Endocannabinoid System Research Articles

Exploring the versatile roles of the endocannabinoid system and phytocannabinoids in modulating bacterial infections.

The endocannabinoid system (ECS), initially identified for its role in maintaining homeostasis, particularly in regulating brain function, has evolved into a complex orchestrator influencing various physiological processes beyond its original association with the nervous system. Notably, an expanding body of evidence emphasizes the ECS's crucial involvement in regulating immune responses. While the specific role of the ECS in bacterial infections remains under ongoing investigation, compelling indications suggest its active participation in host-pathogen interactions. Incorporating the ECS into the framework of bacterial pathogen infections introduces a layer of complexity to our understanding of its functions. While some studies propose the potential of cannabinoids to modulate bacterial function and immune responses, the outcomes inherently hinge on the specific infection and cannabinoid under consideration. Moreover, the bidirectional relationship between the ECS and the gut microbiota underscores the intricate interplay among diverse physiological processes. The ECS extends its influence far beyond its initial discovery, emerging as a promising therapeutic target across a spectrum of medical conditions, encompassing bacterial infections, dysbiosis, and sepsis. This review comprehensively explores the complex roles of the ECS in the modulation of bacteria, the host's response to bacterial infections, and the dynamics of the microbiome. Special emphasis is placed on the roles of cannabinoid receptor types 1 and 2, whose signaling intricately influences immune cell function in microbe-host interactions.

Involvement of the TRPV1 receptor and the endocannabinoid system in schizophrenia

BackgroundSchizophrenia (SCZ) is a severe mental disorder, but its pathogenesis is still unknown, and its clinical treatment effect is very limited. Transient receptor potential vanilloid 1 (TRPV1) channel and the Endocannabinoid System (ECS)have been confirmed to be involved in the pathogenesis of SCZ, although their actions have not been fully clarified yet. The objective is to examine TRPV1 and ECS expression in the blood of schizophrenia patients and investigate their correlation with disease severity. MethodsThis is a cross-sectional investigation. Peripheral blood samples were gathered from normal controls (NC, n=37), as well as individuals with schizophrenia, including first episode (n=30) and recurrent (n=30) cases. We employed western blot and ELISA techniques to quantify TRPV1, cannabinoid receptors 1(CB1), anandamide (AEA), and 2-arachidonoylglycerol (2-AG), and assess the severity of the patient's symptoms by means of the PANSS scale. ResultsCompared to NC, TRPV1 levels showed a noticeable decrease in both first episode schizophrenia (f-SCZ group) and recurrent schizophrenia (r-SCZ group) subjects. Additionally, CB1 levels appeared increased in f-SCZ group. Furthermore, 2-AG levels were found to be elevated in both f-SCZ group and r-SCZ group compared to NC, whereas AEA levels were decreased in f-SCZ group but increased in r-SCZ group. Moreover, among schizophrenia patients, TRPV1 demonstrated a negative correlation with negative symptoms. Within r-SCZ subjects, CB1 displayed a negative correlation with relapse number, while 2-AG showed a correlation in the opposite direction. ConclusionsThis study provides initial clinical evidence of changed TRPV1 expression in schizophrenia, potentially linked to negative symptoms. These results suggest a possible dysfunction of TRPV1 and the endocannabinoid system (ECS), which might offer new avenues for medical interventions.

Anandamide Modulates Thermal Avoidance in Caenorhabditis elegans Through Vanilloid and Cannabinoid Receptor Interplay.

