Medical Cannabis for Epilepsy Part Two by Jeffrey Dach MD

A remarkable development has the news media buzzing, a neurology journal, Epilepsia, has just published the Case for Medical Marijuana in Epilepsy, May 22, 2014.(1-4)

Header Image: Matt Figi, Charlotte, Max, Charlotte’s twin sister Chase Figi and Paige Figi (left to right) courtesy of Army Times.

The first article included testimony from Paige Figi, the energetic mother who administered the Charlotte’s Web Marijuana Strain which controlled her daughter’s intractable seizure disorder.  Paige Figi was instrumental in changing Sanjay Gupta’s mind about medicinal cannabis, and the family was featured in the CNN documentary, Weed. (1)

The Charlotte’s Web strain of medicinal cannabis is high in CBD (cannabidiol), and low in THC (the psycho-active component).  Charlotte’s mom gave her the cannabis oil slowly titrated over weeks, and found it successful in reducing the frequency of seizure epidodes from 50 per day to now 2–3 per month.  The medicinal cannabis allowed Charlotte to completely wean off her conventional anti-epileptic drugs.(1)(20)

A December 2013 report in Epilepsy Behavior described 19 families on a Facebook group using cannabidiol-enriched cannabis for treatment-resistant seizure disorder.(16)  Thirteen of the children children had Dravet syndrome, similar to Charlotte Figi.  On average for the group, twelve different anti-epileptic drugs had been unsuccessfully tried before resorting to medicinal cannabis.(16)   Sixteen (84%) of the children had reduction in their child’s seizure frequency with the cannabis oil.  Two children (11%) had complete relief from seizures. Eight children (42%) enjoyed more than 80% reduction in seizure activity, and another six children (32%) noted seizure frequency reduced by half.(16)

Thirty Per Cent Uncontrolled by Conventional Drugs

Epilepsy affects approximately 50 million people worldwide. Most of whom are controlled by drugs.  However approximately thirty per cent of these patients are refractory to conventional medication.  This highlights the need for more effective therapy for the 17 million who are refractory to drug treatment.(reference link)

The Endocannabinoid System of the Brain

Cannabis extracts have been used to treat epilepsy since antiquity.(36)  The utility of the cannabis plant no doubt arises from the astonishing 1992 discovery by Raphael Mechoulam of the endocannabinoid system in the brain and peripheral tissues.  Not only are there endocannabinoid receptors, CB1 and CB2 present in the brain and peripheral tissues.  There are also endogenous neurotransmitters (also called ligands)  which attach to and activate the CB1 and CB2 receptors.

The first ligand, anandamide was isolated in 1992 by Raphael Mehoulham’s team at Hebrew University in Jerusalem.  Anandamide, is a Sanskrit a word meaning “bliss”.  The second ligand, 2-arachidonoylglycerol (2-AG), was isolated in 1995.

Functions of CB1 and CB2 

Plant Cannabinoids which mimic our endogenous cannabinoids may serve to bind to and activate our own endogenous endocannabinoid system under various circumstances.  In some circumstances the cannabinoids may inhibit degradation of endogenous cannabinoids or even serve to block receptors.

The role of the endocannabinoid system in Seizure Disorders.

In 2008, Dr Anikó Ludányi published a study in the Journal of Neuroscience showing the brain of patients suffering from temporal lobe epilepsy had a dysfunctional endocannabinoid system.(11)

The Synapse- and Neurotransmitters

In the brain the major unit of communication between neurons is called the synapse.  This is the narrow space between the two nerve units in which chemicals known as neurotransmitters are released to allow the nerve impulse to continue on to the next (post-synaptic) neuron.  Since brain tissue is three dimensional, it is possible for these nerve impulses to form a circular feedback loop, with increasing amplitude and strength of the signal.  This may be likened to a chain reaction in a nuclear reactor reaching critical mass, and this may cause a seizure episode, with uncontrollable tonic and clonic motor activity.

Enter the Endocannobinoid System

This is where the endocanabinoid system comes in. Its major function in the brain is to slow down or even halt these synaptic feedback loops, thus preventing unwanted seizure activity.   Normally, neurotransmitters travel from the pre-synaptic neuron to the post-synaptic neuron.   The endocannabinoid system does just the reverse.  Their neurotransmitters, called endocannabinoids, are released by the post-synaptic neuron, and travel backwards to bind with (CB1) receptors on the pre-synaptic neuron where they  suppress neurotransmitter release.  In situations of excess  excitability, retrograde endocannabinoid signaling is the control mechanism that prevents the chain reaction called an epileptic seizure.(11,13-15)

Studies show that endocannabinoid levels are strongly elevated after seizure activity in experimental models of induced epilepsy.(11)  In addition, activation of pre-synaptic CB1 receptors with anandamide or 2-AG prevents epileptic seizures in animal models.  Similarly,  synthetic drugs designed to bind to the CB1 receptor will dampen seizure activity.

Conversely, blocking pre-synaptic CB1 receptors with a drug, or  with genetic manipulation, induces seizure disorder in experimental animals.

In severe long standing epilepsy, the protective endocannabinoid signaling pathway is disrupted, accounting for reduced seizure threshold and increased neuronal damage.(11)

Noise Control ?

