Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4): Alcohol use disorder and cannabinoid hyperemesis syndrome management in the emergency department.

The fourth Society for Academic Emergency Medicine (SAEM) Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4) is on the topic of the emergency department (ED) management of nonopioid use disorders and focuses on alcohol withdrawal syndrome (AWS), alcohol use disorder (AUD), and cannabinoid hyperemesis syndrome (CHS). The SAEM GRACE-4 Writing Team, composed of emergency physicians and experts in addiction medicine and patients with lived experience, applied the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding six priority questions for adult ED patients with AWS, AUD, and CHS. The SAEM GRACE-4 Writing Team reached the following recommendations: (1) in adult ED patients (over the age of 18) with moderate to severe AWS who are being admitted to hospital, we suggest using phenobarbital in addition to benzodiazepines compared to using benzodiazepines alone [low to very low certainty of evidence]; (2) in adult ED patients (over the age of 18) with AUD who desire alcohol cessation, we suggest a prescription for one anticraving medication [very low certainty of evidence]; (2a) in adult ED patients (over the age of 18) with AUD, we suggest naltrexone (compared to no prescription) to prevent return to heavy drinking [low certainty of evidence]; (2b) in adult ED patients (over the age of 18) with AUD and contraindications to naltrexone, we suggest acamprosate (compared to no prescription) to prevent return to heavy drinking and/or to reduce heavy drinking [low certainty of evidence]; (2c) in adult ED patients (over the age of 18) with AUD, we suggest gabapentin (compared to no prescription) for the management of AUD to reduce heavy drinking days and improve alcohol withdrawal symptoms [very low certainty of evidence]; (3a) in adult ED patients (over the age of 18) presenting to the ED with CHS we suggest the use of haloperidol or droperidol (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [very low certainty of evidence]; and (3b) in adult ED patients (over the age of 18) presenting to the ED with CHS, we also suggest offering the use of topical capsaicin (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [very low certainty of evidence].

Cannabinoids and Sleep: Exploring Biological Mechanisms and Therapeutic Potentials.

The endogenous cannabinoid system (ECS) plays a critical role in the regulation of various physiological functions, including sleep, mood, and neuroinflammation. Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinomimimetics, and some N-acylethanolamides, particularly palmitoyethanolamide, have emerged as potential therapeutic agents for the management of sleep disorders. THC, the psychoactive component of cannabis, may initially promote sleep, but, in the long term, alters sleep architecture, while CBD shows promise in improving sleep quality without psychoactive effects. Clinical studies suggest that CBD modulates endocannabinoid signaling through several receptor sites, offering a multifaceted approach to sleep regulation. Similarly, palmitoylethanolamide (PEA), in addition to interacting with the endocannabinoid system, acts as an agonist on peroxisome proliferator-activated receptors (PPARs). The favorable safety profile of CBD and PEA and the potential for long-term use make them an attractive alternative to conventional pharmacotherapy. The integration of the latter two compounds into comprehensive treatment strategies, together with cognitive-behavioral therapy for insomnia (CBT-I), represents a holistic approach to address the multifactorial nature of sleep disorders. Further research is needed to establish the optimal dosage, safety, and efficacy in different patient populations, but the therapeutic potential of CBD and PEA offers hope for improved sleep quality and general well-being.

Phytocannabinoids: Exploring Pharmacological Profiles and Their Impact on Therapeutical Use.

Phytocannabinoids, a diverse group of naturally occurring compounds extracted from the Cannabis plant, have attracted interest due to their potential pharmacological effects and medicinal uses. This comprehensive review presents the intricate pharmacological profiles of phytocannabinoids while exploring the diverse impacts these substances have on biological systems. From the more than one hundred cannabinoids which were identified in the Cannabis plant so far, cannabidiol (CBD) and tetrahydrocannabinol (THC) are two of the most extensively studied phytocannabinoids. CBD is a non-psychoactive compound, which exhibits potential anti-inflammatory, neuroprotective, and anxiolytic properties, making it a promising candidate for a wide array of medical conditions. THC, known for its psychoactive effects, possesses analgesic and antiemetic properties, contributing to its therapeutic potential. In addition to THC and CBD, a wide range of additional phytocannabinoids have shown intriguing pharmacological effects, including cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN). The endocannabinoid system, made up of the enzymes involved in the production and breakdown of endocannabinoids, cannabinoid receptors (CB1 and CB2), and endogenous ligands (endocannabinoids), is essential for preserving homeostasis in several physiological processes. Beyond their effects on the endocannabinoid system, phytocannabinoids are studied for their ability to modify ion channels, neurotransmitter receptors, and anti-oxidative pathways. The complex interaction between phytocannabinoids and biological systems offers hope for novel treatment approaches and lays the groundwork for further developments in the field of cannabinoid-based medicine. This review summarizes the state of the field, points out information gaps, and emphasizes the need for more studies to fully realize the therapeutic potential of phytocannabinoids.

