Cannabis and Cannabinoid Research最新文献

Introduction: The endocannabinoid system (ECS) is a widespread neurotransmitter system. A key characteristic of the ECS is that there are multiple endogenous ligands (endocannabinoids). Of these, the most extensively studied are arachidonoyl ethanolamide (AEA) and 2-arachidonoyl-glycerol (2-AG), both act as agonists at the cannabinoid CB₁ receptor. In humans, three CB₁ variants have been identified: hCB₁, considered the most abundant G protein-coupled receptor in the brain, alongside the less abundant and studied variants, hCB_1a and hCB_1b. CB₁ exhibits a preference for coupling with inhibitory G_i/o proteins, although its interactions with specific members of the G_i/o family remain poorly characterized. This study aimed to compare the AEA and 2-AG-induced activation of various G protein subtypes at CB₁. Furthermore, we compared the response of human CB₁ (hCB₁, hCB_1a, hCB_1b) and explored species differences by examining rodent receptors (mCB₁, rCB₁). Materials and Methods: Activation of individual G protein subtypes in HEK293 cells transiently expressing CB₁ was measured with G protein dissociation assay utilizing TRUPATH biosensors. The performance of the TRUPATH biosensors was evaluated using Z-factor analysis. Pathway potencies and efficacies were analyzed using the operational analysis of bias to determine G protein subtype selectivity for AEA and 2-AG. Results: Initial screening of TRUPATH biosensors performance revealed variable sensitivities within our system. Based on the biosensor performance, the G protein subtypes pursued for further characterization were G_i1, G_i3, G_oA, G_oB, G_Z, G₁₂, and G₁₃. Across all pathways, AEA demonstrated partial agonism, whereas 2-AG exhibited full or high-efficacy agonism. Notably, we provide direct evidence that the hCB₁ receptor couples to G₁₂ and G₁₃ proteins. Our findings do not indicate any evidence of G protein subtype selectivity. Similar observations were made across the human receptor variants (hCB₁, hCB_1a, hCB_1b), as well as at mCB₁ and rCB₁. Discussion: There was no evidence suggesting G protein subtype selectivity for AEA and 2-AG at CB₁, and this finding remained consistent across human receptor variants and different species.

Background: There is an urgent need for novel therapies to treat Alzheimer's disease. Among others, the use of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been proposed as a putative approach based on their anti-inflammatory effects. Methods: The present work was designed to explore the effects of chronic (28 days) treatment with low doses of cannabinoids: CBD (0.273 mg/kg), THC (0.205 mg/kg) or a combination of both (CBD:THC; 0.273 mg/kg:0.205 mg/kg) in the 5xFAD mouse model of AD. Results: Our data revealed that THC-treated 5xFAD mice (but not other treatment groups) exhibited anxiogenic and depressant-like behavior. A significant improvement in spatial memory was observed only in the CBD:THC-treated group. Interestingly, all cannabinoid-treated groups showed significantly increased cortical levels of the insoluble form of beta amyloid 1-42. These effects were not accompanied by changes in molecular parameters of inflammation at the mRNA or protein level. Conclusions: These data reveal differential effects of chronic, low-dose cannabinoids and point to a role of these cannabinoids in the processing of amyloid peptides in the brains of 5xFAD mice.

Background: The endocannabinoid system over-activation is associated with type-2 diabetes mellitus onset, involving physiological, metabolic, and genetic alterations in pancreatic islets. The use of Δ9-Tetrahydrocannabinol (THC) as treatment is still controversial since its effects and mechanisms on insulin secretion are unclear. The aim of this study was to evaluate the effects of THC treatment in pancreatic islets from prediabetic mice. Methods: Prediabetes was induced in mice by hypercaloric diet, and then treated with THC for 3 weeks. Blood glucose and body weight were determined, after behavior tests. Histological changes were evaluated in whole pancreas; in isolated islets we analyzed the effect of THC exposure in glucose-stimulated insulin secretion (GSIS), gene expression, intracellular cyclic adenosine monophosphate (cAMP), and cytosolic calcium changes. Results: THC treatment in prediabetic mice enhanced anxiety and antidepressive behavior without changes in food ingestion, decreased oral-glucose tolerance test, plasma insulin and weight, with small alterations on pancreatic histology. In isolated islets from healthy mice THC increased GSIS, cAMP, and CB1 receptor (CB1r) expression, meanwhile calcium release was diminished. Small changes were observed in islets from prediabetic mice. Conclusions: THC treatment improves some clinical parameters in prediabetic mice, however, in isolated islets, modifies GSIS, intracellular calcium and gene expression, suggesting specific effects related to diabetes evolution.

