Cannabinoids and endocannabinoids as therapeutics for nervous system disorders:preclinical models and clinical studies

Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body.They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.Some of these include central nervous system(CNS)diseases and dysfunctions such as forms of epilepsy,multiple sclerosis,Parkinson’s disease,pain and neuropsychiatric disorders.In addition,the endogenously produced cannabinoid lipids,endocannabinoids,are critical for normal CNS function,and if controlled or modified,may represent an additional therapeutic avenue for CNS diseases.This review discusses in vitro cellular,ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies.In addition,the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

Pharmacologic Effects of Cannabidiol and Its Molecular Mechanism

Cannabidiol(CBD)is the active constituent of Cannabis sativa and exhibits a diverse range of pharmacologic effects,including anticancer,antibacterial,anti-inflammatory,antioxidant,and antiepileptic properties.The pharmacologic effects of CBD and its molecular mechanisms are reviewed with the objective of proposing novel approaches for basic research and clinical applications of CBD and related pharmaceuticals.

The Modulating Role of Cannabis in Insomnia: A Review of the Literature

The objective of this study was to carry out a review of the literature covering the topic of the association between sleep, insomnia and the medicinal use of cannabis. The guiding question for carrying out this study was whether the medicinal use of cannabis could have a significant positive impact on reducing insomnia. To this end, a review of the literature on the topic was prepared, both in English and Portuguese, from 2005 to 2023, in the PubMed, Scielo and LILACS databases. To search the databases, the keywords “cannabis”, “cannabidiol”, “tetrahydrocannabinol”, “insomnia” and “endocannabinoid” were used. In total, the initial search resulted in 17 articles. After a more careful analysis, only 6 of these articles met the inclusion criteria established for this study. Thus, it was concluded that, although some studies link the use of medicinal cannabis with an improvement in sleep quality, the current literature still lacks more studies on the topic.

A Systematic Review of Cannabidiol Effects in Coronary Syndromes: Challenges to Clinical Translation

Background: Myocardial ischemia in addition to other several cardiac syndromes represent a pathological proinflammatory state alongside a complex cellular microenvironment that can be modified by using cannabinoids. Cannabidiol (CBD), a non-psychoactive compound of cannabis has been recently proposed as an immudomodulatory and cardioprotective drug. Objectives: In this systematic review we sought to clarify and summarize the clinical and preclinical evidence of potential benefit of the use of CBD in coronary syndromes. Methods: We conducted a systematic search and review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Review of Animal Data from Experimental Studies (CAMARADES) guidelines, in the electronic database from PubMed, Web of Science and Scopus up to April 2022 using predefined search terms. Pre-specified exclusion and inclusion criteria were considered, finally 11 articles were chosen to be included for this peer review. Results: Currently there are no good-quality clinical trials with the use of CBD in acute or chronic coronary syndromes. A total of 11 preclinical studies where prescreened and 5 demonstrated reproducible positive cardiovascular outcomes on in-vivo models treated with CBD. Mechanisms of CBD cardioprotection observed: 1) reduction in oxidative stress and inflammation, 2) activation of adenosine receptors and 3) increased expression of angiotensin type 2-receptor. Experimental models included ischemia/reperfusion injury, myocardial infarction, arrhythmias, and metabolic syndrome-like conditions. Conclusion: No clinical recommendation can be issued with the current evidence, on the use of CBD in acute and chronic coronary syndromes. Based on preclinical evidence, we considered there is enough evidence to propose the development of well-designed clinical trials that include CBD in the management of coronary syndromes.

Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer

Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.

Pharmacodynamic study of cannabidiol on bleomycin-induced pulmonary fibrosis in rats