Phytocannabinoids in neuromodulation: From omics to epigenetics.

BACKGROUND: Recent developments in metabolomics, transcriptomic and epigenetics open up new horizons regarding the pharmacological understanding of phytocannabinoids as neuromodulators in treating anxiety, depression, epilepsy, Alzheimer's, Parkinson's disease and autism. METHODS: The present review is an extensive search in public databases, such as Google Scholar, Scopus, the Web of Science, and PubMed, to collect all the literature about the neurobiological roles of cannabis extract, cannabidiol, 9-tetrahydrocannabinol specially focused on metabolomics, transcriptomic, epigenetic, mechanism of action, in different cell lines, induced animal models and clinical trials. We used bioinformatics, network pharmacology and enrichment analysis to understand the effect of phytocannabinoids in neuromodulation. RESULTS: Cannabidomics studies show wide variability of metabolites across different strains and varieties, which determine their medicinal and abusive usage, which is very important for its quality control and regulation. CB receptors interact with other compounds besides cannabidiol and Δ9-tetrahydrocannabinol, like cannabinol and Δ8-tetrahydrocannabinol. Phytocannabinoids interact with cannabinoid and non-cannabinoid receptors (GPCR, ion channels, and PPAR) to improve various neurodegenerative diseases. However, its abuse because of THC is also a problem found across different epigenetic and transcriptomic studies. Network enrichment analysis shows CNR1 expression in the brain and its interacting genes involve different pathways such as Rap1 signalling, dopaminergic synapse, and relaxin signalling. CBD protects against diseases like epilepsy, depression, and Parkinson's by modifying DNA and mitochondrial DNA in the hippocampus. Network pharmacology analysis of 8 phytocannabinoids revealed an interaction with 10 (out of 60) targets related to neurodegenerative diseases, with enrichment of ErbB and PI3K-Akt signalling pathways which helps in ameliorating neuro-inflammation in various neurodegenerative diseases. The effects of phytocannabinoids vary across sex, disease state, and age which suggests the importance of a personalized medicine approach for better success. CONCLUSIONS: Phytocannabinoids present a range of promising neuromodulatory effects. It holds promise if utilized in a strategic way towards personalized neuropsychiatric treatment. However, just like any drug irrational usage may lead to unforeseen negative effects. Exploring neuro-epigenetics and systems pharmacology of major and minor phytocannabinoid combinations can lead to success.

Linking the Autotaxin-LPA Axis to Medicinal Cannabis and the Endocannabinoid System.

Over the past few decades, many current uses for cannabinoids have been described, ranging from controlling epilepsy to neuropathic pain and anxiety treatment. Medicines containing cannabinoids have been approved by both the FDA and the EMA for the control of specific diseases for which there are few alternatives. However, the molecular-level mechanism of action of cannabinoids is still poorly understood. Recently, cannabinoids have been shown to interact with autotaxin (ATX), a secreted lysophospholipase D enzyme responsible for catalyzing lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a pleiotropic growth factor that interacts with LPA receptors. In addition, a high-resolution structure of ATX in complex with THC has recently been published, accompanied by biochemical studies investigating this interaction. Due to their LPA-like structure, endocannabinoids have been shown to interact with ATX in a less potent manner. This finding opens new areas of research regarding cannabinoids and endocannabinoids, as it could establish the effect of these compounds at the molecular level, particularly in relation to inflammation, which cannot be explained by the interaction with CB1 and CB2 receptors alone. Further research is needed to elucidate the mechanism behind the interaction between cannabinoids and endocannabinoids in humans and to fully explore the therapeutic potential of such approaches.

Cannabinoids in the treatment of glioblastoma.

