Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock-in mice

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“Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability.

While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits.

We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex.

These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.”

https://pubmed.ncbi.nlm.nih.gov/38654472/

“The current report is the first to show experimental evidence that cannabidiol can mitigate some of the memory and social deficits as well as seizure susceptibility in a well-characterized CDD mouse model. These findings continue to support the emerging clinical observational data that cannabidiol-based compounds have efficacy in CDD patients, especially those in later childhood and adulthood.”

https://onlinelibrary.wiley.com/doi/10.1111/ejn.16350

[Topical Use of Cannabis in Inflammatory Diseases in patients of the IPS Salud Social in Barranquilla, Colombia]

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“Objective: To relate the topical use of cannabis as an analgesic therapeutic alternative in patients with some inflammatory diseases in Salud Social I.P.S during May to July 2023.

Methods: An analytical, retrospective study was carried out. The population from which the sample was obtained corresponds to patients diagnosed with Arthrosis, Unspecified, Non-Toxic Multinodular Goiter, Epilepsy, Unspecified Type Venous Insufficiency (Chronic) (Peripheral), Unspecified Lumbago, Secondary Gonarthrosis, Rotator Cuff Syndrome, Carpal Tunnel Syndrome, in Salud Social I.P.S of Barranquilla, Atlántico. A sample of 23 patients diagnosed with these pathologies was obtained by non-probabilistic convenience sampling.

Results: All patients showed pain relief after two months of follow-up, two experienced adverse effects. Some studies suggest that cannabinoids present in cannabis, such as CBD and THC, may have analgesic and anti-inflammatory properties that could alleviate pain and inflammation associated with these conditions. This is consistent with the present study.

Conclusion: Topical cannabis is presented as a therapeutic alternative in inflammatory diseases, however, it is important to highlight that research on the use of cannabis in these diseases is limited and more studies are needed to fully understand its effects and potential benefits.”

https://pubmed.ncbi.nlm.nih.gov/38683093/

https://revistaalergia.mx/ojs/index.php/ram/article/view/1351

Hemp (Cannabis sativa L.) protein: Impact of extraction method and cultivar on structure, function, and nutritional quality

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“Hemp (Cannabis sativa L.) is increasingly gaining traction as a novel and sustainable source of plant protein.

Accordingly, the aim of this study was to investigate the effectiveness of two protein extraction methods, alkaline extraction coupled with isoelectric precipitation (AE-IEP) and salt extraction coupled with ultrafiltration (SE-UF) in producing hemp protein isolates (pH-HPI and salt-HPI) with high purity and yield. Structural characterization as impacted by extraction method and cultivar was performed and related to functional performance and nutritional quality.

Both extraction methods, with carefully selected parameters, resulted in HPI with high purity (86.6-88.1% protein) and protein extraction yields (81.6-87.3%). All HPI samples had poor solubility (∼9-20%) at neutral pH compared to commercial soy protein and pea protein isolates (cSPI, cPPI). A relatively high surface hydrophobicity and low surface charge contributed to such poor solubility of HPI. However, HPI demonstrated similar solubility at acidic pH (50-67%) and comparable gel strength (up to 24 N) to cSPI. Comparing experimental amino acid composition to the theoretical amino acid distribution in hemp protein provided insights to the functional performance of the protein isolates. While pH-HPI demonstrated better functionality than salt-HPI, minimal structural, functional, and nutritional differences were noted among the pH-HPI samples extracted from four different cultivars.

Overall, results from this work could be used to guide future attempts to further develop successful protein extraction processes, and to provide valuable insights to propel breeding efforts that target enhanced hemp protein characteristics for food applications.”

https://pubmed.ncbi.nlm.nih.gov/38681526/

https://linkinghub.elsevier.com/retrieve/pii/S2665927124000728

Immunostimulatory and Antibacterial Effects of Cannabis sativa L. Leaves on Broilers

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“The aim of this study was to evaluate the effect of dried Cannabis sativa L. leaves as a phytogenic mixture added to broiler feed on CD4+ and CD8+ T lymphocyte subpopulations,