If you find yourself in a noisy room, you can turn down the sound volume on a hearing aid, sparing damage to your hearing.  Similarly, the endocannabinoid system enables our neurons to dampen and reduce the amplitude of the received signal, thus providing protection from over-excitability. (13-15)

Dr Wallace reported in 2003 Journal of Pharmacology the endogenous cannabinoid system regulates seizure frequency and duration in an animal model of temporal lobe epilepsy.(22)  During chemically induced seizures, the amount of endogenous endocannabinoid (2-AG) increased within the epileptic focus. In addition molecular analysis showed increased CB1 receptor protein epileptic focus (in the hippocampus).(22)

A Search for the Active Ingredient – Cannabidiol

There are nearly 100 different molecules in the cannabis plant .  However, the two most studied are THC which has psychoactive properties,  and CBD (cannabidiol) which lacks psychoactive actions.  Since the high CBD cannabis extracts have the most success in treating childhood seizure disorder, it might be reasonable to study CBD further.  This is exactly what was done by  Dr. Jones in a 2012 study using CBD in differing animal models of drug induced seizures. (17,18)

Dr Jones concluded: “when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies.”(17,18)  In addition, Dr. Jones found that the benefits of CBD seem to be independent of CB1 receptor activity. He says: “CBD acts in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo.”(18)

Mechanism of Action Remains Elusive

As of 2009, although cannabidiol CBD is known to have a potent anti-convulsant effect in animal models and human studies, the mechansm of action remains unknown.  CBD seems to exert its effects independent of the CB1 receptor.  Some have proposed the hypothesis that its effects are mediated by reduced degradation of endogenous cannabinoids allowing for increased availability of anandamide and 2-AG at the synaptic clefts. (28-31)

Cannabidiol Anti-Cancer Effects

Although we are writing on anti-seizure activity of cannabis, and cannabidiol, there has been considerable attention and study on the anti-cancer effects of cannabidiol. (33)

Other Beneficial Uses of Cannabidiol

Cannabidiol, which can be isolated from cannabis oil, as well as hemp oil has other beneficial effects which have been studied over the years, including reducing anxiety, reducing inflammation, improving sleep, as a treatment for migraine headache, irritable bowel syndrome (IBS), fibromyalgia pain and Neuropathic pain, opiate addiction, endometriosis, autoimmune disease, crohn’s disease, rheumatoid arthritis, glaucoma, Multiple Sclerosis,  etc.(34,35,36)

Early Studies

Early studies on epilepsy in humans were done in 1980 by Mechoulaham.(19)  The results were prominsing with the small number of subjects remaining the main criticsm.(19)

CBDV –  Cannabidivarin another promising cannabinoid

In 2012 Dr. Hill published a study using the cannabinoid, CBDV, in epilepsy with promising results in a mouse model of chemically induced seizures.(21)  He found CBDV to be effective as an anticonvulsant over a range of different animal seizure models.(21)

Effect of CBD is not CB1 Related

Dr. Wallace studied the role of CB1 receptors in epilepsy finding that “activation of the CB1 receptor has proven to dampen neurotransmission and produce an overall reduction in neuronal excitability.” (23)  He also concluded that the “anticonvulsant effects of THC and the drug WIN 55 are cannabinoid CB1 receptor-mediated while the anticonvulsant activity of cannabidiol is not.”(23)

Its A Little More Complicated Than We Thought

Reporting in 2008 on an electro-shock mouse model of seizures, Dr Naderi evaluated the interactions between cannabinoid compounds and the anti-convulsant drug, diazepam (Valium).(24)  He found the effects of cannabinoids on epilepsy were dependent upon the responsiveness of GABAergic and glutamatergic neurotransmission. The antiepileptic effects of cannabinoids were explained by inhibition of excitatory glutamate neurotransmission.  Yet, Dr Naderi found an antagonistic interaction with diazepam due to cannabinoid inhibition of the  GABAergic system.(24)

A Balance between Inhibition and Excitation

In the brain there is a balance between inhibitory and excitatory neuro-transmission.   If the intensity of excitatory transmission exceeds a certain threshold, then epileptic seizures can occur.(25)  Similarly, Dr Lutz reported in 2004 that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids.(25)

In 2006, Dr Pál Pacher studied the Endocannabinoid System  in a rat model of drug induced epilepsy, CB1 receptor agonists were more effective than commonly used anticonvulsant drugs such as Dilantin and Phenobarbital.(26)

Margaret Gedde Study Links:

WHOLE CANNABIS EXTRACT OF HIGH CONCENTRATION CANNABIDIOL MAY CALM SEIZURES Margaret Gedde 2013

Medical Cannabis Available in Florida:
Cannabinoid Institute of Florida
CTI Florida http://www.ctiflorida.org/
904.586.4633

This article is part two, for part one, click here.

Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie Fl 33314
954-792-4663

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Cannabis epilepsy links
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Epilepsia; Published Online: May 22, 2014

1) http://onlinelibrary.wiley.com/doi/10.1111/epi.12610/full
The Case for Medical Marijuana in Epilepsy.
Edward Maa and Paige Figi. Epilepsia; Published Online: May 22, 2014 (DOI: 10.1111/epi.12610).

Charlotte, a little girl with SCN1A-confirmed Dravet syndrome, was recently featured in a special that aired on CNN. Through exhaustive personal research and assistance from a Colorado-based medical marijuana group (Realm of Caring), Charlotte’s mother started adjunctive therapy with a high concentration cannabidiol/Δ9-tetrahydrocannabinol (CBD:THC) strain of cannabis, now known as Charlotte’s Web. This extract, slowly titrated over weeks and given in conjunction with her existing antiepileptic drug regimen, reduced Charlotte’s seizure frequency from nearly 50 convulsive seizures per day to now 2–3 nocturnal convulsions per month. This effect has persisted for the last 20 months, and Charlotte has been successfully weaned from her other antiepileptic drugs. We briefly review some of the history, preclinical and clinical data, and controversies surrounding the use of medical marijuana for the treatment of epilepsy, and make a case that the desire to isolate and treat with pharmaceutical grade compounds from cannabis (specifically CBD) may be inferior to therapy with whole plant extracts. Much more needs to be learned about the mechanisms of antiepileptic activity of the phytocannabinoids and other constituents of Cannabis sativa.

