Cannabidiol and Epilepsy: Sifting, Winnowing and Buzz

Posted on September 7, 2016 by David

“Over the past few years there has been a phenomenal resurgence in the interest in the use of Cannabis sativa and Cannabis indica for the treatment of epilepsy (among many other disorders as well). Clearly, the media and the proliferation of internet sites offering advice has fueled interest not only among patients and caregivers, but clinicians as well. Mainstream and social media interest in patient testimonials have, for better or worse, created a great deal of buzz. First, to the answer of does CBD provide benefit, the answer appears to be yes. With respect to safety perspective, CBD seemed to be well tolerated in most patients. At least we can finally say with some confidence to our patients, their families, and our colleagues, that there is more to this drug than media hype, and internet buzz.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988076/

http://www.thctotalhealthcare.com/category/epilepsy-2/

From cannabis to cannabidiol to treat epilepsy, where are we?

Posted on September 3, 2016 by David

Image result for Curr Pharm Des.

“Several antiepileptic drugs (AEDs), about 25, are currently clinically available for the treatment of patients with epilepsy. Despite this armamentarium and the many recently introduced AEDs, no major advances have been achieved considering the number of drug resistant patients, while many benefits have been indeed obtained for other clinical outcomes (e.g. better tolerability, less interactions).

Cannabinoids have long been studied for their potential therapeutical use and more recently phytocannabinoids have been considered a valuable tool for the treatment of several neurological disorders including epilepsy.

Among this wide class, the most studied is cannabidiol (CBD) considering its lack of psychotropic effects and its anticonvulsant properties.

Several preclinical studies have tried to understand the mechanism of action of CBD, which still remains largely not understood.

CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures; beneficial effects were reported also in animal models of epileptogenesis and chronic models of epilepsy,

There is indeed sufficient supporting data for clinical development and important antiepileptic effects and the currently ongoing clinical studies will permit the real usefulness of CBD and possibly other cannabinoids.

Undoubtedly, several issues also need to be addressed in the next future (e.g. better pharmacokinetic profiling). Finally, shading light on the mechanism of action and the study of other cannabinoids might represent an advantage for future developments.”

http://www.ncbi.nlm.nih.gov/pubmed/27587196

Marijuana use in adults admitted to a Canadian epilepsy monitoring unit.

Posted on August 30, 2016 by David

Image result for Epilepsy Behav.

“Epidemiologic evidence supporting antiseizure properties of cannabis is limited and controversial.

We determined the prevalence of marijuana use and its perceived effects in patients with and without epilepsy.

Patients with uncontrolled epilepsy or nonepileptic events had a high rate of marijuana use with associated perceived improvements in seizure control, stress, sleep, and drug side effects.

Stress reduction may contribute to the perceived impact of marijuana on seizures and nonepileptic events in adults.”

http://www.ncbi.nlm.nih.gov/pubmed/27568641

Cannabinoid type 1 receptor antagonism ameliorates harmaline-induced essential tremor in rat.

Posted on August 23, 2016 by David

“Essential tremor (ET) is a neurological disorder with unknown etiology. Its symptoms include cerebellar motor disturbances, cognitive and personality changes, hearing and olfactory deficits. Excitotoxic cerebellar climbing fibre hyperactivity may underlie essential tremor and has been emulated in rodents by systemic harmaline administration.

Cannabinoid receptor agonists can cause motor disturbances although there are also anecdotal reports of therapeutic benefits of cannabis in motor disorders. We set out to establish the effects of cannabinoid type 1 receptor agonism and antagonism in an established rodent model of ET using a battery of accepted behaviour assays in order to determine risk and therapeutic potential of endocannabinoid system modulation in ET.

Overall, harmaline induced robust tremor that was typically worsened across the measured behavioural domains by CB type 1 (CB₁ ) receptor agonism but ameliorated by cannabinoid type 1 receptor antagonism.

CONCLUSIONS AND IMPLICATIONS:

These results provide the first evidence of effects of endocannabinoid system modulation on motor function in the harmaline model of essential tremor and suggest that CB₁ receptor manipulation warrants clinical investigation as a therapeutic approach to protection against behavioural disturbances associated with essential tremor.”

http://www.ncbi.nlm.nih.gov/pubmed/27545646

CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a.

Posted on August 16, 2016 by David

“The CB1 cannabinoid receptor is a G-protein coupled receptor that has important physiological roles in synaptic plasticity, analgesia, appetite, and neuroprotection.

We report the discovery of two structurally related CB1 cannabinoid receptor interacting proteins (CRIP1a and CRIP1b) that bind to the distal C-terminal tail of CB1. CRIP1a and CRIP1b are generated by alternative splicing of a gene located on chromosome 2 in humans, and orthologs of CRIP1a occur throughout the vertebrates, whereas CRIP1b seems to be unique to primates.