Newcastle disease virus (NDV) antibody titres, and the presence of E. coli in faecal samples. The study was conducted on 100 male Ross 308 broilers, divided into four groups of 25 broilers, for a 42-day research period. The groups were housed separately in boxes on a litter of softwood shavings and were fed starter mixture from day 1 to day 21 and finisher mixture from day 22 to day 42. Industrial hemp (C. sativa) was grown in the Crkvina area, Croatia (latitude: 45°18’46.8″ N; longitude: 15°31’30″ E). The hemp leaves were manually separated, sun-dried, and ground to a powder. The mixture offered to the control group did not contain cannabis leaves, whereas the three experimental groups received mixtures containing mixed cannabis leaves in a quantity of 10 g/kg, 20 g/kg, or 30 g/kg (E_10, E_20, and E_30, respectively). The mean NDV antibody level was uniform in all study groups until post-vaccination day 14 and increased comparably with time. The percentage of CD4+ and CD8+ lymphocytes in the peripheral blood subpopulation showed statistically significant differences (p < 0.001) in the E_20 group as compared with the control group and both the E_10 and E_30 groups throughout the study period. As the broiler age increased, the CD4+-to-CD8+ ratios also increased and were statistically significant (p < 0.0001) on day 42 in all experimental groups as compared to the control group. Comparing the control group with the experimental groups indicated that the bacterial count was lower in broiler groups having received feed with the addition of 20 g/kg and 30 g/kg C. sativa leaves.

In conclusion, the C. sativa leaves were found to elicit a favourable immunomodulatory effect on cell-mediated and humoral immune responses in broilers via increased CD4+ and CD8+ lymphocyte subpopulations and higher CD4+:CD8+ cell ratios, thus indicating enhanced immune function capacity. In addition, C. sativa leaves may have complementary effects on the broiler post-vaccination immune response, increase broilers’ resistance to infectious diseases, reduce the effect of stress associated with vaccination, and improve broiler health and welfare.”

https://pubmed.ncbi.nlm.nih.gov/38672306/

“Food safety, climate change, the emergence of infectious diseases, the ban on the use of antibiotics as growth promoters, and increasingly demanding intensive production are daily challenges for poultry production. A functional immune system is a prerequisite for animal health, and nutrition is one of the modulators of the immune system; therefore, the appropriate balance of nutrients is extremely important for the proper development and maintenance of the immune system of animals. The antimicrobial and immunomodulatory effects of phytobiotics are properties that make their use important as feed additives for poultry.

Cannabis sativa L. contains many different compounds such as flavonoids, terpenes, and cannabinoids, each with different properties and effects. The effects of C. sativa seeds, essential oils, and cakes as feed additives for poultry have already been investigated, but the effect of C. sativa L. leaves as a feed additive on immunostimulatory and antibacterial activity has not. The results of this study show that C. sativa as a phytogenic additive to animal feed has a favourable antimicrobial and immunomodulatory effect in the production of broiler chickens.”

https://www.mdpi.com/2076-2615/14/8/1159

Cannabis oil extracts for chronic pain: what else can be learned from another structured prospective cohort?

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“Introduction: The use of medicinal cannabis for managing pain expands, although its efficacy and safety have not been fully established through randomized controlled trials.

Objectives: This structured, prospective questionnaire-based cohort was aimed to assess long-term effectiveness and safety of cannabis oil extracts in patients with chronic pain.

Methods: Adult Israeli patients licensed to use cannabis oil extracts for chronic pain were followed prospectively for 6 months. The primary outcome measure was change from baseline in average weekly pain intensity, and secondary outcomes were changes in related symptoms and quality of life, recorded before treatment initiation and 1, 3, and 6 months thereafter. Generalized linear mixed model was used to analyze changes over time. In addition, “responders” (≥30% reduction in weekly pain at any time point) were identified.

