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Cannabidiol alleviates right ventricular fibrosis by inhibiting the transforming growth factor β pathway in monocrotaline-induced pulmonary hypertension in rats

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Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

“Cannabidiol (CBD) is a non-intoxicating compound of Cannabis with anti-fibrotic properties. Pulmonary hypertension (PH) is a disease that can lead to right ventricular (RV) failure and premature death. There is evidence that CBD reduces monocrotaline (MCT)-induced PH, including reducing right ventricular systolic pressure (RVSP), vasorelaxant effect on pulmonary arteries, and decreasing expression of profibrotic markers in the lungs. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on profibrotic parameters in the RVs of MCT-induced PH rats. In MCT-induced PH, we found an increase in profibrotic parameters and parameters related to RV dysfunction, i.e. plasma pro-B-type natriuretic peptide (NT-proBNP), cardiomyocyte width, interstitial and perivascular fibrosis area, amount of fibroblasts and fibronectin, as well as overexpression of the transforming growth of factor β1 (TGF-β1), galectin-3 (Gal-3), suppressor of mothers against decapentaplegic 2 (SMAD2), phosphorylated SMAD2 (pSMAD2) and alpha-smooth muscle actin (α-SMA). In contrast, vascular endothelial cadherin (VE-cadherin) levels were decreased in the RVs of MCT-induced PH rats. Administration of CBD reduced the amount of plasma NT-proBNP, the width of cardiomyocytes, the amount of fibrosis area, fibronectin and fibroblast expression, as well as decreased the expression of TGF-β1, Gal-3, SMAD2, pSMAD2, and increased the level of VE-cadherin. Overall, CBD has been found to have the anti-fibrotic potential in MCT-induced PH. As such, CBD may act as an adjuvant therapy for PH, however, further detailed investigations are recommended to confirm our promising results.”

https://pubmed.ncbi.nlm.nih.gov/37187449/

“CBD may be used in the future as add-on therapy in the treatment of PH.”

https://www.sciencedirect.com/science/article/abs/pii/S0925443923001199?via%3Dihub

Cannabidiol inhibits neuroinflammatory responses and circuit-associated synaptic loss following damage to a songbird vocal pre-motor cortical-like region

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“The non-euphorigenic phytocannabinoid cannabidiol (CBD) has been used successfully to treat childhood-onset epilepsies. These conditions are associated with developmental delays that often include vocal learning. Zebra finch song, like language, is a complex behavior learned during a sensitive period of development. Song quality is maintained through continuous sensorimotor refinement involving circuits that control learning and production. Within the vocal motor circuit, HVC is a cortical-like region that when partially lesioned temporarily disrupts song structure. We previously found CBD (10 mg/kg/day) improves post-lesion vocal recovery. The present studies were done to begin to understand mechanisms possibly responsible for CBD vocal protection. We found CBD markedly reduced expression of inflammatory mediators and oxidative stress markers. These effects were associated with regionally-reduced expression of the microglial marker TMEM119. As microglia are key regulators of synaptic reorganization, we measured synapse densities, finding significant lesion-induced circuit-wide decreases that were largely reversed by CBD. Synaptic protection was accompanied by NRF2 activation and BDNF/ARC/ARG3.1/MSK1 expression implicating mechanisms important to song circuit node mitigation of oxidative stress and promotion of synaptic homeostasis. Our findings demonstrate that CBD promotes an array of neuroprotective processes consistent with modulation of multiple cell signaling systems, and suggest these mechanisms are important to post-lesion recovery of a complex learned behavior.”

https://pubmed.ncbi.nlm.nih.gov/37193782/

“Taken together, our results demonstrate powerful anti-inflammatory and synaptoprotective mechanisms of CBD action following damage to a pre-motor cortical-like region. This efficacy is associated with promotion of multiple homeostasis-related mechanisms within song circuits. Future studies may link these effects with previously-demonstrated learning-dependent vocal recovery.”

https://www.nature.com/articles/s41598-023-34924-z

Study of Cannabis Oils Obtained from Three Varieties of C. sativa and by Two Different Extraction Methods: Phytochemical Characterization and Biological Activities

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“Currently, much effort is being placed into obtaining extracts and/or essential oils from Cannabis sativa L. for specific therapeutic purposes or pharmacological compositions. These potential applications depend mainly on the phytochemical composition of the oils, which in turn are determined by the type of C. sativa and the extraction method used to obtain the oils.