2) http://onlinelibrary.wiley.com/doi/10.1111/epi.12631/full

Cannabidiol_Pharmacology_potential_therapeutic role_Devinsky_epi12631

3) http://onlinelibrary.wiley.com/doi/10.1111/epi.12635/full

Cannabidiol_in_epilepsy_Maria_Roberta_Cilio_Epilepsia_2014
Cilio, Maria Roberta, Elizabeth A. Thiele, and Orrin Devinsky. “The case for assessing cannabidiol in epilepsy.” Epilepsia (2014).

4) http://onlinelibrary.wiley.com/doi/10.1111/epi.12647/full
From the Editors: Cannabidiol and Medical Marijuana for the Treatment Of Epilepsy.”  Gary Mathern, Astrid Nehlig and Michael Sperling. Epilepsia; Published Online: May 22, 2014 (DOI: 10.1111/epi.12647).

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5) http://www.eurekalert.org/pub_releases/2014-05/w-ccc051914.php

Eureka Nes Alert: Could cannabis curb seizures? Experts weed through the evidence.

The therapeutic potential of medical marijuana and pure cannabidiol (CBD), an active substance in the cannabis plant, for neurologic conditions is highly debated. A series of articles published in Epilepsia, a journal of the International League Against Epilepsy (ILAE), examine the potential use of medical marijuana and CBD in treating severe forms of epilepsy such as Dravet syndrome.

6) http://www.universityherald.com/articles/9547/20140522/marijuana-may-reduce-seizures-in-epilepsy-patients.htm
May 22, 2014 10:44 AM EDT By Jaleesa Baulkman, UniversityHerald Reporter  . Marijuana May Reduce Seizures In Epilepsy Patients

8)

 

9)

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Medical Literature

2013

10) http://onlinelibrary.wiley.com/doi/10.1111/bph.12321/abstract  Cannabis and Seizure Disorders.
Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism.  funded by GW pharaceuticals. British Journal of Pharmacology  Volume 170, Issue 3, pages 679–692, October 2013

Epilepsy is the most prevalent neurological disease and is characterized by recurrent seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB1 receptors.Experimental Approach:  The anticonvulsant profiles of two CBDV BDSs (50–422 mg·kg−1) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip strength assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using displacement binding assays.Key Results: CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg·kg−1) and audiogenic seizure models (≥87 mg·kg−1), and suppressed pilocarpine-induced convulsions (≥100 mg·kg−1). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip strength were found.The Δ9-tetrahydrocannabinol and Δ9-tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV.
Conclusions and Implications: CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor and were of comparable efficacy with purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for the treatment of epilepsy.very important article

 

2008 full text  Electron Microscope Study of Hippocampus

CB1 cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus.

11)http://www.jneurosci.org/content/28/12/2976.long

http://www.ncbi.nlm.nih.gov/pubmed/18354002

Downregulation of the CB1 Cannabinoid Receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus. by Anikó Ludányi 1 ,    Loránd Erőss 2 ,    Sándor Czirják 2 ,    János Vajda 2 ,     Péter Halász 3 ,    Masahiko Watanabe 4 ,    Miklós Palkovits 5 ,    Zsófia Maglóczky 1 ,     Tamás F. Freund 1 , and    István Katona 1  The Journal of Neuroscience, 19 March 2008, 28(12): 2976-2990;

Endocannabinoid signaling is a key regulator of synaptic neurotransmission throughout the brain. Compelling evidence shows that its perturbation leads to development of epileptic seizures, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability.To elucidate whether long-term reorganization of endocannabinoid signaling occurs in epileptic patients, we performed comparative expression profiling along with quantitative electron microscopic analysis in control (postmortem samples from subjects with no signs of neurological disorders) and epileptic (surgically removed from patients with intractable temporal lobe epilepsy) hippocampal tissue.

Quantitative PCR measurements revealed that CB1 cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus. Likewise, the cannabinoid receptor-interacting protein-1a mRNA was decreased, whereas 1b isoform levels were unaltered. Expression of diacylglycerol lipase-α, an enzyme responsible for 2-arachidonoylglycerol synthesis, was also reduced by ∼60%, whereas its related β isoform levels were unchanged. Expression level of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and fatty acid amide hydrolase, metabolic enzymes of anandamide, and 2-arachidonoylglycerol’s degrading enzyme monoacylglycerol lipase did not change. The density of CB1 immunolabeling was also decreased in epileptic hippocampus, predominantly in the dentate gyrus, where quantitative electron microscopic analysis did not reveal changes in the ratio of CB1-positive GABAergic boutons, but uncovered robust reduction in the fraction of CB1-positive glutamatergic axon terminals.

These findings show that a neuroprotective machinery involving endocannabinoids is impaired in epileptic human hippocampus and imply that downregulation of CB1 receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.

nice article:

12) http://www.denalihealthcaremi.com/medical-marijuana-epilepsy/How Medical Marijuana and Epilepsy Go Hand in Hand
Robert Townsend, January 20th, 2014

from the above.

very important …full text 2004

Endocannabinoid System and Epilepsy

13) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1176361/?tool=pmcentrez#__ffn_sectitle
Epilepsy Curr. Sep 2004; 4(5): 169–173.  Endocannabinoids and Their Implications for Epilepsy  Bradley E. Alger, Ph.D.

endogenous ligands of the brain’s cannabinoid receptors, or endocannabinoids, serve as retrograde messengers that enable a cell to control the strength of its own synaptic inputs.

Endocannabinoids are released by bursts of action potentials, including events resembling interictal spikes, and probably by seizures as well.

Activation of cannabinoid receptors has been implicated in neuroprotection against excitotoxicity and can help explain the anticonvulsant properties of cannabinoids that have been known since antiquity.

