Effects Of CBD Research Articles

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

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.

Gestational CBD Shapes Insular Cortex in Adulthood.

Many expectant mothers use CBD to alleviate symptoms like nausea, insomnia, anxiety, and pain, despite limited research on its long-term effects. However, CBD passes through the placenta, affecting fetal development and impacting offspring behavior. We investigated how prenatal CBD exposure affects the insular cortex (IC), a brain region involved in emotional processing and linked to psychiatric disorders. The IC is divided into two territories: the anterior IC (aIC), processing socioemotional signals, and the posterior IC (pIC), specializing in interoception and pain perception. Pyramidal neurons in the aIC and pIC exhibit sex-specific electrophysiological properties, including variations in excitability and the excitatory/inhibitory balance. We investigated IC's cellular properties and synaptic strength in the offspring of both sexes from mice exposed to low-dose CBD during gestation (E5-E18; 3 mg/kg, s.c.). Prenatal CBD exposure induced sex-specific and territory-specific changes in the active and passive membrane properties, as well as intrinsic excitability and the excitatory/inhibitory balance, in the IC of adult offspring. The data indicate that in utero CBD exposure disrupts IC neuronal development, leading to a loss of functional distinction between IC territories. These findings may have significant implications for understanding the effects of CBD on emotional behaviors in offspring.

Perioperative Analgesic and Sedative Effects of Cannabidiol in Cats Undergoing Ovariohysterectomy.

The aim of this study was to evaluate the perioperative analgesic and sedative effects of oral CBD in cats undergoing ovariohysterectomy. Twenty-two cats were assigned to receive either oral cannabidiol oil (2 mg/kg, CBD group, n = 12) or placebo oil (0.1 mL/kg, Placebo group, n = 10) 60 min before the premedication. The anesthetic protocol included dexmedetomidine/meperidine, propofol, and isoflurane. Intravenous fentanyl was given to control cardiovascular responses to surgical stimulation. Pain was assessed at 0.5, 1, 2, 4, 6 and 8 h post-extubation using the UNESP-Botucatu multidimensional composite pain scale and the Glasgow feline composite-measure pain scale. Sedation scores were assessed at the same timepoints and at 15 min after the premedication. Morphine was administered as rescue analgesia. Higher sedation scores were recorded in the CBD group at 15 min after premedication (p = 0.041). Intraoperatively, more cats required fentanyl in the Placebo group than in CBD group (p = 0.028). The pain scores did not differ between groups, except at 0.5 h post-extubation when lower scores were detected in the CBD group (p = 0.003-0.005). Morphine was required in 100% of the animals in both groups. CBD increased preoperative sedation and decreased intraoperative analgesic requirements, with minimal evidence of postoperative analgesic benefits over the placebo.

Therapeutic potential of cannabis for surgical wound healing in rats.

This study was conducted to evaluate the wound-healing activities of a Cannabis sativa L. plant extract and cannabidiol on incision wounds. An incision was created and sutured in rats under anaesthesia. Routine wound care procedures were applied for 10 days, followed by histological wound examinations. The cellular bioactivities of the hemp extract and CBD were assessed for MCP-1, EGF, BFGF, IL-8, and COL-1 using ELISA on the rat skin wound healing activity. A one-way ANOVA was used for the data analysis. The EGF values in the plasma were similar in the povidone-iodine, hemp seed oil, and hemp essential oil groups (P > 0.05). However, the EGF levels were lower in the CBD group compared to the other groups (P < 0.001, P < 0.005). The MCP-1 values in the hemp seed oil, hemp essential oil, and CBD were similar (P > 0.05), whereas povidone iodine exhibited lower MCP-1 levels compared to the other groups (P < 0.001, P < 0.005). It was determined that the plasma BFGF, IL-8, and COL 1 values of the groups were similar (P > 0.05). To our knowledge, this study is the first to evaluate the effects of CBD, seed oil, and hemp leaf extract on incision wound healing. It demonstrates that hemp extract holds greater potential benefits for wound healing compared to CBD.

Gestational CBD shapes insular cortex in adulthood.

