Cannabinoids for pediatric epilepsy? Up in smoke or real science?

Posted on February 3, 2016 by David

“Public interest in the use of “medical marijuana” for the treatment of childhood epilepsy has burgeoned in the last few years. This has occurred in parallel with a growing interest in “medical marijuana” in general. Physicians and pediatricians must balance their patients’ desire for immediate access to these products with the tenets of evidence-based medicine. This review discusses the biochemistry of cannabis products (the phytocannabinoids) setting this in the context of the endogenous endocannabinoid system. The differing and potentially modulating effects of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are reviewed. The evidence-base supporting or not the use of cannabis products for the treatment of neurological disease and specifically epilepsy is explored. The potential for adverse effects and particularly of neurotoxicity is addressed. Finally, public health and sociocultural implications are touched upon. Specific recommendations for interested physicians are provided including advocacy for patients and for a change in the “scheduling” of cannabis in order to better foster much-needed high-quality scientific research in this important area.”

http://www.ncbi.nlm.nih.gov/pubmed/26835389

Regulation of Stem Cells by the Endocannabinoid System

Posted on January 30, 2016 by David

“The endocannabinoids, endogenous lipid mediators of related chemical structure to the prototype exogenous cannabinoid Δ⁹-THC found in marijuana, have emerged as important mediators that regulate central and peripheral neural functions as well as immune responses.

Endogenous and exogenous cannabinoid ligands bind to cannabinoid receptors: the predominant central cannabinoid receptor type 1 (CB₁) and the peripheral cannabinoid receptor type 2 (CB₂). CB₁ and CB₂ are members of the G-protein coupled receptor family.

Cannabinoids were shown to modulate the immune system and to affect the migration of blood cells, such as T-cells, monocytes and myeloid leukemia cells, through CB receptors.

Recent data indicate the potential role of cannabinoid ligands and receptors in the regulation of hematopoiesis and hematopoietic stem cell (HSC) migration and trafficking.

These studies may lead to clinical applications of cannabinoid-based compounds as new HSC-mobilizer agents for therapeutic intervention in bone marrow failure.”

http://link.springer.com/chapter/10.1007/978-94-007-2993-3_30

Characterization of a novel adult murine immortalized microglial cell line and its activation by amyloid-beta.

Posted on January 29, 2016 by David

“Alzheimer’s disease is associated with amyloid-beta (Aβ)-induced microglia activation.

This pro-inflammatory response promotes neuronal damage, and therapies are sought to limit microglial activation.

The objective of this study was to characterize Aβ-induced activation of IMG cells, and here, we demonstrate the ability of cannabinoids to significantly reduce this inflammatory response.

Aβ-induced activation of IMG cells was suppressed by delta-9-tetrahydrocannabinol and the CB2-selective agonist JWH-015 in a time- and concentration-dependent manner.

IMG cells recapitulate key features of microglial cell activation. As an example of their potential pharmacological use, cannabinoids were shown to reduce activation of Aβ-induced iNOS gene expression.”

http://www.ncbi.nlm.nih.gov/pubmed/26819091

CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.

Posted on January 23, 2016 by David

“To describe the experience of five Israeli pediatric epilepsy clinics treating children and adolescents diagnosed as having intractable epilepsy with a regimen of medical cannabis oil.

A retrospective study describing the effect of cannabidiol (CBD)-enriched medical cannabis on children with epilepsy.

The cohort included 74 patients (age range 1-18 years) with intractable epilepsy resistant to >7 antiepileptic drugs. Forty-nine (66%) also failed a ketogenic diet, vagal nerve stimulator implantation, or both.

They all started medical cannabis oil treatment between 2-11/2014 and were treated for at least 3 months (average 6 months).

The selected formula contained CBD and tetrahydrocannabinol at a ratio of 20:1 dissolved in olive oil. The CBD dose ranged from 1 to 20mg/kg/d. Seizure frequency was assessed by parental report during clinical visits.

CBD treatment yielded a significant positive effect on seizure load.

Most of the children (66/74, 89%) reported reduction in seizure frequency: 13 (18%) reported 75-100% reduction, 25 (34%) reported 50-75% reduction, 9 (12%) reported 25-50% reduction, and 19 (26%) reported <25% reduction. Five (7%) patients reported aggravation of seizures which led to CBD withdrawal.

In addition, we observed improvement in behavior and alertness, language, communication, motor skills and sleep. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in 5 patients.

CONCLUSIONS:

The results of this multicenter study on CBD treatment for intractable epilepsy in a population of children and adolescents are highly promising. Further prospective, well-designed clinical trials using enriched CBD medical cannabis are warranted.”

http://www.ncbi.nlm.nih.gov/pubmed/26800377

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

Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ9-tetrahydrocannabinol.

