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Cannabidiol/cannabidiolic acid-rich hemp (Cannabis sativa L.) extract attenuates cognitive impairments and glial activations in rats exposed to chronic stress

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“Ethnopharmacological relevance: Hemp (Cannabis sativa L.) is increasingly being recognized for its medicinal properties beside utilizing it for food, oil, and textile fibers. The high level of cannabidiol (CBD) content in hemp’s flowers shows promising neuroprotective properties without causing psychotomimetic or addictive effects. Recently, products containing CBD and its precursor, cannabidiolic acid (CBDA), have been used to treat stress-related cognitive impairment. However, the therapeutic potential of hemp extract remains inadequately explored.

Aim of the study: To investigate the effect of CBD/CBDA-rich hemp extract on learning and memory, neuroendocrine alterations, and hippocampal neuropathological changes in the chronic restraint stress model.

Materials and methods: Chronic restraint stress (CRS) was induced in male Wistar rats by immobilizing them in a restrainer for 6 hours per day for 21 consecutive days. CBD/CBDA-rich hemp extract (10 and 30 mg/kg, intraperitoneal injection) was administered daily, 1 hour before restraint. After the last day of CRS, behavioral tests for cognition were conducted using the Y-maze and object recognition tests. Serum corticosterone (CORT) levels were measured by ELISA. Histopathological changes, neuronal density, and the activation of microglia and astrocytes were visualized using cresyl violet and immunohistochemical staining.

Results: A high dose of CBD/CBDA-rich hemp extract effectively ameliorated CRS-induced cognitive impairment and reversed HPA axis hyperactivity in CRS rats by reducing CORT levels and adrenal gland weight. Additionally, CBD/CBDA-rich hemp extract protected CRS-induced damage to hippocampal neurons. Further analysis showed that CBD/CBDA-rich hemp extract reduced specific markers of microglial activation (ionized calcium-binding adaptor molecule-1, Iba-1) and astrocytic structural protein (glial fibrillary acidic protein, GFAP) in CRS rats.

Conclusion: CBD/CBDA-rich hemp extracts remarkably reversed the stress-induced behavioral perturbations and hippocampal damage, suggesting its ameliorative effect on stress response.”

https://pubmed.ncbi.nlm.nih.gov/39551282/

“Cannabidiol (CBD) and cannabidiolic acid (CBDA) is the major constituent in hemp (Cannabis sativa L.) extract”

“CBD/CBDA-rich hemp extract is effective in relieving the chronic stress-induced cognitive impairment.”

https://linkinghub.elsevier.com/retrieve/pii/S0378874124014120

Cannabis Use and Age-Related Changes in Cognitive Function From Early Adulthood to Late Midlife in 5162 Danish Men

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“Introduction: Cannabis is by far the most widely used and abused drug listed on the Drug Enforcement Administration’s Schedule I, which includes drugs with a high potential for abuse. There is evidence of short-term negative effects of cannabis use on cognition, but only a limited number of studies have explored the association between cannabis use and age-related cognitive decline. The aim of the present study was to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife.

Methods: The study population consisted of 5162 men who had participated in Danish follow-up studies on cognitive aging. These studies included scores on the military intelligence test Børge Prien’s Prøve from both the conscription assessment (mean age = 20 years; p1 and p99: 18 and 26 years) and from the follow-up (mean age = 64 years; p1 and p99: 55 and 72 years) as well as extensive data on lifestyle and health from the follow-up questionnaires. The association between cannabis use and age-related cognitive decline was investigated in linear regression models.

Results: Men with a history of cannabis use had less cognitive decline from early adulthood to late midlife compared to men without a history of cannabis use. Among cannabis users, neither age of initiation of cannabis use nor frequent use was significantly associated with a greater age-related cognitive decline.

Discussion and conclusions: In a sample of more than 5000 men followed for a mean of 44 years, we found no significant harmful effects of cannabis use on age-related cognitive decline.”

https://pubmed.ncbi.nlm.nih.gov/39508467/

“In the present study, we aimed to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife. This study contributes to the sparse knowledge on this subject and aligns with most existing studies, suggesting no association between cannabis use and greater cognitive decline. More specifically, in the present study, cannabis users experienced slightly less cognitive decline compared to nonusers, and the association remained significant when controlling for potential confounders. Among cannabis users, no significant association was found with cognitive decline for either age of initiation of cannabis use or frequent cannabis use. Further studies are needed to investigate whether these findings reflect that there are no adverse effects on cognitive decline or that the effects of cannabis are temporary and disappear after a prolonged period of time.”

https://onlinelibrary.wiley.com/doi/10.1002/brb3.70136

CB1 Receptors In NG2 CELLS MEDIATE CANNABINOID-EVOKED FUNCTIONAL MYELIN REGENERATION

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“Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is still unknown whether this action relies mostly on a cell autonomous effect on oligodendroglial-lineage-NG2 cells.

