A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

 Annals of Clinical and Translational Neurology banner

“Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects.

Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy.

Primary objective was to establish dosing and tolerability of TIL-TC150 – a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life.

RESULTS:

Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%.

CONCLUSIONS:

TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.”

https://www.ncbi.nlm.nih.gov/pubmed/30250864

https://onlinelibrary.wiley.com/doi/abs/10.1002/acn3.621

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Inhibitory effects of cannabidiol on voltage-dependent sodium currents.

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“Cannabis sativa contains many related compounds known as phytocannabinoids. The main psychoactive and non-psychoactive compounds are Δ9-tetrahydrocannabidiol (THC) and cannabidiol (CBD), respectively.

Much of the evidence for clinical efficacy of CBD-mediated anti-epileptic effects has been from case reports or smaller surveys. The mechanisms for CBD’s anticonvulsant effects are unclear and likely involve non-cannabinoid receptor pathways.

CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiology of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels.

Our results show that CBD inhibits hNav1.1-1.7 currents, with an IC50 of 1.9-3.8 μM, suggesting that this inhibition could occur at therapeutically relevant concentrations. A steep Hill slope of ~3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temperature-dependent, with potency increasing at lower temperatures.

We conclude that CBD’s mode of action likely involves (1) compound partitioning in lipid membranes, which alters membrane fluidity affecting gating, and (2) undetermined direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.”

https://www.ncbi.nlm.nih.gov/pubmed/30219789

http://www.jbc.org/content/early/2018/09/14/jbc.RA118.004929

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Cannabis for the Treatment of Epilepsy: an Update.

“For millennia, there has been interest in the use of cannabis for the treatment of epilepsy.

However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.

While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide.

Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release.

We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies.

Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy.

In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD.

While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD’s inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD.

Understanding of CBD’s efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.”

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Acute foot-shock stress decreased seizure susceptibility against pentylenetetrazole-induced seizures in mice: Interaction between endogenous opioids and cannabinoids.

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“Stressful conditions affect the brain’s neurotransmission and neural pathways that are involved in seizure susceptibility. Stress alters the intensity and/or frequency of seizures.

Although evidence indicates that chronic stress exerts proconvulsant effects and acute stress has anticonvulsant properties, the underlying mechanisms which mediate these effects are not well understood.

In the present study, we assessed the role of endogenous opioids, endocannabinoids, as well as functional interaction between opioid and cannabinoid systems in the anticonvulsant effects of acute foot-shock stress (FSS) against pentylenetetrazole (PTZ)-induced seizures in mice.

CONCLUSIONS:

Opioid and cannabinoid systems are involved in the anticonvulsant effects of acute FSS, and these neurotransmission systems interact functionally in response to acute FSS.”

https://www.ncbi.nlm.nih.gov/pubmed/30170259

https://www.epilepsybehavior.com/article/S1525-5050(17)30777-1/fulltext

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Anticonvulsant and Neuroprotective Effects of Cannabidiol During the Juvenile Period.

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“Anticonvulsant effects of cannabidiol (CBD), a nonpsychoactive cannabinoid, have not been investigated in the juvenile brain. We hypothesized that CBD would attenuate epileptiform activity at an age when the brain first becomes vulnerable to neurotoxicity and social/cognitive impairments.

To induce seizures, kainic acid (KA) was injected either into the hippocampus (KAih) or systemically (KAip) on postnatal (P) day 20. CBD was coadministered (KA + CBDih, KA + CBDip) or injected 30 minutes postseizure onset (KA/CBDih, KA/CBDip).

Hyperactivity, clonic convulsions, and electroencephalogram rhythmic oscillations were attenuated or absent after KA + CBDih and reduced after KA + CBDip. NeuN immunohistochemistry revealed neuroprotection.

Augmented reactive glia number and expression were reversed in CA1 but persisted deep within the dentate hilus. Parvalbumin-positive (PV+) interneurons were reduced in both models, whereas immunolabeling was dramatically increased within ipsilateral and contralateral dendritic/neuropilar fields following KA + CBDih. Cannabinoid receptor 1 (CB1) expression was minimally affected after KAih contrasting elevations observed after KAip.

Intracranial coadministration data suggest that CBD has higher efficacy in epilepsy with hippocampal focus rather than when extrahippocampal amygdala/cortical structures are triggered by systemic treatments. Inhibition of surviving PV+ and CB1+ interneurons may be facilitated by CBD implying a protective role in regulating hippocampal seizures and neurotoxicity at juvenile ages.”

https://www.ncbi.nlm.nih.gov/pubmed/30169677

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Cannabidiol for Epilepsy: New Hope on the Horizon?