Introduction: Cannabidiol (CBD) is a nonintoxicating phytocannabinoid used in clinical treatments and sold widely in consumer products. CBD products may be designed for sublingual or oral delivery, but it is unclear whether either is advantageous for CBD absorption. This study compared CBD pharmacokinetics after providing CBD oil as sublingual drops and within orally ingested gelatin capsules, at a dose relevant to consumer products. Materials and Methods: Eight males completed three conditions in a participant-blinded, randomized crossover design. Participants received the following combinations of placebo and CBD-containing (69 mg/mL) hemp oil in capsules and as sublingual drops: placebo capsules/placebo drops (Placebo), CBD capsules/placebo drops (CBD-Caps), and placebo capsules/CBD drops (CBD-Drops). Blood samples, blood pressure, and subjective scales were obtained/completed hourly for 6 h and at 24 h. Discussion: Plasma CBD concentrations were not different between CBD-Caps and CBD-Drops (interaction effect p=0.76). Peak CBD concentration (28.0±15.6 vs. 24.0±22.2 ng/mL), time of peak CBD concentration (4±1 vs. 4±2 h), and area under the concentration curve (45.3±20.3 vs. 41.8±23.3 ng/mL·6 h) were not different between conditions (p≥0.25). Cardiometabolic outcomes (plasma glucose/triacylglycerol, heart rate, blood pressure), liver function (plasma alanine aminotransferase/aspartate aminotransferase), kidney function (plasma creatinine), and subjective feelings/symptoms were not different between conditions (p≥0.07). Conclusions: Plasma CBD profiles were comparable between CBD-Caps and CBD-Drops, suggesting that there were not meaningful differences in routes of CBD absorption between conditions. This implies that CBD oil delivered sublingually is swallowed before oral mucosal CBD absorption occurs, which may have implications for research design, CBD product design, and consumer product choice.

Background: The underlying pathomechanism of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is the immune response to inflammation or infection within the pulmonary microcirculation. Systemic spread of pathogens, activated immune cells, and inflammatory mediators contributes significantly to mortality in patients with ARDS. Objective: The endogenous cannabinoid system is a major modulator of the immune response during inflammation and infection. Phytocannabinoids, such as cannabidiol (CBD), have shown promising anti-inflammatory effects in several pathologies. The overall objective of this study was to evaluate the effects of CBD on local and systemic inflammation in endotoxin-induced ALI in mice. Materials and Methods: ALI was induced by pulmonary endotoxin challenge. Four groups of male C57BL/6 mice were randomized in this study: control, ALI, ALI with CBD treatment, and control with CBD treatment. Analyses of local and systemic cytokine levels, lung histology, and leukocyte activation as visualized by intravital microscopy of the intestinal and pulmonary microcirculation were performed 6 h following intranasal endotoxin administration. Results: Pulmonary endotoxin challenge induced significant inflammation evidenced by local and systemic cytokine and chemokine release, lung histopathology, and leukocyte adhesion. Intraperitoneal CBD treatment resulted in a significant decrease in systemic inflammation as shown by reduced leukocyte adhesion in the intestinal microcirculation and reduced plasma cytokine and chemokine levels. Pulmonary chemokine levels were decreased, while pulmonary cytokine levels were unchanged. Surprisingly, the ALI score was slightly increased by CBD treatment in a manner driven by enhanced neutrophil infiltration of the alveoli. Conclusion: In this model of experimental ALI, CBD administration was associated with reduced systemic inflammation and heterogeneous effects on pulmonary inflammation. Future studies should explore the mechanisms involved as they relate to neutrophil infiltration and proinflammatory mediator production within the lungs.

