from the above.

very important …full text 2004

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.

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  Volume 1, Issue 3, December 2008

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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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.

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.

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.

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.

Charlotte Figi

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.

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 !!!!

Endogenous Cannabinoid  System  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.

Free full text

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://link.springer.com/article/10.1007/BF00413961Psychopharmacologia. 1973;28(1):95-102.
Effect of cannabidiol and of other cannabis sativa compounds on hippocampal seizure discharges. Izquierdo I, Orsingher OA, Berardi AC.

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,*,    Linda A. Parker2 and Ruth Gallily3
Article first published online: 16 JAN 2014

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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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 colocalization 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.

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