In this work, we have evaluated the contents of secondary metabolites, delta-9-tetrahydrocannabinol (THC), and cannabidiol (CBD), in addition to the total phenolic, flavonoids, and anthraquinone content in oils obtained using solid-liquid extraction (SLE) and supercritical fluid extraction (SCF). Different varieties of C. sativa were chosen by using the ratio of THC to CBD concentrations. Additionally, antioxidant, antifungal and anticancer activities on different cancer cell lines were evaluated in vitro.

The results indicate that oils extracted by SLE, with high contents of CBD, flavonoids, and phenolic compounds, exhibit a high antioxidant capacity and induce a high decrease in the cell viability of the tested breast cancer cell line (MCF-7). The observed biological activities are attributed to the entourage effect, in which CBD, phenols and flavonoids play a key role. Therefore, it is concluded that the right selection of C. sativa variety and the solvent for SLE extraction method could be used to obtain the optimal oil composition to develop a natural anticancer agent.”

https://pubmed.ncbi.nlm.nih.gov/37176831/

“Different varieties of C. sativa identified by the ratio of THC:CBD were used to extract cannabis oil using two extraction methods. The evaluation of the biological activities of the oils indicates that they are mostly determined by their chemical composition. For example, all Cannabis oils exhibit an antioxidant capacity and antiproliferative effects on tested cancer cell lines. In both types of experiments, the most active Cannabis oil tested was M4, suggesting a direct relationship between its antioxidant capacity and cancer cell cytotoxicity. In addition, M4 exhibits a high selectivity against breast cancer cell lines, and, therefore, Cannabis oils can be considered potential anticancer agents.”

https://www.mdpi.com/2223-7747/12/9/1772

Goods and bads of endocannabinoid system as a therapeutic target: Lessons learned after 30 years

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Pharmacological Reviews: 75 (3)

“The cannabis derivative marijuana is the most widely used recreational drug in the Western world, that is consumed by an estimated 83 million individuals (~3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the USA and worldwide.

Compelling research evidence and the FDA cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ9-tetrahydrocannabinol (THC) and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS) – made of receptors, metabolic enzymes and transporters – that is also regulated by phytocannabinoids.

The first endocannabinoid to be discovered 30 years ago was anandamide (N-arachidonoyl-ethanolamine); since then, distinct elements of ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here, a critical review of our knowledge of the goods and bads of ECS as a therapeutic target are presented, in order to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health.

Significance Statement The endocannabinoid system plays important roles everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Understanding structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like CB1R and CB2R) and metabolic enzymes (like FAAH and MAGL), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels providing new opportunities to treat patients.”

https://pubmed.ncbi.nlm.nih.gov/37164640/

https://pharmrev.aspetjournals.org/content/early/2023/05/09/pharmrev.122.000600

Assessment of Medical Cannabis and Health-Related Quality of Life

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“Importance: The use of cannabis as a medicine is becoming increasingly prevalent. Given the diverse range of conditions being treated with medical cannabis, as well as the vast array of products and dose forms available, clinical evidence incorporating patient-reported outcomes may help determine safety and efficacy.

Objective: To assess whether patients using medical cannabis report improvements in health-related quality of life over time.

Design, setting, and participants: This retrospective case series study was conducted at a network of specialist medical clinics (Emerald Clinics) located across Australia. Participants were patients who received treatment for any indication at any point between December 2018 and May 2022. Patients were followed up every mean (SD) 44.6 (30.1) days. Data for up to 15 follow-ups were reported. Statistical analysis was conducted from August to September 2022.

Exposure: Medical cannabis. Product types and cannabinoid content varied over time in accordance with the treating physician’s clinical judgement.

Main outcomes and measures: The main outcome measure was health-related quality of life as assessed using the 36-Item Short Form Health Survey (SF-36) questionnaire.

Results: In this case series of 3148 patients, 1688 (53.6%) were female; 820 (30.2%) were employed; and the mean (SD) age was 55.9 (18.7) years at baseline before treatment. Chronic noncancer pain was the most common indication for treatment (68.6% [2160 of 3148]), followed by cancer pain (6.0% [190 of 3148]), insomnia (4.8% [152 of 3148]), and anxiety (4.2% [132 of 3148]). After commencing treatment with medical cannabis, patients reported significant improvements relative to baseline on all 8 domains of the SF-36, and these improvements were mostly sustained over time. After controlling for potential confounders in a regression model, treatment with medical cannabis was associated with an improvement of 6.60 (95% CI, 4.57-8.63) points to 18.31 (95% CI, 15.86-20.77) points in SF-36 scores, depending on the domain (all P < .001). Effect sizes (Cohen d) ranged from 0.21 to 0.72. A total of 2919 adverse events were reported, including 2 that were considered serious.