2008 Endocannabinoid System

14) http://www.myhealthywaist.org/cmrejournal/articles/vol1/v1i3a3.php
PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL FUNCTIONS OF THE ENDOCANNABINOID SYSTEM IN THE CENTRAL NERVOUS SYSTEM.  By Beat Lutz, PhD Johannes Gutenberg University Mainz, Mainz, Germany  CMR Journal . Volume 1, Issue 3, December 2008

cannabinoid receptor type 1 (CB1 receptor) is expressed in two very different neuronal subpopulations: in inhibitory GABAergic neurons and in excitatory glutamatergic neurons.

endocannabinoids are involved in retrograde signalling processes, where endocannabinoids are released from the postsynapse and, after crossing the synaptic cleft, they bind to pre-synaptic CB1 receptors, leading to the suppression of neurotransmitter release. As CB1 receptors are present on the synaptic terminals of different neurotransmitters, the physiological and pathophysiological consequences of retrograde endocannabinoid-mediated suppression of neurotransmission may be rather divergent, depending on the exact neurotransmitter that is modulated.

depending on the site of dysregulation of the ECS, either blocking or enhancing endocannabinoid signalling may be of therapeutic benefit

2006 Endocannabinoid System and Epilepsy
full text very important….

15) http://www.sciencedirect.com/science/article/pii/S0896627306005460

Neuron Volume 51, Issue 4, 17 August 2006, Pages 455–466
The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus      Krisztina Monory1, 2, 9,    Federico Massa1, 2, 9,  Michaela Egertová3, 9,    Matthias Eder2,     Heike Blaudzun2,

Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.

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2013 Report by Parent: Case Reports of 19 cases-
Survey of parents in Facebook Group

16) http://www.ncbi.nlm.nih.gov/pubmed/24237632
Epilepsy Behav. 2013 Dec;29(3):574-7.
Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy.  Porter BE1, Jacobson C.

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 following 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 antiepileptic 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 their 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 are 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 pediatric population with difficult-to-treat seizures.

2012 Cannabidiol in Animal Model of Seizures

17) http://www.ncbi.nlm.nih.gov/pubmed/22520455
Seizure. 2012 Jun;21(5):344-52.
Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures.  Jones NA1, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE, Burnett MD, Yamasaki Y, Stephens GJ, Whalley BJ, Williams CM.

Cannabis sativa has been associated with contradictory effects upon seizure states despite its medicinal use by numerous people with epilepsy. We have recently shown that the phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the well-established in vivo model of pentylenetetrazole-induced generalised seizures, suggesting that earlier, small-scale clinical trials examining CBD effects in people with epilepsy warrant renewed attention.

Here, we report the effects of pure CBD (1, 10 and 100mg/kg) in two other established rodent seizure models, the acute pilocarpine model of temporal lobe seizure and the penicillin model of partial seizure. Seizure activity was video recorded and scored offline using model-specific seizure severity scales. In the pilocarpine model CBD (all doses) significantly reduced the percentage of animals experiencing the most severe seizures. In the penicillin model, CBD (≥ 10 mg/kg) significantly decreased the percentage mortality as a result of seizures; CBD (all doses) also decreased the percentage of animals experiencing the most severe tonic-clonic seizures. These results extend the anti-convulsant profile of CBD; when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies.

2010 Cannabidiol Seizures- ANimal Model

CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo.

18) http://www.ncbi.nlm.nih.gov/pubmed/19906779
J Pharmacol Exp Ther. 2010 Feb;332(2):569-77. doi: 10.1124/jpet.109.159145. Epub 2009 Nov 11.
Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo.  Jones NA1, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ.

Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings.

In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions).

In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions).

In Vivo Model

CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in [(35)S]guanosine 5′-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.

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Early Studies

1980 – Human Study 1980 – Mechoulam R

19) http://www.ncbi.nlm.nih.gov/pubmed/7413719
Pharmacology. 1980;21(3):175-85.  Chronic administration of cannabidiol to healthy volunteers and epileptic patients.  Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Sanvito WL, Lander N, Mechoulam R.

In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8 health human volunteers. Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting. Neurological and physical examinations, blood and urine analysis, ECG and EEG were performed at weekly intervals. In phase 2 of the study, 15 patients suffering from secondary generalized epilepsy with temporal focus were randomly divided into two groups. Each patient received, in a double-blind procedure, 200-300 mg daily of CBD or placebo. The drugs were administered for along as 4 1/2 months. Clinical and laboratory examinations, EEG and ECG were performed at 15- or 30-day intervals. Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment, although these drugs no longer controlled the signs of the disease. All patients and volunteers tolerated CBD very well and no signs of toxicity or serious side effects were detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved. The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed.

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Article on Charlotte Figi And Dravets Syndrome

20) http://neurosciencefundamentals.unsw.wikispaces.net/Marijuana+and+Epilepsy
Marijuana and Epilepsy.

On August 7th 2013, a news article on CNN informs its readers of the journey of a young 6 year old girl named Charlotte Figi (shown in the images below), who has Dravet Syndrome, a rare form of epilepsy. Dravet Syndrome is a branch of generalised epilepsy with febrile seizures (GEFS+) that denotes severe myoclonic epilepsy of infants (SMEI). Caused by dysfunction in GABA receptors and sodium and calcium ion channels, it hinders development in conscious mental activity, causes tonic clonic and myoclonic seizures, and ataxia. It is distinguished in its severity and resistance to treatments, and as the name implies, begins in infancy.

Numerous failed treatment attempts led to the parental decision to try a specific strain of marijuana for Charlotte which was tentatively endorsed by two medical practitioners. The particular strain of marijuana which was high in cannabidiol (CBD) was by far the most successful treatment, and was thought of as a potential viable option for others in similar situations. The article discussed scientific and clinical implications of using CBD to treat epilepsy as it contends with current preconceived misconceptions about the unethical use of medicinal marijuana.

