Monthly Archives: January 2016

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

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“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.

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“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

Rescue of Impaired mGluR5-Driven Endocannabinoid Signaling Restores Prefrontal Cortical Output to Inhibit Pain in Arthritic Rats.

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“Rescue of Impaired metabotropic glutamate receptor 5 (mGluR5)-Driven Endocannabinoid Signaling Restores Prefrontal Cortical Output to Inhibit Pain in Arthritic Rats…

Restoring endocannabinoid signaling allows mGluR5 activation to increase infralimbic output hence inhibit pain behaviors and mitigate pain-related cognitive deficits.”

http://www.ncbi.nlm.nih.gov/pubmed/26791214

http://www.thctotalhealthcare.com/category/arthritis/

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

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“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/

Opposite regulation of cannabinoid CB1 and CB2 receptors in the prefrontal cortex of rats treated with cocaine during adolescence.

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“The endocannabinoid system is implicated in the neurobiology of cocaine addiction, although it is not clear how cocaine regulates brain CB1 and CB2receptors, especially during adolescence, a critical moment for shaping adult response to drug use.

This study evaluated CB1 and CB2 protein levels in prefrontal cortex (PFC) and hippocampus (HC) by western blot analysis with specific and validated antibodies: (1) basally during adolescence (post-natal day PND 40, PND 47, PND 54), (2) by a sensitizing regimen of cocaine (15mg/kg, 7 d, i.p.) during different windows of adolescence vulnerability (PND 33-39, PND 40-46, PND 47-53), and (3) following repeated cocaine administration during adolescence (PND 33-39) in adulthood (PND 64).

The results demonstrated a dynamic and opposite basal modulation of CB1 and CB2 receptors in PFC and HC during adolescence. CB1 receptor levels were increased while CB2 receptors were decreased as compared to adulthood with asymptotes values around mid adolescence (PND 47) both in PFC (CB1: +45±22, p<0.05; CB2: -24±6%, p<0.05) and HC (CB1: +53±23, p<0.05; CB2: -20±8%, p<0.05).

Interestingly, cocaine only altered CB1(+55±10%, p<0.05) and CB2 (-25±10%, p<0.05) receptors when administered during early adolescence and only in PFC. However, the changes observed in PFC by repeated cocaine administration in adolescence were transient and did not endure into adulthood.

These results identified a period of vulnerability during adolescence at which cocaine dysregulated the content of CB receptors in PFC, suggesting an opposite role for these receptors in the effects mediated by cocaine.“

Prevention of drug priming- and cue-induced reinstatement of MDMA-seeking behaviors by the CB1 cannabinoid receptor antagonist AM251.

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“3,4-Methylenedioxymethamphetamine (MDMA), a methamphetamine (METH) derivative, exhibits METH-like actions at monoamine transporters and positive reinforcing effects in rodents and primates.
The purposes of the present study were to determine whether cross-reinstatement would be observed between MDMA and METH and if the cannabinoid receptor, a receptor known to play critical roles in the brain reward system, could modulate MDMA craving…
These findings show that MDMA has obvious addictive potential for reinstating drug-seeking behavior and that METH can be an effective stimulus for reinstating MDMA-seeking behaviors.
Furthermore, based on the attenuating effect of AM251 in the reinstatement of MDMA-seeking behaviors, drugs that suppress CB1 receptors may be used in treatment of MDMA dependence.”

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

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“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.

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“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/

Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala.

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“The basolateral nucleus of the amygdala (BLA) is critical to the pathophysiology of anxiety-driven alcohol drinking and relapse.

The endogenouscannabinoid/type 1 cannabinoid receptor (eCB/CB1 ) system curbs BLA-driven anxiety and stress responses via a retrograde negative feedback system that inhibits neurotransmitter release, and BLA CB1 activation reduces GABA release and drives anxiogenesis.

Additionally, decreased amygdala CB1 is observed in abstinent alcoholic patients and ethanol withdrawn rats.

Here, we investigated the potential disruption of eCB/CB1signaling on GABAergic transmission in BLA pyramidal neurons of rats exposed to 2-3 weeks intermittent ethanol.

In the naïve rat BLA, the CB1agonist WIN 55,212-2 (WIN) decreased GABA release, and this effect was prevented by the CB1 antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent activity.

This retrograde tonic eCB/CB1 signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB1 system.

In contrast, acute ethanol increased GABAergic transmission similarly in naïve and chronic ethanol exposed rats, via both presynaptic and postsynaptic mechanisms.

Notably, CB1 activation impaired ethanol’s facilitation of GABAergic transmission across both groups, but the AM251-induced and ethanol-induced facilitation of GABA release was additive, suggesting independent presynaptic sites of action.

Collectively, the present findings highlight a critical CB1 influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and, thus, may contribute to the alcohol-dependent state.”

The endocannabinoid system and neuropathic pain.

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“The research of new therapeutic strategies for neuropathic pain represents a major current priority.

Important drawbacks to advance in the development of these therapies are the limited translational value of the animal models now available and the elucidation of the complex neuronal and immune pathophysiological mechanisms underlying neuropathic pain.

One of the neurotransmitter systems participating in neuropathic pain control that has recently raised a particular interest is the endocannabinoid system.

This system is highly expressed in neurons and immune cells, and it plays a crucial role in the development of neuropathic pain.

Preclinical studies have provided important findings, revealing the potential interest of the endocannabinoid system for the treatment of neuropathic pain.

These studies have reported the analgesic effects of cannabinoid agonists in multiple neuropathic pain models, and they have identified specific targets within this system to develop more effective and safe analgesic compounds.

Several clinical studies suggest that cannabinoids significantly reduced neuropathic pain…“

http://www.ncbi.nlm.nih.gov/pubmed/26785153