Background: Dysregulation of the endocannabinoid (eCB) system is implicated in various stress-related neuropsychiatric disorders (SRDs), including anxiety, depression, and post-traumatic stress disorder (PTSD). In this systematic review and meta-analysis, our objectives were to characterize circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) concentrations at rest and in response to acute laboratory-based psychosocial stress in individuals with SRDs and without (controls). Our primary aims were to assess the effects of acute psychosocial stress on eCB concentrations in controls (Aim 1), compare baseline (prestress) eCB concentrations between individuals with SRDs and controls (Aim 2), and explore differential eCB responses to acute psychosocial stress in individuals with SRDs compared with controls (Aim 3). Methods: On June 8, 2023, a comprehensive review of the MEDLINE (PubMed) database was conducted to identify original articles meeting inclusion criteria. A total of 1072, 1341, and 400 articles were screened for inclusion in Aims 1, 2, and 3, respectively. Results: Aim 1, comprised of seven studies in controls, revealed that most studies reported stress-related increases in AEA (86%, with 43% reporting statistical significance) and 2-AG (83%, though none were statistically significant except for one study in saliva). However, meta-analyses did not support these patterns (p's>0.05). Aim 2, with 20 studies, revealed that most studies reported higher baseline concentrations of both AEA (63%, with 16% reporting statistical significance) and 2-AG (60%, with 10% reporting statistical significance) in individuals with SRDs compared with controls. Meta-analyses confirmed these findings (p's<0.05). Aim 3, which included three studies, had only one study that reported statistically different stress-related changes in 2-AG (but not AEA) between individuals with PTSD (decrease) and controls (increase), which was supported by the meta-analysis (p<0.001). Meta-analyses showed heterogeneity across studies and aims (I²=14-97%). Conclusion: Despite substantial heterogeneity in study characteristics, samples, and methodologies, consistent patterns emerged, including elevated baseline AEA and 2-AG in individuals with SRDs compared with controls, as well as smaller stress-related increases in 2-AG in individuals with SRDs compared with controls. To consider eCBs as reliable biomarkers and potential intervention targets for SRDs, standardized research approaches are needed to clarify the complex relationships between eCBs, SRDs, and psychosocial stress.

Early studies suggest medical cannabis (MC) has the potential to benefit people who suffer from chronic pain by offering a less addictive alternative to opioids; however, most investigators agree more research is indicated. Today, in 2023, cannabis remains a Schedule I drug and is an illegal substance in the United States under the Controlled Substances Act of 1970. Despite this designation, as of February 2022, 37 states, three territories, and the District of Columbia allowed using cannabis products to treat certain painful medical conditions. The contradictory status of federal and state legislation regarding cannabis use has resulted in delays and restrictions on relevant research. As a result, an inadequate foundation of knowledge exists needed to inform policy, program, and practice decisions concerning MC to treat pain. Implementing and controlling access to MC is influenced by overlapping individual, interpersonal, community, and organizational influences that all fall under the umbrella of federal and state policies. Increasingly, the legalization and expanded access to MC necessitates the integration of evidence, policy, and social-ecological reality. To adequately delineate these complex factors to anticipate and plan future interventions at multiple levels, we propose a social-ecological framework (SEF) for using MC to treat pain. This SEF assumes the transactional relationship between the individual and the environment and that no single factor can predict behavior or health outcomes. Our framework illustrates five dynamic levels of analysis that interact between dimensions. Key elements and intersections are discussed at the intrapersonal, interpersonal, institutional, community, and policy levels.

