Studies have shown CBD is effective at significantly decreasing the frequency of Epilepsy & Seizure Disorders: Cannabinoids and CBD Research Overview. Dravet syndrome is a type of severe epilepsy that develops during the first year of childhood and is characterized by frequent febrile seizures. Studies have. Although use of cannabis in epilepsy having a diagnosis of Dravet syndrome and fewer seizures while on CBD-enriched Overall, review of the available studies.
Seizure Disorders: & Overview CBD Cannabinoids Research Epilepsy and
Experimentally, many studies reviewed in recent articles 10 , 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.
Cannabinoids have numerous and complex pharmacological properties. In experimental models, for example, THC displays complex psychoactive effects, variable anticonvulsant effects, and analgesic, cognitive, muscle relaxant, anti-inflammatory, appetite stimulant, and antiemetic activity. A list of targets and actions reported for CBD based on results of studies in different experimental models and systems 24 — The list is not exhaustive and not all reported actions may be relevant to anti-seizure activity.
Among the many active principles found in the cannabis plant, THC is the most widely investigated for its many actions, including its psychoactive effects and risks associated with overdose and abuse. THC shows some anticonvulsant effects in certain seizure models, but there have also been studies suggesting a proconvulsant effect. In preclinical studies, CBD has been found to be active in a variety of seizures models, including seizures induced by maximal electro-shock 39 — 41 and by pentylentetrazole in rats and mice, 42 — 44 audiogenic seizures in rats 45 and seizures induced by 3-mercaptopropionic acid, bicuculline, picrotoxin, cocaine and isoniazid but not strychnine in mice.
These effects were observed at doses that did not cause motor impairment. 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.
CBDV, another cannabinoid present in the cannabis plant, has been the focus of many recent studies. In the cannabis plant, most cannabinoids are synthesized in their acidic form.
These acidic cannabinoids undergo decarboxylation to their neutral counterparts e. In most common extraction and delivery methods, plant materials are exposed to heat, resulting in the conversion of the acidic forms to the neutral constituents.
THCA has been found to possess anticonvulsant activity in preliminary preclinical investigations, and be devoid of adverse psychoactive effects. 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.
The clearance of CBD has been reported to be increased after co-administration with the enzyme inducer rifampicin. However, at least one clinically important interaction mediated by inhibition of drug metabolism has been reported. This interaction, which was considered to be mediated by inhibition of CYP2C19, is particularly relevant because clobazam is frequently used in epileptic encephalopathies for which CBD appears to be a promising new treatment.
In a safety and pharmacokinetic study in children with Dravet syndrome, there were minimal changes in clobazam levels, but concentrations of N-desmethyl clobazam increased independently of CBD dose, except for patients on stiripentol in whom N-desmethyl-clobazam levels appeared to be unaffected by CBD.
In adults, there were also increases in serum levels of zonisamide and eslicarbazepine. The results of this study are difficult to interpret, because of the confounding effects of changes in the dose of comedications. Serum clobazam levels, for example, decreased during CBD coadministration, primarily due to a reduction in clobazam dose. In any case, assessment of the data suggested that changes in serum levels of concomitant AEDs during CBD administration were generally minor, with the exception of clobazam and N-desmethylclobazam levels.
CBD may also be involved in pharmacodynamic interactions, i. In particular, acutely administered CBD may antagonize some of the effects of THC at CB1 receptor sites, 78 — 80 an observation which may explain why patients taking marijuana with higher CBD content are less likely to develop adverse THC-related psychotropic symptoms, and may tolerate high-ecr THC doses.
The observation has been made that elevations in liver enzymes associated with CBD treatment occur much more frequently among patients comedicated with valproate than among patients comedicated with other AEDs. 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 mg, as well as multiple doses of mg once daily over 5 days. The 7-hydroxy- and 6-hydroxy-metabolites could be detected shortly after dosing.
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 , Consroe et al. 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.