Objective:To study the protective effect of cannabidiol(CBD)on rats with pulmonary fibrosis and explore the possible mechanism of the use of CBD in the treatment of pulmonary fibrosis.Methods:Sixty SD rats were randomly divided into the normal control group,model group,prednisone group,CBD low,medium and high dose groups(12,36,108 mg/kg,ig),10 rats in each group.Except for the normal control group,the other 5 groups were all induced by tracheal injection of bleomycin to rat models of pulmonary fibrosis.After modeling,the rats were given intragastric administration once a day for 28 consecutive days and samples were taken.The degree of pulmonary edema was detected;the pathological changes of lung tissue were observed by HE and Masson staining;tumor necrosis factorα(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6)and lung tissue superoxide dismutase(SOD),malondialdehyde(MDA),hydroxyproline(HYP)contents were measured by ELISA,transforming growth factor-β1(TGF-β1)andα-smooth muscle protein(α-SMA)concentration were detected by immunocytochemical method,real-time fluorescent quantitative PCR(qRT-PCR)method was used to detect the mRNA expression levels of TGF-β1,α-SMA,Nrf2 and nuclear transcription factor-κB p65(NF-κB p65).Results:The lung organ coefficient and W/D value were significantly decreased in the CBD administration group(P<0.05);medium and high doses of CBD could reduce the number of collagen fibers and fibroblasts;the pulmonary fibrosis in the low,medium,and high dose groups of CBD was significantly lower.The levels of TNF-α,IL-1β,and IL-6 in rat serum,as well as MDA and HYP in lung tissue,were significantly lower compared to the model group.Additionally,the level of SOD was significantly increased(P<0.05);The expression ofα-SMA was decreased compared with the model group(P<0.05);the contents of TGF-β1,α-SMA and NF-κB p65 mRNA in lung tissue decreased,and the expression level of Nrf2 mRNA increased(P<0.05).Especially,the high-dose group had the most significant effect.Conclusion:CBD can significantly reduce the degree of pulmonary fibrosis in rats,and its potential mechanism may be related to inhibiting inflammatory response,enhancing antioxidant capacity and inhibiting the protein expression of TGF-β1 andα-SMA.

Cannabidiol-Mediated Sequestration of Alzheimer’s Amyloid-β Peptides in ADDL Oligomers

Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits processes relating to amyloid beta (Aβ)-induced neurotoxicity in mouse models of Alzheimer’s disease, though the detailed molecular mechanism underlying the CBD neurotoxicity modulation is not fully understood. In this study, using atomic force microscopy, we find that CBD promotes the aggregation of Aβ peptides, enhancing the formation of Aβ oligomers, also known as Aβ-derived diffusible ligands (ADDLs). The CBD-mediated sequestration of Aβ monomers in soluble ADDLs could reduce neurotoxicity. This study highlights a possible role of CBD in modulating the formation of ADDL aggregates and provides insight into potentially neuroprotective properties of CBD in Alzheimer’s disease.

GC Determination of Active Cannabinoids in Cannabis of Chinese Origin and Survey of Their Contents

A method of GC determination using tetracosane as the internal standard for active cannabinoids cannabidiol.△~9-tetrahydrocannabinol and cannabinol of cannabis is described.The method is simple and accurate and has been applied to investigate the contents of active cannabinoids in cannabis of Chinese origin.Information was obtained from provinces and autonomous region of China. Three pure cannabinoids used as the reference substances were extracted and isolated successfully from cannabis.

Diabetic retinopathy:Role of inflammation and potential therapies for anti-inflammation

Diabetic retinopathy is a leading cause of blindness among working-age adults.Despite many years of research,treatment options for diabetic retinopathy remain limited and with adverse effects.Discovery of new molecular entities with adequate clinical activity for diabetic retinopathy remains one of the key research priorities in ophthalmology.This review is focused on the therapeutic effects of cannabidiol(CBD),a nonpsychoactive native cannabinoid,as an emerging and novel therapeutic modality in ophthalmology based on systematic studies in animal models of inflammatory retinal diseases including diabetic retinopathy-a retinal disease associated with vascular-neuroinflammation.Special emphasis is placed on novel mechanisms which may shed light on the pharmacological activity asso c iated with CBD preclinically.These include a selfdefence system against inflammation and neurodegeneration mediated by inhibition of equilibrat ive nucleoside transporter and activation of adenosine receptor by treatment with CBD.

<i>In Vitro</i>Anticancer Activity of Plant-Derived Cannabidiol on Prostate Cancer Cell Lines