Results: The study included 218 patients at baseline, and 188, 154, and 131 at 1, 3, and 6 months, respectively. At 6 months, the mean daily doses of cannabidiol and Δ9-tetrahydrocannabinol were 22.4 ± 24.0 mg and 20.8 ± 30.1 mg, respectively. Pain decreased from 7.9 ± 1.7 at baseline to 6.6 ± 2.2 at 6 months (F(3,450) = 26.22, P < 0.0001). Most secondary parameters also significantly improved. Of the 218 participants, 24% were “responders” but could not be identified by baseline parameters. “Responders” exhibited higher improvement in secondary outcomes. Adverse events were common but mostly nonserious.

Conclusion: This prospective cohort demonstrated a modest overall long-term improvement in chronic pain and related symptoms and a reasonable safety profile with the use of relatively low doses of individually titrated Δ9-tetrahydrocannabinol and cannabidiol.”

https://pubmed.ncbi.nlm.nih.gov/38680212/

“In conclusion, this structured, prospective cohort study demonstrated modest improvements in pain, associated symptoms, functioning, and quality of life, and a reduction in opioid use. The reduction in “disease burden” was more pronounced in nearly a quarter of the patients, but no predictors for treatment success could be identified before treatment initiation. The doses of THC and CBD in the oil extracts were modest and considerably lower than those required to achieve similar magnitude of effect by cannabis inflorescence. Although medical cannabis treatment appears to be generally safe for most patients, some still experience SAEs.”

https://journals.lww.com/painrpts/fulltext/2024/04000/cannabis_oil_extracts_for_chronic_pain__what_else.12.aspx

Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer’s Disease Treatment

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“Despite decades of rigorous research and numerous clinical trials, Alzheimer’s disease (AD) stands as a notable healthcare challenge of this century, with effective therapeutic solutions remaining elusive.

Recently, the endocannabinoid system (ECS) has emerged as an essential therapeutic target due to its regulatory role in different physiological processes, such as neuroprotection, modulation of inflammation, and synaptic plasticity. This aligns with previous research showing that cannabinoid receptor ligands have the potential to trigger the functional structure of neuronal and brain networks, potentially impacting memory processing.

Therefore, our study aims to assess the effects of prolonged, intermittent exposure (over 90 days) to JWH-133 (0.2 mg/kg) and an EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos, 2.5 mg/kg) on recognition memory, as well as their influence on brain metabolism and modulation of the expanded endocannabinoid system in APP/PS1 mice. Chronic therapy with cannabinoid receptor ligands resulted in reduced anxiety-like behavior and partially reversed the cognitive deficits. Additionally, a reduction was observed in both the number and size of Aβ plaque deposits, along with decreased cerebral glucose metabolism, as well as a decline in the expression of mTOR and CB2 receptors. Furthermore, the study revealed enlarged astrocytes and enhanced expression of M1 mAChR in mice subjected to cannabinoid treatment.

Our findings highlight the pivotal involvement of the extended endocannabinoid system in cognitive decline and pathological aspects associated with AD, presenting essential preclinical evidence to support the continued exploration and assessment of cannabinoid receptor ligands for AD treatment.”

https://www.mdpi.com/1424-8247/17/4/530

“In conclusion, our current findings suggest that pharmacological activation of the expanded ECS via the selective CB2 agonist JWH-133 or Cannabixir® Medium Flos—15.6% THC and <1% CBD ameliorates the Alzheimer-like phenotype in APP/PS1 mice by mitigating neuroinflammation and accumulation of Aβ plaque deposits, reducing cerebral glucose metabolism, and increasing glial reactivity. These results support the notion that targeting the ECS using cannabinoid receptor ligands, which lack psychoactive side effects, is a promising target for the development of novel therapeutic approaches against AD.”

https://pubmed.ncbi.nlm.nih.gov/38675490/

“Prevention of Alzheimer’s Disease Pathology by Cannabinoids. Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.”

https://www.jneurosci.org/content/25/8/1904

Antimicrobial, Probiotic, and Immunomodulatory Potential of Cannabis sativa Extract and Delivery Systems

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“The compounds present in hemp show multidirectional biological activity. It is related to the presence of secondary metabolites, mainly cannabinoids, terpenes, and flavonoids, and the synergy of their biological activity. The aim of this study was to assess the activity of the Henola Cannabis sativae extract and its combinations with selected carriers (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, magnesium aluminometasilicate, and hydroxypropyl-β-cyclodextrin) in terms of antimicrobial, probiotic, and immunobiological effects.

