Topical cannabis-based medicines – A novel paradigm and treatment for non-uremic calciphylaxis leg ulcers: An open label trial

“Non-Uremic Calciphylaxis (NUC) is a rare condition that often manifests as intractable and painful integumentary wounds, afflicting patients with a high burden of co-morbidity.

The Endocannabinoid System (ECS) is a ubiquitous signalling system that is theorised to be dysregulated within wound beds and associated peri-wound tissues.

Preclinical research has shown that the dominant chemical classes derived from the cannabis plant, cannabinoids, terpenes, and flavonoids, interact with the integumentary ECS to promote wound closure and analgesia.

This is a prospective open label cohort study involving two elderly Caucasian females with recalcitrant NUC leg ulcers of greater than 6 months duration.

Topical Cannabis-Based Medicines (TCBM) composed of cannabinoids, terpenes, and flavonoids were applied daily to both the wound bed and peri-wound tissues until complete wound closure was achieved.

Wounds were photographed regularly, and the digital images were subjected to planimetric analysis to objectively quantify the degree of granulation and epithelization. Analgesic utilisation, as a surrogate/proxy for pain scores, was also tracked. The cohort had a mean M3 multimorbidity index score of 3.31. Complete wound closure was achieved in a mean of 76.3 days. Additionally, no analgesics were required after a mean of 63 days.

The treatments were well tolerated with no adverse reactions. The positive results demonstrated in very challenging wounds such as NUC, among highly complex patients, suggest that TCBM may have an even broader role within integumentary and wound management.

This treatment paradigm warrants being trialled in other wound types and classes, and ultimately should be subjected to randomised controlled trials.”

https://pubmed.ncbi.nlm.nih.gov/32875692/

“Topical Cannabis‐Based Medicines, applied to both wound beds and peri‐wound tissues, represent a promising novel, non‐invasive, and safe treatment option for NUC leg ulcers.”

https://onlinelibrary.wiley.com/doi/full/10.1111/iwj.13484

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A molecular basis for the anti-inflammatory and anti-fibrosis properties of cannabidiol

“Cannabidiol (CBD) is considered a non-psychoactive, antioxidant, and anti-inflammatory compound derived from the Cannabis sativa plant.

There are various reports on the versatile function of CBD, including ameliorating chronic inflammation and fibrosis formation in several tissue types.

This review focused on the anti-inflammation and anti-fibrotic effects of CBD based on modulating the associated chemokines/cytokines and receptor-mediated pathways.

This review thus recommends the continued study of CBD’s molecular mechanism in treating established and emerging inflammatory and fibrosis-related diseases.”

https://pubmed.ncbi.nlm.nih.gov/32885502/

“In all, CBD shows immense promise as a possible treatment for chronic inflammation and the progression or development of fibrosis.”

https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202000975R

Cannabidiol (CBD): a killer for inflammatory rheumatoid arthritis synovial fibroblasts

 Cell Death & Disease“Cannabidiol (CBD) is a non-intoxicating phytocannabinoid from cannabis sativa that has demonstrated anti-inflammatory effects in several inflammatory conditions including arthritis.

In this study, we show that CBD increases intracellular calcium levels, reduces cell viability and IL-6/IL-8/MMP-3 production of rheumatoid arthritis synovial fibroblasts (RASF).

CBD reduced cell viability, proliferation, and IL-6/IL-8 production of RASF. Moreover, CBD increased intracellular calcium and uptake of the cationic viability dye PoPo3 in RASF, which was enhanced by pre-treatment with TNF.

Thus, CBD possesses anti-arthritic activity and might ameliorate arthritis via targeting synovial fibroblasts under inflammatory conditions.”

https://pubmed.ncbi.nlm.nih.gov/32873774/

“In conclusion, CBD might be beneficial as an adjuvant treatment in rheumatoid arthritis that might support the action of currently used disease-modifying anti-rheumatic drugs.”

https://www.nature.com/articles/s41419-020-02892-1

Δ9 Tetrahydrocannabinol attenuates Staphylococcal enterotoxin B-induced inflammatory lung injury and prevents mortality in mice by modulation of miR-17-92 cluster and induction of T-regulatory cells

Logo of brjpharm“Staphylococcal enterotoxin B (SEB) is a potent activator of Vβ8+T-cells resulting in the clonal expansion of ∼30% of the T-cell pool. Consequently, this leads to the release of inflammatory cytokines, toxic shock, and eventually death.