For medicinal use, oral intake provides a more easily controllable route of drug delivery than inhalation. Therefore, particularly during the last twenty years, users of cannabis for seizure control have generally preferred oral preparations. At the same time, increasing realization that CBD is superior to THC in safety and potential anti-seizure activity has resulted in preferential use of whole plant preparations or cannabis-based oil or liquid extracts enriched in CBD content.
A number of such products are accessible in many countries and states under widely different legal and regulatory scenarios. In this regard, a recent report described two children with manifestations suggestive of THC intoxication, including seizure exacerbation, in whom clinical symptoms remitted after switching their treatment from a CBD-enriched edible cannabis preparation to a formulation of purified CBD.
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.
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. The median duration of therapy was 6. 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, of the respondents reported to be using, or having previously used, cannabis products for the treatment of their seizures. Positive results with cannabis use were also reported in another recent online survey directed to parents of children with refractory epilepsy in Mexico. In addition to web-based surveys, there have several reports based on chart reviews. Comparable findings were reported in a similar report from Colorado, which included data from patients it is unclear whether this population partly overlapped with that described in the earlier report by the same group.
The average duration of cannabis use in this cohort was As in previous reports, many patients reported improvements in behavior, alertness, language, communication, motor skills and sleep. 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. 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.
To date, the largest exploratory study of the tolerability and anti-seizure activity of CBD relates to a recent physician-sponsored expanded-access programme at 11 epilepsy centres in the USA. Tolerability and safety were analysed for the group of patients who achieved at least 12 weeks of follow-up—this included 33 patients with Dravet syndrome and 31 patients with Lennox-Gastaut syndrome. Patients on clobazam, however, were also more likely to develop adverse effects, particularly somnolence and fatigue.
These differences in outcome in relation to type of comedication may be explained by the increase in plasma clobazam and N-desmethyl-clobazam levels caused by CBD. Overall, the main value of these studies is in providing a preliminary characterization of CBD safety profile. Data concerning improvement in seizure control, however, are difficult to assess in view of the uncontrolled nature of the observations. 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, , febrile infection-related epilepsy syndrome FIRES , Sturge-Weber syndrome and malignant migrating partial seizures in infancy.
The recent flurry of research focused on the potential usefulness of cannabinoids in epilepsy has resulted in the completion of three well controlled randomized trials, all of which evaluated a liquid proprietary oral formulation of CBD. As an indication of the high interest of the medical community in the application of cannabinoids to epilepsy management, the first randomized placebo-controlled double-blind trial of CBD in Dravet syndrome was published in the New England Journal of Medicine in May The duration of treatment was 14 weeks, including a 2-week-titration phase.
Compared with baseline, the median monthly frequency of convulsive seizures defined as the sum of tonic-clonic, tonic, clonic, and atonic seizures decreased from Median percent changes in seizure frequency are shown in Fig. Non-convulsive seizures were not significantly affected by CBD therapy. 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 syndrome 85 and Lennox-Gastaut syndrome.
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. For further details, see text.
Somnolence, diarrhea, and decreased appetite were the most common CBD-associated adverse events Table 2. Eighteen of the 22 CBD-treated patients who developed somnolence were on clobazam comedication. Adverse events appeared mostly during the first two weeks of therapy, and there were instances in which the dose of CBD or other medications were reduced. No information, however, was reported on how often the dose of concomitant clobazam was reduced. Eight patients in the CBD group discontinued the trial prematurely due to adverse events in three cases, marked elevation of liver enzymes , compared with one patient in the placebo group who also had a marked elevation in liver enzymes.
Overall, elevated aminotransferases levels occurred in 12 patients in the CBD group and one in the placebo group, all of whom were on concomitant valproate therapy. In the nine patients with raised aminotransferases who did not discontinued treatment, liver enzymes reverted to normal on continuation of therapy. Adverse events most commonly reported in the randomized double-bind placebo-controlled trial of CBD in comparison with placebo in patients with Dravet syndrome Overall, this trial provides for the first time robust evidence that CBD added-on to pre-existing AED treatment reduces the frequency of convulsive seizures in children and young adults with Dravet syndrome.
Interestingly, no significant differences between groups were found in sleep scores, behavioral adaptation Vineland-II scores, and Quality of Life in Childhood Epilepsy scores, even though duration of treatment was relatively short and possibly insufficient to determine changes in these parameters. A major weakness in the presentation of the trial results is the failure to report changes in plasma concentrations of concomitant AEDs and, most notably, clobazam and N-desmethylclobazam.
Two well controlled double-blind trials in patients with Lennox-Gastaut syndrome have been completed, but results to date have only been reported in summary form.
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. Duration of the trial was 14 weeks 2-week titration and week maintenance. Total seizures were also significantly reduced in both CBD groups compared with placebo. Some elevations in transaminases were seen. Published reports, however, provide no information on concomitant therapies, and most notably whether, and to what extent, the clinical improvement on CBD therapy could be related to elevation in serum concentrations of other medications, most notably clobazam and N-desmethylclobazam.
The interest in cannabis preparations in the treatment of epilepsies, particularly drug refractory childhood epilepsies, has skyrocketed in recent years. Marijuana and other cannabis products with moderate to high THC content utilized primarily for recreational purposes are generally unsuitable for this indication, not only because evidence for an anti-seizure activity of THC is equivocal and risk of seizure aggravation cannot be excluded, but also because THC is associated with many undesired effects, including addiction liability, psychiatric disorders, cognitive and motor impairment — and, possibly, also cardiovascular toxicity.
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. 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.
Evidence concerning the potential anti-seizure efficacy of cannabinoids reached a turning point in the last 12 months, with the completion of the first high-quality placebo-controlled trials of a purified oil-based liquid CBD preparation in patients with Dravet syndrome and Lennox-Gastaut syndrome. Therefore there is now for the first time class 1 evidence that CBD improves seizure control when added on to other AEDs in patients with two difficult-to-treat epileptic encephalopathies.
Available data, however, do not allow to conclude that CBD per se has anti-seizure activity. At least for the trial published in full, 85 a majority of patients were receiving concomitant clobazam therapy, and it is unclear whether the reported seizure benefits, as well as adverse effects, were related to a direct action of CBD, or were mediated by a previously described 5-fold elevation in plasma N-desmethylclobazam levels.
For the two studies in Lennox-Gastaut syndrome, the proportion of patients on concomitant clobazam therapy was not reported, but it is likely to have been significant because clobazam is a frequently used comedication in patients with this syndrome. Clarification of the independent effects of CBD would require re-assessment of trial data for the subgroup of patients not comedicated with clobazam, or the conduction of further studies after excluding such patients or, alternatively, adjusting blindly clobazam dosages to maintain unaltered concentration of N-desmethylclobazam.
Additional well controlled studies are also desirable to determine the potential value of CBD in other seizure types and epilepsy syndromes, including refractory focal epilepsies. 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.
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.
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.
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. National Center for Biotechnology Information , U. Journal List J Epilepsy Res v. Published online Dec Emilio Perucca 1, 2.
Author information Article notes Copyright and License information Disclaimer. Received Jul 11; Accepted Sep This article has been cited by other articles in PMC. Abstract The interest in cannabis-based products for the treatment of refractory epilepsy has skyrocketed in recent years. Cannabis, Cannabidiol, Epilepsy, Seizures, Review.
Introduction The history of human use of the Cannabis plant goes back to the dawn of mankind. Open in a separate window. Chemistry and mechanisms of action The genus Cannabis refers to a flowering plant of which there are three main species, Cannabis sativa , Cannabis indica and Cannabis ruderalis.
Table 1 A list of targets and actions reported for CBD based on results of studies in different experimental models and systems 24 — Pharmacological profile in experimental models of seizures and epilepsy Among the many active principles found in the cannabis plant, THC is the most widely investigated for its many actions, including its psychoactive effects and risks associated with overdose and abuse. CBD In preclinical studies, CBD has been found to be active in a variety of seizures models, including seizures induced by maximal electro-shock 39 — 41 and by pentylentetrazole in rats and mice, 42 — 44 audiogenic seizures in rats 45 and seizures induced by 3-mercaptopropionic acid, bicuculline, picrotoxin, cocaine and isoniazid but not strychnine in mice.
Clinical evidence of efficacy and safety: Well controlled randomized trials The recent flurry of research focused on the potential usefulness of cannabinoids in epilepsy has resulted in the completion of three well controlled randomized trials, all of which evaluated a liquid proprietary oral formulation of CBD.
Table 2 Adverse events most commonly reported in the randomized double-bind placebo-controlled trial of CBD in comparison with placebo in patients with Dravet syndrome Double-blind trials in Lennox-Gastaut syndrome Two well controlled double-blind trials in patients with Lennox-Gastaut syndrome have been completed, but results to date have only been reported in summary form. Conclusions and future perspectives The interest in cannabis preparations in the treatment of epilepsies, particularly drug refractory childhood epilepsies, has skyrocketed in recent years.
Marijuana and the Cannabinoids. Friedman D, Sirven JI. Historical perspective on the medical use of cannabis for epilepsy: Phytochemical and genetic analyses of ancient cannabis from Central Asia. On the preparations of the Indian hemp, or Gunjah: Cannabis indica their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Epilepsy and other chronic convulsive disorders. ElSohly M, Gul W.
Constituents of cannabis sativa. Oxford University Press; The pharmacological basis of cannabis therapy for epilepsy. J Pharmacol Exp Ther. Marijuana, endocannabinoids, and epilepsy: Mechoulam R, Parker LA.
The endocannabinoid system and the brain. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. Cannabinoids as hippocampal network administrators. Cannabis and endocannabinoid signaling in epilepsy.
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Therefore, any reliance you place on such information is strictly at your own risk. Please check with your medical doctor before starting or changing your CBD routine. I accept the terms and conditions and am aware that this notification will not appear again during an unspecified time.
Overview of Dravet Syndrome Dravet syndrome, which is also referred to as severe myoclonic epilepsy of infancy SMEI , is a severe form of epilepsy that typically develops during the first year of life. Effects of Cannabinoids and CBD on Dravet Syndrome One of the major cannabinoids found in cannabis, cannabidiol CBD , has been determined to be a well-tolerated therapeutic treatment that can reduce or even eliminate seizures in a variety of childhood epilepsy disorders 1,2,12, Expert Opinion on Pharmacology , 16 13 , Epilepsia , 55 6 , Journal of Clinical Pharmacology and Therapeutics , 40 2 , Cannabinoids in the Treatment of Epilepsy.
The New England Journal of Medicine , 11 , Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. British Journal of Pharmacology , 3 , Phytocannabinoids as novel therapeutic agents in CNS disorders.
Cannabis, endocannabinoids, and epilepsy: Experimental Neurology , , The case for medical Cannabis in epilepsy. National Institute of Neurological Disorders and Stroke. Neurotherapeutics , Epub ahead of print. Cannabis, cannabidiol, and epilepsy—from receptors to clinical response.
Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. European Journal of Pharmacology , 1 , What is Dravet syndrome? What you can read next What is CBD? Leave a Reply Cancel reply Your email address will not be published. Receive the latest ECHO news by joining our newsletter.
Dravet Syndrome: Cannabinoids and CBD Research Overview
The FDA recently approved the use of Epidiolex (a plant-based formulation of CBD) to treat seizures for people 2 years of age and older with Dravet syndrome . A collection of published research articles, videos, and other educational resources about epilepsy and CBD (cannabidiol). Epilepsy & Seizure Disorders. This use of a cannabinoid to treat seizures is not unfounded, the ever-popular THC molecule has been studied in children with seizure disorders. The results of early cannabinoid clinical studies and anecdotal findings for epilepsy are an overview and a lot of background information on cannabinoids for.