As a result of the conducted research, the antimicrobial activity of the extract was confirmed in relation to the following microorganisms: Clostridium difficile, Listeria monocytogenes, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus pyrogenes, Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, Pseudomonas aereuginosa, and Candida albicans (microorganism count was reduced from ~102 CFU mL-1 to <10 CFU mL-1 in most cases). Additionally, for the system with hydroxypropyl-β-cyclodextrin, a significant probiotic potential against bacterial strains was established for strains Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus brevis, Lactobacillus rhamnosus, Lactobacillus reuteri, Pediococcus pentosaceus, Lactococcus lactis, Lactobacillus fermentum, and Streptococcus thermophilus (microorganism count was increased from ~102 to 104-107). In terms of immunomodulatory properties, it was determined that the tested extract and the systems caused changes in IL-6, IL-8, and TNF-α levels.”

https://pubmed.ncbi.nlm.nih.gov/38667045/

“This study investigated the antimicrobial potential of Cannabis sativa extract, Henola variety, and systems with carriers. The extract showed antimicrobial activity against pathogenic microorganisms, suggesting its possible application as support in combating infections. Additionally, the system with hydroxypropyl-β-cyclodextrin may possess prebiotic properties, stimulating the growth of probiotic microorganisms. Furthermore, the investigated systems exhibit immunomodulatory and immunostimulatory effects, with potential therapeutic implications for modulating inflammatory responses. Overall, these findings underscore the multifaceted therapeutic potential of Cannabis sativa extracts. The delivery systems might be used as powder-based food additives, but they might also be subjected to formulation studies for the development of an oral dietary supplement.”

https://www.mdpi.com/2079-6382/13/4/369

Antibiofilm and Immune-Modulatory Activity of Cannabidiol and Cannabigerol in Oral Environments-In Vitro Study

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“Objective: To evaluate the in vitro antimicrobial and antibiofilm properties and the immune modulatory activity of cannabidiol (CBD) and cannabigerol (CBG) on oral bacteria and periodontal ligament fibroblasts (PLF).

Methods: Cytotoxicity was assessed by propidium iodide flow cytometry on fibroblasts derived from the periodontal ligament. The minimum inhibitory concentration (MIC) of CBD and CBG for S. mutans and C. albicans and the metabolic activity of a subgingival 33-species biofilm under CBD and CBG treatments were determined. The Quantification of cytokines was performed using the LEGENDplex kit (BioLegend, Ref 740930, San Diego, CA, USA).

Results: CBD-treated cell viability was greater than 95%, and for CBG, it was higher than 88%. MIC for S. mutans with CBD was 20 µM, and 10 µM for CBG. For C. albicans, no inhibitory effect was observed. Multispecies biofilm metabolic activity was reduced by 50.38% with CBD at 125 µg/mL (p = 0.03) and 39.9% with CBG at 62 µg/mL (p = 0.023). CBD exposure at 500 µg/mL reduced the metabolic activity of the formed biofilm by 15.41%, but CBG did not have an effect. CBG at 10 µM caused considerable production of anti-inflammatory mediators such as TGF-β and IL-4 at 12 h. CBD at 10 µM to 20 µM produced the highest amount of IFN-γ.

Conclusion: Both CBG and CBD inhibit S. mutans; they also moderately lower the metabolic activity of multispecies biofilms that form; however, CBD had an effect on biofilms that had already developed. This, together with the production of anti-inflammatory mediators and the maintenance of the viability of mammalian cells from the oral cavity, make these substances promising for clinical use and should be taken into account for future studies.”

https://pubmed.ncbi.nlm.nih.gov/38667018/

“The role of bacteria, together with the production of anti-inflammatory mediators and the maintenance of the viability of mammalian cells from the oral cavity, make these substances promising for clinical use and should be considered for future in vivo studies. In the near future, it will be useful to study Cannabis derivatives uses on biofilm formation as well as to functionalize different regeneration biomaterials with cannabinoids, which could be a useful approach to improve clinical outcomes after periodontal therapy.”

https://www.mdpi.com/2079-6382/13/4/342

Anti-Inflammatory Properties of Cannabidiol and Beta-Caryophyllene Alone or Combined in an In Vitro Inflammation Model

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“Cannabis contains over 500 different compounds, including cannabinoids, terpenoids, and flavonoids. Cannabidiol (CBD) is a non-psychoactive constituent, whereas beta-caryophyllene (BCP) is one of most the well-known terpenoids of Cannabis sativa.