In the current study, we investigated if Δ9tetrahydrocannabinol (THC), a cannabinoid known for its anti-inflammatory properties, could prevent SEB-induced mortality and alleviate symptoms of toxic shock.

Key Results

Exposure to SEB resulted in acute mortality, while THC treatment led to 100% survival of mice. SEB induced the miRNA-17-92 cluster, specifically miRNA-18a, which targeted Pten (phosphatase and tensin homologue), an inhibitor of the PI3K/Akt signalling pathway, thereby suppressing T-regulatory cells. In contrast, THC treatment inhibited the individual miRNAs in the cluster, reversing the effects of SEB.

Conclusions and Implications

We report, for the first time a role for the miRNA 17–92 cluster in SEB-mediated inflammation. Furthermore, our results suggest that THC is a potent anti-inflammatory compound that may serve as a novel therapeutic to suppress SEB-induced pulmonary inflammation by modulating critical miRNA involved in SEB-induced toxicity and death.

Δ9-Tetrahydrocannabinol (THC) is a marijuana plant-derived cannabinoid known for its robust anti-inflammatory and immunosuppressive properties. The anti-inflammatory and immunosuppressive effects of THC are diverse and function effectively to abrogate a number of inflammatory processes.

Taken together, our data demonstrate that THC is a strong anti-inflammatory agent capable of rescuing mice from SEB-mediated toxicity and death.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376457/

Coronavirus Disease-2019 Treatment Strategies Targeting Interleukin-6 Signaling and Herbal Medicine

View details for OMICS: A Journal of Integrative Biology cover image“Coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is evolving across the world and new treatments are urgently needed as with vaccines to prevent the illness and stem the contagion. The virus affects not only the lungs but also other tissues, thus lending support to the idea that COVID-19 is a systemic disease. The current vaccine and treatment development strategies ought to consider such systems medicine perspectives rather than a narrower focus on the lung infection only.

COVID-19 is associated with elevated levels of the inflammatory cytokines such as interleukin-6 (IL-6), IL-10, and interferon-gamma (IFN-γ). Elevated levels of cytokines and the cytokine storm have been linked to fatal disease. This suggests new therapeutic strategies through blocking the cytokine storm. IL-6 is one of the major cytokines associated with the cytokine storm. IL-6 is also known to display pleiotropic/diverse pathophysiological effects. We suggest the blockage of IL-6 signaling and its downstream mediators such as Janus kinases (JAKs), and signal transducer and activators of transcription (STATs) offer potential hope for the treatment of severe cases of COVID-19. Thus, repurposing of already approved IL-6-JAK-STAT signaling inhibitors as well as other anti-inflammatory drugs, including dexamethasone, is under development for severe COVID-19 cases.

We conclude this expert review by highlighting the potential role of precision herbal medicines, for example, the Cannabis sativa, provided that omics technologies can be utilized to build a robust scientific evidence base on their clinical safety and efficacy. Precision herbal medicine buttressed by omics systems science would also help identify new molecular targets for drug discovery against COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/32857671/

Cannabis sativa is a plant known to contain anti-inflammatory compounds such as cannabinoid cannabidiol. In addition to other compounds such as terpenes, these compounds have been suggested to have potential anticancer properties. Like other herbal plants, we suggest C. sativa warrants further mechanistic research in relationship to putative effects in COVID-19.”

https://www.liebertpub.com/doi/10.1089/omi.2020.0122

Cannflavins – From plant to patient: A scoping review

Fitoterapia Cannflavins are a group of prenylflavonoids derived from Cannabis sativa L.. Cannflavin A (CFL-A), B (CFL-B) and C (CFL-C) have been heralded for their anti-inflammatory properties in pre-clinical evaluations.