Conclusions and relevance: In this case series study, patients using medical cannabis reported improvements in health-related quality of life, which were mostly sustained over time. Adverse events were rarely serious but common, highlighting the need for caution with prescribing medical cannabis.”

https://pubmed.ncbi.nlm.nih.gov/37159196/

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2804653

Neuroprotective Effect of a Pharmaceutical Extract of Cannabis with High Content on CBD Against Rotenone in Primary Cerebellar Granule Cell Cultures and the Relevance of Formulations

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“Introduction: Preclinical research supports the benefits of pharmaceutical cannabis-based extracts for treating different medical conditions (e.g., epilepsy); however, their neuroprotective potential has not been widely investigated. 

Materials and Methods: Using primary cultures of cerebellar granule cells, we evaluated the neuroprotective activity of Epifractan (EPI), a cannabis-based medicinal extract containing a high level of cannabidiol (CBD), components like terpenoids and flavonoids, trace levels of Δ9-tetrahydrocannabinol, and the acid form of CBD. We determined the ability of EPI to counteract the rotenone-induced neurotoxicity by analyzing cell viability and morphology of neurons and astrocytes by immunocytochemical assays. The effect of EPI was compared with XALEX, a plant-derived and highly purified CBD formulation (XAL), and pure CBD crystals (CBD). 

Results: The results revealed that EPI induced a significant reduction in the rotenone-induced neurotoxicity in a wide range of concentrations without causing neurotoxicity per se. EPI showed a similar effect to XAL suggesting that no additive or synergistic interactions between individual substances present in EPI occurred. In contrast, CBD did show a different profile to EPI and XAL because a neurotoxic effect per se was observed at higher concentrations assayed. Medium-chain triglyceride oil used in EPI formulation could explain this difference. 

Conclusion: Our data support a neuroprotective effect of EPI that may provide neuroprotection in different neurodegenerative processes. The results highlight the role of CBD as the active component of EPI but also support the need for an appropriate formulation to dilute pharmaceutical cannabis-based products that could be critical to avoid neurotoxicity at very high doses.”

https://pubmed.ncbi.nlm.nih.gov/37155642/

https://www.liebertpub.com/doi/10.1089/can.2022.0289

Cannabidiol for musculoskeletal regenerative medicine

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“Chronic musculoskeletal (MSK) pain is one of the most prevalent causes, which lead patients to a physician’s office. The most common disorders affecting MSK structures are osteoarthritis, rheumatoid arthritis, back pain, and myofascial pain syndrome, which are all responsible for major pain and physical disability.

Although there are many known management strategies currently in practice, phytotherapeutic compounds have recently begun to rise in the medical community, especially cannabidiol (CBD). This natural, non-intoxicating molecule derived from the cannabis plant has shown interesting results in many preclinical studies and some clinical settings. CBD plays vital roles in human health that go well beyond the classic immunomodulatory, anti-inflammatory, and antinociceptive properties. Recent studies demonstrated that CBD also improves cell proliferation and migration, especially in mesenchymal stem cells (MSCs).

The foremost objective of this review article is to discuss the therapeutic potential of CBD in the context of MSK regenerative medicine. Numerous studies listed in the literature indicate that CBD possesses a significant capacity to modulate mammalian tissue to attenuate and reverse the notorious hallmarks of chronic musculoskeletal disorders (MSDs). The most of the research included in this review report common findings like immunomodulation and stimulation of cell activity associated with tissue regeneration, especially in human MSCs.

CBD is considered safe and well tolerated as no serious adverse effects were reported. CBD promotes many positive effects which can manage detrimental alterations brought on by chronic MSDs. Since the application of CBD for MSK health is still undergoing expansion, additional randomized clinical trials are warranted to further clarify its efficacy and to understand its cellular mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/37158062/

https://journals.sagepub.com/doi/10.1177/15353702231162086

Impact of Cannabinoid Receptors in the Design of Therapeutic Agents against Human Ailments