By using conditional genetic mouse models, here we found that cannabinoid CB1 receptors located on NG2 cells are required for oligodendroglial differentiation and myelin regeneration after demyelination. Selective CB1 receptor gene depletion in NG2 cells following toxin-induced demyelination disrupted oligodendrocyte regeneration and functional remyelination and exacerbated axonal damage. These deficits were rescued by pharmacological blockade of the RhoA/ROCK/Cofilin pathway.

Conversely, tetrahydrocannabinol administration promoted oligodendrocyte regeneration and functional remyelination in wild-type but not Ng2-CB1-deficient mice.

Overall, this study identifies CB1 receptors as essential modulators of remyelination and support the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/39528076/

“Cannabinoids have been shown to modulate myelin development and regeneration in mice. Here, using OPC-specific reporter mouse lines in combination with models of toxin-induced demyelination, we found that CB1 receptors located on NG2 cells, by modulating RhoA/ROCK/cofilin and mTORC1 signaling in a coordinated manner, exert an essential function in controlling NG2 cell differentiation, OL regeneration, myelin regeneration and functional recovery following demyelination, thus supporting the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.”

https://www.sciencedirect.com/science/article/abs/pii/S0301008224001199?via%3Dihub

Effects of cannabidiol on AMPKα2 /HIF-1α/BNIP3/NIX signaling pathway in skeletal muscle injury

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“Cannabidiol: (CBD) is a non-psychoactive natural active ingredient from cannabis plant, which has many pharmacological effects, including neuroprotection, antiemetic, anti-inflammatory and anti-skeletal muscle injury. However, the mechanism of its effect on skeletal muscle injury still needs further research.

In order to seek a scientifically effective way to combat skeletal muscle injury during exercise, we used healthy SD rats to establish an exercise-induced skeletal muscle injury model by treadmill training, and systematically investigated the effects and mechanisms of CBD, a natural compound in the traditional Chinese medicine Cannabis sativa L., on combating skeletal muscle injury during exercise.

CBD effectively improved the fracture of skeletal muscle tissue and reduced the degree of inflammatory cell infiltration. Biochemical indexes such as CK, T, Cor, LDH, SOD, MDA, and GSH-Px in serum of rats returned to normal. Combining transcriptome and network analysis results, CBD may play a protective role in exercise-induced skeletal muscle injury through HIF-1 signaling pathway. The experimental results implied that CBD could down-regulate the expression of IL-6, NF-κB, TNF-α, Keap1, AMPKα2, HIF-1α, BNIP3 and NIX, and raised the protein expression of IL-10, Nrf2 and HO-1.

These results indicate that the protective effect of CBD on exercise-induced skeletal muscle injury may be related to the inhibition of oxidative stress and inflammation, thus inhibiting skeletal muscle injury through AMPKα2/HIF-1α/BNIP3/NIX signal pathways.”

https://pubmed.ncbi.nlm.nih.gov/39502531/

“This study preliminarily explored the protective effect of CBD on skeletal muscle in the rat model of acute exercise-induced skeletal muscle injury. The CBD intervention can reduce CK and LDH levels and increase T/COR ratio. The MDA content in the low-dose and high-dose groups of CBD was declined, while the SOD and GSH-Px content were raised. The intervention of CBD can reduce the level of oxidative stress and inflammatory response, and then reduce the expressions of AMPKα2, HIF-1α, BNIP3 and NIX, thus protecting skeletal muscle from injury. This study could provide a new potential target for the treatment of exercise-induced skeletal muscle injury. It can provide new ideas for the basic research and clinical treatment of CBD repairing skeletal muscle injury in the future.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1450513/full

Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway

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“Cannabidiol (CBD), a cannabinoid that does not create psychoactive activities, has been identified as having a multitude of therapeutic benefits.

This study delves into the chemical properties, pharmacokinetics, safety and toxicity, pharmacological effects, and most importantly, the association between the therapeutic potential of CBD and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.

The relationship between Nrf2 and CBD is closely linked to certain proteins that are associated with cardiovascular dysfunctions, cancers, and neurodegenerative conditions. Specifically, Nrf2 is connected to the initiation and progression of diverse health issues, including nephrotoxicity, bladder-related diseases, oral mucositis, cancers, obesity, myocardial injury and angiogenesis, skin-related inflammations, psychotic disorders, neuropathic pain, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, neuroinflammation, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis.