Many expectant mothers use CBD to alleviate symptoms like nausea, insomnia, anxiety, and pain, despite limited research on its long-term effects. However, CBD passes through the placenta, affecting fetal development and impacting offspring behavior. We investigated how prenatal CBD exposure affects the insular cortex (IC), a brain region involved in emotional processing and linked to psychiatric disorders. The IC is divided into two territories: the anterior IC (aIC), processing socioemotional signals, and the posterior IC (pIC), specializing in interoception and pain perception. Pyramidal neurons in the aIC and pIC exhibit sex-specific electrophysiological properties, including variations in excitability and the excitatory/inhibitory balance. We investigated IC's cellular properties and synaptic strength in the offspring of both sexes from mice exposed to low-dose CBD during gestation (E5-E18; 3mg/kg, s.c.). Prenatal CBD exposure induced sex-specific and territory-specific changes in the active and passive membrane properties, as well as intrinsic excitability and the excitatory/inhibitory balance, in the IC of adult offspring. The data indicate that in-utero CBD exposure disrupts IC neuronal development, leading to a loss of functional distinction between IC territories. These findings may have significant implications for understanding the effects of CBD on emotional behaviors in offspring.

Cutaneous Wound Healing and the Effects of Cannabidiol.

Cutaneous wounds, both acute and chronic, begin with loss of the integrity, and thus barrier function, of the skin. Surgery and trauma produce acute wounds. There are 22 million surgical procedures per year in the United States alone, based on data from the American College of Surgeons, resulting in a prevalence of 6.67%. Acute traumatic wounds requiring repair total 8 million per year, 2.42% or 24.2 per 1000. The cost of wound care is increasing; it approached USD 100 billion for just Medicare in 2018. This burden for wound care will continue to rise with population aging, the increase in metabolic syndrome, and more elective surgeries. To heal a wound, an orchestrated, evolutionarily conserved, and complex series of events involving cellular and molecular agents at the local and systemic levels are necessary. The principal factors of this important function include elements from the neurological, cardiovascular, immune, nutritional, and endocrine systems. The objectives of this review are to provide clinicians engaged in wound care and basic science researchers interested in wound healing with an updated synopsis from recent publications. We also present data from our primary investigations, testing the hypothesis that cannabidiol can alter cutaneous wound healing and documenting their effects in wild type (C57/BL6) and db/db mice (Type 2 Diabetes Mellitus, T2DM). The focus is on the potential roles of the endocannabinoid system, cannabidiol, and the important immune-regulatory wound cytokine IL-33, a member of the IL-1 family, and connective tissue growth factor, CTGF, due to their roles in both normal and abnormal wound healing. We found an initial delay in the rate of wound closure in B6 mice with CBD, but this difference disappeared with time. CBD decreased IL-33 + cells in B6 by 70% while nearly increasing CTGF + cells in db/db mice by two folds from 18.6% to 38.8% (p < 0.05) using a dorsal wound model. We review the current literature on normal and abnormal wound healing, and document effects of CBD in B6 and db/db dorsal cutaneous wounds. CBD may have some beneficial effects in diabetic wounds. We applied 6-mm circular punch to create standard size full-thickness dorsal wounds in B6 and db/db mice. The experimental group received CBD while the control group got only vehicle. The outcome measures were rate of wound closure, wound cells expressing IL-33 and CTGF, and ILC profiles. In B6, the initial rate of wound closure was slower but there was no delay in the time to final closure, and cells expressing IL-33 was significantly reduced. CTGF + cells were higher in db/bd wounds treated with CBD. These data support the potential use of CBD to improve diabetic cutaneous wound healing.

Cannabidiol alleviates suture-induced corneal pathological angiogenesis and inflammation by inducing myeloid-derived suppressor cells

BackgroundCurrently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to investigate the anti-angiogenic and anti-inflammatory effects of cannabidiol and its mechanism of action. MethodAn in vivo corneal neovascularization (CNV) model was established using the suture method to investigate the inhibitory effects of CBD on suture-induced corneal inflammation, pathological blood vessel formation, and lymphangiogenesis. Additionally, the impact of CBD on immune cells was studied. In vitro methodologies, including cell sorting and co-culture, were employed to elucidate its mechanism of action. ResultsCompared with the CNV group, CBD can inhibit CNV, lymphangiogenesis, and inflammation induced via the suture method. In addition, CBD specifically induced CD45+CD11b+Gr-1+ cell upregulation, which significantly inhibited the proliferation of CD4+ T lymphocytes in vitro and exhibited a CD31+ phenotype, proving that they were myeloid-derived suppressor cells (MDSCs). We administered anti-Gr-1 to mice to eliminate MDSCs in vivo and found that anti-Gr-1 partially reversed the anti-inflammatory and angiogenic effects of CBD. Furthermore, we found that compared with MDSCs in the normal group, CBD-induced MDSCs overexpress peroxisome proliferator-activated receptor-gamma (PPAR-γ). Administering PPAR-γ inhibitor in mice almost reversed the induction of MDSCs by CBD, demonstrating the role of PPAR-γ in the function of CBD. ConclusionThis study indicates that CBD may induce MDSCs upregulation by activating the nuclear receptor PPAR-γ, exerting anti-inflammatory, antiangiogenic, and lymphangiogenic effects, and revealing potential therapeutic targets for corneal neovascularization and lymphangiogenesis.