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2012 CBDV Anti-Convulsant

21) http://www.ncbi.nlm.nih.gov/pubmed/22970845
Br J Pharmacol. 2012 Dec;167(8):1629-42.
Cannabidivarin is anticonvulsant in mouse and rat.
Hill AJ1, Mercier MS, Hill TD, Glyn SE, Jones NA, Yamasaki Y, Futamura T, Duncan M, Stott CG, Stephens GJ, Williams CM, Whalley BJ.

Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models.
EXPERIMENTAL APPROACH:The effect of CBDV (1-100 μM) on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4-aminopyridine (4-AP) application or Mg(2+) -free conditions was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBDV (50-200 mg·kg(-1) ) in vivo was investigated in four rodent seizure models: maximal electroshock (mES) and audiogenic seizures in mice, and pentylenetetrazole (PTZ) and pilocarpine-induced seizures in rats. The effects of CBDV in combination with commonly used antiepileptic drugs on rat seizures were investigated. Finally, the motor side effect profile of CBDV was investigated using static beam and grip strength assays.
KEY RESULTS:CBDV significantly attenuated status epilepticus-like epileptiform LFPs induced by 4-AP and Mg(2+) -free conditions. CBDV had significant anticonvulsant effects on the mES (≥100 mg·kg(-1) ), audiogenic (≥50 mg·kg(-1) ) and PTZ-induced seizures (≥100 mg·kg(-1) ). CBDV (200 mg·kg(-1) ) alone had no effect against pilocarpine-induced seizures, but significantly attenuated these seizures when administered with valproate or phenobarbital at this dose. CBDV had no effect on motor function.
CONCLUSIONS AND IMPLICATIONS:These results indicate that CBDV is an effective anticonvulsant in a broad range of seizure models. Also it did not significantly affect normal motor function and, therefore, merits further investigation as a novel anti-epileptic in chronic epilepsy models.
LINKED ARTICLES:This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

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very important !!!!

2003 Endogenous Cannabinoid  System Regulates Seizure Activity

Free PMC Article- 2-AG endocannabinoid

22) http://www.ncbi.nlm.nih.gov/pubmed/12954810
J Pharmacol Exp Ther. 2003 Oct;307(1):129-37. Epub 2003 Sep 3.  The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy.  Wallace MJ1, Blair RE, Falenski KW, Martin BR, DeLorenzo RJ.

Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Delta9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures.

Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus.

Furthermore, we determined that during an short-term pilocarpine-induced seizure, levels of the endogenous CB1 ligand 2-arachidonylglycerol increased significantly within the hippocampal brain region.

These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was significantly increased throughout the CA regions of epileptic hippocampi. By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.

2001 Free full text

Activation of the CB1 receptor has proven to dampen neurotransmission and produce an overall reduction in neuronal excitability.

anticonvulsant effects of delta9-tetrahydrocannabinol and WIN 55,212-2 are cannabinoid CB1 receptor-mediated while the anticonvulsant activity of cannabidiol is not.

23) http://www.ncbi.nlm.nih.gov/pubmed/11779037
Eur J Pharmacol. 2001 Sep 28;428(1):51-7.
Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Wallace MJ1, Wiley JL, Martin BR, DeLorenzo RJ.

The cannabinoid CB1 receptor has been shown to be the primary site of action for cannabinoid-induced effects on the central nervous system. Activation of this receptor has proven to dampen neurotransmission and produce an overall reduction in neuronal excitability. Cannabinoid compounds like delta9-tetrahydrocannabinol and cannabidiol have been shown to be anticonvulsant in maximal electroshock, a model of partial seizure with secondary generalization. However, until now, it was unknown if these anticonvulsant effects are mediated by the cannabinoid CB1 receptor. Likewise, (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2), a cannabimimetic compound that has been shown to decrease hyperexcitability in cell culture models via the cannabinoid CB1 receptor, has never been evaluated for anticonvulsant activity in an animal seizure model. We first show that the cannabinoid compounds delta9-tetrahydrocannabinol (ED50 = 42 mg/kg), cannabidiol (ED50 = 80 mg/kg), and WIN 55,212-2 (ED50 = 47 mg/kg) are anticonvulsant in maximal electroshock. We further establish, using the cannabinoid CB1 receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) (AD50 = 2.5 mg/kg), that the anticonvulsant effects of delta9-tetrahydrocannabinol and WIN 55,212-2 are cannabinoid CB1 receptor-mediated while the anticonvulsant activity of cannabidiol is not. This study establishes a role for the cannabinoid CB1 receptor in modulating seizure activity in a whole animal model.

24) http://www.ncbi.nlm.nih.gov/pubmed/18575801
J Neural Transm. 2008 Nov;115(11):1501-11.  Evaluation of interactions between cannabinoid compounds and diazepam in electroshock-induced seizure model in mice.  Naderi N1, Aziz Ahari F, Shafaghi B, Najarkolaei AH, Motamedi F.

Several studies have shown that cannabinoids have anticonvulsant properties that are mediated through activation of the cannabinoid CB1 receptors. In addition, endogenous cannabinoid compounds (endocannabinoids) regulate synaptic transmission and dampen seizure activity via activation of the same receptors.