Cannabinoids, the active components of Cannabis sativa Linnaeus, have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects and tumor regression, but their use in chemotherapy is limited by their psychotropic activity. To date, cannabinoids have been successfully used in the treatment of nausea and vomiting, two common side effects that accompany chemotherapy in cancer patients. Most non-THC plant cannabinoids e.g. cannabidiol and cannabigerol, seem to be devoid of psychotropic properties. However, the precise pathways through which these molecules produce an antitumor effect have not yet been fully characterized. We therefore investigated the antitumor and anti-inflammatory activities of cannabidiol (CBD) in human prostate cancer cell lines LNCaP, DU145, PC3, and assessed whether there is any advantage in using cannabis extracts enriched in cannabidiol and low in THC. Results obtained in a panel of prostate cancer cell lines clearly indicate that cannabidiol is a potent inhibitor of cancer cell growth, with significantly lower potency in non-cancer cells. The mRNA expression level of cannabinoid receptors CB1 and CB2, vascular endothelial growth factor (VEGF), PSA (prostate specific antigen) are significantly higher in human prostate cell lines. Treatment with Cannabis extract containing high CBD down regulates CB1, CB2, VEGF, PSA, pro-inflammatory cytokines/chemokine IL-6/IL-8. Our overall findings support the concept that cannabidiol, which lacks psychotropic activity, may possess anti-inflammatory property and down regulates both cannabinoid receptors, PSA, VEGF, IL-6 and IL-8. High CBD cannabis extracts are cytotoxic to androgen responsive LNCaP cells and may effectively inhibit spheroid formation in cancer stem cells. This activity may contribute to its anticancer and chemosensitizing effect against prostate cancer. Cannabidiol and other non-habit forming cannabinoids could be used as novel therapeutic agents for the treatment of prostate cancer.

Overcoming the Bell‐Shaped Dose‐Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol

Cannabidiol (CBD), a major constituent of Cannabis, has been shown to be a powerful anti-inflammatory and anti-anxiety drug, without exerting a psychotropic effect. However, when given either intraperitoneally or orally as a purified product, a bell-shaped dose-response was observed, which limits its clinical use. In the present study, we have studied in mice the anti-inflammatory and anti-nociceptive activities of standardized plant extracts derived from the Cannabis sativa L., clone 202, which is highly enriched in CBD and hardly contains any psychoactive ingredients. In stark contrast to purified CBD, the clone 202 extract, when given either intraperitoneally or orally, provided a clear correlation between the anti-inflammatory and anti-nociceptive responses and the dose, with increasing responses upon increasing doses, which makes this plant medicine ideal for clinical uses. The clone 202 extract reduced zymosan-induced paw swelling and pain in mice, and prevented TNFα production in vivo. It is likely that other components in the extract synergize with CBD to achieve the desired anti-inflammatory action that may contribute to overcoming the bell-shaped dose-response of purified CBD. We therefore propose that Cannabis clone 202 (Avidekel) extract is superior over CBD for the treatment of inflammatory conditions.

The Current Status of Regulations for Industrial Cannabis and Its Research and Application in Cosmetics

Cannabis sativa has a long history of medication,which is often medicated with seeds.Moreover,cannabidiol(CBD),the active ingredient extracted from the flowers and leaves of industrial hemp,has high medicinal value.With the acceptance of CBD by the World Health Organization(WHO)in 2017 and being in the international list as a non-controlled substance,the international strict policy on industrial hemp has been slowly liberalized.It has been proved that the industrial hemp has great economic value and application potential in many aspects.In order to make better use of the unique efficacy of industrial hemp,the definition of industrial hemp and its current laws in the domestic and overseas are systematically studied and summarized in this paper.At the same time,the research status of hemp seed oil and hemp leaves extractive in cosmetics is expounded,which is helpful to the comprehensive development and application of industrial hemp.

Δ 9-Tetrahydrocannabinol Toxicity and Validation of Cannabidiol on Brain Dopamine Levels: An Assessment on Cannabis Duplicity

Δ9-tetrahydrocannabinol(THC)of cannabis is the main psychoactive component which is a global significant concern to human health.Evaluation on THC reported its drastic effect on the brain dopaminergic(DAergic)system stimulating mesolimbic DA containing neurons thereby increasing the level of striatal DA.Cannabidiol(CBD),with its anxiolytic and anti-psychotic property,is potent to ameliorate the THC-induced DAergic variations.Legal authorization of cannabis use and its analogs in most countries led to a drastic dispute in the elicitation of cannabis products.With a recent increase in cannabis-induced disorder rates,the present review highlighted the detrimental effects of THC and the effects of CBD on THC induced alterations in DA synthesis and release.Alongside the reported data,uses of cannabis as a therapeutic medium in a number of health complications are also being briefly reviewed.These evaluated reports led to an anticipation of additional research contradictory to the findings of THC and CBD activity in the brain DAergic system and their medical implementations as therapeutics.