Effect of CBD on anti-tumor immune response and interaction with GPR55 on MAPK signaling in head and neck squamous cell carcinoma.

6060 Background: Head and neck squamous cell carcinoma (HNSCC) is a lethal malignancy and comprises two distinct etiology: human papillomavirus (HPV)+ve and -ve. Marijuana use is associated with HPV+ oropharyngeal infection and conflicting data show positive and negative associations of daily marijuana use with HPV+ and tobacco-associated HPV- HNSCC. However, cannabinoid use continues to increase in the US general population for recreational purposes as well as in cancer patients for palliative care. G-protein coupled receptors (GPCRs), including cannabinoid GPCRs, stimulated by specific ligands interact with multiple G proteins creating diversity and complexity of signaling. In this study, we aimed to investigate the CBD-induced GPCR coupling and its effect on anti-tumor activity by modulating immune response in HNSCC by using pre-clinical models. Methods: The anti-cancer effect of CBD was measured by cell proliferation, apoptosis and migration analysis. Next, TGF-α shedding assay was performed to identify the CBD-induced GPCR coupling with different cannabinoid receptors. The cannabinoid receptor GPR55 was subjected to silencing by siRNA and western blot analysis was performed to evaluate its role in activation of p38 MPAK pathway. Next, the anti-tumor immune response of CBD was evaluated by using an immunocompetent syngeneic C57BL/6 mEER RasG12D+/- HPV E6/E7 transformed tongue epithelial cell model that serves as a model for HPV+ HNSCC and the 4MOSC1 orthotopic, syngeneic, 4NQO (4-nitroquinoline-1 oxide)-induced murine oral tongue squamous cell carcinoma C57BL/6 mouse model that serve as HPV- HNSCC model as well as in immune-deficient Rag1 -/- and athymic nude mouse followed by measurement of immune cell infiltration by IHC analysis. Results: We found that 10μM of CBD treatment inhibited cell proliferation and migration in HNSCC cells by promoting apoptosis. Interestingly, we observed that CBD resulted in GPCR coupling for Gαi with GPR55 and Gαq/o and Gαq/s for CNR1, CNR2 and GPR55. Furthermore, we silenced GPR55 and observed that 10μM of CBD treatment inhibits the activation of p38 MAPK pathway whereas it promotes activation in non-silenced HNSCC cells. Next, we observed that treatment with 10μM of CBD significantly inhibited tumor growth compared to control in both HPV- and HPV+ models in immune-intact animals whereas, no significant difference in the tumor growth was observed in immune-deficient (Rag1 -/- and athymic nude) mouse, indicating role of CBD in modulating tumor immune microenvironment. We also observed CBD treatment enhanced CD4+ and CD8+ T cell infiltration into the primary tumors of HPV+ and HPV- mice models, implicating a downstream cytotoxic T cell response. Conclusions: Our study suggests that CBD promotes anti-tumor activity by modulating the immune microenvironment and interacts with GPR55 to activate intrinsic MAPK signaling pathway.

