Cannabidiol (CBD).

Cover of StatPearls“Cannabis sativa or Indian hemp (subfamily Cannaboideae of family Moraceae) is an annual herbaceous plant, native to central and western Asia, cultivated for medicinal properties and for hemp, which is a natural textile fiber. The plant contains over 400 chemical compounds, of which approximately 80 biologically active chemical molecules. The most important cannabis compounds are cannabinoids formed by a terpene combined with resorcinol, or, according to a different nomenclature, by a benzopyranic ring system. There are about sixty cannabinoids, of which the most important psychoactive compound is tetrahydrocannabinol (TCH), in particular the isomer delta (Δ9-THC). Other identified compounds are cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and olivetol. In addition to cannabinoids, the plant contains terpenoids such as beta-myrcene, beta-caryophyllene, d-limonene, linalool, piperidine, and p-cymene, as well as flavonoids such as quercetin.”

https://www.ncbi.nlm.nih.gov/pubmed/32310508

https://www.ncbi.nlm.nih.gov/books/NBK556048/

Uncovering the hidden antibiotic potential of Cannabis.

 Go to Volume 0, Issue ja“The spread of antimicrobial resistance continues to be a priority health concern worldwide, necessitating exploration of alternative therapies.

Cannabis sativa has long been known to contain antibacterial cannabinoids, but their potential to address antibiotic resistance has only been superficially investigated.

Here, we show that cannabinoids exhibit antibacterial activity against MRSA, inhibit its ability to form biofilms and eradicate pre-formed biofilms and stationary phase cells persistent to antibiotics.

We show that the mechanism of action of cannabigerol is through targeting the cytoplasmic membrane of Gram-positive bacteria and demonstrate in vivo efficacy of cannabigerol in a murine systemic infection model caused by MRSA.

We also show that cannabinoids are effective against Gram-negative organisms whose outer membrane is permeabilized, where cannabigerol acts on the inner membrane.

Finally, we demonstrate that cannabinoids work in combination with polymyxin B against multi-drug resistant Gram-negative pathogens, revealing the broad-spectrum therapeutic potential for cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/32017534

https://pubs.acs.org/doi/10.1021/acsinfecdis.9b00419

Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus.

antioxidants-logo “Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic terpenophenols isolated from Cannabis sativa, which, besides their anti-inflammatory/antioxidant effects, are able to inhibit, the first, and to stimulate, the second, the appetite although there are no studies elucidating their role in the hypothalamic appetite-regulating network. Consequently, the aim of the present research is to investigate the role of CBD and CBG in regulating hypothalamic neuromodulators. Comparative evaluations between oxidative stress and food intake-modulating mediators were also performed.

RESULTS:

Both CBD and CBG inhibited NPY and POMC gene expression and decreased the 3-HK/KA ratio in the hypothalamus. The same compounds also reduced hypothalamic NE synthesis and DA release, whereas the sole CBD inhibited 5-HT synthesis.

CONCLUSION:

The CBD modulates hypothalamic neuromodulators consistently with its anorexigenic role, whereas the CBG effect on the same mediators suggests alternative mechanisms, possibly involving peripheral pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/31941059

https://www.mdpi.com/2076-3921/9/1/71

Cannabinoids and Opioids in the Treatment of Inflammatory Bowel Diseases.

Image result for clinical and translational gastroenterology“In traditional medicine, Cannabis sativa has been prescribed for a variety of diseases. Today, the plant is largely known for its recreational purpose, but it may find a way back to what it was originally known for: a herbal remedy. Most of the plant’s ingredients, such as Δ-tetrahydrocannabinol, cannabidiol, cannabigerol, and others, have demonstrated beneficial effects in preclinical models of intestinal inflammation. Endogenous cannabinoids (endocannabinoids) have shown a regulatory role in inflammation and mucosal permeability of the gastrointestinal tract where they likely interact with the gut microbiome. Anecdotal reports suggest that in humans, Cannabis exerts antinociceptive, anti-inflammatory, and antidiarrheal properties. Despite these reports, strong evidence on beneficial effects of Cannabis in human gastrointestinal diseases is lacking. Clinical trials with Cannabis in patients suffering from inflammatory bowel disease (IBD) have shown improvement in quality of life but failed to provide evidence for a reduction of inflammation markers. Within the endogenous opioid system, mu opioid receptors may be involved in anti-inflammation of the gut. Opioids are frequently used to treat abdominal pain in IBD; however, heavy opioid use in IBD is associated with opioid dependency and higher mortality. This review highlights latest advances in the potential treatment of IBD using Cannabis/cannabinoids or opioids.”

