Cannabinoids in treatment-resistant epilepsy: A review.

Posted on February 12, 2017 by David

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“Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality.

Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative.

Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations.

These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS).

The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents.

We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs.

Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day. This article is part of a Special Issue titled “Cannabinoids and Epilepsy”.”

https://www.ncbi.nlm.nih.gov/pubmed/28188044

Neuronal and Molecular Effects of Cannabidiol on the Mesolimbic Dopamine System: Implications for Novel Schizophrenia Treatments.

Posted on February 12, 2017 by David

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“Growing clinical and pre-clinical evidence points to a critical role for cannabidiol (CBD), the largest phytochemical component of cannabis, as a potential pharmacotherapy for various neuropsychiatric disorders.

In contrast to delta-9-tetrahydrocannabinol (THC), which is associated with acute and neurodevelopmental pro-psychotic side-effects, CBD possesses no known psychoactive or dependence-producing properties.

However, evidence has demonstrated that CBD strongly modulates the mesolimbic dopamine (DA) system and may possess promising anti-psychotic properties.

Despite the psychotropic differences between CBD and THC, little is known regarding their molecular and neuronal effects on the mesolimbic DA system, nor how these differential effects may relate to their potential pro vs. anti-psychotic properties.

This review summarizes clinical and pre-clinical evidence demonstrating CBD’s modulatory effects on DA activity states within the mesolimbic pathway, functional interactions with the serotonin 5-HT_1A receptor system, and their downstream molecular signaling effects.

Together with clinical evidence showing that CBD may normalize affective and cognitive deficits associated with schizophrenia, CBD may represent a promising treatment for schizophrenia, acting through novel molecular and neuronal mesolimbic substrates.”

https://www.ncbi.nlm.nih.gov/pubmed/28185872

Modulation of Human Peripheral Blood Mononuclear Cell Signaling by Medicinal Cannabinoids.

Posted on February 9, 2017 by David

“Medical marijuana is increasingly prescribed as an analgesic for a growing number of indications, amongst which terminal cancer and multiple sclerosis.

In this study we aimed to investigate the immune-cell modulatory properties of medical cannabis.

Healthy volunteers were asked to ingest medical cannabis, and kinome profiling was used to generate comprehensive descriptions of the cannabis challenge on inflammatory signal transduction in the peripheral blood of these volunteers.

Results were related to both short term and long term effects in patients experimentally treated with a medical marijuana preparation for suffering from abdominal pain as a result of chronic pancreatitis or other causes.

The results reveal an immunosuppressive effect of cannabinoid preparations via deactivation of signaling through the pro-inflammatory p38 MAP kinase and mTOR pathways and a concomitant deactivation of the pro-mitogenic ERK pathway. However, long term cannabis exposure in two patients resulted in reversal of this effect.

While these data provide a powerful mechanistic rationale for the clinical use of medical marijuana in inflammatory and oncological disease, caution may be advised with sustained use of such preparations.”

https://www.ncbi.nlm.nih.gov/pubmed/28174520

http://journal.frontiersin.org/article/10.3389/fnmol.2017.00014/full

Cannabinoid Receptors in Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance.

Posted on February 6, 2017 by David

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“Cannabinoid receptors are fundamentally involved in all aspects of intestinal physiology, such as motility, secretion, and epithelial barrier function. They are part of a broader entity, the so-called endocannabinoid system which also includes their endocannabinoid ligands and the ligands’ synthesizing/degrading enzymes.

The system has a strong impact on the pathophysiology of the gastrointestinal tract and is believed to maintain homeostasis in the gut by controlling hypercontractility and by promoting regeneration after injury.

For instance, genetic knockout of cannabinoid receptor 1 leads to inflammation and cancer of the intestines. Derivatives of Δ⁹-tetrahydrocannabinol, such as nabilone and dronabinol, activate cannabinoid receptors and have been introduced into the clinic to treat chemotherapy-induced emesis and loss of appetite; however, they may cause many psychotropic side effects.

New drugs that interfere with endocannabinoid degradation to raise endocannabinoid levels circumvent this obstacle and could be used in the future to treat emesis, intestinal inflammation, and functional disorders associated with visceral hyperalgesia.”

https://www.ncbi.nlm.nih.gov/pubmed/28161834

The effects of synthetic cannabinoids on executive function.

Posted on February 6, 2017 by David

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“There is a growing use of novel psychoactive substances (NPSs) including synthetic cannabinoids. Synthetic cannabinoid products have effects similar to those of natural cannabis but the new synthetic cannabinoids are more potent and dangerous and their use has resulted in various adverse effects. The purpose of the study was to assess whether persistent use of synthetic cannabinoids is associating with impairments of executive function in chronic users.

Synthetic cannabinoid users performed significantly worse than both recreational and non-cannabis users on the n-back task (less accuracy), the Stroop task (overall slow responses and less accuracy), and the long-term memory task (less word recall). Additionally, they have also shown higher ratings of depression and anxiety compared with both recreational and non-users groups.

This study showed impairment of executive function in synthetic cannabinoid users compared with recreational users of cannabis and non-users. This may have major implications for our understanding of the long-term consequences of synthetic cannabinoid based drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/28160034

A selective CB2R agonist (JWH133) restores neuronal circuit after Germinal Matrix Hemorrhage in the preterm via CX3CR1+ microglia.