Triple Negative Breast Cancer (TNBC): Cannabis sativa-Role of Phytocannabinoids

This review paper highlights the role of phytocannabinoids in controlling triple-negative breast cancer (TNBC). Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2), which has clinical features that include high invasiveness, high metastatic potential, proneness to relapse, and poor prognosis. TNBC is one of the most aggressive subtypes of breast cancer that is often associated with poor patient outcomes because of the development of metastases in secondary organisms like in the brain, bone, and lungs. Triple-negative breast cancer (TNBC) is a kind of breast cancer that does not have any of the receptors that are commonly found in breast cancer. The highest number of TNBC cases has been recorded in India. Currently, TNBC is highly prevalent among Indian women and develops approximately 20% to 43% of all patients with breast cancer. Triple-negative breast cancer (TNBC) is an aggressive malignancy that requires effective targeted drug therapy. Patients with TNBC develop metastasis and recurrence over time and have reduced survival compared to patients with other subtypes of breast cancer. Pre-clinical studies have demonstrated that phytocannabinoids exert important antitumor properties in the main breast cancer subtypes, particularly in TNBC, where different phytocannabinoids and synthetic cannabinoids have shown interesting therapeutic actions. Neither CBD nor THC are universally efficacious in reducing cancer cell viability. Focusing on in vitro studies, the effect of CBD on cancer cell viability ranges from no effect, to a modest reduction, and to significant cytotoxicity depending on concentrations, cancer cell lines, cell growth conditions, the performed assays, and the time of CBD exposure. However, it should also be noted that research into the efficacy, dosage and drug safety of cannabinoids in tumor therapy still has a long way to go, especially with regard to human clinical trials to be conducted, through which alone the benefits and advantages for cancer patients but also possible risks can be defined.

The anti-depression effect and potential mechanism of the petroleum ether fraction of CDB: Integrated network pharmacology and metabolomics

The combination of Chaidangbo (CDB) is an antidepressant traditional Chinese medicine (TCM) prescription simplified by Xiaoyaosan (a classic antidepressant TCM prescription) through dismantling research, which has the effect of dispersing stagnated liver qi and nourishing blood in TCM theory. Although the antidepressant effect of CBD has been confirmed in animal studies, the material basis and possible molecular mechanism for antidepressant activity in CBD have not been clearly elucidated. Herein, we investigated the effects and potential mechanisms of CDB antidepressant fraction (petroleum ether fraction of CDB, PEFC) on chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice using network pharmacology and metabolomics. First, a UPLC-QE/MS was employed to identify the components of PEFC. To extract active ingredients, SwissADME screening was used to the real PEFC components that were found. Potential PEFC antidepressant targets were predicted based on a network pharmacology approach, and a pathway enrichment analysis was performed for the predicted targets. Afterward, a CUMS mouse depression model was established and LC-MS-based untargeted hippocampal metabolomics was performed to identify differential metabolites, and related metabolic pathways. Finally, the protein expressions in mouse hippocampi were determined by Western blot to validate the network pharmacology and metabolomics deduction. A total of 16 active compounds were screened in SwissADME that acted on 73 core targets of depression, including STAT3, MAPKs, and NR3C1; KEGG enrichment analysis showed that PEFC modulated signaling pathways such as PI3K-Akt signaling pathway, endocrine resistance, and MAPK to exert antidepressant effects. PEFC significantly reversed abnormalities of hippocampus metabolites in CUMS mice, mainly affecting the synthesis and metabolism of glycine, serine, and threonine, impacting catecholamine transfer and cholinergic synapses and regulating the activity of the mTOR signaling pathway. Furthermore, Western blot analysis confirmed that PEFC significantly influenced the main protein levels of the PI3K/Akt/mTOR signaling pathways in the hippocampus of mice subjected to CUMS. This study integrated metabolomics, network pharmacology and biological verification to explore the potential mechanism of PEFC in treating depression, which is related to the regulation of amino acid metabolism dysfunction and the activation of PI3K/Akt/mTOR signaling pathways in the hippocampus. The comprehensive strategy also provided a reasonable way for unveiling the pharmacodynamic mechanisms of multi-components, multi-targets, and multi-pathways in TCM with antidepressant effect.

The longitudinal effects of cannabidiol on brain temperature in patients with treatment-resistant epilepsy

Neuroinflammation (NI) is a key pathophysiological contributor to treatment-resistant epilepsy (TRE) that remains challenging to observe in vivo. Magnetic resonance spectroscopic imaging and thermometry (MRSI-t) is an emerging technique that can be used to non-invasively map brain temperature, whereby brain temperature elevations serve as a surrogate for the cellular and biochemical processes associated with NI. In a previous multimodal imaging study of focal epilepsy patients, we observed MRSI-t-based brain temperature elevations ipsilateral to the seizure onset zone (SOZ) that were concordant with evidence of edema (Sharma et al., 2023). Despite its potential as tool, it is unclear if MRSI-t can monitor changes in brain temperature in response to treatment. We imaged 25 participants approximately 12-weeks apart. Eight patients with TRE were imaged before receiving highly-purified pharmaceutical grade cannabidiol (CBD; pre-CBD) and after 12-weeks of CBD (on-CBD) therapy. Seventeen healthy controls (HCs) were also imaged twice. Repeated measures t-tests computed changes in TRE patients’ seizure symptoms, mood, and brain temperature within their respective SOZs. Repeated measures ANOVAs tested Group*Time changes in imaging data. Participants with TRE had abnormally high peak brain temperatures within their SOZs that decreased after CBD initiation (p < 0.0001). Seizure severity scores also improved after CBD initiation (p < 0.001). These findings provide insights into the possible neural effects of CBD, and further demonstrate MRSI-t’s potential as a tool for delineating SOZ. Further investigations into MRSI-t as a longitudinal measure of therapy-induced changes in NI are warranted.

