Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

“The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30100226

https://www.epilepsybehavior.com/article/S1525-5050(18)30473-6/fulltext

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Treatment of Periodontal Ligament Stem Cells with MOR and CBD Promotes Cell Survival and Neuronal Differentiation via the PI3K/Akt/mTOR Pathway.

ijms-logo

“Periodontal ligament mesenchymal stem cells (hPDLSCs), as well as all mesenchymal stem cells, show self-renewal, clonogenicity, and multi-tissue differentiation proprieties and can represent a valid support for regenerative medicine. We treated hPDLSCs with a combination of Moringin (MOR) and Cannabidiol (CBD), in order to understand if treatment could improve their survival and their in vitro differentiation capacity. Stem cells survival is fundamental to achieve a successful therapy outcome in the re-implanted tissue of patients. Through NGS transcriptome analysis, we found that combined treatment increased hPDLSCs survival, by inhibition of apoptosis as demonstrated by enhanced expression of anti-apoptotic genes and reduction of pro-apoptotic ones. Moreover, we investigated the possible involvement of PI3K/Akt/mTOR pathway, emphasizing a differential gene expression between treated and untreated cells. Furthermore, hPDLSCs were cultured for 48 h in the presence or absence of CBD and MOR and, after confirming the cellular viability through MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide) assay, we examined the presence of neuronal markers, through immunofluorescence analysis. We found an increased expression of Nestin and GAP43 (growth associated protein 43) in treated cells. In conclusion, hPDLSCs treated with Moringin and Cannabidiol showed an improved survival capacity and neuronal differentiation potential.”

https://www.ncbi.nlm.nih.gov/pubmed/30096889

http://www.mdpi.com/1422-0067/19/8/2341

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.

Image result for Med J Aust.

“To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment.

The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved.

Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Neuronal preservation and reactive gliosis attenuation following neonatal sciatic nerve axotomy by a fluorinated cannabidiol derivative.

Neuropharmacology

“Immature peripheral nervous system damage, such as the transection of a peripheral nerve, results in the extensive degeneration of motoneurons and dorsal root ganglia (DRG) sensory neurons, mostly due to apoptotic events.

We have previously shown that cannabidiol (CBD), the most abundant non-psychotropic molecule present in the Cannabis sativa plant, exhibits neuroprotective action when administered daily at a dose of 15 mg/kg.

This study shows that use of the fluorinated synthetic version of CBD (4′-fluoro-cannabidiol, HUF-101) significantly improves neuronal survival by 2-fold compared to that achieved with traditional CBD at one-third the dose. Furthermore, we show that HUF-101 administration significantly upregulates anti-apoptotic genes and blocks the expression of pro-apoptotic nuclear factors.

Two-day-old Wistar rats were subjected to unilateral sectioning of the sciatic nerve and treated daily with HUF-101 (1, 2.5, 5 mg/kg/day, i.p.) or a vehicle solution for five days.

The results were evaluated by Nissl staining, immunohistochemistry, and qRT-PCR. Neuronal counting revealed a 47% rescue of spinal motoneurons and a 79% rescue of DRG neurons (HUF-101, 5 mg/kg). Survival was associated with complete depletion of p53 and a 60-fold elevation in BCL2-like 1 gene expression.

Additionally, peroxisome proliferator-activated receptor gamma (PPAR-gamma) gene expression was downregulated by 80%. Neuronal preservation was coupled with a high preservation of synaptic coverage and a reduction in astroglial and microglial reactions that were evaluated in nearby spinal motoneurons present in the ventral horn of the lumbar intumescence.

Overall, these data strongly indicate that HUF-101 exerts potent neuroprotective effects that are related to anti-apoptotic protection and the reduction of glial reactivity.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to Confirmation in Human Trials.

 Related image

“Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects.

Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD.

Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of Δ9-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system.

These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well.

Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD.

The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.”

https://www.ncbi.nlm.nih.gov/pubmed/30087591

https://www.frontiersin.org/articles/10.3389/fnins.2018.00502/full

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs.

Image result for frontiers in veterinary science

“The objectives of this study were to determine basic oral pharmacokinetics, and assess safety and analgesic efficacy of a cannabidiol (CBD) based oil in dogs with osteoarthritis (OA).

Results: Pharmacokinetics revealed an elimination half-life of 4.2 h at both doses and no observable side effects. Clinically, canine brief pain inventory and Hudson activity scores showed a significant decrease in pain and increase in activity (p < 0.01) with CBD oil. Veterinary assessment showed decreased pain during CBD treatment (p < 0.02). No side effects were reported by owners, however, serum chemistry showed an increase in alkaline phosphatase during CBD treatment (p < 0.01).

Clinical significance: This pharmacokinetic and clinical study suggests that 2 mg/kg of CBD twice daily can help increase comfort and activity in dogs with OA.”

https://www.ncbi.nlm.nih.gov/pubmed/30083539

https://www.frontiersin.org/articles/10.3389/fvets.2018.00165/full

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, alleviates bleomycin-induced skin and lung fibrosis.

Elsevier

“Systemic sclerosis (SSc) or scleroderma is a chronic multi-organ autoimmune disease characterized by vascular, immunological, and fibrotic abnormalities.

The etiology of SSc is unknown, but there is growing evidence that dysfunction of the endocannabinoid system (ECS) plays a critical role in its development.

Since the semi-synthetic cannabinoquinoid VCE-004.8 could alleviate bleomycin (BLM)-induced skin fibrosis, we have investigated an oral lipid formulation (EHP-101) of this dual PPARγ/CB2 receptors activator for the prevention of skin- and lung fibrosis and of collagen accumulation in BLM challenged mice.