https://www.ncbi.nlm.nih.gov/pubmed/31899693

https://journals.lww.com/ctg/Abstract/latest/Cannabinoids_and_Opioids_in_the_Treatment_of.99898.aspx

Could the Combination of Two Non-Psychotropic Cannabinoids Counteract Neuroinflammation? Effectiveness of Cannabidiol Associated with Cannabigerol.

medicina-logo“Neuroinflammation is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this study, we investigate the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of two non-psychoactive phytocannabinoids, cannabigerol (CBG) and cannabidiol (CBD).

Results: Pre-treatment with CBG (at 2.5 and 5 µM doses) alone and in combination with CBD (at 2.5 and 5 µM doses) was able to reduce neuroinflammation induced by a culture medium of LPS-stimulated macrophages. In particular, the pre-treatment with CBD at a 5 µM dose decreased TNF-α levels and increased IL10 and IL-37 expression. CBG-CBD association at a 5 µM dose also reduced NF-kB nuclear factor activation with low degradation of the inhibitor of kappaB alpha (IkBα). CBG and CBD co-administered at a 5 µM dose decreased iNOS expression and increased Nrf2 levels. Furthermore, the pre-treatment with the association of two non-psychoactive cannabinoids downregulated Bax protein expression and upregulated Bcl-2 expression. Our data show the anti-inflammatory, anti-oxidant, and anti-apoptotic effects PPARγ-mediated.

Conclusions: Our results provide preliminary support on the potential therapeutic application of a CBG-CBD combination for further preclinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31752240

https://www.mdpi.com/1010-660X/55/11/747

Evaluation of the effects of cannabinoids CBD and CBG on human ovarian cancer cells in vitro

University of Huddersfield“Ovarian cancer, with over a 90% reoccurrence within 18 months of treatment, and approximately a 30% mortality rate after 5 years, is the leading cause of death in cases of gynaecological malignancies. Acquired resistance, and toxic side effects by clinically used agents are major challenges associated with current treatments, indicating the need for new approaches in ovarian cancer treatment.

Increased tumour cell proliferation associated with upregulation of cannabinoid (CB) receptors has been observed in ovarian cancer. As cannabinoids reported to bind to CB receptors, and can potentially modulate their downstream signalling, this raises the possibility of cannabinoids as potential anticancer drugs for ovarian cancer treatment.

Amongst the cannabinoids, non-psychoactive CBD and CBG have been shown to have anticancer activities towards prostate and colon cancer cells through multiple mechanisms of action. However, CBD and CBG have yet to be investigated in relation to ovarian cancer therapy either in vitro or in vivo.

Aim:

The aims of this study were to evaluate the potential cytotoxic effects of CBD and CBG in human ovarian cancer cells, their ability to potentiate existing clinically used agents for ovarian cancer, and to perform initial mode of action studies in vitro.

Conclusions:

Both CBD and CBG showed preferential cytotoxicity against the ovarian cancer cells analysed compared to the non-cancer cells; however, this was less than for carboplatin. Importantly, in contrast to carboplatin, CBD and CBG showed similar activity towards cisplatin sensitive and cisplatin resistant cells indicating distinctive mechanisms of action to platinum drugs.

Preferential cytotoxicity towards cancer cells in vitro and ability to potentiate carboplatin and overcome cisplatin resistance identify CBD and CBG as promising candidates that warrant further investigation, both in terms of detailed mechanism of action studies and also in vivo studies to assess whether this promising activity translates into an in vivo setting and their potential for further progression towards the clinic.”

http://eprints.hud.ac.uk/id/eprint/34866/

Development of An Oral Treatment with the PPAR-γ-Acting Cannabinoid VCE-003.2 Against the Inflammation-Driven Neuronal Deterioration in Experimental Parkinson’s Disease.

molecules-logo “In a recent study, we described the neuroprotective properties of VCE-003.2-an aminoquinone derivative of the non-psychotropic phytocannabinoid cannabigerol (CBG)-administered intraperitoneally (i.p.) in an inflammatory model of Parkinson’s disease (PD). We also demonstrated that these properties derive from its activity on the peroxisome proliferator-activated receptor-γ, in particular at a regulatory site within this receptor type.