In recent years, there has been an emerging idea that the beneficial activities of these compounds are greater when they are combined.

The aim of this study was to evaluate the anti-inflammatory effect of CBD and BCP using the in vitro model of lipopolysaccharide (LPS)-stimulated human keratinocytes (HaCaT) cells. The vitality of the cells was quantified using LDH and MTT assays. The levels of the following pro-inflammatory proteins and genes were quantified: IL-1β, COX-2, and phospho-NF-κB p65 (p-p65) through Western blotting (WB) and interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) through quantitative real-time polymerase chain reaction (RT-qPCR).

When present in the incubation medium, CBD and BCP reduced the increased levels of pro-inflammatory proteins (IL-1β, COX-2, and p-NF-kB) induced by LPS. The anti-inflammatory effects of CBD were blocked by a PPARγ antagonist, whereas a CB2 antagonist was able to revert the effects of BCP. Selected concentrations of CBD and BCP were able to revert the increases in the expression of pro-inflammatory genes (IL-1β, IL-6, and TNFα), and these effects were significant when the drugs were used in combination.

Our results suggest that CBD and BCP work in concert to produce a major anti-inflammatory effect with good safety profiles.”

https://pubmed.ncbi.nlm.nih.gov/38675427/

“Our data suggest that the topical use of a combination of CBD and BCP should be efficacious for treating skin inflammation and/or other inflammatory disorders.”

https://www.mdpi.com/1424-8247/17/4/467

Phytocannabinoids: Exploring Pharmacological Profiles and Their Impact on Therapeutical Use

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“Phytocannabinoids, a diverse group of naturally occurring compounds extracted from the Cannabis plant, have attracted interest due to their potential pharmacological effects and medicinal uses.

This comprehensive review presents the intricate pharmacological profiles of phytocannabinoids while exploring the diverse impacts these substances have on biological systems. From the more than one hundred cannabinoids which were identified in the Cannabis plant so far, cannabidiol (CBD) and tetrahydrocannabinol (THC) are two of the most extensively studied phytocannabinoids.

CBD is a non-psychoactive compound, which exhibits potential anti-inflammatory, neuroprotective, and anxiolytic properties, making it a promising candidate for a wide array of medical conditions.

THC, known for its psychoactive effects, possesses analgesic and antiemetic properties, contributing to its therapeutic potential.

In addition to THC and CBD, a wide range of additional phytocannabinoids have shown intriguing pharmacological effects, including cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN).

The endocannabinoid system, made up of the enzymes involved in the production and breakdown of endocannabinoids, cannabinoid receptors (CB1 and CB2), and endogenous ligands (endocannabinoids), is essential for preserving homeostasis in several physiological processes. Beyond their effects on the endocannabinoid system, phytocannabinoids are studied for their ability to modify ion channels, neurotransmitter receptors, and anti-oxidative pathways.

The complex interaction between phytocannabinoids and biological systems offers hope for novel treatment approaches and lays the groundwork for further developments in the field of cannabinoid-based medicine. This review summarizes the state of the field, points out information gaps, and emphasizes the need for more studies to fully realize the therapeutic potential of phytocannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/38673788/

“Phytocannabinoids offer diverse therapeutic applications, ranging from pain management to neurological disorders and inflammatory diseases. Their antimicrobial and anti-inflammatory properties make them valuable candidates for combating antibiotic resistance and modulating inflammatory pathways. By leveraging the synergistic effects of combination therapies and targeting multiple disease pathways, phytocannabinoids hold immense potential to revolutionize the future of pharmacotherapy and improve human health outcomes. “

https://www.mdpi.com/1422-0067/25/8/4204