The association between CBD and Nrf2 is a zone of great interest in the medical field, as it has the potential to significantly impact the treatment and prevention of wide-ranging health conditions. Additional investigation is necessary to entirely apprehend the mechanisms underlying this crucial interplay and to develop effective therapeutic interventions.”

https://pubmed.ncbi.nlm.nih.gov/39491419/

“CBD plays a protective role in cardiovascular dysfunctions, cancers, and neurodegenerative conditions by targeting the Nrf2 signaling pathway.”

https://www.sciencedirect.com/science/article/pii/S0753332223016037?via%3Dihub

A recent update on the antibacterial effects of distinct bioactive molecules derived from the Cannabis plant

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“The number of human infections with multidrug-resistant (MDR) bacteria is increasing worldwide and constitutes a serious threat to human health. Given the lack of novel antibiotic compounds worsening this dilemma, alternative antibiotic-independent treatment and prevention strategies of infectious diseases applying natural compounds appear highly appreciable.

Given the long-known health-beneficial and disease-alleviating properties of Cannabis, we performed a literature search summarizing current knowledge regarding the antibacterial effects of extracts from different parts of the Cannabis sativa plant and of defined Cannabis-derived molecules and their potential mode of action.

The included studies revealed that various extracts and essential oils of C. sativa as well as major cannabinoids exerted potent activities against a broad spectrum of Gram-positive bacteria and against some Gram-negative bacterial species including MDR strains. Particularly the disruption of the bacterial cytoplasmic membrane by some cannabinoids resulted in potent antibacterial effects against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. Furthermore, defined cannabinoids inhibited the formation of and eradicated existing bacterial biofilms.

In conclusion, given their antibacterial properties distinct Cannabis-derived molecules expand the repertoire of antibiotics-independent treatment options in the combat of bacterial infectious diseases which should be further addressed in future studies including clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/39470741/

“Collectively, results from the here reviewed studies open future perspectives for cannabis-derived molecules as alternative antibiotic-independent treatment and prevention strategies in the combat of bacterial infectious diseases which should be further addressed in future studies including clinical trials.”

https://akjournals.com/view/journals/1886/aop/article-10.1556-1886.2024.00098/article-10.1556-1886.2024.00098.xml

Harnessing Cannabis sativa Oil for Enhanced Skin Wound Healing: The Role of Reactive Oxygen Species Regulation

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“Cannabis sativa emerges as a noteworthy candidate for its medicinal potential, particularly in wound healing. This review article explores the efficacy of cannabis oil in reducing reactive oxygen species (ROS) during the healing of acute and chronic wounds, comparing it to the standard treatments.

ROS, produced from various internal and external sources, play a crucial role in wound development by causing cell and tissue damage. Understanding the role of ROS on skin wounds is essential, as they act both as signaling molecules and contributors to oxidative damage.

Cannabis oil, recognized for its antioxidant properties, may help mitigate oxidative damage by scavenging ROS and upregulating antioxidative mechanisms, potentially enhancing wound healing.

This review emphasizes ongoing research and the future potential of cannabis oil in dermatological treatments, highlighted through clinical studies and patent updates. Despite its promising benefits, optimizing cannabis oil formulations for therapeutic applications remains a challenge, underscoring the need for further research to realize its medicinal capabilities in wounds.”

https://pubmed.ncbi.nlm.nih.gov/39458608/

“Cannabis oil, especially its primary bioactive constituents, CBD and THC, demonstrates considerable potential in facilitating skin wound healing by modifying oxidative stress via the regulation of reactive oxygen species. CBD’s therapeutic effects in wound healing are largely attributed to its antioxidant, anti-inflammatory, and antimicrobial properties. Increased ROS levels can hinder wound healing by exacerbating inflammation and cellular damage; however, CBD’s antioxidant properties mitigate these effects, fostering a more conducive environment for tissue regeneration. Additionally, the antibacterial and analgesic properties of cannabis contribute to reducing the microbial load and minimizing the complications associated with chronic wounds, thereby enhancing the overall healing efficacy. Integrating cannabis oil into drug delivery systems for wound management represents a promising strategy for treating both acute and chronic wounds.”

https://www.mdpi.com/1999-4923/16/10/1277

Cannabis-Based Phytocannabinoids: Overview, Mechanism of Action, Therapeutic Application, Production, and Affecting Environmental Factors

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“This review provides an overview of cannabis-based phytocannabinoids, focusing on their mechanisms of action, therapeutic applications, and production processes, along with the environmental factors that affect their quality and efficacy.