Introduction: In the wake of continued consumer demand despite increasing regulatory scrutiny, there is a need to develop systematic methods for identifying the harm profile of new psychoactive substances derived from hemp. Tetrahydrocannabinol-O (THC-O)-acetate, colloquially known as THCO, is the acetate ester of the principal psychoactive compound in cannabis. The heating of THCO can create ketene gas, which is harmful to the lungs. Materials and Methods: The research team used a multidisciplinary, iterative process to develop a survey to incorporate consumers' perspectives of semisynthetic cannabinoids. The survey was then distributed across the social media platform Reddit to learn about delivery device preferences and associated use styles when consuming THCO. Results: Most participants (74.9%) vaped THCO and one-quarter of participants (24.3%) dabbed THCO and tended to report higher temperatures for dabbing than vaping THCO. A small portion (12.0%) of participants reported concerns regarding ketene risk. Conclusion: As there are multiple variables associated with the formation of ketene, and consumer responses indicate temperatures use that might enable ketene formation, more research is needed to understand the risk profile of hemp-derived substances like THCO. Further studies are needed to understand the how various routes of administration and delivery devices used with THCO may exacerbate the risk of ketene formation and other potential harms.

Background: In the course of the legalization of cannabis for therapeutic purposes in Germany, there has been growing interest in the medical use of cannabinoids. To date, the therapeutic potential of cannabinoids for the treatment of critically ill patients has not been explored. Objectives: This study aims to understand better whether and how frequently cannabinoids have been administered to critically ill patients in recent years. Study Design: Initially, a survey was conducted among physicians working in intensive care units (ICUs) at the Hannover Medical School. Subsequently, 653 physicians working in ICUs throughout Germany were surveyed. The frequency and regimen of cannabinoid therapy initiated by the participating physicians in the last 2 years at the time of the survey were characterized. Results: Eight out of 9 physicians at Hannover Medical School and 59 out of 653 physicians in ICUs in Germany participated. At Hannover Medical School, 6 out of 8 physicians and in ICUs in Germany, 16 out of 59 physicians had used cannabinoids in some patients (mainly 9-10) during the 2-year period studied, with dronabinol in doses between 1 and 20 mg being their cannabinoid of choice. Metabolic and psychological distress and medication savings, followed by pain and nausea/vomiting, were the most frequently cited indications for cannabinoid therapy. No relevant safety issues arrived. Lack of personal experience, limited evidence, and gaps in knowledge were the most commonly cited reservations about cannabinoid use. Conclusions: During a 2-year period, dronabinol is used in a few critically ill patients in ICUs. The main indications are to reduce metabolic and psychological distress and to save medication. The majority of participating physicians indicated that the use of cannabinoids in the context of critical care medicine needs further exploration.

Background: The efficacy of cannabis treatment is determined by the active pharmaceutical ingredients (APIs) of the ingested composition. Despite smoking predominancy in cannabis treatment, very little is known regarding its yield and provision rate of cannabis APIs. Material and Methods: Ten experiments were performed, studying changes in APIs content during smoking, using a designated smoking machine. APIs content was evaluated via analysis of a cigarette's residuals and of the smoke composition; cannabinoid and terpene content were assessed. Results: Results demonstrated increased cannabinoid content in the cigarette sections closer to the mouth, as compared with those closer to the lit end. Similarly, cannabinoid content in the inhaled smoke increases as smoking progresses. Similar results are found for sesquiterpenes. Monoterpenes, having lower boiling points reach the smoke before the sesquiterpenes and cannabinoids do. Conclusion: A mechanism is proposed, including: (i) decarboxylation and evaporation of APIs adjacent to the lit end, (ii) transition of API vapors away from the hot zone, (iii) condensation of APIs in cigarette's sections closer to the mouth, and (iv) re-evaporation of APIs as the hot zone approaches, thereby reaching the smoke. Differences in the boiling points between the various APIs result in varying composition along the cigarette and in the inhaled smoke. The main implications are: (i) APIs delivery through smoking cannot be uniform, (ii) APIs amount per puff increases as smoking progresses, and (iii) terpenes are inhaled before the cannabinoids are. Thus, in addition to its known health-threatening hazards, smoking entails nonuniform provision of APIs, even within the same cigarette.