Understanding the endocannabinoid system in C. elegans may offer insights into basic biological processes and potential therapeutic targets for managing pain and inflammation in human. It is well established that anandamide modulates pain perception by binding to cannabinoid and vanilloid receptors, regulating neurotransmitter release and neuronal activity. One objective of this study was to demonstrate the suitability of C. elegans as a model organism for assessing the antinociceptive properties of bioactive compounds and learning about the role of endocannabinoid system in C. elegans. The evaluation of the compound anandamide (AEA) revealed antinociceptive activity by impeding C. elegans nocifensive response to noxious heat. Proteomic and bioinformatic investigations uncovered several pathways activated by AEA. Enrichment analysis unveiled significant involvement of ion homeostasis pathways, which are crucial for maintaining neuronal function and synaptic transmission, suggesting AEA's impact on neurotransmitter release and synaptic plasticity. Additionally, pathways related to translation, protein synthesis, and mTORC1 signaling were enriched, highlighting potential mechanisms underlying AEA's antinociceptive effects. Thermal proteome profiling identified NPR-32 and NPR-19 as primary targets of AEA, along with OCR-2, Cathepsin B, Progranulin, Transthyretin, and ribosomal proteins. These findings suggest a complex interplay between AEA and various cellular processes implicated in nociceptive pathways and inflammation modulation. Further investigation into these interactions could provide valuable insights into the therapeutic potential of AEA and its targets for the management of pain-related conditions.

The role of fatty acid-binding protein 5 and 7 on locomotor, anxiety and social behavior: Interaction with NMDA signaling

The endocannabinoid system has been shown to be a powerful mediator of anxiety, learning and memory, as well as nociception behaviors. Exogenous cannabinoids like delta-9-tetrahydrocannabinol mimic the naturally occurring endogenous cannabinoids found in the mammalian central and peripheral nervous system. The hydrophobic properties of endocannabinoids mean that these psychoactive compounds require help with cellular transport. A family of lipid intracellular carriers called fatty acid-binding proteins (FABPs) can bind to endocannabinoids. Pharmacological inhibition or genetic deletion of FABP subtypes 5 and 7 elevates whole-brain anandamide (AEA) levels, a type of endocannabinoid. This study examined locomotor behavior, anxiety-like behavior, and social behavior in FABP5-/- and FABP7-/- mice. Furthermore, we measured N-methyl-D-aspartate (NMDA) receptor levels in the brain to help identify potential underlying mechanisms related to the behavioral findings. Results showed that both male and female FABP5-/- mice exhibited significantly lower activity when compared with both FABP5/7+/+ (control) and FABP7-/-. For social behavior, male, but not female, FABP5-/- mice spent more time interacting with novel mice compared with controls (FABP5/7+/+) and FABP7-/- mice. No significant difference was found for anxiety-like behavior. Results from the NMDA autoradiography revealed [3H] MK-801 binding to be significantly increased within sub-regions of the striatum in FABP7-/- compared with control. In summary, these results show that FABP5 deficiency plays a significant role in locomotion activity, exploratory behavior, as well as social interaction. Furthermore, FABP7 deficiency is shown to play an important role in NMDA receptor expression, while FABP5 does not.

High-performance supercritical fluid chromatography hyphenated to high-resolution quadrupole-time of flight hybrid mass spectrometry (SFC-HR-QTOF-MS/MS) for the determination of cannabinoids in edible products

A growing number of papers suggest the positive action of cannabinoids in the treatment of several diseases, which is ascribed to the ability of phytocannabinoids to affect the human endocannabinoid system. In particular, this activity is characteristic of CBD, a non-psychoactive variation of 9-THC. It initiated a trend in the manufacturing of edible and cosmetic products containing CBD that can be easily acquired in drugstores. However, the composition of such products has rarely been tested. Hence, there is a need for data regarding their safety. Considering the possibility of cannabinoid interconversions as well as the complexity and diversity of edible products’ matrix, their analysis requires a suitable preparation and cleanup procedure. In this paper, the perspective of the application of Supercritical Fluid Chromatography (SFC) coupled to High-Resolution (HR) Quadrupole-Time of Flight (Q-TOF) tandem mass spectrometry (MS/MS) with electrospray ionization (ESI) in quality control of cannabis-containing food products was examined. The focus is on six neutral (CBD, 9-THC, CBC, CBG, CBN, and THCV) and three acidic (CBDA, THCA, and CBGA) cannabinoids. The study covers the thorough optimization of conditions for chromatographic separation with the use of the supercritical CO2 (scCO2)-based mobile phase and the working parameters of MS/MS detection with the elucidation of fragmentation patterns. Thanks to the utilization of scCO2, a short analysis time of 17 min., high intensity and small width of peaks, as well as low consumption of toxic organic solvent have been achieved at the 2-EP column with a 5 μm grain size. To reach such performance in LC, the utilization of more expensive columns packed with sub-2 μm particles is needed. In the case of the solvent matrix, the LOD was equal to 8 ng mL−1 for CBDA, THCA, and CBGA, 15 ng mL−1 for CBG and THCV, and 21 ng mL−1 for THC, CBD, CBC, and CBN. In the case of tea, an LOD of 25 ng mL−1 for acidic and 75 ng mL−1 for neutral cannabinoids has been obtained. The accuracy and precision were within the ± 15 % tolerance limit. Finally, the devised protocol has been applied for cannabinoid determination in hemp tea infusions.

