Tag Archives: cannabidiol

Cannabimovone, a Cannabinoid with a Rearranged Terpenoid Skeleton from Hemp

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“An investigation of the polar fractions from a nonpsychotropic variety of hemp (Cannabis sativa L.) afforded cannabimovone, a polar cannabinoid with a rearranged 2(34) abeo-terpenoid skeleton, biogenetically originating from the intramolecular aldolization of a 2′,3′-seco-menthanyl precursor.

The structure of cannabimovone was elucidated by spectroscopic analysis, whereas attempts to mimic its biogenetic derivation from cannabidiol gave only anhydrocannabimovone, the intramolecular oxy-Michael adduct of the crotonized version of the elusive natural products.

Biological evaluation of cannabimovone against metabotropic (CB1, CB2) and ionotropic (TRPs) cannabinoid receptors showed a significant activity only for ionotropic receptors, especially TRPV1, whereas anhydrocannabimovone exhibited strong activity at both ionotropic and metabotropic cannabinoid receptors.

Overall, the biological profile of anhydrocannabimovone was somewhat similar to that of THC, suggesting a remarkable tolerance to constitutional and configurational changes.”

http://onlinelibrary.wiley.com/doi/10.1002/ejoc.200901464/abstract

Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrheic skin and acne treatment.

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“Acne is a common skin disease characterized by elevated sebum production and inflammation of the sebaceous glands.

We have previously shown that a non-psychotropic phytocannabinoid ((-)-cannabidiol [CBD]) exerted complex anti-acne effects by normalizing “pro-acne agents”-induced excessive sebaceous lipid production, reducing proliferation and alleviating inflammation in human SZ95 sebocytes.

Therefore, in the current study we aimed to explore the putative anti-acne effects of further non-psychotropic phytocannabinoids ((-)-cannabichromene [CBC], (-)-cannabidivarin [CBDV], (-)-cannabigerol [CBG], (-)-cannabigerovarin [CBGV] and (-)-Δ9 -tetrahydrocannabivarin [THCV]).

Viability and proliferation of human SZ95 sebocytes were investigated by MTT- and CyQUANT-assays; cell death and lipid synthesis were monitored by DilC1 (5)-SYTOX Green labelling and Nile Red staining, respectively. Inflammatory responses were investigated by monitoring expressions of selected cytokines upon lipopolysaccharide treatment (RT-qPCR, ELISA). Up to 10 μM, the phytocannabinoids only negligibly altered viability of the sebocytes, whereas high doses (≥50 μM) induced apoptosis.

Interestingly, basal sebaceous lipid synthesis was differentially modulated by the substances: CBC and THCV suppressed it, CBDV had only minor effects, whereas CBG and CBGV increased it.

Importantly, CBC, CBDV and THCV significantly reduced arachidonic acid (AA)-induced “acne-like” lipogenesis.

Moreover, THCV suppressed proliferation, and all phytocannabinoids exerted remarkable anti-inflammatory actions.

Our data suggest that CBG and CBGV may have potential in the treatment of dry-skin syndrome, whereas CBC, CBDV and especially THCV show promise to become highly efficient, novel anti-acne agents.

Moreover, based on their remarkable anti-inflammatory actions, phytocannabinoids could be efficient, yet safe novel tools in the management of cutaneous inflammations.”

http://www.ncbi.nlm.nih.gov/pubmed/27094344

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

Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability.

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“Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models.

Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure.

Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability.

Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and “drug likeness”, while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group.

Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations.

Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.”

http://www.ncbi.nlm.nih.gov/pubmed/27096053

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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Image result for Curr Clin Pharmacol.

“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

Cannabidiol promotes browning in 3T3-L1 adipocytes.

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“Recruitment of the brown-like phenotype in white adipocytes (browning) and activation of existing brown adipocytes are currently being investigated as a means to combat obesity.

The present study was designed to investigate the effects of cannabidiol (CBD), a major nonpsychotropic phytocannabinoid of Cannabis sativa, on induction of browning in 3T3-L1 adipocytes.

These data suggest possible roles for CBD in browning of white adipocytes, augmentation of lipolysis, thermogenesis, and reduction of lipogenesis.

In conclusion, the current data suggest that CBD plays dual modulatory roles in the form of inducing the brown-like phenotype as well as promoting lipid metabolism.

Thus, CBD may be explored as a potentially promising therapeutic agent for the prevention of obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/27067870

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

Analysis of endocannabinoid signaling elements and related proteins in lymphocytes of patients with Dravet syndrome.

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“Cannabidiol (CBD) reduces seizures in childhood epilepsy syndromes including Dravet syndrome (DS).

A formulation of CBD has obtained orphan drug designation for these syndromes and clinical trials are currently underway.

We believe of interest to investigate whether these potential targets are altered in DS, in particular whether the endocannabinoid system is dysregulated. To this end, lymphocytes from patients and controls were used for analysis of gene expression of transmitter receptors and transporters, ion channels, and enzymes associated with CBD effects, as well as endocannabinoid genes.