Glioblastoma (GBM) is the most prevalent primary malignant tumor of the nervous system. While the treatment of other neoplasms is increasingly more efficacious the median survival rate of GBM patients remains low and equals about 14 months. Due to this fact, there are intensive efforts to find drugs that would help combat GBM. Nowadays cannabinoids are becoming more and more important in the field of cancer and not only because of their properties of antiemetic drugs during chemotherapy. These compounds may have a direct cytotoxic effect on cancer cells. Studies indicate GBM has disturbances in the endocannabinoid system-changes in cannabinoid metabolism as well as in the cannabinoid receptor expression. The GBM cells show expression of cannabinoid receptors 1 and 2 (CB1R and CB2R), which mediate various actions of cannabinoids. Through these receptors, cannabinoids inhibit the proliferation and invasion of GBM cells, along with changing their morphology. Cannabinoids also induce an intrinsic pathway of apoptosis in the tumor. Hence the use of cannabinoids in the treatment of GBM may be beneficial to the patients. So far, studies focusing on using cannabinoids in GBM therapy are mainly preclinical and involve cell lines and mice. The results are promising and show cannabinoids inhibit GBM growth. Several clinical studies are also being carried out. The preliminary results show good tolerance of cannabinoids and prolonged survival after administration of these drugs. In this review, we describe the impact of cannabinoids on GBM and glioma cells in vitro and in animal studies. We also provide overview of clinical trials on using cannabinoids in the treatment of GBM.

Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.

Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.

Cannabis and Cannabinoids in Adults With Cancer: ASCO Guideline.

PURPOSE: To guide clinicians, adults with cancer, caregivers, researchers, and oncology institutions on the medical use of cannabis and cannabinoids, including synthetic cannabinoids and herbal cannabis derivatives; single, purified cannabinoids; combinations of cannabis ingredients; and full-spectrum cannabis. METHODS: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and cohort studies on the efficacy and safety of cannabis and cannabinoids when used by adults with cancer. Outcomes of interest included antineoplastic effects, cancer treatment toxicity, symptoms, and quality of life. PubMed and the Cochrane Library were searched from database inception to January 27, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: The evidence base consisted of 13 systematic reviews and five additional primary studies (four RCTs and one cohort study). The certainty of evidence for most outcomes was low or very low. RECOMMENDATIONS: Cannabis and/or cannabinoid access and use by adults with cancer has outpaced the science supporting their clinical use. This guideline provides strategies for open, nonjudgmental communication between clinicians and adults with cancer about the use of cannabis and/or cannabinoids. Clinicians should recommend against using cannabis or cannabinoids as a cancer-directed treatment unless within the context of a clinical trial. Cannabis and/or cannabinoids may improve refractory, chemotherapy-induced nausea and vomiting when added to guideline-concordant antiemetic regimens. Whether cannabis and/or cannabinoids can improve other supportive care outcomes remains uncertain. This guideline also highlights the critical need for more cannabis and/or cannabinoid research.Additional information is available at www.asco.org/supportive-care-guidelines.

Immune and glial cell alterations in the rat brain after repeated exposure to the synthetic cannabinoid JWH-018.

The use of synthetic cannabinoid receptor agonists (SCRAs) poses major psychiatric risks. We previously showed that repeated exposure to the prototypical SCRA JWH-018 induces alterations in dopamine (DA) transmission, abnormalities in the emotional state, and glial cell activation in the mesocorticolimbic DA circuits of rats. Despite growing evidence suggesting the relationship between substance use disorders (SUD) and neuroinflammation, little is known about the impact of SCRAs on the neuroimmune system. Here, we investigated whether repeated JWH-018 exposure altered neuroimmune signaling, which could be linked with previously reported central effects. Adult male Sprague-Dawley (SD) rats were exposed to JWH-018 (0.25 mg/kg, i.p.) for fourteen consecutive days, and the expression of cytokines, chemokines, and growth factors was measured seven days after treatment discontinuation in the striatum, cortex, and hippocampus. Moreover, microglial (ionized calcium-binding adaptor molecule 1, IBA-1) and astrocyte (glial fibrillary acidic protein, GFAP) activation markers were evaluated in the caudate-putamen (CPu). Repeated JWH-018 exposure induces a perturbation of neuroimmune signaling specifically in the striatum, as shown by increased levels of cytokines [interleukins (IL) -2, -4, -12p70, -13, interferon (IFN) γ], chemokines [macrophage inflammatory protein (MIP) -1α, -3α], and growth factors [macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor (VEGF)], together with increased IBA-1 and GFAP expression in the CPu. JWH-018 exposure induces persistant brain region-specific immune alterations up to seven days after drug discontinuation, which may contribute to the behavioral and neurochemical dysregulations in striatal areas that play a role in the reward-related processes that are frequently impaired in SUD.