Islet protection and amelioration of diabetes type 2 in <i>Psammomys obesus</i>by treatment with cannabidiol

Background and purpose: Cannabidiol (CBD), a non-psychoactive component of Cannabis sativa, has been shown by us, to have an anti-inflammatory effect in collagen-induced arthritis in DBA mice and in type 1 diabetes in NOD mice. As inflammation is a process involved in diabetes type 2, we administered CBD to Psammomys obesus (sand rats), a species which develops diabetes type 2 when fed high-energy (HE) diet, to investigate whether we can hinder the development of the disease. Experimental Approach: Male Psammomys obesus were kept on a high energy diet during the experiments. They were treated with CBD (i.p injection, 5 mg/kg, 5 times/week) for 4 weeks and kept (without CBD) for another 29 - 39 days. The weights of the animals as well as blood glucose and plasma insulin levels were determined and the morphology of the pancreatic islets was examined. Key results: CBD significantly reduced blood glucose levels in Psammomys obesus, without effecting body weight. Plasma insulin levels were significantly higher in the CBD-treated group. The most striking effect noted was the marked decrease of the destruction of pancreatic islets and beta cells. Conclusions and implications: CBD partially protects pancreatic islets and beta cells from destruction. CBD lowers significantly the blood glucose level and increases insulin level in Psammomys obesus with diabetes type 2, but does not lead to obesity. As CBD already has been administered to patients for other medical indications we propose its use as a therapeutic agent in diabetes type 2.

The Safety and Efficacy of CBD—A Pharmacist’s Perspective

Here in the United States Cannabidiol (CBD) is legal in all 50 states if the Tetrahydrocannabinol (THC) concentration of the product is no more than 0.3%. The largest retailers of CBD in 2019 were located inCalifornia, Florida, and New York, which sold $730 million, $291 million, and $215 million, respectively. Of the patients who use CBD, the most common reasons for their use were pain, anxiety, and insomnia. As the use of CBD for the relief of different issues increases, it is important to assess the safety and efficacy of CBD as it pertains to drug-drug interactions, lab interactions, and its actual benefits. This subject of safety and efficacy is increasingly important as the use of CBD has increased, with approximately 64 million Americans having tried CBD between 2017 and 2019. In this article, we will discuss these different aspects of CBD use from the point of view of a pharmacist. Not only do pharmacists commonly get questions on different aspects of CBD use, but they are also drug experts in areas including drug-drug interactions, drug toxicities, pharmacokinetics and pharmacodynamic profiles of medications, and guideline-recommended therapeutic options. Although there is a limited amount of data, there is still accessible data that may serve to inform pharmacists to become aware of the safety and efficacy of CBD. This information will serve pharmacists to educate patients that CBD contains properties to be used in a variety of conditions such as Lennox-Gastaut Syndrome, Dravet Syndrome, pain, and sports enhancement.

Long-Term Impact in the Quality of Life of Patients with Drug-Resistant Epilepsy That Use Cannabidiol

Introduction: Epilepsy is considered a chronic neurological condition that manifests itself with seizures, where 30% - 40% of patients do not achieve control of their seizures despite proper management. Seizures represent a significant limitation in the patient’s daily activities and are often accompanied by emotional and relational difficulties that have a great impact on the quality of life of the patient and their families. Cannabidiol (CBD) has been found to be effective in controlling seizures and may also improve cognitive and behavioral abilities. Material and Methods: The Quality of Life of the Patient with Epilepsy (CAVE) scale was applied to patients with refractory epilepsies who use Cannabidiol (CBD) added to their base therapy, before the use of CBD and after 12 months of follow-up. The presentation of collateral effects was also evaluated. Results: Out of 34 patients, 26 (76.5%) increased their CAVE value at the end of the study and only 1 (2.9%) decreased. 19 (55.9%) improved in learning and behavior, 55.8% in the frequency of seizures and 79.4% reported a decrease in the intensity of seizures. There were other positive side effects such as improvement in alertness, language, sleep and behavior. The main side effects were mild and transitory, including drowsiness, and constipation. There was a correlation between the global perception of improvement and seizure control. Conclusions: This study shows that in the long term CBD improves the quality of life of patients with refractory epilepsies, through the control of seizures and the improvement of cognitive and behavioral functions.

