UNASSIGNED: Cannabinoid receptor type 2 (CB2R), predominantly expressed in immune tissues, is believed to play a crucial role within the body\'s protective mechanisms. Its modulation holds immense therapeutic promise for addressing a wide spectrum of dysbiotic conditions, including cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, and autoimmune diseases, as well as lung disorders, cancer, and pain management.
UNASSIGNED: This review is an account of patents from 2016 up to 2023 which describes novel CB2R ligands, therapeutic applications, synthesis, as well as formulations of CB2R modulators.
UNASSIGNED: The patents cover a vast, structurally diverse chemical space. The focus of CB2R ligand development has shifted from unselective dual-cannabinoid receptor type 1 (CB1R) and 2 agonists toward agonists with high selectivity over CB1R, particularly for indications associated with inflammation and tissue injury. Currently, there are at least eight CB2R agonists and one antagonist in active clinical development. A better understanding of the endocannabinoid system (ECS) and in particular of CB2R pharmacology is required to unlock the receptor\'s full therapeutic potential.

To provide a comprehensive framework of the current information on the potency and efficacy of interaction between phyto- and synthetic cannabinoids and their respective receptors, an electronic search of the PubMed, Scopus, and EMBASE literature was performed. Experimental studies included reports of mechanistic data providing affinity, efficacy, and half-maximal effective concentration (EC50). Among the 108 included studies, 174 structures, and 16 targets were extracted. The most frequent ligands belonged to the miscellaneous category with 40.2% followed by phytocannabinoid-similar, indole-similar, and pyrrole-similar structures with an abundance of 17.8%, 16.6%, and 12% respectively. 64.8% of structures acted as agonists, 17.1 % appeared as inverse agonists, 10.8% as antagonists, and 7.2% of structures were reported with antagonist/inverse agonist properties. Our outcomes identify the affinity, EC50, and efficacy of the interactions between cannabinoids and their corresponding receptors and the subsequent response, evaluated in the available evidence. Considering structures\' significance and very important effects of on the activities, the obtained results also provide clues to drug repurposing.

To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB1) and 2 (CB2) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] - 24.83, 95% confidence interval [95%CI] - 34.89, - 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB1/2-non-selective) and AM1241 (CB2-selective) (MD - 28.73, 95%CI - 45.43, - 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB2-selective) increased paw withdrawal threshold (MD 0.89, 95%CI 0.79, 0.99, p < 0.00001), and ACEA (CB1-selective), AM1241 and JWH015 (CB2-selective) reduced spontaneous flinches (MD - 4.85, 95%CI - 6.74, - 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB1/2-non-selective), JWH015 and AM1241 (CB2-selective) in osteolysis-bearing females (MD 8.18, 95%CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB2-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95%CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB1/2 ligands in rodents. In human, treatment of cancer patients with medical cannabis (standardized MD - 0.19, 95%CI - 0.35, - 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95%CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity. Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB1 and CB2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.

Currently, few treatments are available for craving in general, and none of them have received approval for cannabis craving. The objective of this review is to evaluate existing studies analysing treatments for cannabis craving and explore novel treatment possibilities for these patients. The study followed PRISMA guidelines and conducted an extensive database search. Inclusion criteria included human randomised controlled trials examining drug effects on craving symptoms. Exclusion criteria involved studies unrelated to craving, non-pharmacological treatments, duplicates, and non-English/Spanish/Portuguese articles. Our included 22 studies that investigated a wide range of compounds used for cravings related to other drugs, as well as interventions based on healthcare professionals\' empirical knowledge. The current pharmacological treatments largely involve off-label drug use and the utilisation of cannabinoid-based medications, such as combinations of THC and lofexidine, oxytocin, progesterone, and N-acetylcysteine. These emerging treatments show promise and have the potential to revolutionise current clinical practices, but further investigation is needed to establish their efficacy. In this context, it is essential to consider non-pharmacological interventions, such as psychotherapy and behavioural treatments. These approaches play a crucial role in complementing pharmacological interventions and addressing the complex nature of the disorder.