Taken together, these data provide a rationale for further developing VCE-004.8 as an orally active agent to alleviate scleroderma and, possibly, other fibrotic diseases as well.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice.

Image result for Br J Pharmacol.

“Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, results in chronic inflammation and irreversible skeletal muscle degeneration. Moreover, the associated impairment of autophagy leads to the accumulation of damaged intracellular organelles that greatly contribute to the aggravation of muscle damage.

We explored the possibility of using non-euphoric compounds present in Cannabis sativa, including cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabidivarin (THCV) to reduce inflammation, restore functional autophagy and positively enhance muscle function in vivo.

We found that CBD and CBDV promote the differentiation of murine C2C12 myoblast cells into myotubes by increasing [Ca2+ ]i mostly via TRPV1 activation, an effect that undergoes rapid desensitization. CBD and CBDV also promoted the differentiation of myoblasts from DMD donors. In primary cultures prepared from satellite cells isolated from healthy donors, not only CBD and CBDV but also THCV promoted myotube formation, in this case mostly via TRPA1 activation. In mdx mice, CBD (60 mg Kg-1), CBDV (60 mg Kg-1 ) prevented the loss of locomotor activity at two distinct ages (from 5 to 7 and 32 to 34 weeks of age). This effect was associated with a reduction in tissue and plasma pro-inflammatory markers, together with the restoration of autophagy.

CONCLUSION AND IMPLICATIONS:

We provide new insights into plant cannabinoid interactions with TRP channels in skeletal muscle, highlighting a potential opportunity for novel co-adjuvant therapies to prevent muscle degeneration in DMD patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30074247

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine

Image result for oncogene

“The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed.

Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression.

Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival.

Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone.

Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice.

Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p.

Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients’ outcome.”

https://www.nature.com/articles/s41388-018-0390-1

“Cannabinoid improves survival rates of mice with pancreatic cancer”  https://medicalxpress.com/news/2018-07-cannabinoid-survival-mice-pancreatic-cancer.html

“Study: CBD From Marijuana Plus Chemotherapy Tripled Cancer Survival Rates In Mice” https://www.forbes.com/sites/daviddisalvo/2018/07/31/study-cbd-from-marijuana-plus-chemotherapy-triples-cancer-survival-rates-in-mice/#491942d44630

“Cannabis drug may help pancreatic-cancer patients live almost THREE TIMES longer, study finds” http://www.dailymail.co.uk/health/article-6007275/Cannabis-drug-help-pancreatic-cancer-patients-live-THREE-TIMES-longer-study-finds.html

“Substance in cannabis ‘could boost pancreatic cancer treatments’. Scientists say cannabidiol could extend patients’ lives by a matter of years”  https://www.theguardian.com/science/2018/jul/30/substance-in-cannabis-could-boost-pancreatic-cancer-treatments

“Cannabinoid mice trial holds hope for pancreatic cancer patients”  https://www.smh.com.au/national/cannabinoid-mice-trial-holds-hope-for-pancreatic-cancer-patients-20180731-p4zuls.html

“Medical cannabis extract could help pancreatic cancer patients live longer, early study suggests” https://www.independent.co.uk/news/health/pancreatic-cancer-medical-cannabis-cbd-oil-cannabidiol-chemotherapy-a8470406.html

“Cancer ‘remarkable’ treatment – cannabis CBD could improve survival rate by THREE times. CANCER symptoms could be prevented with a “remarkable” new treatment, which includes cannabis CBD, scientists have revealed. Pancreatic cancer survival rates could be improved by three times, by adding CBD into chemotherapy treatments, they said.” https://www.express.co.uk/life-style/health/996657/cancer-treatment-pancreatic-symptoms-cannabis-cbd

“Compound in cannabis could help pancreatic cancer patients live significantly longer” https://www.deccanchronicle.com/lifestyle/health-and-wellbeing/310718/compound-in-cannabis-could-help-pancreatic-cancer-patients-live-signif.html

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabidiol restores differentiation capacity of LPS exposed adipose tissue mesenchymal stromal cells.

Experimental Cell Research

“Multipotent mesenchymal stromal cells (MSCs) support wound healing processes. These cells express toll-like receptors (TLRs). TLRs perform important key functions when the immune system is confronted with danger signals. TLR ligation by lipopolysaccharides (LPS) activates MSCs and induces intracellular signaling cascades, which affect their differentiation profile, increase the release of inflammatory cytokines and the production of reactive oxygen species. Continuing exposure to LPS triggers prolonged inflammatory reactions, which may lead to deleterious conditions, e.g. non-healing wounds.

Cannabidiol (CBD) exerts anti-inflammatory processes through cannabinoid receptor dependent and independent mechanisms. In the present study, we examined whether CBD could influence the inflammatory MSC phenotype.

Exposure to LPS increased the release of IL-6, as well as other soluble factors, and elevated levels of oxidized macromolecules found in cell homogenisates. While the amount of IL-6 was unaffected, co-treatment with CBD reduced the oxidative stress acting on the cells. LPS inhibited adipogenic as well as chondrogenic differentiation, which was attenuated by CBD treatment. In the case of adipogenesis, the disinhibitory effect probably depended on CBD interaction with the peroxisome proliferator-activated receptor-γ.

CBD could exert mild immunosuppressive properties on MSCs, while it most effectively acted anti-oxidatively and by restoring the differentiation capacity upon LPS treatment.” https://www.ncbi.nlm.nih.gov/pubmed/30036540

“Cannabidiol (CBD) reduces oxidative stress and restores adipogenesis and chondrogenesis of mesenchymal stromal cells (MSCs) upon lipopolysaccharides (LPS)  exposure.” https://linkinghub.elsevier.com/retrieve/pii/S0014482718304312

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous