Cannabinoids and Epilepsy.

“Cannabis has been used for centuries to treat seizures.

Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies.

In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy.

These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures.

Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.”

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Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release.

“Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa, has therapeutic potential for certain psychiatric and neurological disorders.

Studies in laboratory animals and limited human trials indicate that CBD has anticonvulsant and neuroprotective properties.

Its effects against cocaine neurotoxicity, however, has remained unclear. Thus, the present study tested the hypothesis that CBD protects against cocaine-induced seizures and investigated the underlying mechanisms.

In conclusion, CBD protects against seizures in a model of cocaine intoxication.

CBD should be further investigated as a strategy for alleviating psychostimulant toxicity.”

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A 4-Week Pilot Study With the Cannabinoid Receptor Agonist Dronabinol and Its Effect on Metabolic Parameters in a Randomized Trial.

“Dronabinol (synthetic Δ9- tetrahydrocannabinol) is used in patients with nausea and vomiting from chemotherapy and in AIDS patients for appetite stimulation.

Recently, dronabinol was used to successfully treat visceral hypersensitivity causing noncardiac chest pain. With widening uses of this medication, we aim to explore its effects on metabolic parameters in long-term dosing and hypothesize that it will not affect major metabolic parameters.

A double-blind, placebo-controlled, 28-day trial was performed with patients 18 to 75 years old without cardiac disease…

Dronabinol administration does not significantly affect basic metabolic components after a period of 28 days.

The implications of these findings are important because dronabinol may be able to be used in patients with metabolic disorders. The favorable trends observed here warrant further exploration into its long-term effects.”

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The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases.

“Endocannabinoids (eCBs) are endogenous lipid ligands that bind to cannabinoid receptors that also mediate the effects of marijuana.

The eCB system is comprised of eCBs, anandamide, and 2-arachidonoyl glycerol, their cannabinoid-1 and cannabinoid-2 receptors (CB1 and CB2, respectively), and the enzymes involved in their biosynthesis and degradation.

It is present in both the central nervous system and peripheral organs including the kidney.

The current review focuses on the role of the eCB system in normal kidney function and various diseases, such as diabetes and obesity, that directly contributes to the development of renal pathologies.

Normally, activation of the CB1 receptor regulates renal vascular hemodynamics and stimulates the transport of ions and proteins in different nephron compartments. In various mouse and rat models of obesity and type 1 and 2 diabetes mellitus, eCBs generated in various renal cells activate CB1 receptors and contribute to the development of oxidative stress, inflammation, and renal fibrosis.

These effects can be chronically ameliorated by CB1 receptor blockers.

In contrast, activation of the renal CB2 receptors reduces the deleterious effects of these chronic diseases.

Because the therapeutic potential of globally acting CB1 receptor antagonists in these conditions is limited due to their neuropsychiatric adverse effects, the recent development of peripherally restricted CB1 receptor antagonists may represent a novel pharmacological approach in treating renal diseases.”

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[The endocannabinoid system role in the pathogenesis of obesity and depression].

“Excessive consumption and obesity do not always have to be strictly pathological. The adjustment of food intake as well as the pleasure of eating are the results of the circulation of neurotransmitters, hormones and glucocorticoids which have an ability to regulate the activity of many receptors connected with G protein, including endocannabinoid receptors.

The key role of endocannabinoids in pathogenesis of obesity is their overproduction by adipose cells.

Endocannabinoids (eCBs) affect CB1 receptors and increase hunger, willingness to intake food, decrease peristalsis and delay stomach emptying.

In obese people increased levels of both central and peripheral endocannabinoids are observed. It may be connected with higher availability of endocannabinoid precursors to synthesis from adipose tissue and lipids.

Raised concentration of eCBs in the body may be the consequence of their catabolism dysfunction. There is a positive correlation between amount the number of receptors in the peripheral tissues and obesity increase.

It is thought that expression of CB1 receptors in mesolimbic system is connected with motivation to consume food in response to rewarding factor.

The appetite increase after cannabinoids use is probably caused by rewarding action of the consumed food and it results from excessive dopaminergic transmission in award system.

The pharmacological inhibition of endocannabinoids activity leads to weight loss, but may also have negative consequences such as decreased mood, reduced tolerance of pain, intensified anxiety, anhedonia, depressive symptoms, even suicidal thoughts.

In post mortem examinations a decrease in CB1 receptor density in grey matter of glial cells in patients with major depression was identified. The pleiotropic and extensive activity of endocannabinoid system can influence a range of neurotransmitters thereby modulating the psychiatric life phenomena, simultaneously being involved in metabolism control and energetic system of human body.

Hence it is a link between metabolic disorders and depression and anxiety disorders. Therefore, in obese people depressive comorbidity is higher and it significantly worsens prognosis and decreases life quality.”

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Synthesis and biological evaluation of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist.

“Cannabinoid receptor 2 (CB2) selective agonists and inverse agonists possess significant potential as therapeutic agents for regulating inflammation and immune function.

Although CB2 agonists have received the greatest attention, it is emerging that inverse agonists also manifest anti-inflammatory activity.

In process of designing new cannabinoid ligands we discovered that the 2,6-dihydroxy-biphenyl-aryl methanone scaffold imparts inverse agonist activity at CB2 receptor without functional activity at CB1. To further explore the scaffold we synthesized a series of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone analogs and evaluated the CB1 and CB2 affinity, potency, and efficacy.

The studies reveal that an aromatic C ring is required for inverse agonist activity and that substitution at the 4 position is optimum. The resorcinol moiety is required for optimum CB2 inverse agonist activity and selectivity. Antagonist studies against CP 55,940 demonstrate that the compounds 41 and 45 are noncompetitive antagonists at CB2.”

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Molecular Targets of Cannabidiol in Neurological Disorders.

“Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plantcannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD’s beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD’s relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug’s action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD’s effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD’s therapeutic mechanism of action.”

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Neuropeptide VF Enhances Cannabinoid Agonist WIN55,212-2-Induced Antinociception in Mice.

“Cannabinoids produce analgesia in several pain models, but the undesirable side effects from high doses of cannabinoid drugs limit their clinic use.

Our recent results indicate that cannabinoid-induced antinociception was enhanced by neuropeptide VF (NPVF).

Here, we investigate whether low-dose cannabinoid agonists combined with NPVF can produce effective antinociception with limited side effects…

These data suggest that the cannabinoid agonist combined with NPVF produces effective antinociception-lacking tolerance via both cannabinoid receptor type 1 and neuropeptide FF receptors in the brain.”

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HU-444, A Novel, Potent Anti-Inflammatory, Non-Psychotropic Cannabinoid.

“Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas.

In contrast to Δ9-tetrahydrocannabinol (Δ9-THC) it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of TNF-α, a proinflammatory cytokine, and was found to be an oral anti-arthritic therapeutic in murine collagen-induced arthritis in vivo.

However in acidic media it can cyclize to the psychoactive Δ9-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ9-THC-like compound.

In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-a production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ9-THC- like effects in mice.

We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.”

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Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer’s Disease.

“Alzheimer’s disease (AD) is frequently associated with neuropsychiatric symptoms (NPS) such as agitation and aggression, especially in the moderate to severe stages of the illness. The limited efficacy and high-risk profiles of current pharmacotherapies for the management of agitation and aggression in AD have driven the search for safer pharmacological alternatives.

Over the past few years, there has been a growing interest in the therapeutic potential of medications that target the endocannabinoid system (ECS).

The behavioural effects of ECS medications, as well as their ability to modulate neuroinflammation and oxidative stress, make targeting this system potentially relevant in AD.

This article summarizes the literature to date supporting this rationale and evaluates clinical studies investigating cannabinoids for agitation and aggression in AD.

Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids-dronabinol or nabilone-on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies.

Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD.”

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