This scoping review aims to synthesise the evidence base on cannflavins to provide an overview of the current research landscape to inform research strategies to aid clinical translation.

Results: 26 full text articles were included. CFL-A and CFL-B demonstrated potent anti-inflammatory activity via inhibition of 12-o-tetradecanoylphorbol 13-acetate induced PGE2 release (CFL-A half maximal inhibitory concentration (IC50): 0.7 μM; CFL-B IC50: 0.7 μM) and microsomal prostaglandin E synthase-1 (CFL-A IC50: 1.8 μM; CFL-B IC50: 3.7 μM). Outcomes were also described in preclinical models of anti-oxidation (CFL-A), anti-parasitic activity (CFL-A, CFL-C), neuroprotection (CFL-A) and cancer (Isocannflavin B, a CFL-B isomer). In-silico screening identified that CFL-A has binding affinity with viral proteins that warrant further investigation.

Conclusions: Cannflavins demonstrate a number of promising therapeutic properties, most notably as an anti-inflammatory agent. Low yields of extraction however have previously limited research to small pre-clinical investigations. Identification of cannflavin-rich chemovars, novel extraction techniques and recent identification of a biosynthetic pathway will hopefully allow research to be scaled appropriately. In order to fully evaluate the therapeutic properties of cannflavins focused research now needs to be embedded within institutions with a track-record of clinical translation.”

https://pubmed.ncbi.nlm.nih.gov/32858172/

“Cannflavins are prenylated flavonoids derived from the Cannabis sativa L. plant with many touted therapeutic properties.”

https://www.sciencedirect.com/science/article/abs/pii/S0367326X2030294X?via%3Dihub

Targeting Endocannabinoid Signaling: FAAH and MAG Lipase Inhibitors

Annual Reviews adds Remarq® across its collection of 47 journals – RedLink“Inspired by the medicinal properties of the plant Cannabis sativa and its principal component (-)-trans9-tetrahydrocannabinol (THC), researchers have developed a variety of compounds to modulate the endocannabinoid system in the human brain.

Inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which are the enzymes responsible for the inactivation of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, respectively, may exert therapeutic effects without inducing the adverse side effects associated with direct cannabinoid CB1 receptor stimulation by THC.

Here we review the FAAH and MAGL inhibitors that have reached clinical trials, discuss potential caveats, and provide an outlook on where the field is headed.”

https://pubmed.ncbi.nlm.nih.gov/32867595/

https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-030220-112741

Chronic Cannabidiol Administration Attenuates Skeletal Muscle De Novo Ceramide Synthesis Pathway and Related Metabolic Effects in a Rat Model of High-Fat Diet-Induced Obesity

biomolecules-logo“Numerous studies showed that sustained obesity results in accumulation of bioactive lipid derivatives in several tissues, including skeletal muscle, which further contributes to the development of metabolic disturbances and insulin resistance (IR).

The latest data indicate that a potential factor regulating lipid and glucose metabolism is a phytocannabinoid-cannabidiol (CBD), a component of medical marijuana (Cannabis). Therefore, we aimed to investigate whether chronic CBD administration influences bioactive lipid content (e.g., ceramide (CER)), as well as glucose metabolism, in the red skeletal muscle (musculus gastrocnemius) with predominant oxidative metabolism.

All experiments were conducted on an animal model of obesity, i.e., Wistar rats fed a high-fat diet (HFD) or standard rodent chow, and subsequently injected with CBD in a dose of 10 mg/kg or its solvent for two weeks. The sphingolipid content was assessed using high-performance liquid chromatography (HPLC), while, in order to determine insulin and glucose concentrations, immunoenzymatic and colorimetric methods were used. The protein expression from sphingolipid and insulin signaling pathways, as well as endocannabinoidome components, was evaluated by immunoblotting.