Cannabinoid Analgesia in Postoperative Pain Management: From Molecular Mechanisms to Clinical Reality.

Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results.

Melatonin and resveratrol alleviate molecular and metabolic toxicity induced by Bisphenol A in endometrial organoids

Bisphenol A (BPA), a widespread environmental contaminant, poses concerns due to its disruptive effects on physiological functions of the uterine endometrium. In contrast, melatonin (MT) and Resveratrol (RSV) are under scrutiny for their potential protective roles against BPA-induced damage. For the efficacy and ethical concerns in the animal test, endometrial organoids, three-dimensional models mimicking endometrium, serve as crucial tools for unraveling the impact of environmental factors on reproductive health. This study aimed to comprehensively characterize the morphological, molecular and metabolic responses of porcine endometrial organoids to BPA and assess the potential protective effects of MT and RSV. Porcine uteri were prepared, digested with collagenase, mixed with Matrigel, and incubated at 38°C with 5 % CO2. Passaging involved dissociation through trypsin-EDTA treatment and subculturing. The culture medium was refreshed every 2–3 days. To investigate the environmental impact on reproductive health, endometrial organoids were treated with BPA (0.5 µM), MT (with/without BPA at 0.1 µM), and/or RSV (10 µM). Various molecular screening using gene expression, western blotting, immunofluorescence staining, and metabolites profiling were assessed the effects of BPA, MT, and RSV in terms of cell viability, morphology, reproductivity, and metabolism alteration in the endometrial organoids. As expected, BPA induced structural and molecular disruptions in organoids, affecting cytoskeletal proteins, Wnt/β-catenin signaling, and epithelial/mesenchymal markers. It triggered oxidative stress and apoptotic pathways, altered miRNA expression, and disrupted the endocannabinoid system. The level of glucose, galactose, and essential amino acids were increased or decreased by approximately 1.5–3 times in BPA-treated groups compared to the control groups (p-value < 0.05), indicating metabolic changes. Moreover, MT and RSV treated groups exhibited protective effects, mitigating BPA-induced disruptions across multiple pathways. For the first time, our study models endometrial organoids, advancing understanding of environmental impacts on reproductive health.

PARKINSON'S DISEASE AND ENDOCANNABINOID SYSTEM: A BRIEF UPDATE

In Parkinson's disease, dopaminergic neurons located in the substantia nigra of the brain are destroyed, affecting the patients' motor function. The endocannabinoid system is responsible for controlling neuronal homeostasis and its alteration is related to neurodegenerative diseases, such as Parkinson's. A literature review regarding the relationship between the endocannabinoid system and Parkinson's disease was carried out through a search in the Pubmed database. Complete publications from the last year were included, using 15 papers. Treatment with cannabinoid medications for Parkinson's patients should not be the first choice, being restricted to adjuvant therapy as they are elderly and vulnerable. Cannabis extracts have shown in experimental studies neuroprotective and inflammation modulating actions. Pure cannabidiol is safe, with few side effects. Computational analyzes demonstrated that the binding of cannabidiol to the CB1 and CB2 receptors induced structural changes in them. Levels of CB1 receptors were lower in specific areas of the brain of Parkinson's patients and the decline in these receptors was correlated with worse severity of motor symptoms. Selective CB2 receptor agonists have neuroprotective and immunomodulatory actions, reducing inflammation and the formation of defective proteins. Hyperpolarized current-induced inhibition of CB1 receptors improved muscle stiffness but worsened symptoms of depression and anxiety in animals. The use of exogenous cannabinoids in patients with Parkinson's disease is not yet consolidated, and more clinical studies are needed to confirm the safety of the interaction with the endocannabinoid system.