The aim of this study was to evaluate the possible interactions between antiepileptic effects of cannabinoid compounds and diazepam using electroshock-induced model of seizure in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, fixed current intensity 35 mA, stimulus duration 0.2 s) and tonic hindlimb extension was taken as the endpoint. All experiments were performed on groups of ten mice and the number of animals who did not display seizure reported as percent protection. Intraperitoneal (i.p.) administration of diazepam (0.25-2 mg/kg) and CB1 receptor agonist WIN55212-2 (0.5-4 mg/kg) dose dependently produced an antiepileptic effect evaluated in terms of increased percentage of protection against electroshock-induced seizure. Logistic regression analysis indicated synergistic interactions in anticonvulsant action after co-administration of diazepam and WIN55212-2 in fixed-ratio combination of 3:1 (diazepam:WIN55212-2), while an additive effect was resulted after co-administration of 1:1 and 1:3 fixed-ratio combinations. Administration of various doses of the endocannabinoid reuptake inhibitor, AM404, did not produce any effect on electroshock-induced seizure. Moreover, co-administration of AM404 and diazepam did not produce significant interaction in antiepileptic properties of these compounds. Administration of the fatty acid amide hydrolase inhibitor, URB597, produced significant antiepileptic effect. Co-administration of URB597 and diazepam led to an antagonistic interaction in protection against shock-induced seizure. Co-administration of different doses of the cannabinoid CB1 receptor antagonist, AM251 did not alter the antiepileptic effect of diazepam in the electroshock-induced seizure test.

These results demonstrate that endocannabinoid system participates in the modulation of seizure and combination of small doses of exogenous CB1 receptor agonists with diazepam may have effective consequences in seizure control. Furthermore, inhibiting the endocannabinoid degradation could be more efficacious in modulating seizure than preventing their uptake.

This study also suggests that the effects of cannabinoids on epilepsy depend on the relative cannabinoid responsiveness of GABAergic and glutamatergic neurotransmission. While, the antiepileptic effects of cannabinoid compounds are likely by affecting excitatory glutamate neurotransmission, the antagonistic interaction between cannabinoid compounds and diazepam to protect seizure is due to the cannabinoid action on inhibitory GABAergic system.

25) http://www.ncbi.nlm.nih.gov/pubmed/15450934
Biochem Pharmacol. 2004 Nov 1;68(9):1691-8.
On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.  Lutz B.

Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids.

Systemic activation of CB1 receptors by exogenous cannabinoids, however, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.

26) http://pharmrev.aspetjournals.org/content/58/3/389.long
The Endocannabinoid System as an Emerging Target of Pharmacotherapy.  Pharmacol Rev. 2006 Sep;58(3):389-462. Pál Pacher,    Sándor Bátkai, and     George Kunos –   Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

Remarkably, in a rat model of pilocarpine-induced status epilepticus, CB1 receptor agonists were more effective in reducing seizure frequency than clinically used anticonvulsants, such as phenytoin or phenobarbital.

1973 early

27)  http://www.ncbi.nlm.nih.gov/pubmed/4714680

Psychopharmacologia. 1973;28(1):95-102.
Effect of cannabidiol and of other cannabis sativa compounds on hippocampal seizure discharges. Izquierdo I, Orsingher OA, Berardi AC.  Mouse model showed CBD effective for seizures.

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2002 Mechoulam R   Cannabidiol  effects – full pdf

28) http://www.ncbi.nlm.nih.gov/pubmed/12412831
J Clin Pharmacol. 2002 Nov;42(11 Suppl):11S-19S.
Cannabidiol: an overview of some pharmacological aspects.  Mechoulam R1, Parker LA, Gallily R.

Over the past few years, considerable attention has focused on cannabidiol (CBD), a major nonpsychotropic constituent of cannabis. The authors present a review on the chemistry of CBD and discuss the anticonvulsive, antianxiety, antipsychotic, antinausea, and antirheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors, and its mechanism of action is yet unknown. It is possible that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its antioxidative effect.

2009 Raphael Mechoulam

29) http://onlinelibrary.wiley.com/doi/10.1002/j.1552-4604.2002.tb05998.x/citedby
Cannabidiol: An Overview of Some Pharmacological Aspects
Raphael Mechoulam1,*, Journal of Clinical Pharmacology V 42 2002    Linda A. Parker2 and Ruth Gallily3

Over the past few years, considerable attention has focused on cannabidiol (CBD), a major nonpsychotropic constituent of cannabis. The authors present a review on the chemistry of CBD and discuss the anticonvulsive, antianxiety, antipsychotic, antinausea, and antirheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors, and its mechanism of action is yet unknown. It is possible that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its antioxidative effect.

30) Link to pdf of article: mechoulam-2007_CBD_review
Chem Biodivers. 2007 Aug;4(8):1678-92.
Cannabidiol–recent advances.
Mechoulam R1, Peters M, Murillo-Rodriguez E, Hanus LO.
The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity.

31) http://www.ncbi.nlm.nih.gov/pubmed/18844286
Phytother Res. 2009 May;23(5):597-602. doi: 10.1002/ptr.2625.
Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders.  Scuderi C1, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G.

Cannabidiol (CBD) is the main non-psychotropic component of the glandular hairs of Cannabis sativa. It displays a plethora of actions including anticonvulsive, sedative, hypnotic, antipsychotic, antiinflammatory and neuroprotective properties.

However, it is well established that CBD produces its biological effects without exerting significant intrinsic activity upon cannabinoid receptors. For this reason, CBD lacks the unwanted psychotropic effects characteristic of marijuana derivatives, so representing one of the bioactive constituents of Cannabis sativa with the highest potential for therapeutic use.The present review reports the pharmacological profile of CBD and summarizes results from preclinical and clinical studies utilizing CBD, alone or in combination with other phytocannabinoids, for the treatment of a number of CNS disorders.

1973

32) http://dx.doi.org/10.1016/0024-3205(73)90141-0
The anticonvulsant activity of cannabidiol and cannabinol
Volume 13, Issue 11, 1 December 1973, Pages 1527–1531
Ralph Karler,    William Cely,    Stuart A. Turkanis
Abstract   The anticonvulsant activity of delta-9-tetrahydrocannabinol was compared with that of two other naturally occurring cannabinoids, cannabidiol and cannabinol, in a maximal electroshock test in mice. The drugs were administered as an emulsion of sesame seed oil, Tween 80 and saline to mice i.p. The results indicate that all three cannabinoids are effective anticonvulsants. The time for peak effect is about 2 hr. In terms of relative potencies, cannabidiol and delta-9-THC are similar but both of them are more active than cannabinol.
Copyright © 1973 Published by Elsevier Inc.

