Source of cannabinoids: what is available, what is used, and where does it come from?

John Libbey Eurotext“Cannabis sativa L. is an ancient medicinal plant wherefrom over 120 cannabinoids are extracted. In the past two decades, there has been increasing interest in the therapeutic potential of cannabis-based treatments for neurological disorders such as epilepsy, and there is now evidence for the medical use of cannabis and its effectiveness for a wide range of diseases.

Cannabinoid treatments for pain and spasticity in patients with multiple sclerosis (Nabiximols) have been approved in several countries. Cannabidiol (CBD), in contrast to tetra-hydro-cannabidiol (THC), is not a controlled substance in the European Union, and over the years there has been increasing use of CBD-enriched extracts and pure CBD for seizure disorders, particularly in children. No analytical controls are mandatory for CBD-based products and a pronounced variability in CBD concentrations in commercialized CBD oil preparations has been identified.

Randomized controlled trials of plant-derived CBD for treatment of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) have provided evidence of anti-seizure effects, and in June 2018, CBD was approved by the Food and Drug Administration as an add-on antiepileptic drug for patients two years of age and older with LGS or DS. Medical cannabis, with various ratios of CBD and THC and in different galenic preparations, is licensed in many European countries for several indications, and in July 2019, the European Medicines Agency also granted marketing authorisation for CBD in association with clobazam, for the treatment of seizures associated with LGS or DS.

The purpose of this article is to review the availability of cannabis-based products and cannabinoid-based medicines, together with current regulations regarding indications in Europe (as of July 2019). The lack of approval by the central agencies, as well as social and political influences, have led to significant variation in usage between countries.”

https://www.ncbi.nlm.nih.gov/pubmed/31941643

https://www.jle.com/fr/revues/epd/e-docs/source_of_cannabinoids_what_is_available_what_is_used_and_where_does_it_come_from__316043/article.phtml

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The role of cannabinoids in epilepsy treatment: a critical review of efficacy results from clinical trials.

Image result for Epileptic Disorders journal “CBD was shown to have anti-seizure activity based on in vitro and in vivo models.

However, several reports of small series or case reports of the use of cannabis extracts in epilepsy yielded contradictory results and the efficacy of cannabis use in patients with epilepsy have also been inconclusive.

In 2013, the first Phase 1 trial for a purified form of CBD (Epidiolex/Epidyolex; >99% CBD), developed by GW Pharma, showed some efficacy signals and subsequently, a comprehensive program on the efficacy and tolerability of this compound for the treatment of drug-resistant epilepsies was initiated.

Results of these trials led to the FDA and EMA approval respectively in 2018 and 2019 for the treatment of seizures associated with two rare epilepsies: Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients two years of age and older.

Thus, CBD became the first FDA-approved purified drug substance derived from cannabis and also the first FDA-approved drug for the treatment of seizures in DS.

We detail the clinical studies using purified CBD (Epidiolex/Epidyolex), including the first open interventional exploratory study and Randomized Control Ttrials for DS and LGS.”

https://www.ncbi.nlm.nih.gov/pubmed/31916540

https://www.jle.com/fr/revues/epd/e-docs/the_role_of_cannabinoids_in_epilepsy_treatment_a_critical_review_of_efficacy_results_from_clinical_trials_316030/article.phtml

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The proposed mechanism of action of CBD in epilepsy.

Image result for Epileptic Disorders journal“Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials.

While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy.

Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).”

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Efficacy and Tolerance of Synthetic Cannabidiol for Treatment of Drug Resistant Epilepsy.

Image result for frontiers in neurology“Controlled and open label trials have demonstrated efficacy of cannabidiol for certain epileptic encephalopathies.

However, plant derived cannabidiol products have been used almost exclusively. Efficacy of synthetically derived cannabidiol has not been studied before.

The objective of this study was to evaluate tolerability and efficacy of synthetic cannabidiol in patients with pharmacoresistant epilepsy.

Efficacy and tolerance in our study of synthetic CBD treatment in pharmacoresistant epilepsy is similar to open label studies using plant derived CBD.