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“The cannabinoid (CB) signalling cascade is widely located in the human body and is as-sociated with several pathophysiological processes. The endocannabinoid system comprises canna-binoid receptors CB1 and CB2, which belong to G-protein coupled receptors (GPCRs). CB1 recep-tors are primarily located on nerve terminals, prohibiting neurotransmitter release, whereas CB2 are present predominantly on immune cells, causing cytokine release. The activation of CB system con-tributes to the development of several diseases which might have lethal consequences, such as CNS disorders, cancer, obesity, and psychotic disorders on human health. Clinical evidence revealed that CB1 receptors are associated with CNS ailments such as Alzheimer’s disease, Huntington’s disease, and multiple sclerosis, whereas CB2 receptors are primarily connected with immune disorders, pain, inflammation, etc. Therefore, cannabinoid receptors have been proved to be promising targets in therapeutics and drug discovery. Experimental and clinical outcomes have disclosed the success sto-ry of CB antagonists, and several research groups have framed newer compounds with the binding potential to these receptors. In the presented review, we have summarized variously reported heter-ocycles with CB receptor agonistic/antagonistic properties against CNS disorders, cancer, obesity, and other complications. The structural activity relationship aspects have been keenly described along with enzymatic assay data. The specific outcomes of molecular docking studies have also been highlighted to get insights into the binding patterns of the molecules to CB receptors.”

https://pubmed.ncbi.nlm.nih.gov/37132103/

https://www.eurekaselect.com/article/131385

Repositioning Cannabinoids and Terpenes as Novel EGFR-TKIs Candidates for Targeted Therapy Against Cancer: A virtual screening model using CADD and biophysical simulations

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“This study examines the potential of Cannabis sativa L. plants to be repurposed as therapeutic agents for cancer treatment through designing of hybrid Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). A set of 50 phytochemicals was taken from Cannabinoids and Terpenes and subjected for screening using Semi-flexible and Flexible Molecular Docking methods, MM-GBSA free binding energy computations, and pharmacokinetic/pharmacodynamic (ADME-Tox) predictions.

Nine promising phytochemicals, Cannabidiolic acid (CBDA), Cannabidiol (CBD), Tetrahydrocannabivarin (THCV), Dronabinol (Δ-9-THC), Delta-8-Tetrahydrocannabinol (Δ-8-THC), Cannabicyclol (CBL), Delta9-tetrahydrocannabinolic acid (THCA), Beta-Caryophyllene (BCP), and Gamma-Elemene (γ-Ele) were identified as potential EGFR-TKIs natural product candidates for cancer therapy.

To further validate these findings, a set of Molecular Dynamics simulations were conducted over a 200 ns trajectory. This hybrid early drug discovery screening strategy has the potential to yield a new generation of EGFR-TKIs based on natural cannabis products, suitable for cancer therapy. In addition, the application of this computational strategy in the virtual screening of both natural and synthetic chemical libraries could support the discovery of a wide range of lead drug agents to address numerous diseases.”

https://pubmed.ncbi.nlm.nih.gov/37128337/

https://www.cell.com/heliyon/fulltext/S2405-8440(23)02752-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405844023027524%3Fshowall%3Dtrue

SELECTED CANNABIS TERPENES SYNERGIZE WITH THC TO PRODUCE INCREASED CB1 RECEPTOR ACTIVATION

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Biochemical Pharmacology

“The cannabis plant exerts its pharmaceutical activity primarily by the binding of cannabinoids to two G protein-coupled cannabinoid receptors, CB1 and CB2. The role that cannabis terpenes play in this activation has been considered and debated repeatedly, based on only limited experimental results. In the current study we used a controlled in-vitro heterologous expression system to quantify the activation of CB1 receptors by sixteen cannabis terpenes individually, by tetrahydrocannabinol (THC) alone and by THC-terpenes mixtures. The results demonstrate that all terpenes, when tested individually, activate CB1 receptors, at about 10-50% of the activation by THC alone. The combination of some of these terpenes with THC significantly increases the activity of the CB1 receptor, compared to THC alone. In some cases, several fold. Importantly, this amplification is evident at terpene to THC ratios similar to those in the cannabis plant, which reflect very low terpene concentrations. For some terpenes, the activation obtained by THC- terpene mixtures is notably greater than the sum of the activations by the individual components, suggesting a synergistic effect. Our results strongly support a modulatory effect of some of the terpenes on the interaction between THC and the CB1 receptor. As the most effective terpenes are not necessarily the most abundant ones in the cannabis plant, reaching “whole plant” or “full spectrum” composition is not necessarily an advantage. For enhanced therapeutic effects, desired compositions are attainable by enriching extracts with selected terpenes. These compositions adjust the treatment for various desired medicinal and personal needs.”

https://pubmed.ncbi.nlm.nih.gov/37084981/

https://www.sciencedirect.com/science/article/pii/S0006295223001399?via%3Dihub