33) http://scholar.google.com/scholar?cites=12517775152161936523&as_sdt=40005&sciodt=0,10&hl=en
The anticonvulsant activity of cannabidiol and cannabinol

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Anti-Cancer Effects

full text 2013

33) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877544/

Cell Death Dis. Dec 2013; 4(12): e949.
Published online Dec 5, 2013. doi: 10.1038/cddis.2013.471
PMCID: PMC3877544
Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death
N Rimmerman,1,* D Ben-Hail,2 Z Porat,3 A Juknat,1 E Kozela,1 M P Daniels,4 P S Connelly,4 E Leishman,5 H B Bradshaw,5 V Shoshan-Barmatz,2 and Z Vogel1

Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown.

Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells. Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed co-localization of CBD with protein markers of mitochondria.

Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.

In summary, in this study we have identified VDAC1 as a new molecular target for CBD. Our study suggests that CBD-induced cell death may occur through the inhibition of VDAC1 conductance and that this interaction may be responsible for the anticancer and immunosuppressive properties of CBD. However, we cannot rule out the possibility that the interaction of VDAC1 with CBD leads to cell death indirectly, for example by increasing the concentration of CBD in the mitochondria, thus leading to the increased formation of ROS and mitochondrial membrane permeability. We hypothesize that cancer and immune cells are more susceptible to CBD-induced cell death compared with other cell types due to their high proliferative rate, metabolic rate, and VDAC1 activity.

2008 Endocannabinoid Deficiency Syndrome

34) http://www.ncbi.nlm.nih.gov/pubmed/18404144
Neuro Endocrinol Lett. 2008 Apr;29(2):192-200.
Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?
Russo EB.Author information GW Pharmaceuticals, 2235 Wylie Avenue, Missoula, MT 59802, USA

35) http://www.ncbi.nlm.nih.gov/pubmed/15159679

Full pdf Clinical Endocannabinoid Deficiency_Russo_2004
Neuro Endocrinol Lett. 2004 Feb-Apr;25(1-2):31-9.
Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?
Russo EB.
This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis.
METHODS:Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources.
RESULTS:Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging.
CONCLUSION:Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.
The Idea Of Cannabinoid Deficiency

The list of conditions tied to cannabis is wide-ranging and steadily growing. Whether cannabinoids are providing relief from migraines, fibromyalgia, or irritable bowel syndrome (IBS), the mechanism involved is largely the same; success is often attributed to activation of the body’s cannabinoid receptors.
“Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines,” he explained.

36) http://www.parl.gc.ca/Content/SEN/Committee/371/ille/presentation/kalant-e.htm
http://www.ncbi.nlm.nih.gov/pubmed/11854770
Pain Res Manag. 2001 Summer;6(2):80-91.
Medicinal use of cannabis: history and current status.
Kalant H.
To provide an overview of the history and pharmacology of cannabis in relation to current scientific knowledge concerning actual and potential therapeutic uses of cannabis preparations and pure cannabinoids.
METHODS:The literature on therapeutic uses of cannabis and cannabinoids was assessed with respect to type of study design, quality and variability of data, independent replications by the same or other investigators, magnitude of effects, comparison with other available treatments and reported adverse effects. The results of this review were also compared with those of major international reviews of this topic in the past five years.
CONCLUSIONS:Pure tetrahydrocannabinol and several analogues have shown significant therapeutic benefits in the relief of nausea and vomiting, and stimulation of appetite in patients with wasting syndrome. Recent evidence clearly demonstrates analgesic and anti-spasticity effects that will probably prove to be clinically useful. Reduction of intraocular pressure in glaucoma and bronchodilation in asthma are not sufficiently strong, long lasting or reliable to provide a valid basis for therapeutic use. The anticonvulsant effect of cannabidiol is sufficiently promising to warrant further properly designed clinical trials. There is still a major lack of long term pharmacokinetic data and information on drug interactions. For all the present and probable future uses, pure cannabinoids, administered orally, rectally or parenterally, have been shown to be effective, and they are free of the risks of chronic inflammatory disease of the airways and upper respiratory cancer that are associated with the smoking of crude cannabis. Smoking might be justified on compassionate grounds in terminally ill patients who are already accustomed to using cannabis in this manner. Future research will probably yield new synthetic analogues with better separation of therapeutic effects from undesired psychoactivity and other side effects, and with solubility properties that may permit topical administration in the eye, or aerosol inhalation for rapid systemic effect without the risks associated with smoke inhalation.

 

 

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) https://www.facebook.com/RealmofCaring  Realm of Caring Stanley Cannabis Oil High Cannabidiol Low THC

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links

https://www.indiegogo.com/projects/help-florida-get-charlotte-s-web-oil
As a consequence of repeated seizure activity and side effects of anti-epileptic drugs, many of these children also have significant comorbidities, including cognitive delay or regression, behavioral disturbance, social disabilities or maladjustment, sleep disturbance and injury.