Preparation of cannabidiol and its application in daily chemical industry

Cannabidiol(CBD)is a physiologically active natural substance,usually extracted from the flowers and leaves of hemp.CBD not only has the function of alleviating the symptoms of many mental disorders,but also has the function of anti-inflammation,anti-oxidation and treatment of skin diseases.Because of its beneficial effects,CBD has been used as an important raw material in the production of health care products and skin care products,which have already been sold on the market.This paper reviewed the main preparation techniques of CBD.The author developed a new refining process for CBD purification combining molecular distillation and crystallization.This new process is both environmental friendly and economical.The obtained samples meet the requirements of the cosmetic industry.The paper also introduces the application prospect of CBD products in daily Chemical Industry,especially in skin care.

Market Status and Development of Cannabis Aativa Cosmetics in the Times of “Secondary-Constituent Community”

Since 2020,with the advent of the COVID-19 epidemic,the upsurge of the concept of“Constituent community”in the cosmetics industry has gradually subsided.The phenomenon of only focuing on the components but not on the synergies of the product system has gradually ebbed.On the other hand,with the popularity of the concept of industrial Cannabis sativa and Cannabis sativa cosmetics both at home and abroad,the Cannabis sativa cosmetics that replace the single effect propaganda of the Constituent community have been increasingly recognized by consumers,and industrial Cannabis sativa is increasingly widely used in cosmetics.For the development of Cannabis sativa cosmetics in the times of“Secondary-Constituent community”,the market status of Cannabis sativa cosmetics in China and abroad was analyzed in this paper.At the same time,the future development prospect of domestic Cannabis sativa cosmetics was preliminarily estimated and prospected,which was helpful for the development of Cannabis sativa cosmetics and provided the evaluation basis for the investment and development of domestic Cannabis sativa cosmetics.

Neuroprotective potential of cannabidiol:Molecular mechanisms and clinical implications

Cannabidiol(CBD),a nonpsychotropic phytocannabinoid that was once largely disregarded,is currently the subject of significant medicinal study.CBD is found in Cannabis sativa,and has a myriad of neuropharmacological impacts on the central nervous system,including the capacity to reduce neuroinflammation,protein misfolding and oxidative stress.On the other hand,it is well established that CBD generates its biological effects without exerting a large amount of intrinsic activity upon cannabinoid receptors.Because of this,CBD does not produce undesirable psychotropic effects that are typical of marijuana derivatives.Nonetheless,CBD displays the exceptional potential to become a supplementary medicine in various neurological diseases.Curently,many clinical trials are being conducted to investigate this possibility.This review focuses on the therapeutic effects of CBD in managing neurological disorders like Alzheimer's disease,Parkinson's disease and epilepsy.Overall,this review aims to build a stronger understanding of CBD and provide guidance for future fundamental scientific and clinical investigations,opening a new therapeutic window for neuroprotection.

Engineering cannabidiol synergistic carbon monoxide nanocomplexes to enhance cancer therapy via excessive autophagy

Although carbon monoxide(CO)-based treatments have demonstrated the high cancer efficacy by promoting mitochondrial damage and core-region penetrating ability,the efficiency was often compromised by protective autophagy(mitophagy).Herein,cannabidiol(CBD)is integrated into biomimetic carbon monoxide nanocomplexes(HMPOC@M)to address this issue by inducing excessive autophagy.The biomimetic membrane not only prevents premature drugs leakage,but also prolongs blood circulation for tumor enrichment.After entering the acidic tumor microenvironment,carbon monoxide(CO)donors are stimulated by hydrogen oxide(H_(2)O_(2))to disintegrate into CO and Mn^(2+).The comprehensive effect of CO/Mn^(2+)and CBD can induce ROS-mediated cell apoptosis.In addition,HMPOC@Mmediated excessive autophagy can promote cancer cell death by increasing autophagic flux via classⅢPI3K/BECN1 complex activation and blocking autolysosome degradation via LAMP1 downregulation.Furthermore,in vivo experiments showed that HMPOC@M+laser strongly inhibited tumor growth and attenuated liver and lung metastases by downregulating VEGF and MMP9 proteins.This strategy may highlight the pro-death role of excessive autophagy in TNBC treatment,providing a novel yet versatile avenue to enhance the efficacy of CO treatments.Importantly,this work also indicated the applicability of CBD for triple-negative breast cancer(TNBC)therapy through excessive autophagy.