The circulating and central endocannabinoid system in obesity and weight loss.

Major advances have been made in obesity treatment, focusing on restoring disturbances along the gut-brain axis. The endocannabinoid system (ECS) is a neuromodulatory signaling system, present along the entire gut-brain axis, that plays a critical role in central and peripheral regulation of food intake and body weight. Evidence on the impact of weight loss on the ECS is, however, more limited. Therefore, we set out to review the existing literature for changes in central and circulating endocannabinoid levels after bariatric surgery and other weight loss strategies in humans. The PubMed, Embase and Web of Science databases were searched for relevant articles. Fifty-six human studies were identified. Most studies measuring circulating 2-arachidonoylglycerol (2-AG) found no difference between normal weight and obesity, or no correlation with BMI. In contrast, studies measuring circulating arachidonoylethanolamine (AEA) found an increase or positive correlation with BMI. Two studies found a negative correlation between BMI and cannabinoid receptor type 1 (CB1) receptor availability in the brain. Only one study investigated the effect of pharmacological weight management on circulating endocannabinoid concentrations and found no effect on AEA concentrations. So far, six studies investigated potential changes in circulating endocannabinoids after bariatric surgery and reported conflicting results. Available evidence does not univocally support that circulating endocannabinoids are upregulated in individuals with obesity, which may be explained by variability across studies in several potential confounding factors (e.g. age and sex) as well as heterogeneity within the obesity population (e.g. BMI only vs. intra-abdominal adiposity). While several studies investigated the effect of lifestyle interventions on the circulating ECS, more studies are warranted that focus on pharmacologically and surgically induced weight loss. In addition, we identified several research needs which should be fulfilled to better understand the role of the ECS in obesity and its treatments.

Exposure to Benzo(a)pyrene Enhances Acetaminophen-Induced Liver Injury in Mice at Non-Hepatotoxic Doses

Acetaminophen (APAP) is a widely used analgesic, especially for children. Its primary mechanism involves inhibiting cyclooxygenase enzymes and activating the endocannabinoid and TRPV1 systems. Though its toxicity is low, it can harm the liver in a dose-dependent manner. Low APAP doses can also increase pollutant-induced liver damage. Little is known about interactions between APAP and benzo[a]pyrene (B[a]P). This study aimed to assess if co-exposure to non-hepatotoxic doses of B[a]P and APAP causes liver injury in mice, exploring the underlying mechanisms. Female ICR mice received 50 mg/kg B[a]P or a vehicle for three days, followed by 200 mg/kg APAP or a vehicle. Liver injury was assessed through histopathological examination, serum transaminase activity, and gene expression analysis. In the B[a]P/APAP group, several histology changes were observed, including ballooning injury, steatosis, necrosis, inflammation, and apoptosis. Transaminase levels correlated with histopathological scores, and there was an increase in hepatic cytochrome P450 family 1 subfamily a member 1 (Cyp1a1) mRNA levels and a decrease in aryl hydrocarbon receptor (Ahr), cytochrome P450 family 2 subfamily e polypeptide 1 (Cyp2e1), superoxide dismutase 1 (Sod1), peroxisome proliferator activated receptor gamma (Ppar-γ), and caspase 3 (Casp3). This suggests that prior exposure to B[a]P makes mice more susceptible to APAP-induced liver injury, involving changes in gene expression related to metabolism, redox balance, and cell proliferation. Therefore, using therapeutic APAP doses after exposure to B[a]P could lead to liver injury.