In conclusion, together with changes in the voltage-dependent calcium channel α-1h subunit, we found an upregulation of CB 2 receptors, associated with an activation of lymphocytes and changes in inflammation-related genes, in DS patients. Such changes were also reported in inflammatory disorders and may indirectly support the occurrence of a potential dysregulation of the endocannabinoid system in the brain.”

http://www.ncbi.nlm.nih.gov/pubmed/27069631

http://www.thctotalhealthcare.com/category/dravet-syndome/

Industrial hemp decreases intestinal motility stronger than indian hemp in mice.

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“Indian hemp has shown beneficial effects in various gastrointestinal conditions but it is not widely accepted due to high content of tetrahydrocannabinol resulting in unwanted psychotropic effects.

Since industrial hemp rich in cannabidiol lacks psychotropic effects the aim of research was to study the effects of industrial hemp on intestinal motility.

Although not completely without psychotropic activity cannabidiol could be a potential replacement for tetrahydrocannabinol.

Since industrial hemp infuse rich in cannabidiol reduces intestinal motility in healthy mice cannabidiol should be further evaluated for the treatment of intestinal hypermotility.”

http://www.ncbi.nlm.nih.gov/pubmed/23467947

The therapeutic use of cannabinoids: Forensic aspects.

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“Since 2013 in the Italian market has been introduced the Nabiximols, a drug containing two of the main active cannabinoids: Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This drug has been approved in Italy in the treatment of Multiple Sclerosis (MS). It is an oral spray formulation and each puff of 100μl contains 2.7mg of Δ9-THC and 2.5mg of CBD.

In the present study we analyzed urine and blood samples collected from a group of 20 patients treated with Nabiximols in order to evaluate: blood Δ9-THC concentrations in relation to the dose administered and the duration of treatment and the potentiality of this medication to be used for drug habit.

The study was conducted on a sample group of patients affected by MS, of both sexes, age: 49-61 years, treated with Nabiximols for short (28 days) or long-term.

The results of our study allow affirming that it is unlikely to use this medication for drug habit or to sale it in the black market because of the low blood concentrations available and of its high costs.

These statements were confirmed by: (a) the low Δ9-THC concentrations in the pharmaceutical formulation; (b) the low blood concentrations produced by Nabiximols administration, more than 10 times smaller than the blood concentrations known to produce psychotropic effects; (c) the presence of CBD (Δ9-THC natural antagonist); (d) the route of administration (inhaled, not smoked).”

http://www.ncbi.nlm.nih.gov/pubmed/27038587

In vitro and in vivo efficacy of non-psychoactive cannabidiol in neuroblastoma.

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“Neuroblastoma (nbl) is one of the most common solid cancers in children. Prognosis in advanced nbl is still poor despite aggressive multimodality therapy. Furthermore, survivors experience severe long-term multi-organ sequelae. Hence, the identification of new therapeutic strategies is of utmost importance.

Cannabinoids and their derivatives have been used for years in folk medicine and later in the field of palliative care. Recently, they were found to show pharmacologic activity in cancer, including cytostatic, apoptotic, and antiangiogenic effects.

We investigated, in vitro and in vivo, the anti-nbl effect of the most active compounds in Cannabis, Δ(9)-tetrahydrocannabinol (thc) and cannabidiol (cbd)…

Both compounds have antitumourigenic activity in vitro and impeded the growth of tumour xenografts in vivo. Of the two cannabinoids tested, cbd was the more active. Treatment with cbd reduced the viability and invasiveness of treated tumour cells in vitro and induced apoptosis. Moreover, cbd elicited an increase in activated caspase 3 in treated cells and tumour xenografts.

 

Our results demonstrate the antitumourigenic action of cbd on nbl cells. Because cbd is a nonpsychoactive cannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anticancer drug in the management of nbl.”

http://www.ncbi.nlm.nih.gov/pubmed/27022310

“Neuroblastomas are cancers that start in early nerve cells (called neuroblasts) of the sympathetic nervous system, so they can be found anywhere along this system.”  http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-what-is-neuroblastoma

Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation?

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“The Cannabis sativa plant has been used to treat various physiological and psychiatric conditions for millennia.

Current research is focused on isolating potentially therapeutic chemical constituents from the plant for use in the treatment of many central nervous system disorders.

Of particular interest is the primary nonpsychoactive constituent cannabidiol (CBD).

Unlike Δ9-tetrahydrocannabinol (THC), CBD does not act through the cannabinoid type 1 (CB1) receptor but has many other receptor targets that may play a role in psychiatric disorders.

Here we review preclinical and clinical data outlining the therapeutic efficacy of CBD for the treatment of motivational disorders such as drug addiction, anxiety, and depression.

Across studies, findings suggest promising treatment effects and potentially overlapping mechanisms of action for CBD in these disorders and indicate the need for further systematic investigation of the viability of CBD as a psychiatric pharmacotherapy.”

http://www.ncbi.nlm.nih.gov/pubmed/27023732