Posted on January 23, 2016 by David

“Anatomical, biochemical and pharmacological evidences suggest the existence of a cross-talk between the orexinergic and the endocannabinoid system.

The hypothermia, supraspinal antinociception and anxiolytic-like effects induced by THC were modulated by orexins through OX2 signalling.

OX1 did not seem to be involved in these THC responses. No differences in CB1 receptor levels were found between wild-type and PPO KO mice…

Our results provide new findings to further clarify the interaction between orexins and cannabinoids. OX1 and OX2 are differently implicated in the pharmacological effects of cannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/26799708

The selective monoacylglycerol lipase inhibitor MJN110 produces opioid sparing effects in a mouse neuropathic pain model.

Posted on January 23, 2016 by David

“Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction.

A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents.

The combination of opiates with the primary active constituent of cannabis, Δ9-tetrahydrocannabinol, produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing…

Here, we tested whether elevating the endogenous cannabinoid 2-arachidonylglycerol (2-AG) through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid sparing effects…

These findings, taken together, suggest that MAGL inhibition produces opiate sparing events with diminished tolerance, constipation, and cannabimemetic side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/26791602

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

Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis.

Posted on January 21, 2016 by David

“Spasticity, one of the main symptoms of multiple sclerosis (MS), can affect more than 80% of MS patients during the course of their disease and is often not treated adequately.

δ-9-Tetrahydrocannabinol-cannabidiol (THC-CBD) oromucosal spray is a plant-derived, standardized cannabinoid-based oromucosal spray medicine for add-on treatment of moderate to severe, resistant multiple sclerosis-induced spasticity.

This article reviews the current evidence for the efficacy and safety, with dizziness and fatigue as the most common treatment-related adverse events, being mostly mild to moderate in severity.

Results from both randomized controlled phase III studies involving about,1600 MS patients or 1500 patient-years and recently published studies on everyday clinical practice involving more than 1000 patients or more than,1000 patient-years are presented.”

http://www.ncbi.nlm.nih.gov/pubmed/26788128

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710104/

http://www.thctotalhealthcare.com/category/multiple-sclerosis-ms/

The Pharmacological Basis of Cannabis Therapy for Epilepsy.

Posted on January 21, 2016 by David

“Recently, cannabis has been suggested as a potential alternative therapy for refractory epilepsy, which affects 30% of epilepsy patients including children who do not respond to current medications.

There is a large unmet medical need for new antiepileptics for refractory epilepsy and conditions associated with refractory seizures that would not interfere with normal function.

The two chief cannabinoids are delta-9-tetrahyrdrocannabinol, the major psychoactive component of marijuana, and cannabidiol (CBD), the major non-psychoactive component of marijuana.

There are claims of clinical efficacy of CBD-predominant cannabis or medical marijuana for epilepsy, mostly from limited studies, surveys or case reports.

However, the mechanisms underlying the antiepileptic efficacy of cannabis remain unclear. This article highlights the pharmacological basis of cannabis therapy, with an emphasis on the endocannabinoid mechanisms underlying the emerging neurotherapeutics of CBD in epilepsy.

CBD is anticonvulsant, but it has a low affinity for the cannabinoid CB1 and CB2 receptors; therefore the exact mechanism by which it affects seizures remains poorly understood.

A rigorous clinical evaluation of pharmaceutical CBD products is needed to establish the safety and efficacy for the treatment of epilepsy.

Identification of mechanisms underlying the anticonvulsant efficacy of CBD is additionally critical to identify other potential treatment options.”

http://www.ncbi.nlm.nih.gov/pubmed/26787773

http://jpet.aspetjournals.org/content/early/2016/01/19/jpet.115.230151.long

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

Cannabinoids inhibit cellular respiration of human oral cancer cells.

Posted on January 15, 2016 by David

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“The primary cannabinoids, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on the mitochondrial O(2) consumption in human oral cancer cells (Tu183). This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs. A rapid decline in the rate of respiration was observed when Delta(9)-THC or Delta(8)-THC was added to the cells. The inhibition was concentration-dependent, and Delta(9)-THC was the more potent of the two compounds. Anandamide (an endocannabinoid) was ineffective; suggesting the effects of Delta(9)-THC and Delta(8)-THC were not mediated by the cannabinoid receptors. These results show the cannabinoids are potent inhibitors of human oral cancer cells (Tu183) cellular respiration and are toxic to this highly malignant tumor.” http://www.ncbi.nlm.nih.gov/pubmed/20516734

https://www.karger.com/Article/Abstract/312686

http://www.thctotalhealthcare.com/category/oral-cancer/

Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis.

Posted on January 15, 2016 by David

“Pain is a common symptom of MS, affecting up to 70% of patients.

Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results.

The aim of our study was to better investigate the role of Sativex® in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment.

One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life.

Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.”

http://www.ncbi.nlm.nih.gov/pubmed/26764336