In the present study, we wanted to further confirm this neuroprotective potential using an oral lipid formulation of VCE-003.2, developed to facilitate the clinical development of this phytocannabinoid derivative.

To this end, we evaluated VCE-003.2, administered orally at two doses (10 and 20 mg/kg), to mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS), a classic model of inflammation-driven neuronal deterioration that recapitulates characteristics of PD.

In summary, our data confirm the neuroprotective potential of an oral formulation of VCE-003.2 against neuronal injury in an in vivo model of PD based on neuroinflammation, and this study opens the possibility to further the development of oral VCE-003.2 in the clinic.”

https://www.ncbi.nlm.nih.gov/pubmed/31349553

https://www.mdpi.com/1420-3049/24/15/2702

Chemotherapy-induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol.

Publication cover image

“Muscle wasting, anorexia, and metabolic dysregulation are common side-effects of cytotoxic chemotherapy, having a dose-limiting effect on treatment efficacy, and compromising quality of life and mortality.

Extracts of Cannabis sativa, and analogues of the major phytocannabinoid Δ9-tetrahydrocannabinol, have been used to ameliorate chemotherapy-induced appetite loss and nausea for decades. However, psychoactive side-effects limit their clinical utility, and they have little efficacy against weight loss.

We recently established that the non-psychoactive phytocannabinoid (CBG) stimulates appetite in healthy rats, without neuromotor side-effects. The present study assessed whether CBG attenuates anorexia and/or other cachectic effects induced by the broad-spectrum chemotherapy agent cisplatin.

RESULTS:

CBG (120 mg/kg) modestly increased food intake, predominantly at 36-60hrs (p<0.05), and robustly attenuated cisplatin-induced weight loss from 6.3% to 2.6% at 72hrs (p<0.01). Cisplatin-induced skeletal muscle atrophy was associated with elevated plasma corticosterone (3.7 vs 13.1ng/ml, p<0.01), observed selectively in MHC type IIx (p<0.05) and IIb (p<0.0005) fibres, and was reversed by pharmacological rescue of dysregulated Akt/S6-mediated protein synthesis and autophagy processes. Plasma metabonomic analysis revealed cisplatin administration produced a wide-ranging aberrant metabolic phenotype (Q2Ŷ=0.5380, p=0.001), involving alterations to glucose, amino acid, choline and lipid metabolism, citrate cycle, gut microbiome function, and nephrotoxicity, which were partially normalized by CBG treatment (Q2Ŷ=0.2345, p=0.01). Lipidomic analysis of hypothalami and plasma revealed extensive cisplatin-induced dysregulation of central and peripheral lipoamines (29/79 and 11/26 screened, respectively), including reversible elevations in systemic N-acyl glycine concentrations which were negatively associated with the anti-cachectic effects of CBG treatment.

CONCLUSIONS:

Endocannabinoid-like lipoamines may have hitherto unrecognized roles in the metabolic side-effects associated with chemotherapy, with the N-acyl glycine subfamily in particular identified as a potential therapeutic target and/or biomarker of anabolic interventions. CBG-based treatments may represent a novel therapeutic option for chemotherapy-induced cachexia, warranting investigation in tumour-bearing cachexia models.”

https://www.ncbi.nlm.nih.gov/pubmed/31035309

Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling.”
“Cannabigerol displayed significant antitumor activity.” https://link.springer.com/article/10.1007/BF02976895
Antitumor activity of cannabigerol against human oral epitheloid carcinoma cells. Cannabigerol exhibited the highest growth-inhibitory activity against the cancer cell lines.” https://www.ncbi.nlm.nih.gov/pubmed/9875457

Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration.

 “The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids.

METHODS:

We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro.

RESULTS:

Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis.

CONCLUSIONS:

The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.”

https://www.ncbi.nlm.nih.gov/pubmed/30899454

https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-019-0148-x

Cannabigerol Action at Cannabinoid CB1 and CB2 Receptors and at CB1-CB2 Heteroreceptor Complexes.

Image result for frontiers in pharmacology

“Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties.

The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB1 (CB1R) and CB2 (CB2R) receptors and the effects of the compound on agonist activation of those receptors and of CB1-CB2 heteroreceptor complexes.

The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/29977202

https://www.frontiersin.org/articles/10.3389/fphar.2018.00632/full