Driving is a critical everyday task necessitating the rapid and seamless integration of dynamic visually derived information to guide neurobehaviour. Biological markers are frequently employed to detect Δ9-tetrahydrocannabinol (THC) consumption among drivers during roadside tests, despite not necessarily indicating impairment. Characterising THC-specific alterations to oculomotor behaviour may offer a more sensitive measure for indexing drug-related impairment, necessitating discrimination between acute THC effects, chronic use and potential tolerance effects. The present review aims to synthesise current evidence on the acute and chronic effects of THC on driving-relevant oculomotor behaviour. The review was prospectively registered (10.17605/OSF.IO/A4H9W), and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines informed reporting standards. Overall, 20 included articles comprising 12 experimental acute dosing trials, 5 cross-sectional chronic use studies and 3 roadside epidemiological studies examined the effects of cannabis/THC on oculomotor parameters including saccadic activity gaze behaviour, nystagmus, smooth pursuit and eyelid/blink characteristics. Acute THC consumption selectively impacts oculomotor control, notably increasing saccadic latency and inaccuracy and impairing inhibitory control. Chronic cannabis users, especially those with early age of use onset, display enduring oculomotor deficits that affect visual scanning efficiency. The presence of eyelid tremors appears to be a reliable indicator of cannabis consumption while remaining distinct from direct impairment associated with visual attention and motor control. Cannabis selectively influences oculomotor activity relevant to driving, highlighting the role of cannabinoid systems in these processes. Defining cannabis/THC-specific changes in oculomotor control may enhance the precision of roadside impairment assessments and vehicle safety systems to detect drug-related impairment and assess driving fitness.

BACKGROUND: Cannabis use is a risk factor of psychiatric illness, such as bipolar disorder type-I (BDI). Indeed, cannabis use strongly influences the onset and clinical course of BDI, although the biological mechanisms underlying this interaction remain unknown. Therefore, we have reviewed the biological mechanisms affected by cannabis use that may trigger BD.
METHODS: A systematic review was carried out of articles in which gene expression was studied in cannabis users or human-derived cells exposed to tetrahydrocannabinol (THC) or cannabidiol (CBD). A second systematic review was then performed to identify articles in which gene expression was studied in BDI samples, highlighting those that described alterations to the same molecular and cellular mechanisms affected by cannabis/THC/CBD.
RESULTS: The initial search identified 82 studies on cannabis and 962 on BDI. After removing duplicates and applying the inclusion/exclusion criteria, 9 studies into cannabis and 228 on BDI were retained. The molecular and cellular mechanisms altered by cannabis use or THC/CBD exposure were then identified, including neural development and function, cytoskeletal function, cell adhesion, mitochondrial biology, inflammatory related pathways, lipid metabolism, the endocannabinoid system, the hypocretin/orexin system, and apoptosis. Alterations to those activities were also described in 19 of 228 focused on BDI.
CONCLUSIONS: The biological mechanisms described in this study may be good candidates to the search for diagnostic biomarkers and therapeutic targets for BDI. Because cannabis use can trigger the onset of BD, further studies would be of interest to determine whether they are involved in the early development of the disorder, prompting early treatment.

Introduction: The endocannabinoid system (ECS) mediates the actions of cannabis and has been implicated in playing critical roles in key developmental events, including axon guidance. Although several recent studies have demonstrated ECS involvement in neurodevelopment, an emphasis on its putative role in axon guidance has not been reviewed comprehensively. Objective: The purpose of this literature review is to evaluate the interrelationships between the ECS and axon guidance. Methodology: This literature review analyzes existing literature demonstrating the normal role of endocannabinoid (eCB) signaling in axon guidance, with evidence from diverse animal models. Studies were obtained from a search strategy involving terms related to the ECS and axon guidance, and cross-checking cited literature to ensure a complete evaluation. Discussion: Cannabinoid receptors, as well as eCB synthesis and degradation machinery, appear necessary for normal axon guidance during neurodevelopment. Genetic and/or pharmacological disruption of eCB signaling results in axon growth and guidance errors, implying high sensitivity to exogenous cannabinoids. Conclusion: Overall, this review highlights the intricate connections between the ECS and axon guidance in normal neurodevelopment. The mechanistic evidence discussed suggests that alterations of the ECS through genetic and pharmacological interference disrupt its normal functioning and by extension its normal role in regulating neural circuitry formation. A comprehensive understanding of this topic will be valuable in potentially uncovering the mechanisms responsible for the neurodevelopmental defects associated with pre-natal cannabis use.

