Category Archives: Epilepsy

The potential role of cannabinoids in epilepsy treatment.

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“Epilepsy is one of the world’s oldest recognized and prevalent neurological diseases. It has a great negative impact on patients’ quality of life (QOL) as a consequence of treatment resistant seizures in about 30% of patients together with drugs’ side effects and comorbidities. Therefore, new drugs are needed and cannabinoids, above all cannabidiol, have recently gathered attention.

This review summarizes the scientific data from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including drugs acting on the endocannabinoid system.

Despite the fact that cannabis has been used for many purposes over 4 millennia, the development of drugs based on cannabinoids has been very slow. Only recently, research has focused on their potential effects and CBD is the first treatment of this group with clinical evidence of efficacy in children with Dravet syndrome; moreover, other studies are currently ongoing to confirm its effectiveness in patients with epilepsy.

On the other hand, it will be of interest to understand whether drugs acting on the endocannabinoid system will be able to reach the market and prove their known preclinical efficacy also in patients with epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/28845714   http://www.tandfonline.com/doi/abs/10.1080/14737175.2017.1373019

 

“The role of cannabinoids and endocannabinoid system in the treatment of epilepsy. Cannabis has been used for thousands of years in the treatment of various diseases. Cannabinoids have been shown in preliminary animal model studies and in studies of patients with epilepsy to have antiepileptic activity. ” https://www.degruyter.com/view/j/joepi.ahead-of-print/joepi-2015-0034/joepi-2015-0034.xml
 
“Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects.”

Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: Pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels.

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“Cannabidiol (CBD), the main nonpsychotomimetic compound from Cannabis sativa, inhibits experimental seizures in animal models and alleviates certain types of intractable epilepsies in patients.

Here we tested the hypothesis that CBD anticonvulsant mechanisms are prevented by cannabinoid (CB1 and CB2) and vanilloid (TRPV1) receptor blockers. We also investigated its effects on electroencephalographic (EEG) activity and hippocampal cytokines in the pentylenetetrazole (PTZ) model.

Pretreatment with CBD (60mg/kg) attenuated seizures induced by intraperitoneal, subcutaneous, and intravenous PTZ administration in mice. The effects were reversed by CB1, CB2, and TRPV1 selective antagonists (AM251, AM630, and SB366791, respectively). Additionally, CBD delayed seizure sensitization resulting from repeated PTZ administration (kindling). This cannabinoid also prevented PTZ-induced EEG activity and interleukin-6 increase in prefrontal cortex.

In conclusion, the robust anticonvulsant effects of CBD may result from multiple pharmacological mechanisms, including facilitation of endocannabinoid signaling and TRPV1 mechanisms. These findings advance our understanding on CBD inhibition of seizures, EEG activity, and cytokine actions, with potential implications for the development of new treatments for certain epileptic syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/28821005

http://www.epilepsybehavior.com/article/S1525-5050(17)30322-0/fulltext

Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid.

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“The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection.

The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis. CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies.

The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes.”

https://www.ncbi.nlm.nih.gov/pubmed/28788104

http://www.mdpi.com/1422-0067/18/8/1669

Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy?

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 “Epilepsy is an important disease that affects brain function, particularly in those under 3 years old. Uncontrolled seizures can affect cognitive function and quality of life. For these reasons, many trials have been conducted to investigate treatments for pediatric epilepsy. Currently, many antiepileptic drugs are available for the treatment of epilepsy, but cases of intractable epilepsy continue to exist.

In the past, cannabis has been tested as a potential treatment of intractable epilepsy.

Since 2013, 10 epilepsy centers in America have conducted research regarding the efficacy of cannabis to treat epilepsy. Cannabis has many components, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). THC has psychoactive properties exerted through its binding of the cannabinoid receptor (CBR) whereas CBD is a CBR antagonist. The inhibition of epilepsy by CBD may therefore be caused by various mechanisms, although the detailed mechanisms of CBD actions have not yet been well defined. In most studies, trial doses of CBD were 2-5 mg/kg/day.

Several such studies have shown that CBD does have efficacy for treatment of epilepsy.

Reported adverse effects of CBD were mostly mild, including drowsiness, diarrhea, and decreased appetite. Severe adverse reactions requiring treatment, such as status epilepticus, have also been reported but it is not clear that this is related to CBD. Furthermore, many previous studies have been limited by an open-label or survey design. In future, double-blind, controlled trials are required and the use of CBD to treat other neurological problems should also be investigated.”  https://www.ncbi.nlm.nih.gov/pubmed/28775950

“Most studies suggest anticonvulsant effects of CBD, and consider most adverse effects to be mild. It must be borne in mind that CBD is still illegal in many contexts. However, it has the potential to treat various neurological problems, including epilepsy.” http://www.j-epilepsy.org/journal/view.php?doi=10.14581/jer.17003

Cannabidiol reduces seizure frequency in Dravet syndrome

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“Cannabidiol is effective in treating drug-resistant seizures in Dravet syndrome, according to a new clinical trial. For the first time, a multinational, randomized, double-blind, placebo-controlled trial has confirmed controversial anecdotal evidence supporting the efficacy of cannabinoids in epilepsy.” https://www.nature.com/nrneurol/journal/v13/n7/full/nrneurol.2017.86.html

“Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome”  http://www.nejm.org/doi/10.1056/NEJMoa1611618

“Cannabinoids for Epilepsy — Real Data, at Last”  http://www.nejm.org/doi/full/10.1056/NEJMe1702205

Fewer Seizures With Cannabidiol in Catastrophic Epilepsy

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Cannabidiol reduces frequency of seizures in patients with Dravet syndrome.