Phytocannabinoids such as THC (∆9-tetrahydrocannabinol), CBD (cannabidiol), CBG (cannabigerol), CBN (cannabinol), and CBC (cannabichromene) exhibit significant therapeutic potential in treating various physical and mental health conditions, including chronic pain, epilepsy, neurodegenerative diseases, skin disorders, and anxiety.

The cultivation of cannabis plays a crucial role in determining cannabinoid profiles, with indoor cultivation offering more control and consistency than outdoor methods. Environmental factors such as light, water, temperature, humidity, nutrient management, CO2, and the drying method used are key to optimizing cannabinoid content in inflorescences.

This review outlines the need for broader data transfer between the health industry and technological production, especially in terms of what concentration and cannabinoid ratios are effective in treatment. Such data transfer would provide cultivators with information on what environmental parameters should be manipulated to obtain the required final product.”

https://pubmed.ncbi.nlm.nih.gov/39457041/

“Phytocannabinoids, including THC, CBD, CBG, CBN, and CBC, present broad therapeutic potential in a wide range of physical and mental conditions. They have shown efficacy in treating chronic pain, reducing seizure activity, slowing neurodegenerative processes, psoriasis, acne, loss of appetite, sleep disorders, and psychosis. Dose dependence was notable in most cases, and thus, this requires careful management.”

https://www.mdpi.com/1422-0067/25/20/11258

Cannabinoids-Multifunctional Compounds, Applications and Challenges-Mini Review

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“Cannabinoids represent a highly researched group of plant-derived ingredients. The substantial investment of funds from state and commercial sources has facilitated a significant increase in knowledge about these ingredients.

Cannabinoids can be classified into three principal categories: plant-derived phytocannabinoids, synthetic cannabinoids and endogenous cannabinoids, along with the enzymes responsible for their synthesis and degradation. All of these compounds interact biologically with type 1 (CB1) and/or type 2 (CB2) cannabinoid receptors.

A substantial body of evidence from in vitro and in vivo studies has demonstrated that cannabinoids and inhibitors of endocannabinoid degradation possess anti-inflammatory, antioxidant, antitumour and antifibrotic properties with beneficial effects. This review, which spans the period from 1940 to 2024, offers an overview of the potential therapeutic applications of natural and synthetic cannabinoids. The development of these substances is essential for the global market of do-it-yourself drugs to fully exploit the promising therapeutic properties of cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/39459291/

https://www.mdpi.com/1420-3049/29/20/4923

Cannabidiol exerts antipyretic effects by downmodulating inflammatory mediators in LPS-induced fever

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“Contrasting to tetrahydrocannabinol (THC), cannabidiol (CBD) has virtually no psychoactive effects and thus presents a minor risk for abuse. Furthermore, emerging preclinical and clinical evidence indicates that CBD exerts several beneficial pharmacological effects, including anti-inflammatory and antioxidant properties.

Even though fever is one of the responses associated with systemic inflammation, no previous study assessed the putative impact of CBD on lipopolysaccharide (LPS)-induced fever.

The present study aimed to evaluate whether CBD exerts effects on febrile responses, by modulating the hypothalamic-pituitary-adrenal (HPA) axis, and the inflammatory reflex, in this response. CBD caused no change in euthermic mice, indicating that it does not alter euthermia. Conversely, CBD blunted all the assessed systemic inflammation parameters including fever (a hallmark of infection), plasma pro-inflammatory cytokines and prostaglandin E2 (PGE2) surges, and hypothalamic PGE2 (the proximal mediator of fever) synthesis. Moreover, CBD also reduced LPS-induced increase in plasma corticosterone levels and spleen TNF-α.

These data are consistent with the notion that CBD has antipyretic effects, reducing peripheral febrigenic signaling (plasma pro-inflammatory cytokines levels), and eventually down-modulating hypothalamic PGE2 production, possibly in a corticosterone- and inflammatory reflex-dependent manner.”

https://pubmed.ncbi.nlm.nih.gov/39437961/

“Cannabidiol (CBD) reduces fever by downmodulating inflammatory mediators in mice.”

https://www.sciencedirect.com/science/article/abs/pii/S027858462400246X?via%3Dihub

“Antipyretic refers to a type of drug therapy that is used to reduce fever and enhance patient comfort.” https://www.sciencedirect.com/topics/neuroscience/antipyretic