Posted on February 6, 2017 by David

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“Microglia play dual roles after germinal matrix hemorrhage, and the neurotrophic phenotype maybe neuroprotective.

We raise the hypothesis that a cannabinoid receptor2 agonist (JWH133) accelerates the CX3CR1⁺ microglia secreting neurotrophic factors and restores damaged neuronal circuit.

Overall, this study provides evidence that JWH133 promoted a neurotrophic phenotype of microglia (CX3CR1⁺ microglia), beyond merely alleviating microglial proliferation and inflammation.

Moreover, JWH133 restored impaired neuronal circuit, which represent a novel therapeutic strategy following GMH in clinic.”

https://www.ncbi.nlm.nih.gov/pubmed/28153531

Tumor-promoting effects of cannabinoid receptor type 1 in human melanoma cells.

Posted on January 31, 2017 by David

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“The role of endocannabinoid system in melanoma development and progression is actually not fully understood.

This study was aimed at clarifying whether cannabinoid-type 1 (CB1) receptor may function as tumor-promoting or -suppressing signal in human cutaneous melanoma.

Findings of this study suggest that CB1 receptor might function as tumor-promoting signal in human cutaneous melanoma.”

https://www.ncbi.nlm.nih.gov/pubmed/28131817

“Antitumor effects of THC.” http://www.ncbi.nlm.nih.gov/pubmed/11097557

“Cannabinoids (CB) like ∆9-tetrahydrocannabinol (THC) can induce cancer cell apoptosis and inhibit angiogenesis. Our results confirm the value of exogenous cannabinoids for the treatment of melanoma” http://www.ncbi.nlm.nih.gov/pubmed/25921771

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

The involvement of cannabinoids and mTOR in the reconsolidation of an emotional memory in the hippocampal-amygdala-insular circuit.

Posted on January 31, 2017 by David

“Memory reconsolidation is the process in which reactivated long-term memory becomes transiently sensitive to amnesic agents.

We evaluated the ability of post reactivation administration of the mTOR inhibitor rapamycin, separately and in combination with the cannabinoid CB1/2 receptor agonist WIN55,212-2 (WIN), given systemically or specifically into the hippocampal CA1 area, basolateral amygdala (BLA) or insular cortex (IC), to reduce inhibitory avoidance fear in rats.

Taken together, the results suggest that rapamycin or a combined treatment that involves blocking mTOR and activating cannabinoids may be a promising pharmacological approach for the attenuation of reactivated emotional memories, and thus, it could represent a potential treatment strategy for disorders associated with traumatic memories.”

https://www.ncbi.nlm.nih.gov/pubmed/28131675

A cannabigerol-rich Cannabis sativa extract, devoid of [INCREMENT]9-tetrahydrocannabinol, elicits hyperphagia in rats.

Posted on January 27, 2017 by David

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“Nonpsychoactive phytocannabinoids (pCBs) from Cannabis sativa may represent novel therapeutic options for cachexia because of their pleiotropic pharmacological activities, including appetite stimulation.

We have recently shown that purified cannabigerol (CBG) is a novel appetite stimulant in rats.

As standardized extracts from Cannabis chemotypes dominant in one pCB [botanical drug substances (BDSs)] often show greater efficacy and/or potency than purified pCBs, we investigated the effects of a CBG-rich BDS, devoid of psychoactive [INCREMENT]-tetrahydrocannabinol, on feeding behaviour.

CBG-BDS is a novel appetite stimulant, which may have greater potency than purified CBG, despite the absence of [INCREMENT]-tetrahydrocannabinol in the extract.”

https://www.ncbi.nlm.nih.gov/pubmed/28125508

Topical application of THC containing products is not able to cause positive cannabinoid finding in blood or urine.

Posted on January 26, 2017 by David

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“A male driver was checked during a traffic stop.

A blood sample was collected 35min later and contained 7.3ng/mL THC, 3.5ng/mL 11-hydroxy-THC and 44.6ng/mL 11-nor-9-carboxy-THC. The subject claimed to have used two commercially produced products topically that contained 1.7ng and 102ng THC per mg, respectively. In an experiment, three volunteers (25, 26 and 34 years) applied both types of salves over a period of 3days every 2-4h. The application was extensive (50-100cm²). Each volunteer applied the products to different parts of the body (neck, arm/leg and trunk, respectively). After the first application blood and urine samples of the participants were taken every 2-4h until 15h after the last application (overall n=10 urine and n=10 blood samples, respectively, for each participant).

All of these blood and urine samples were tested negative for THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC by a GC-MS method (LoD (THC)=0.40ng/mL; LoD (11-hydroxy-THC)=0.28ng/mL; LoD (THC-COOH)=1.6ng/mL;. LoD (THC-COOH in urine)=1.2ng/mL).

According to our studies and further literature research on in vitro testing of transdermal uptake of THC, the exclusive application of (these two) topically applied products did not produce cannabinoid findings in blood or urine.”

https://www.ncbi.nlm.nih.gov/pubmed/28122323