The objective of this study is to evaluate the comparative benefits and harms of opioids and cannabis for medical use for chronic non-cancer pain.
Systematic review and network meta-analysis.
EMBASE, MEDLINE, CINAHL, AMED, PsycINFO, PubMed, Web of Science, Cannabis-Med, Epistemonikos and the Cochrane Library (CENTRAL) from inception to March 2021.
Randomised trials comparing any type of cannabis for medical use or opioids, against each other or placebo, with patient follow-up ≥4 weeks.
Paired reviewers independently extracted data. We used Bayesian random-effects network meta-analyses to summarise the evidence and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to evaluate the certainty of evidence and communicate our findings.
Ninety trials involving 22 028 patients were eligible for review, among which the length of follow-up ranged from 28 to 180 days. Moderate certainty evidence showed that opioids provide small improvements in pain, physical functioning and sleep quality versus placebo; low to moderate certainty evidence supported similar effects for cannabis versus placebo. Neither was more effective than placebo for role, social or emotional functioning (all high to moderate certainty evidence). Moderate certainty evidence showed there is probably little to no difference between cannabis for medical use and opioids for physical functioning (weighted mean difference (WMD) 0.47 on the 100-point 36-item Short Form Survey physical component summary score, 95% credible interval (CrI) -1.97 to 2.99), and cannabis resulted in fewer discontinuations due to adverse events versus opioids (OR 0.55, 95% CrI 0.36 to 0.83). Low certainty evidence suggested little to no difference between cannabis and opioids for pain relief (WMD 0.23 cm on a 10 cm Visual Analogue Scale (VAS), 95% CrI -0.06 to 0.53) or sleep quality (WMD 0.49 mm on a 100 mm VAS, 95% CrI -4.72 to 5.59).
Cannabis for medical use may be similarly effective and result in fewer discontinuations than opioids for chronic non-cancer pain.
CRD42020185184.

Cannabis use is consistently associated with both increased incidence of frank psychotic disorders and acute exacerbations of psychotic symptoms in healthy individuals and people with psychosis spectrum disorders. Although there is uncertainty around causality, cannabis use may be one of a few modifiable risk factors for conversion to psychotic disorders in individuals with Clinical High Risk for Psychosis (CHR-P) syndromes, characterized by functionally impairing and distressing subthreshold psychotic symptoms. To date, few recommendations beyond abstinence to reduce adverse psychiatric events associated with cannabis use have been made. This narrative review synthesizes existing scientific literature on cannabis\' acute psychotomimetic effects and epidemiological associations with psychotic disorders in both CHR-P and healthy individuals to bridge the gap between scientific knowledge and practical mental health intervention. There is compelling evidence for cannabis acutely exacerbating psychotic symptoms in CHR-P, but its impact on conversion to psychotic disorder is unclear. Current evidence supports a harm reduction approach in reducing frequency of acute psychotic-like experiences, though whether such interventions decrease CHR-P individuals\' risk of conversion to psychotic disorder remains unknown. Specific recommendations include reducing frequency of use, lowering delta-9-tetrahydrocannabinol content in favor of cannabidiol-only products, avoiding products with inconsistent potency like edibles, enhancing patient-provider communication about cannabis use and psychotic-like experiences, and utilizing a collaborative and individualized therapeutic approach. Despite uncertainty surrounding cannabis\' causal association with psychotic disorders, cautious attempts to reduce acute psychosis risk may benefit CHR-P individuals uninterested in abstinence. Further research is needed to clarify practices associated with minimization of cannabis-related psychosis risk.

Following the discovery of various effects on skin function by modifying endocannabinoid systems, multiple preclinical studies have revealed the promise of cannabis and cannabinoids in the treatment of a variety of skin diseases. However, its clinical efficacy is still debated.
The protocol has been prepared using the Preferred Items for Systematic Review and Meta-analysis Protocols guidelines. A systematic search will be conducted using PubMed, EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials and Web of Science. We will include randomised controlled trials and observational studies investigating alterations to dermatological characteristics following administration of cannabis and cannabinoids for dermatological diseases and disorders. The two reviewers will perform both the title and abstract and full-text screenings. The Cochrane Risk-of-Bias 2 and ROBINS-1 tools will be used to evaluate the risk of bias. If a group of comparable studies for each quantitative outcome can be discovered, we will conduct a random effects meta-analysis. We will investigate heterogeneity using a combination of visual inspection of the forest plot, the Cochran\'s Q test and Higgins\' test [I2]. Sensitivity analyses will be performed to assess the statistical robustness of the primary outcome. To evaluate a publication bias, the Egger\'s regression asymmetry test and funnel plots will be considered.
This study does not require ethical approval because no original data will be collected. The findings will be presented at conferences and published in peer-reviewed journals.
CRD42023397189.