Unexpectedly, our experimental model revealed that the significantly intensified intramuscular de novo CER synthesis pathway in the HFD group was attenuated by chronic CBD treatment. Additionally, due to CBD administration, the content of other sphingolipid derivatives, i.e., sphingosine-1-phosphate (S1P) was restored in the high-fat feeding state, which coincided with an improvement in skeletal muscle insulin signal transduction and glycogen recovery.”

https://pubmed.ncbi.nlm.nih.gov/32859125/

https://www.mdpi.com/2218-273X/10/9/1241

Hemp in Veterinary Medicine: From Feed to Drug

 See the source image“Hemp (Cannabis sativa) is an angiosperm plant belonging to the Cannabaceae family. Its cultivation dates back to centuries. It has always been cultivated due to the possibility of exploiting almost all the parts of the plant: paper, fabrics, ropes, bio-compounds with excellent insulating capacity, fuel, biodegradable plastic, antibacterial detergents, and food products, such as flour, oils, seeds, herbal teas, and beer, are indeed obtained from hemp.

Hemp flowers have also always been used for their curative effects, as well as for recreational purposes due to their psychotropic effects. Cannabis contains almost 500 chemical compounds, such as phytocannabinoids, terpenes, flavonoids, amino acids, fatty acids, vitamins, and macro-, and micro-elements, among others.

When utilized as a food source, hemp shows excellent nutritional and health-promoting (nutraceutical) properties, mainly due to the high content in polyunsaturated fatty acids (especially those belonging to the ω-3 series), as well as in phenolic compounds, which seem effective in the prevention of common diseases such as gastrointestinal disorders, neurodegenerative diseases, cancer, and others.

Moreover, hemp oil and other oils (i.e., olive oil and medium-chain triglyceride-MCT-oil) enriched in CBD, as well as extracts from hemp dried flowers (Cannabis extracts), are authorized in some countries for therapeutic purposes as a second-choice approach (when conventional therapies have failed) for a certain number of clinical conditions such as pain and inflammation, epilepsy, anxiety disorders, nausea, emesis, and anorexia, among others.

The present review will synthetize the beneficial properties of hemp and hemp derivatives in animal nutrition and therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/32850997/

C. sativa has been an important source of food in the Old World, as hempseeds and seed meal are excellent sources of dietary oil, fiber, and protein. Many of the constituents of C. sativa can be classified as either nutrients, nutraceuticals, or pharmaceutical ingredients.”

https://www.frontiersin.org/articles/10.3389/fvets.2020.00387/full

Cannabidiol inhibits febrile seizure by modulating AMPA receptor kinetics through its interaction with the N-terminal domain of GluA1/GluA2

Pharmacological Research “Cannabidiol (CBD) is a major phytocannabinoid in Cannabis sativa. CBD is being increasingly reported as a clinical treatment for neurological diseases.

Febrile seizure is one of the most common diseases in children with limited therapeutic options. We investigated possible therapeutic effects of CBD on febrile seizures and the underlying mechanism.

Use of a hyperthermia-induced seizures model revealed that CBD significantly prolonged seizure latency and reduced the severity of thermally-induced seizures. Hippocampal neuronal excitability was significantly decreased by CBD. Further, CBD significantly reduced the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated evoked excitatory postsynaptic currents (eEPSCs) and the amplitude and frequency of miniature EPSCs (mEPSCs).

Furthermore, CBD significantly accelerated deactivation in GluA1 and GluA2 subunits. Interestingly, CBD slowed receptor recovery from desensitization of GluA1, but not GluA2. These effects on kinetics were even more prominent when AMPAR was co-expressed with γ-8, the high expression isoform 8 of transmembrane AMPAR regulated protein (TARPγ8) in the hippocampus. The inhibitory effects of CBD on AMPAR depended on its interaction with the distal N-terminal domain of GluA1/GluA2.

CBD inhibited AMPAR activity and reduced hippocampal neuronal excitability, thereby improving the symptoms of febrile seizure in mice. The putative binding site of CBD in the N-terminal domain of GluA1/GluA2 may be a drug target for allosteric gating modulation of AMPAR.”

https://pubmed.ncbi.nlm.nih.gov/32805354/

“Cannabidiol (CBD) significantly prolonged seizure latency and reduced seizure severity.”

https://www.sciencedirect.com/science/article/abs/pii/S1043661820314365?via%3Dihub