Treatment-Resistant Depression and Medications

The management of treatment-resistant depression (TRD) is challenging. Researchers have identified novel targets, especially the glutamatergic system, in the pathogenesis of depressive disorder. N-methyl-D-aspartate (NMDA) receptor antagonists, like ketamine, have revolutionized the treatment of TRD due to their rapid antidepressant and antisuicidal effect. Various other receptor systems, including GABAergic, opioid receptors, the endogenous cannabinoid system, and cholinergic receptors, are novel targets to produce an antidepressant response. The US Food and Drug Administration (FDA) has approved intra-nasal ketamine as an add-on therapy to conventional antidepressants for TRD. Other compounds are in various stages of development. Identification and development of novel compounds by future research can help in overcoming the challenges of treating TRD. [ Psychiatr Ann . 2024;54(6):e177–e181.]

Examining 1-year mortality risk among patients with malignant melanoma undergoing immune checkpoint inhibitor therapy with a history of cannabis use.

11046 Background: Cannabis use has become an increased topic of discussion in the United States due to rise in legalization, thereby increasing its accessibility for recreational and medicinal use in diseases like cancer. Immune Checkpoint Inhibitor (ICI) therapy has also recently been increasing in patient with metastatic cancers such as melanoma by targeting PD1 or PD-L1 receptors to manipulate the body’s immune response to induce cancer cell death. Cannabis is mediated in part by the CB1 and CB2 receptors in the endocannabinoid system that is present in the natural immune system. Due to the body’s immune response to cannabis, it is hypothesized this could interfere with the activity of ICI therapy. However, research examining this is sparse. Therefore, the goal was to assess mortality in malignant melanoma patients with a history of cannabis use who undergo ICI therapy. Methods: A retrospective cohort study was performed with TriNetX, a federated database of ~100 million patients across 84 healthcare organizations. Patients &gt;17 years from 2012-2023 were identified based on ICI-therapy initiation within 1 month of malignant melanoma diagnosis. Cohorts were then created by history of those with and without cannabis use disorder. 1:1 propensity score matching was conducted to control for confounding comorbidities and demographics. Unadjusted and adjusted hazard ratios (aHR) with 95% CI were calculated for 1-year mortality after therapy initiation. HR’s were estimated using the Cox proportional hazard model. Survival curves were compared using the log-rank test. Results: A total 14589 melanoma patients who underwent ICI therapy were identified, of which 2.3% had documented cannabis use disorder. Prior to matching, melanoma patients with cannabis history had a statistically significant higher 1-year mortality compared to those with no cannabis history (HR [95%CI] = 1.29 [1.04,1.6], log rank test: p=0.0197). After matching, two balanced cohorts of 344 patients remained and adjusting for confounders revealed that melanoma patients with cannabis history had no significant difference in 1-year mortality risk compared to patients without cannabis history (1.18 [0.87,1.6], log rank test: p=0.293). Conclusions: Cannabis use among melanoma patients was shown to not have any meaningful difference in 1-year mortality risk compared to patients without cannabis use history while undergoing ICI-therapy. Additional studies, such as examining cannabis frequency and dosage, is warranted to further examine its effect.

Effect of TT-816, a novel immune response modifier targeting cannabinoid CB2 receptor, on antitumor immunity and cancer growth.