“Cannabidiol reduced the frequency of convulsive seizures compared with placebo in Dravet syndrome, a childhood epilepsy disorder with a high mortality rate and no approved treatment in the United States, reported a clinical trial in the New England Journal of Medicine.” http://jamanetwork.com/journals/jama/fullarticle/2645099

“Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome”  http://www.nejm.org/doi/full/10.1056/NEJMoa1611618#t=abstract

“EPILEPSY AND MARIJUANA: CANNABIS DRUG REDUCES DRAVET SYNDROME SEIZURES IN LARGE-SCALE CLINICAL TRIAL” http://www.newsweek.com/cannabis-marijuana-dravet-syndrome-epilepsy-clinical-trial-614982

[Cannabidiol: its use in refractory epilepsies].

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“Some epileptic syndromes are characterised by seizures that are difficult to control and are associated to delayed neuropsychomotor development, which results in a deterioration in the patient’s quality of life as well as in that of his or her family.

AIM:

To evaluate the use of cannabidiol as adjuvant therapy in patients with refractory epilepsies.

PATIENTS AND METHODS:

An observational study was conducted by means of a survey addressed to the patient’s caregiver. Data collected included information about the patient and the caregiver, changes observed in the seizures, neuropsychological effects, side effects and the family’s overall perception following the use of cannabidiol.

RESULTS:

The evaluation examined 15 patients with refractory epilepsies, who received cannabidiol over a period ranging from one month to one year. The frequency of seizures decreased in 40% of the patients, 60% of the patients were seen to have control over 50% of their seizures and in 27% of them the seizures disappeared completely. Neurocognitive changes were also reported: behaviour improved in 73%; 60% reported an improvement in language; in 50% sleep improved; 43% reported improvements in eating habits; and 100% said their mood had improved. The overall perception of the illness was that there had been improvements in 73% of respondents. The most common side effects were drowsiness and fatigue.

CONCLUSIONS:

These results suggest a possible beneficial effect of cannabidiol on the control of seizures and on the improvement of certain neurocognitive aspects in patients with refractory epilepsies.”

https://www.ncbi.nlm.nih.gov/pubmed/28726233

An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol.

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“Cannabidiol (CBD) has been traditionally used in Cannabis-based preparation, however historically, it has received far less interest as a single drug than the other components of Cannabis. Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging.”  https://www.ncbi.nlm.nih.gov/pubmed/28701957

http://journal.frontiersin.org/article/10.3389/fphar.2017.00422/full

Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats.

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“Although drugs targeting the cannabinoid system (e.g., CB1 receptor agonists) display anticonvulsant efficacy in adult animal models of seizures/epilepsy, they remain unexplored in developing animal models. However, cannabinoid system functions emerge early in development, providing a rationale for targeting this system in neonates.

We examined the therapeutic potential of drugs targeting the cannabinoid system in three seizure models in developing rats.

The mixed CB1/2 agonist and the CB1-specific agonist, but no other drugs, displayed anticonvulsant effects against clonic seizures in the DMCM model. By contrast, both CB1 and CB2 antagonism increased seizure severity. Similarly, we found that the CB1/2 agonist displayed antiseizure efficacy against acute hypoxia-induced seizures (automatisms, clonic and tonic-clonic seizures) and tonic-clonic seizures evoked by PTZ.

Early life seizures represent a significant cause of morbidity, with 30-40% of infants and children with epilepsy failing to achieve seizure remission with current pharmacotherapy. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority.

These data indicate that the anticonvulsant action of the CB system is specific to CB1 receptor activation during early development and provide justification for further examination of CB1 receptor agonists as novel antiepileptic drugs targeting epilepsy in infants and children.” https://www.ncbi.nlm.nih.gov/pubmed/28691158

http://onlinelibrary.wiley.com/doi/10.1111/epi.13842/abstract

Cannabinoids in Pediatrics.

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“Despite its controversial nature, the use of medical marijuana and cannabis-derived medicinal products grows more popular with each passing year. As of November 2016, over 40 states have passed legislation regarding the use of either medical marijuana or cannabidiol products. Many providers have started encountering patients experimenting with cannabis products for a wide range of conditions. While the debate continues regarding these agents for both medicinal and recreational use in the general population, special consideration needs to be made for pediatric use. This review will deliver the history of marijuana use and legislation in the United States in addition to the currently available medical literature to equip pediatric health care providers with resources to provide patients and their parents the best recommendation for safe and appropriate use of cannabis-containing compounds.” https://www.ncbi.nlm.nih.gov/pubmed/28638299     http://www.jppt.org/doi/10.5863/1551-6776-22.3.176?code=ppag-site

“Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy.” https://www.ncbi.nlm.nih.gov/pubmed/24237632

“The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law.”  https://www.ncbi.nlm.nih.gov/pubmed/28169144