting of CB1-receptor expressing GABAergic axons (or increased expression of CB1-receptors on these fibers) in sclerotic human hippocampi;20 and PET evidence of differential changes in CB1 receptor availability in the seizure onset zone and in the insula of patients with temporal lobe epilepsy and hippocampal sclerosis.21.

The first studies on the medical use of cannabis date back to the Chinese Emperor Shen Nung (about 2,700 B.C.).2 As evidence of the important role of the plant in ancient Chinese culture, archeological excavations in the Xinjiang-Uighur Autonomous Region of China have recently unearthed a 2,700-year-old grave of a shaman which contained a large cache of cannabis, perfectly preserved by climatic and burial conditions, presumably employed as a medicinal or psychoactive agent, or as an aid to divination.3 Early written records of medical applications can be traced to Sumerian and Akkadian tablets, around 1,800 B.C., which mention the use of a medicinal plant, most likely cannabis, to treat a variety of ailments, including nocturnal convulsions.2,4 In less ancient times, there are records in the Arabic and Islamic literature which mention explicitly cannabis as a treatment for seizures and epilepsy.4.

The history of human use of the Cannabis plant goes back to the dawn of mankind. The plant, which originated in Central Asia or in the foothills of the Himalayas, was initially cultivated in China for fiber and seed production, and in India for resin production.1 For many centuries, European and East Asian societies have used mostly Cannabis strains containing low amounts (< 1% dry weight) of the psychoactive principle 9-Δ-tetrahydrocannabidiol (THC), and their main utilization was for fiber and food. Conversely, African, Middle-Eastern, South Asian, and Southeast Asian societies have used cannabis primarily for its psychoactive properties, with strains from these regions often containing 5–10% THC.1.

Compared with THC, CBD shows a better defined anticonvulsant profile in animal models considered to be predictive of efficacy against focal and generalized seizures. Moreover, CBD is largely devoid of adverse psychoactive effects, and is considered to lack the abuse liability associated with THC-containing products.134 In the last decade, this has led to an increasing use of CBD-enriched extracts as a potential treatment for epilepsy, particularly in children. Improvement in seizure control, often associated with additional benefits on sleep and behaviour, have been reported in a sizeable proportion of cases,87 but interpretation of these data is made difficult by the uncontrolled nature of the observations. Additionally, as discussed in this article, there are concerns about the quality and variability of many of the products used,98 particularly because cannabis treatment is often initiated spontaneously by patients or caregivers without adequate medical supervision.105.