Regarding economic and ecological aspects, synthetic cannabidiol might be a reasonable alternative to plant derived cannabidiol.”

https://www.ncbi.nlm.nih.gov/pubmed/31920934

“Over the last decade, the therapeutic use of cannabidiol (CBD) in intractable epilepsies has increased considerably. Its anticonvulsant properties have been shown in several animal models for acute and chronic epilepsy.

Recent randomized, controlled trials have demonstrated that CBD is superior to placebo in seizure reduction in children with Dravet syndrome and patients with Lennox-Gastaut syndrome. In addition, open label studies indicate that cannabidiol has anticonvulsive properties in a broader range of epilepsy syndromes and etiologies.

In summary, the results of this study provide class III evidence of efficacy and safety of synthetic cannabidiol in children and adults with pharmacoresistant epilepsy. Additional studies investigating efficacy and tolerance of synthetic CBD in larger cohorts are needed.”

https://www.frontiersin.org/articles/10.3389/fneur.2019.01313/full

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Exploiting cannabinoid and vanilloid mechanisms for epilepsy treatment.

“This review focuses on the possible roles of phytocannabinoids, synthetic cannabinoids, endocannabinoids, and “transient receptor potential cation channel, subfamily V, member 1” (TRPV1) channel blockers in epilepsy treatment.

The phytocannabinoids are compounds produced by the herb Cannabis sativa, from which Δ9-tetrahydrocannabinol (Δ9-THC) is the main active compound. The therapeutic applications of Δ9-THC are limited, whereas cannabidiol (CBD), another phytocannabinoid, induces antiepileptic effects in experimental animals and in patients with refractory epilepsies.

Synthetic CB1 agonists induce mixed effects, which hamper their therapeutic applications. A more promising strategy focuses on compounds that increase the brain levels of anandamide, an endocannabinoid produced on-demand to counteract hyperexcitability. Thus, anandamide hydrolysis inhibitors might represent a future class of antiepileptic drugs. Finally, compounds that block the TRPV1 (“vanilloid”) channel, a possible anandamide target in the brain, have also been investigated.

In conclusion, the therapeutic use of phytocannabinoids (CBD) is already in practice, although its mechanisms of action remain unclear. Endocannabinoid and TRPV1 mechanisms warrant further basic studies to support their potential clinical applications.”

https://www.ncbi.nlm.nih.gov/pubmed/31839498

“Cannabidiol is in clinical use for refractory epilepsies.”

https://www.epilepsybehavior.com/article/S1525-5050(19)30373-7/fulltext

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The use of medical grade cannabis in Italy for drug-resistant epilepsy: a case series.

 “In Italy, medical grade cannabis (MGC) can be prescribed for different medical conditions, including drug-resistant epilepsy (DRE), once standard and approved therapies have failed, or caused non-tolerable side effects.

Here, we present a retrospective case series report of five patients with DRE who started therapy with MGC. Authorized ISO 9001:2008 pharmacies prepared MGC according to Italian laws. Olive oil extracts (OOEs) were prepared following standard extraction protocols, and cannabinoids were measured on each OOE to check for successful extraction.

After treatment with MGC, all patients reported a reduction in seizure frequency and severity, and some reported improved mood, sleep quality, and general well-being without relevant side effects.

Despite the small sample size and open-label nature of the data, we show that MGC may be successfully used to treat DRE. This is especially true when considering that no valid therapeutic option exists for these patients and that MGC was extremely well tolerated.”

https://www.ncbi.nlm.nih.gov/pubmed/31776867

https://link.springer.com/article/10.1007%2Fs10072-019-04162-1

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Cannabinoids for drug-resistant seizures in a critically ill patient-Case report and literature review.

Publication cover image“Drug-resistant seizures are life-threatening and contribute to sustained hospitalization.

We present the case of a critically ill 28-year-old male with Lennox-Gastaut syndrome who had approximately 30 seizures/day in the intensive care unit.