http://cannabisnowmagazine.com/current-events/florida-cbd-only-bill-passes-first-hurdle
Florida CBD-only Bill Passes First Hurdle
By Angela Bacca on March 6, 2014

http://www.mountainjackpot.com/2014/04/15/the-straight-dope-about-kids-seizures-and-medical-marijuana/  The Straight Dope about Kids, Seizures, and Medical Marijuana
April 15, 2014    By Beth Dodd:

http://www.wakingtimes.com/2014/04/10/brief-history-outlook-cannabis-extract-medicine/
A Brief History And Outlook Of Cannabis Extract Medicine
April 10, 2014 | By WakingTimes

http://www.medicalmarijuanatampa.org/meet-children-rely-marijuana-survive/
Meet The Children Who Rely On Marijuana To Survive.
Posted by Karly Jones in Medical Marijuana News

http://www.prnewswire.com/news-releases/medical-marijuana-operators-and-facility-providers-expand-operations—company-adds-well-known-major-marijuana-authority-to-board-of-directors-255306401.html
Medical Marijuana Operators and Facility Providers Expand Operations – Company Adds Well Known, Major Marijuana Authority to Board of Directors

http://www.cnn.com/2014/03/10/health/medical-marijuana-refugees/
Medical marijuana refugees: ‘This was our only hope’
By Saundra Young, CNN  updated 1:54 PM EDT, Mon March 10, 2014

http://america.aljazeera.com/watch/shows/techknow/blog/2014/3/7/touring-the-marijuanafacilitygrowingplantstosavechildrenslives.html
Touring the marijuana facility growing plants to save children’s lives by Tracy Martinez

http://www.huffingtonpost.com/the-/ohio-mother-moving-to-col_b_4034498.html
Ohio Mother Moving to Colorado to Treat Daughter’s Epilepsy With Cannabidiol Oil  Posted: 10/03/2013 10:33 am

http://www.clinicalneurologynews.com/specialty-focus/epilepsy-spells/single-article-page/orphan-drug-designation-spurs-trials-for-cannabidiol-in-dravet-syndrome/3cdddf60b53b06d4ebe0e707970b5e1c.html
Epilepsy & Seizures.  Orphan drug designation spurs trials for cannabidiol in Dravet syndrome
By: JEFF EVANS, Clinical Neurology News Digital Network 03/21/14

http://blogs.discovermagazine.com/d-brief/
Marijuana Chemical Could Treat Children with Epilepsy
By Carl Engelking | February 21, 2014 4:24 pm   DIsCOVER MAGAZINE

http://www.epilepsycolorado.org/index.php?s=10904
Epilepsy Foundation of Colorado

http://www.projectcbd.org/conditions/epilepsyseizure-2/
project cbd

http://hope4childrenwithepilepsy.com/research-links/
ResearchCannabidiol is rapidly gaining attention as the key to the medicinal value of the cannabis plant. We have compiled links to the most relevant published research articles. This page will continue to be modified as new research is developed.
Recently PublishedJacobson & Porter

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

Dr. Margaret Gedde
Whole cannabis extract of high concentration cannabidiol may calm seizures in highly refractory pediatric epilepsies

NYU Langone Medical Center
Cannabidiol Conference 2013
Cannabidiols: Potential Uses in Epilepsy and Other Neurological Disorders

Endocannabinoid System and Pain

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834283/

CNS Neurol Disord Drug Targets. 2009 Dec;8(6):403-21.
The endocannabinoid system and pain.
Guindon J1, Hohmann AG.

The therapeutic potential of cannabinoids has been the topic of extensive investigation following the discovery of cannabinoid receptors and their endogenous ligands. Cannabinoid receptors and their endogenous ligands are present at supraspinal, spinal and peripheral levels. Cannabinoids suppress behavioral responses to noxious stimulation and suppress nociceptive processing through activation of cannabinoid CB(1) and CB(2) receptor subtypes. Endocannabinoids, the brain’s own cannabis-like substances, share the same molecular target as Delta(9)-tetrahydrocannabinol, the main psychoactive component in cannabis. Endocannabinoids serve as synaptic circuit breakers and regulate multiple physiological and pathological conditions, e.g. regulation of food intake, immunomodulation, inflammation, analgesia, cancer, addictive behavior, epilepsy and others. This review will focus on uncovering the roles of anandamide and 2-arachidonoylglycerol, the two best characterized endocannabinoids identified to date, in controlling nociceptive responding. The roles of anandamide and 2-arachidonoylglycerol, released under physiological conditions, in modulating nociceptive responding at different levels of the neuraxis will be emphasized in this review. Effects of modulation of endocannabinoid levels through inhibition of endocannabinoid hydrolysis and uptake is also compared with effects of exogenous administration of synthetic endocannabinoids in acute, inflammatory and neuropathic pain models. Finally, the therapeutic potential of the endocannabinoid signaling system is discussed in the context of identifying novel pharmacotherapies for the treatment of pain.

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FULL Free

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375509/
J Biol Chem. Jun 15, 2012; 287(25): 20851–20865.
Published online Apr 24, 2012. doi: 10.1074/jbc.M111.335273
PMCID: PMC3375509
Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain*
Lucía Callén,‡§,1 Estefanía Moreno,‡§ Pedro Barroso-Chinea,§¶ David Moreno-Delgado,‡§ Antoni Cortés,‡§ Josefa Mallol,‡§ Vicent Casadó,‡§ José Luis Lanciego,§¶ Rafael Franco,¶ Carmen Lluis,‡§ Enric I. Canela,‡§,2 and Peter J. McCormick‡§,2,3
From the ‡Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain

http://sensiseeds.com/en/blog/what-is-clinical-endocannabinoid-deficiency/
Seshata Seshata is a freelance cannabis writer currently based in Amsterdam, Netherlands

What is clinical endocannabinoid deficiency?
posted by Seshata on March 25th 2013

Links and References

Pediatric Cannabis Therapy Website

Pediatric Cannabis Therapy! My name is Rebecca Brown and I am the founder of Pediatric Cannabis Therapy. My journey began almost two years ago when I started treating my then 14 year old son who has Dravet syndrome with a high cbd low thc ratio medical cannabis. I reached out to other parents in the Dravet community who were also treating their children with cannabis and the Pediatric Cannabis Therapy facebook group was born. We started with 6 parents but have grown to a staggering 2500 members and are growing daily.