The NLRP3 inflammasome: a vital player in inflammation and mediating the anti-inflammatory effect of CBD.

The NLRP3 inflammasome is a vital player in the emergence of inflammation. The priming and activation of the NLRP3 inflammasome is a major trigger for inflammation which is a defense response against adverse stimuli. However, the excessive activation of the NLRP3 inflammasome can lead to the development of various inflammatory diseases. Cannabidiol, as the second-most abundant component in cannabis, has a variety of pharmacological properties, particularly anti-inflammation. Unlike tetrahydrocannabinol, cannabidiol has a lower affinity for cannabinoid receptors, which may be the reason why it is not psychoactive. Notably, the mechanism by which cannabidiol exerts its anti-inflammatory effect is still unclear. We have performed a literature review based on published original and review articles encompassing the NLRP3 inflammasome and cannabidiol in inflammation from central databases, including PubMed and Web of Science. In this review, we first summarize the composition and activation process of the NLRP3 inflammasome. Then, we list possible molecular mechanisms of action of cannabidiol. Next, we explain the role of the NLRP3 inflammasome and the anti-inflammatory effect of cannabidiol in inflammatory disorders. Finally, we emphasize the capacity of cannabidiol to suppress inflammation by blocking the NLRP3 signaling pathway, which indicates that cannabidiol is a quite promising anti-inflammatory compound.

Acciones protectoras y reparadoras tisulares del CBD (cannabidiol) y efectos inmunitarios

This paper intents to investigate in depth on the molecular mechanisms involved in the aging dependent tissular damage and the possible protective effect of cannabidiol CBD on these lesions in the muscle, liver, lungs and the immune system. CBD was administered for 10 weeks at the daily dosage of 10 mg/ Kg body weight / day in a special rat chow prepared for that purpose to 15 months old male Long Evans rats. Half of the animals (n=14) were given CBD during 2,5 months whereas the other half (n= 15) were given standard rat chow for the same time. Additional male rats of 2 (n=10) and 5 (n= 8) months of age fed with standard rat chow were used as young controls. Muscle, liver and lung tissues were obtained after sacrifice to investigate the gene expression by PCR and the protein expression by Western blotting of the main oxidative stress, inflammation and apoptosis markers. Antioxidants were measured by ELISA. In the blood and spleen several markers for immune function like NK activity, lymphoproliferation and oxidative situation were also measured. Aging is associated with the increase of markers for tissular damage that involve the enhancement of nearly all oxidative stress, inflammation and apoptosis parameters Chronic administration of CBD reduces significantly all these parameters in muscle, liver and lungs and potentiates the immune system increasing NK activity and lymphoproliferation and reducing also oxidative stress. CBD has demonstrated to be a very good protective substance against age generated tissular damage in muscle, liver and lungs and an immune system enhancer.

Cannabidiol and Depression: Promise and Challenge in Building an Evidence Base

Background: Interest in the potential mental health effects of cannabidiol (CBD) has increased recently, with a surge in commercial and pharmaceutical development of CBD products and a concomitant rise in consumer use. However, despite the widespread and growing use of CBD products by adults and adolescents, the mental health effects of CBD remain largely unknown. Objective: The goals of this review are: 1) to briefly review the evidence base for the mental health effects of CBD, using depression as an exemplar, and 2) to systematically outline complementary study designs needed to test CBD effects, together with challenges and special considerations related to each design. Methods: This review integrates empirical findings related to CBD's effects on mental health outcomes with the literature on intervention trial design and current legal regulations pertaining to CBD. Conclusion: Complementary controlled and observational studies of CBD are necessary to substantiate claims of mental health benefits, including for clinical depression and in pediatric populations. Investigators must consider challenges and opportunities specific to CBD as an intervention, including legal regulations, commercial or pharmaceutical product choice, dosing and bioavailability, and safety.

The dual role of cannabidiol on monocyte-derived dendritic cell differentiation and maturation.

Extracts and compounds isolated from hemp (Cannabis sativa) are increasingly gaining popularity in the treatment of a number of diseases, with topical formulations for dermatological conditions leading the way. Phytocannabinoids such as ( )-cannabidiol, ( )-cannabinol and ( )-Δ9-tetrahydrocannabivarin (CBD, CBN, and THCV, respectively), are present in variable amounts in the plant, and have been shown to have mostly anti-inflammatory effects both in vitro and in vivo, albeit dominantly in murine models. The role of phytocannabinoids in regulating responses of dendritic cells (DCs) remains unclear. Our research aimed to investigate the effects of CBD, CBN, and THCV on human DCs differentiated from monocytes (moDCs). moDCs were treated with up to 10 μM of each phytocannabinoid, and their effects on viability, differentiation, and maturation were assessed both alone, and in conjunction with TLR agonists. The effects of CBD on cytokine production, T cell activation and polarization as well as the transcriptome of moDCs was also determined. Phytocannabinoids did not influence the viability of moDCs up to 10 μM, and only CBD had effects on maturational markers of moDCs, and neither compound influenced LPS-induced activation at 10 μM. Since only CBD had measurable effects on moDCs, in our subsequent experiments we tested the effect only of that pCB. On moDCs differentiated in the presence of CBD subsequent activation by LPS induced a markedly different, much more tolerogenic response. CBD-treated moDCs also produced significantly more interleukin (IL)-6, TNFα and, importantly, IL-10 in response to LPS, which shows a shift toward anti-inflammatory signaling, as well as a more robust secretory response in general. To rule out the possibility that these effects of CBD are specific to TLR4 signaling, we determined the effect of CBD on TLR7/8-induced maturation as well, and saw similar, although less marked responses. CBD-treated moDCs were also less efficient at activating naïve T cells after LPS stimulation, further supporting the tolerogenic effect of this phytocannabinoid on moDCs. Reactome pathway analysis showed an inflammatory response to LPS in moDCs, and to a lesser extent to CBD as well. In contrast CBD-treated moDCs responded to LPS with a shift towards a more tolerogenic phenotype, as IL-10 signaling was the most prominently induced pathway in this group. Our results show that CBD achieves an anti-inflammatory effect on adaptive immune responses only in the presence of an activating stimuli on moDCs by reprogramming cells during long-term treatment, and not through acute, short-term effects.

Cannabidiol interactions in the voltage-gated calcium channel by molecular docking

Objective: to analyzer the interactions of cannabidiol in the CaV3.2 through molecular docking. Methodology: this is a research with in silico approach, which CBD and gabapentin (GBP) were employed as test substances, and CaV3.2 channel the target protein. Molecular docking experiments were realized by Dockthor. The drugs simulations were classified in order of highest affinity in the channel. The binding energy scores were linked using Student t-test by GraphPad Prism software, the values were significantly different (p &lt; 0.05). Results: the spatial positions into CBD or GBP and CaV3.2 were 1,000,000 conformers. Our data showed that the binding energies of CaV3.2 channel and CBD or GBP were - 6.493 ± 0.07 and - 6.842 ± 0.19 kcal/mol, respectively. Those values did not show statistically difference (p = 0.08), suggesting that both drugs bind similarly the CaV3.2, however both chemicals connected the distinct sites. Conclusions: CBD binds to CaV3.2, which corroborates its blockade channel. Those data support the analgesic effect of CBD through the neuronal inhibitory pathway.

Cannabidiol Protects Dopaminergic-like Neurons against Paraquat- and Maneb-Induced Cell Death through Safeguarding DJ-1CYS106 and Caspase 3 Independently of Cannabinoid Receptors: Relevance in Parkinson's Disease.

Parkinson's disease (PD), a progressive neurodegenerative movement disorder, has reached pandemic status worldwide. This neurologic disorder is caused primarily by the specific deterioration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). Unfortunately, there are no therapeutic agents that slow or delay the disease progression. Herein, menstrual stromal cell-derived dopamine-like neurons (DALNs) intoxicated with paraquat (PQ2+)/maneb (MB) were used as a model system to elucidate the mechanism by which CBD protects the neural cell from apoptosis in vitro. According to immunofluorescence microscopy, flow cytometry, cell-free assay, and molecular docking analysis, we demonstrate that CBD offers protection to DALNs against PQ2+ (1 mM)/MB (50 μM)-induced oxidative stress (OS) by simultaneously (i) decreasing reactive oxygen species (ROS: O2•-, H2O2), (ii) maintaining the mitochondrial membrane potential (ΔΨm), (iii) directly binding to stress sensor protein DJ-1, thereby blunting its oxidation from DJ-1CYS106-SH into DJ-1CYS106-SO3, and (iv) directly binding to pro-apoptotic protease protein caspase 3 (CASP3), thereby disengaging neuronal dismantling. Furthermore, the protective effect of CBD on DJ-1 and CASP3 was independent of CB1 and CB2 receptor signaling. CBD also re-established the Ca2+ influx in DALNs as a response to dopamine (DA) stimuli under PQ2+/MB exposure. Because of its powerful antioxidant and antiapoptotic effects, CBD offers potential therapeutic utility in the treatment of PD.

24 Effects of Oral Supplementation of Cannabidiol on Young Stallion Behavior

Abstract Cannabidiol (CBD) has become a popular product in the recent months due to change in legislation with the passing of the Agricultural Improvement Act in 2018. Cannabidiol comes from the plant Cannabis sativa L. and binds to cannabinoid receptors throughout the endocannabinoid system. These receptors are located throughout the body and are prominent in the brain and reproduction tract. Although the effects of CBD on physiology have been researched, little data on the behavioral effects exist, even less so in horses. Calming supplements that may negate aggressive stallion behavior are not suitable due to potential soporific effects that can affect libido. In addition to the effectiveness of CBD to modify behavior in horses, it is also unclear if CBD influences stallion libido. The objective of this study was to evaluate sexual behavior in stallions given a daily CBD supplement for 70 days. Two-year old stallions (n = 8) were assigned to either a Control (CON; n = 3) or Cannabidiol (CBD; n = 4) treatment groups. Cannabidiol was administered at a rate of 0.6 mg/kg BW daily, and equal volume of olive oil was given as a placebo to CON. Horses were weighed every Monday at which time dosages were recalculated to adjust for body weight changes. Behavior data collection occurred twice per week during semen collections. Video data were recorded by placing two cameras, one placed in view of the tease area, and one placed in view of the mount, for behavior data backup. Behavioral data was tallied by handlers calmly calling each behavior as it occurred during collection. The behaviors collected included Flehman’s response, bites, strikes, mounts, high pitch vocalizations, and low pitch vocalizations. Data were analyzed using a Chi Square Test within R Statistical Program (R Core Team). Results were considered significant at P &amp;lt; 0.05. Throughout the duration of the study, all stallions exhibited normal sexual behavior, regardless of treatment. Results showed that total low and high pitch vocalizations, bites, and Flehman’s were affected by treatment (P &amp;lt; 0.01). Cannabidiol-treated stallions had more low pitches (60), compared to CON (58). Cannabidiol-treated stallions had fewer bites (145) compared to the CON (146). Cannibidiol stallions displayed Flehman’s more frequently (270) than CON (236). Flehman’s response and bites were lower for stallions on cannabidiol in Week 1 but increased by Week 10 (P &amp;lt; 0.01), while only Flehman’s response increased in the CON group over time (P &amp;lt; 0.01). These findings indicate that CBD may influence breeding behavior in young stallions specifically when supplemented over time. Further research should focus on the impact of CBD on breeding behaviors in mature stallions and the longevity of the behavioral response to CBD.

Cannabidiol improves haloperidol-induced motor dysfunction in zebrafish: a comparative study with a dopamine activating drug

BackgroundCannabidiol (CBD) extracted from the cannabis plant is believed to have a medicinal value due to its neuroprotective effect via anti-inflammatory and antioxidant action. Recent behavioral studies in rats have reported that CBD mediates serotonin (5-HT1A) receptor action to improve motor dysfunction induced by dopamine (D2) receptor blockade. In particular, its effect on D2 receptor blockade in the striatum is an important function associated with neurological disorders resulting from various extrapyramidal motor dysfunctions. Dopaminergic neurodegeneration associated with this site is known for inducing Parkinson’s disease (PD), which often affects the elderly. It is also known to cause drug-induced Parkinsonism. This study examines the ameliorating effect of CBD, which does not act directly on D2 receptors, against drug-induced motor dysfunction induced by the antipsychotic drug (haloperidol).MethodsWe created a drug-induced Parkinsonism model in zebrafish larvae using an antipsychotic drug (haloperidol). We evaluated the distance traveled and repetitive light-stimulation response. Furthermore, we examined whether administration of several concentrations of CBD ameliorates symptoms of the Parkinsonism model and compared its effects with those of antiparkinsonian drug ropinirole.ResultsCBD concentrations equal to half of haloperidol’s resulted in an almost complete reversal of haloperidol-induced motor dysfunction, as measured by the distance traveled by the zebrafish and their response to light-stimulus. While ropinirole also significantly reversed haloperidol’s effects at the same concentration as CBD, CBD was more effective than ropinirole.ConclusionsCBD-induced motor dysfunction improvement via D2 receptor blockade is a potential novel mechanism for the treatment of haloperidol-induced motor dysfunction.

Abstract P1-02-08: CBD-oil: a potential solution in case of severe tamoxifen-related side effects

Abstract Background Tamoxifen is frequently used in the adjuvant treatment of hormone sensitive breast cancer. Unfortunately, tamoxifen can lead to bothersome side effects resulting in non-adherence in 40% of patients. Patients searching for relief from these side effects are increasingly turning to cannabinoids such as CBD. However, since tamoxifen is mainly metabolised by CYP2D6, and CBD is suggested to be an inhibitor of CYP2D6, the use of CBD might affect tamoxifen pharmacokinetics (PK). Since the effect of CBD on both tamoxifen PK as tamoxifen-related side effects has never been investigated, the aims of this study were to determine the pharmacokinetic interaction between CBD and tamoxifen, and to subsequently investigate whether there is a beneficial influence of CBD on tamoxifen-related side effects. Methods Patients had to be treated with tamoxifen for at least 3 months, have steady-state endoxifen levels &amp;gt;16 nM (conservative threshold) and experience tamoxifen-related side effects. PK sampling was done at initiation of CBD-oil and 28 days thereafter. Bio-equivalence could be concluded if the 90% confidence interval (CI) for the difference in endoxifen area under the curve (AUC) fell within the [-20%; +25%] interval (n = 15, two-sided α 0.05, β 0.20). In addition, endoxifen PK was analyzed for each CYP2D6 phenotype separately. The effect of CBD on side effects was evaluated with the FACT-ES questionnaire (n = 25, two-sided α 0.05, β 0.20). An improvement &amp;gt; 0.5 times standard deviation (SD) of baseline score was considered clinically relevant. Last, potential side effects of CBD were assessed. Results In this study 15 patients were included for PK analysis and 24 patients for side effect analysis. Endoxifen AUC decreased after CBD by 12.6% (90% CI -18.7%, -6,1%) but remained within bio-equivalence boundaries. The decrease seemed more pronounced in patients with intermediate (IM) CYP2D6 phenotype (-20.8%, 90% CI -26.4%, -14.8%, n = 8) compared to normal CYP2D6 phenotype (-2.2%, 90% CI -11.1%, 7.6%, n = 7). There was no difference in tamoxifen AUC (with or without CBD). On average, the endocrine sub-scale of the FACT-ES improved with a clinically relevant improvement of 8.3 points (95% CI 4.9 – 11.7) after using CBD (baseline SD = 12.8). CBD itself has a mild toxicity profile with few side effects in 10 of 24 patients. Side effects were headache (n=2), dry mouth (n=3), fatigue (n=3), gastroesophageal reflux (n=1), abdominal pain (n=1) and nausea (n=1) and all graded CTCAE 1. Conclusions As endoxifen levels with or without CBD remained within bio-equivalence boundaries and CBD-oil might have a positive effect on tamoxifen-related side effects, it could be considered in case of treatment-related side effects. However, caution is needed in patients with IM or poor metabolizer CYP2D6 phenotypes. Citation Format: Sanne Buijs, Louwrens Braal, Stefan Buck, Noud F. van Maanen, Lonneke van der Meijden-Erkelens, Heleen Kuijper-Tissot van Patot, Esther Oomen-de Hoop, Lotte Saes, Sophia van den Boogerd, Liesbeth Struik, Quirine van Rossum-Schornagel, Ron Mathijssen, Stijn Koolen, Agnes Jager. CBD-oil: a potential solution in case of severe tamoxifen-related side effects [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-08.