CASE DESCRIPTION:

Patient required mechanical ventilation and pharmacologically induced thiopentone coma.

He was commenced on cannabidiol and subsequently extubated.

He remained seizure-free thereafter on a combination of cannabidiol and anti-epileptic medication that predated his critical illness.

WHAT IS NEW AND CONCLUSION:

Our case report provides a unique perspective on the role of cannabidiol in achieving remission from drug-resistant seizures in critically ill patients.”

https://www.ncbi.nlm.nih.gov/pubmed/31770462

https://onlinelibrary.wiley.com/doi/abs/10.1111/jcpt.13082

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Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice.

Publication cover image“The endocannabinoid system (ECS) is comprised of cannabinoid receptors 1 and 2 (CB1R and CB2R), endogenous ligands, and regulatory enzymes, and serves to regulate several important physiological functions throughout the brain and body.

Recent evidence suggests that the ECS may be a promising target for the treatment of epilepsy, including epilepsy subtypes that arise from mutations in the voltage-gated sodium channel SCN1A.

The objective of this study was to explore the effects of modulating CB2R activity on seizure susceptibility.

Our results demonstrate that reduced CB2R activity is associated with increased seizure susceptibility. CB2Rs might therefore provide a therapeutic target for the treatment of some forms of epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/31758544

https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.16388

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Cannabis Influences the Putative Cytokines-Related Pathway of Epilepsy among Egyptian Epileptic Patients.

brainsci-logo“The study aims to investigate: (1) the prevalence of cannabis among epileptic patients seen at Mansoura University Hospital, (2) serum levels and gene expression of cytokines in epilepsy patients and the controls. and (3) the possibility that cannabis use affects the cytokine levels in epilepsy patients, triggering its future use in treatment.

We recruited 440 epilepsy patients and 200 controls matched for age, gender, and ethnicity. Of the epileptic patients, 37.5% demonstrated lifetime cannabis use with a mean duration of 15 ± 73 years. Serum levels of interleukin IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α), were analyzed and gene expression analysis was conducted only for those cytokines that were different between groups in the serum analysis.

The “Epilepsy-only” patients had significantly higher serum and mRNA levels of IL-1α, β, IL-2,6,8, and TNF-α compared to the controls and the “Cannabis+Epilepsy” group (p = 0.0001). IL-10 showed significantly lower levels in the “Epilepsy-only” patients compared to the controls and “Cannabis+Epilepsy” (p = 0.0001). Cannabis use is prevalent among epilepsy patients.

Epilepsy is characterized by a pro-inflammatory state supported by high serum and gene expression levels.

Cannabis users demonstrated significantly lower levels of inflammatory cytokines compared to epilepsy non-cannabis users which might contribute to its use in the treatment of resistant epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/31757102

https://www.mdpi.com/2076-3425/9/12/332

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Efficacy and adverse event profile of cannabidiol and medicinal cannabis for treatment-resistant epilepsy: Systematic review and meta-analysis.

“This paper aimed to systematically examine the efficacy and adverse event (AE) profile of cannabidiol and medicinal cannabis by analyzing qualitative and meta-analytic data.

According to the results, a statistically meaningful effect of cannabidiol compared with placebo was observed (p < 0.00001). When comparing treatment with cannabidiol or medicinal cannabis, significance was not found for the AE profile (p = 0.74). As AEs for cannabidiol were more common under short-term than under long-term treatment (p < 0.00001), this approach was favorable in the long term.

Furthermore, cannabidiol is more effective than placebo, regardless of the etiology of epileptic syndromes and dosage.

Overall, the AE profile did not differ across treatments with cannabidiol or medicinal cannabis, though it did differ favorably for long-term than for short-term treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31731110

“CBD treatments were effective compared with placebo, regardless of the dose administered. The safety analysis is related to tolerable SEs found in studies with both CBD and medicinal CNB. There was a greater tendency for adverse events in short-term treatment compared with long-term treatment.”

https://www.epilepsybehavior.com/article/S1525-5050(19)30862-5/fulltext

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