e14595 Background: The endocannabinoid system is widely expressed in the human body, including the innate and adaptive immune system, where endocannabinoids, Δ9-tetrahydrocannabinol and synthetic ligands regulate immune suppression. The effects of endocannabinoids on immune regulation are primarily mediated by G-protein coupled cannabinoid CB2 receptors (CB2R) via several mechanisms, including immune cell development, migration, proliferation and T and NK cell effector functions. The upregulated expression of CB2R and elevated levels of endocannabinoids have been observed in a variety of tumor microenvironments and are associated with the aggressiveness of cancer. Methods: NK cell function was determined by co-culturing TT-816 pretreated NK cells with K562 cancer cells for 24 hours. The mixed lymphocyte reaction assay was conducted by co-culturing human CD4+ T cells with monocyte-derived dendritic cells. Cell viability was measured by FACS and IFN-g by MSD. The in vivo efficacy of TT-816 was determined in the murine syngeneic B16F10 melanoma and MC38 colorectal cancer models. Tumor-bearing C57BL/6 mice were randomized 6 days after inoculation and treated with vehicle (0.5% CMC, QD) or with TT-816 at 1, 4 or 10 mg/kg (QD) orally, or anti-PD1 (RMP1 14) at 5 mg/kg (Q3D), intraperitoneally. Tumor size and body weight were determined every 2 to 3 days. Data represent mean±SEM. Results: TT-816 concentration-dependently enhanced the functions of NK cells, dendritic cells and T cells. It increased NK cell killing of the human cancer cells and IFN-g production, significantly stimulated the expression of CD86, HLA-DR, IL-12 and TNF-a in monocyte-derived dendritic cells, and enhanced CD4+ T cell proliferation and IFN-g production in a mixed lymphocyte reaction assay. In B16F10 melanoma and MC38 colorectal cancer models, TT-816 dose-dependently inhibited the tumor growth. Furthermore, combination of TT-816 with anti-PD1 synergistically inhibited both tumor growth. In B16F10 model, treatment with TT 816 (4 mg/kg, QD) alone significantly inhibited the tumor growth by 45%. By contrast, anti-PD1 had little effect (TGI 5%). However, the combination of TT-816 with anti-PD1 resulted in a TGI of 72%. In the MC38 model, treatment with TT-816 (4 mg/kg, QD) and anti-PD1 alone, achieved TGI of 50% and 36%, respectively. When combined, TGI was increased to 88%. Conclusions: TT-816 is a novel, oral small molecule immune response modifier that selectively blocks CB2R on immune cells and cancer cells. Preclinical data have demonstrated that it stimulates antitumor immune response and inhibits cancer growth in both hot and cold tumor models. TT-816 is currently undergoing phase 1 clinical trials for the treatment of a broad range of solid tumors.

Examining the risk of immune checkpoint inhibitor-related toxicity among patients with melanoma and their history of cannabis use.

e21539 Background: With cannabis use rising due to better availability for recreational and medicinal uses, there is a need for studies examining cannabinoids interactions. Immune Checkpoint Inhibitors have been increasing in popularity among metastatic cancer patients like those with melanoma. The biological impact of cannabis is mediated in part by the CB1 and CB2 receptors present in the endocannabinoid system that is present in the immune system. ICI therapy also targets the immune system through manipulating PD-1/PD-L1 receptors to induce cancer cell death. Therefore, concurrent cannabis use with ICI therapy could have potentiating effects on toxicities and negatively impact efficacy. There is limited information in the literature examining this and therefore the goal was to examine the impact of ICI toxicity risk among melanoma patients on any form of ICI therapy. Methods: A retrospective cohort study was conducted using TriNetX, a multicenter database comprised of ~100 million patients across 84 healthcare organizations. Adults ( &gt; 17 years) from 2012-2023 were identified based on ICI-therapy initiation within 1 month of malignant melanoma diagnosis. Patients were then stratified by history of those with and without cannabis use disorder. ICI toxicity categories were determined a priori and included cardiac, nephrological, gastrointestinal, endocrine, respiratory, ocular, hematological, hepatological, musculoskeletal, and neurological toxicities. 1:1 propensity score matching was conducted to control for comorbidities and demographics. Adjusted hazard ratios (aHR) with 95% CI were calculated at 1-year follow-up after therapy initiation for ICI toxicities between the cohorts. aHR was estimated using the Cox proportional hazard model. Results: A total 14589 melanoma patients who underwent ICI therapy were identified where 2.3% had history of cannabis use. Matching revealed two balanced cohorts of 344 patients. Melanoma patients with a history of cannabis use did not have any significant differences with controls for cardiotoxicity (aHR[95%CI] = 0.94[0.54,1.6]), Nephrotoxicity (0.86[0.51,1.5]), GI toxicity (1.44[0.95,2.2]), endocrine toxicity (1.2[0.82,1.8]), respiratory toxicity (0.93[0.55,1.6]), ocular toxicity (0.63[0.25,1.6]), hematologic toxicity (1.04[0.7,1.6]), neurotoxicity (1.04[0.6,1.7]), liver toxicity (1.41[0.78,2.5]), or musculoskeletal toxicity (1.53[0.62,3.8]). Conclusions: With cannabis use rising due in part to recreational use and in part to medical marijuana, the implications of use must be a topic of research. Cannabis use among melanoma patients did not provide any significant differences in risk of developing ICI-therapy-related toxicities. Additional studies are needed to validate this finding.