 Clinical Therapeutics Home

“Epilepsy is a common neurologic disorder; it is estimated that ∼50 million people are affected worldwide. About one third of those patients are drug resistant, defined as failure to stop all seizures despite adequate trials of at least 2 appropriate medications. There has been an enormous interest in developing antiepileptic drugs with novel mechanisms of action. This review discusses the evidence supporting the anticonvulsant properties of cannabis in humans, focusing on cannabidiol. We begin by exploring the early and somewhat anecdotal evidence that was recently replaced by high-quality data from randomized controlled studies, which subsequently led to the US Food and Drug Administration approval of a purified cannabidiol extract for the treatment of 2 highly refractory pediatric epilepsy syndromes (Dravet and Lennox-Gastaut).”

https://www.ncbi.nlm.nih.gov/pubmed/30150078

https://www.clinicaltherapeutics.com/article/S0149-2918(18)30325-4/fulltext

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Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community

Scientific Reports

“Recent surveys suggest that many parents are using illicit cannabis extracts in the hope of managing seizures in their children with epilepsy. In the current Australian study we conducted semi-structured interviews with families of children with diverse forms of epilepsy to explore their attitudes towards and experiences with using cannabis extracts.

Contrary to family’s expectations, most samples contained low concentrations of cannabidiol, while Δ9-tetrahydrocannabinol was present in nearly every sample. These findings highlight profound variation in the illicit cannabis extracts being currently used in Australia and warrant further investigations into the therapeutic value of cannabinoids in epilepsy.

The phenomenon is not without supporting scientific evidence. Many preclinical studies have identified potent anticonvulsant effects of various cannabinoids in animal models of epilepsy, and a mechanistic understanding of such effects is emerging.

A considerable proportion of families reported cannabis extracts being “effective” in reducing their child’s seizure burden and improving their overall condition, with one family reporting seizure-freedom in their child for at least 12 months. Over half of the cannabis extracts were associated with families reducing or ceasing their use of the child’s conventional antiepileptic drugs.”

https://www.nature.com/articles/s41598-018-28127-0

“Cannabis chemical THC could be missing ‘piece to the puzzle’ in treating kids with epilepsy” http://www.abc.net.au/news/2018-07-05/epilepsy-treatment-cannabis-chemical-thc/9944878

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Investigational cannabinoids in seizure disorders, what have we learned thus far?

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“The anticonvulsant activity of cannabinoids attracted much attention in the last decade. Cannabinoids that are currently investigated with the intention of making them drugs for the treatment of epilepsy are cannabidiol, cannabidivarin, Δ9-tetrahydrocannabivarin and Δ9-tetrahydrocannabinolic acid.

Areas covered. In this review, the authors look at the results of pre-clinical and clinical studies with investigational cannabinoids. Relevant literature was searched for in MEDLINE, SCOPUS, EBSCO, GOOGLE SCHOLAR and SCINDEX databases.

Expert opinion. Pre-clinical studies confirmed anticonvulsant activity of cannabidiol and cannabidivarin in a variety of epilepsy models. While the results of clinical trials with cannabidivarin are still awaited, cannabidiol showed clear therapeutic benefit and good safety in patients with therapy resistant seizures associated with Dravet syndrome and in patients with Lennox-Gastaut syndrome who have drop seizures. However, the full therapeutic potential of cannabinoids in treatment-resistant epilepsy needs to be investigated in the near future.”

https://www.ncbi.nlm.nih.gov/pubmed/29842819

https://www.tandfonline.com/doi/abs/10.1080/13543784.2018.1482275

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Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin.

 Epilepsia Open banner

“Cannabidivarin (CBDV) and cannabidiol (CBD) have recently emerged among cannabinoids for their potential antiepileptic properties, as shown in several animal models.

We report the case of a patient affected by symptomatic partial epilepsy who used cannabis as self-medication after the failure of countless pharmacological/surgical treatments.

After cannabis administration, a dramatic clinical improvement, in terms of both decrease in seizure frequency and recovery of cognitive functions, was observed, which might parallel high CBDV plasma concentrations.

Our patient’s electroclinical improvement supports the hypothesis that cannabis could actually represent an effective, well-tolerated antiepileptic drug.

Moreover, the experimental data suggest that CBDV may greatly contribute to cannabis anticonvulsant effect through its possible GABAergic action.”

https://www.ncbi.nlm.nih.gov/pubmed/29588939

https://onlinelibrary.wiley.com/doi/abs/10.1002/epi4.12015

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Pharmacological characterization of the cannabinoid receptor 2 agonist, β-caryophyllene on seizure models in mice.

Seizure - European Journal of Epilepsy Home

“Activation of CB1 receptors, produces anticonvulsant effect accompanied by memory disturbance both in animal seizure tests and in patients with epilepsy.

Few reports considered the role of CB2 receptor on seizure susceptibility and cognitive functions. The aim of the present study was to explore the effect of a selective CB2 receptor agonist β-caryophyllene (BCP) in models of seizures and cognition in mice.

CONCLUSION:

Our results suggest that the CB2 receptor agonists might be clinically useful as an adjunct treatment against seizure spread and status epilepticus and concomitant oxidative stress, neurotoxicity and cognitive impairments.”

https://www.ncbi.nlm.nih.gov/pubmed/29547827

http://www.seizure-journal.com/article/S1059-1311(17)30611-8/fulltext

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

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