CRIP1a coimmunoprecipitates with CB1receptors derived from rat brain homogenates, indicating that CRIP1a and CB1 interact in vivo. Furthermore, in superior cervical ganglion neurons coinjected with CB1 and CRIP1a or CRIP1b cDNA, CRIP1a, but not CRIP1b, suppresses CB1-mediated tonic inhibition of voltage-gated Ca2+ channels.

Discovery of CRIP1a provides the basis for a new avenue of research on mechanisms of CB1 regulation in the nervous system and may lead to development of novel drugs to treat disorders where modulation of CB1 activity has therapeutic potential (e.g., chronic pain, obesity, and epilepsy).”

http://www.ncbi.nlm.nih.gov/pubmed/17895407

Medical Marijuana-Opportunities and Challenges

Posted on August 11, 2016 by David

“Over the recent years, public and political opinions have demonstrated increasing support for the legalization of medical marijuana.

To date, 24 states as well as the District of Columbia have legalized cannabis for medical use, 4 states have legalized the recreational use of Marijuana.

Marijuana is derived from the hemp plant Cannabis sativa. Δ-9-tetrahydrocannabinol (THC) is the major psychoactive constituent of cannabis, while cannabidiol (CBD) is the major non-psychoactive constituent. THC is a partial agonist at CB1 and CB2 receptors, while CBD at high levels is an antagonist CB1 and CB2.

CB1 is abundantly expressed in the brain, and CB2 is expressed on immune cells (expression of CB2 on neurons remains controversial). The brain also produces endogenous cannabis-like substances (endocannabinoids) that bind and activate the CB1/CB2 receptors.

There is tremendous interest in harnessing the therapeutic potential of plant-derived and synthetic cannabinoids.

This Editorial provides an overview of diseases that may be treated by cannabinoids.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948749/

Crucial Roles of the Endocannabinoid 2-Arachidonoylglycerol in the Suppression of Epileptic Seizures.

Posted on July 28, 2016 by David

“Endocannabinoid signaling is considered to suppress excessive excitability of neural circuits and to protect the brain from seizures. However, the precise mechanisms of this effect are poorly understood.

Here, we report that 2-arachidonoylglycerol (2-AG), one of the two major endocannabinoids, is crucial for suppressing seizures.

We found that kainate-induced seizures in mice lacking the 2-AG synthesizing enzyme, diacylglycerol lipase α, were much more severe compared with those in cannabinoid CB₁ receptor knockout mice and were comparable to those in mice lacking both CB₁– and CB₂-receptor-mediated signaling.

In the dentate gyrus, 2-AG suppressed excitatory input around the inner and middle molecular layers through CB₁ and presumably CB₂ receptors, respectively.

This 2-AG-mediated suppression contributed to decreased granule cell excitability and the dampening of seizures. Furthermore, lack of 2-AG signaling enhanced kindling epileptogenesis and spontaneous seizures after kainate-induced status epilepticus.

These results highlight critical roles of 2-AG signaling in the suppression of epileptic seizures.”

http://www.ncbi.nlm.nih.gov/pubmed/27452464

Medical Marijuana for Epilepsy?

Posted on July 5, 2016 by David

“Treatment-refractory epilepsy remains an important clinical problem. There is considerable recent interest by the public and physicians in using medical marijuana or its derivatives to treat seizures. The endocannabinoid system has a role in neuronal balance and ictal control. There is clinical evidence of success in diminishing seizure frequencies with cannabis derivatives, but also documentation about exacerbating epilepsy or of no discernible effect. There are lay indications and anecdotal reports of success in attenuating the severity of epilepsy, but without solid investigational corroboration. Marijuana remains largely illegal, and may induce adverse consequences. Clinical applications are not approved, thus are restricted and only recommended in selected treatment unresponsive cases, with appropriate monitoring.”

http://www.ncbi.nlm.nih.gov/pubmed/27354925

Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy

Posted on June 21, 2016 by David

“Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments.

This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child’s seizures.

Nineteen responses met the inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic epilepsy.

The average number of anti-epileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child’s seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction.

Other beneficial effects included increased alertness, better mood and improved sleep. Side effects included drowsiness and fatigue.

Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children is not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated and efficacious at controlling seizures in this difficult-to-treat pediatric population.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157067/

Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents.

Posted on June 11, 2016 by David

“There is growing pressure for states and the federal government to legalize the use of cannabis products for medical purposes in the United States.

Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted Δ⁹ -tetrahydrocannabinol (Δ⁹ -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader.

The objectives of this review are to provide an overview of the pharmacology and toxicology of CBD; to summarize some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and to assess the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States.

Unlike Δ⁹ -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors (CB₁ and CB₂ ), whose activation results in the psychotropic effects characteristic of Δ⁹ -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use.

CBD exhibits antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties.

In combination with Δ⁹ -THC, CBD has received regulatory approvals in several European countries and is currently under study in U.S. Food and Drug Administration-registered trials in the United States.

A number of states have passed legislation to allow for the use of CBD-rich, limited Δ⁹ -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications.

Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain.”

http://www.ncbi.nlm.nih.gov/pubmed/27285147