Endocannabinoid Hydrolase Inhibitors: Potential Novel Anxiolytic Drugs.

Over the past decade, the idea of targeting the endocannabinoid system to treat anxiety disorders has received increasing attention. Previous studies focused more on developing cannabinoid receptor agonists or supplementing exogenous cannabinoids, which are prone to various adverse effects due to their strong pharmacological activity and poor receptor selectivity, limiting their application in clinical research. Endocannabinoid hydrolase inhibitors are considered to be the most promising development strategies for the treatment of anxiety disorders. More recent effortshave emphasized that inhibition of two major endogenous cannabinoid hydrolases, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), indirectly activates cannabinoid receptors by increasing endogenous cannabinoid levels in the synaptic gap, circumventing receptor desensitization resulting from direct enhancement of endogenous cannabinoid signaling. In this review, we comprehensively summarize the anxiolytic effects of MAGL and FAAH inhibitors and their potential pharmacological mechanisms, highlight reported novel inhibitors or natural products, and provide an outlook on future directions in this field.

Exploring the Possible Role of Cannabinoids in Managing Post-cardiac Surgery Complications: A Narrative Review of Preclinical Evidence and a Call for Future Research Directions.

Open-heart surgery with cardiopulmonary bypass often leads to complications including pain, systemic inflammation, and organ damage. Traditionally managed with opioids, these pain relief methods bring potential long-term risks, prompting the exploration of alternative treatments. The legalization of cannabis in various regions has reignited interest in cannabinoids, such as cannabidiol, known for their anti-inflammatory, analgesic, and neuroprotective properties. Historical and ongoing research acknowledges the endocannabinoid system's crucial role in managing physiological processes, suggesting that cannabinoids could offer therapeutic benefits in postsurgical recovery. Specifically, cannabidiol has shown promise in managing pain, moderating immune responses, and mitigating ischemia/reperfusion injury, underscoring its potential in postoperative care. However, the translation of these findings into clinical practice faces challenges, highlighting the need for extensive research to establish effective, safe cannabinoid-based therapies for patients undergoing open-heart surgery. This narrative review advocates for a balanced approach, considering both the therapeutic potential of cannabinoids and the complexities of their integration into clinical settings.

Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks

Adolescence is a time of rapid neurodevelopment and the endocannabinoid system is particularly prone to change during this time. Cannabis is a commonly used drug with a particularly high prevalence of use among adolescents. The two predominant phytocannabinoids are Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which affect the endocannabinoid system. It is unknown whether this period of rapid development makes adolescents more or less vulnerable to the effects of cannabis on brain-network connectivity, and whether CBD may attenuate the effects of THC. Using fMRI, we explored the impact of vaporized cannabis (placebo, THC: 8 mg/75 kg, THC + CBD: 8 mg/75 kg THC & 24 mg/75 kg CBD) on resting-state networks in groups of semi-regular cannabis users (usage frequency between 0.5 and 3 days/week), consisting of 22 adolescents (16–17 years) and 24 young adults (26–29 years) matched for cannabis use frequency. Cannabis caused reductions in within-network connectivity in the default mode (F[2,88] = 3.97, P = 0.022, η² = 0.018), executive control (F[2,88] = 18.62, P < 0.001, η² = 0.123), salience (F[2,88] = 12.12, P < 0.001, η² = 0.076), hippocampal (F[2,88] = 14.65, P < 0.001, η² = 0.087), and limbic striatal (F[2,88] = 16.19, P < 0.001, η² = 0.102) networks compared to placebo. Whole-brain analysis showed cannabis significantly disrupted functional connectivity with cortical regions and the executive control, salience, hippocampal, and limbic striatal networks compared to placebo. CBD did not counteract THC’s effects and further reduced connectivity both within networks and the whole brain. While age-related differences were observed, there were no interactions between age group and cannabis treatment in any brain network. Overall, these results challenge the assumption that CBD can make cannabis safer, as CBD did not attenuate THC effects (and in some cases potentiated them); furthermore, they show that cannabis causes similar disruption to resting-state connectivity in the adolescent and adult brain.

Immunomodulatory effects of cannabinoids against viral infections: a review of its potential use in SARS-CoV2 infection.

The COVID-19 pandemic is a global health crisis affecting millions of people worldwide. Along with vaccine development, there is also a priority to discover new drugs and treatments. One approach involves modulating the immune system to manage inflammation and cytokine storms. Patients with a high severity of complications exhibit a high level of inflammatory cytokines, particularly IL-6, in the airways and other infected tissues. Several studies have reported the function of the endocannabinoid system in regulating inflammation and different immune responses. Cannabinoids are a class of natural chemicals found in the Cannabis plant. Recently, the anti-inflammatory properties of cannabinoids and their mediatory immunosuppression mechanisms through the endocannabinoid system have engrossed scientists in the health field for infectious conditions. Research suggests that the immune system can regulate cytokine activation through cannabinoid receptors, particularly with Cannabidiol (CBD), the second most prevalent compound in cannabis. While CBD has been deemed safe by the World Health Organization and shows no signs of abuse potential, excessive CBD use may lead to respiratory depression. CBD shows promise in reducing immune cell recruitment and cytokine storms in organs affected by SARS-CoV2. However, before clinical use, it's crucial to evaluate cannabinoid-based medications' active ingredient concentrations and potential interactions with other drugs, along with associated side effects. Indication-based dosing, consistent formulations, and ensuring purity and potency are essential. This review highlights cannabinoids' effects on COVID-19 management and prognosis, drawing from preclinical and clinical studies.

Modulation of neuroinflammation and oxidative stress by targeting GPR55 - new approaches in the treatment of psychiatric disorders.

Pharmacological treatment of psychiatric disorders remains challenging in clinical, pharmacological, and scientific practice. Even if many different substances are established for treating different psychiatric conditions, subgroups of patients show only small or no response to the treatment. The neuroinflammatory hypothesis of the genesis of psychiatric disorders might explain underlying mechanisms in these non-responders. For that reason, recent research focus on neuroinflammatory processes and oxidative stress as possible causes of psychiatric disorders. G-protein coupled receptors (GPCRs) form the biggest superfamily of membrane-bound receptors and are already well known as pharmacological targets in various diseases. The G-protein coupled receptor 55 (GPR55), a receptor considered part of the endocannabinoid system, reveals promising modulation of neuroinflammatory and oxidative processes. Different agonists and antagonists reduce pro-inflammatory cytokine release, enhance the synthesis of anti-inflammatory mediators, and protect cells from oxidative damage. For this reason, GPR55 ligands might be promising compounds in treating subgroups of patients suffering from psychiatric disorders related to neuroinflammation or oxidative stress. New approaches in drug design might lead to new compounds targeting different pathomechanisms of those disorders in just one molecule.

Prenatal MAM exposure raises kynurenic acid levels in the prefrontal cortex of adult rats.

Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. Pregnant Sprague-Dawley rats were treated with MAM (22mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.