Cannabinoids in the Treatment of Selected Mental Illnesses: Practical Approach and Overview of the Literature.

Although an increasing number of patients suffering from mental illnesses self-medicate with cannabis, current knowledge about the efficacy and safety of cannabis-based medicine in psychiatry is still extremely limited. So far, no cannabis-based finished product has been approved for the treatment of a mental illness. There is increasing evidence that cannabinoids may improve symptoms in autism spectrum disorder (ASD), Tourette syndrome (TS), anxiety disorders, and post-traumatic stress disorder (PTSD). According to surveys, patients often use cannabinoids to improve mood, sleep, and symptoms of attention deficit/hyperactivity disorder (ADHD). There is evidence suggesting that tetrahydrocannabinol (THC) and THC-containing cannabis extracts, such as nabiximols, can be used as substitutes in patients with cannabis use disorder.Preliminary evidence also suggests an involvement of the endocannabinoid system (ECS) in the pathophysiology of TS, ADHD, and PTSD. Since the ECS is the most important neuromodulatory system in the brain, it possibly induces beneficial effects of cannabinoids by alterations in other neurotransmitter systems. Finally, the ECS is an important stress management system. Thus, cannabinoids may improve symptoms in patients with mental illnesses by reducing stress.Practically, cannabis-based treatment in patients with psychiatric disorders does not differ from other indications. The starting dose of THC-containing products should be low (1-2.5 mg THC/day), and the dose should be up-titrated slowly (by 1-2.5 mg every 3-5 days). The average daily dose is 10-20 mg THC. In contrast, cannabidiol (CBD) is mainly used in high doses>400 mg/day.

Cannabinoids for Behavioral Symptoms in Dementia: An Overview.

Dementia, with loss of memory, cognitive abilities, and independent daily functioning, is increasing worldwide, related to an aging population. Currently, there is no curative treatment for dementia. Treatment of the frequently occurring behavioral and psychological symptoms of dementia (BPSD) is partially effective and associated with significant side effects. Cannabinoids are lipophilic molecules acting on the CB1 end CB2 receptors, essential for main biological processes such as sleep, appetite, memory, and pain. Cannabinoids might have a positive impact on amyloid formation in Alzheimer's disease, the main form of dementia, and on BPSD symptoms. Most knowledge currently concerns delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In the context of dementia and BPSD, THC might be beneficial for associated spasticity and possible pain or lack of appetite and CBD probably works better on sleep, agitation, and anxiety. This overview of prospective clinical studies and randomized clinical trials, published between 2005 and April 2023, using cannabinoids for BPSD suggests that older studies using low-dose oral synthetic THC showed no positive results. Still, more recent studies using THC/CBD-based oral medication at higher doses show promising results and are feasible and safe in this elderly polymedicated population. Several RCTs are ongoing and planned worldwide, and we hope other trials will follow to establish clinical efficiency and optimal dosing, as well as other outcomes such as deprescribing other medications and facilitation of care. We suggest that researchers also address the more sociological aspects of prescribing cannabinoids for dementia and BPSD in their specific context.

Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation.

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.

Anti-proliferative and apoptotic effect of cannabinoids on human pancreatic ductal adenocarcinoma xenograft in BALB/c nude mice model.

Human pancreatic ductal adenocarcinoma (PDAC) is a highly malignant and lethal tumor of the exocrine pancreas. Cannabinoids extracted from the hemp plant Cannabis sativa have been suggested as a potential therapeutic agent in several human tumors. However, the anti-tumor effect of cannabinoids on human PDAC is not entirely clarified. In this study, the anti-proliferative and apoptotic effect of cannabinoid solution (THC:CBD at 1:6) at a dose of 1, 5, and 10 mg/kg body weight compared to the negative control (sesame oil) and positive control (5-fluorouracil) was investigated in human PDAC xenograft nude mice model. The findings showed that cannabinoids significantly decreased the mitotic cells and mitotic/apoptotic ratio, meanwhile dramatically increased the apoptotic cells. Parallelly, cannabinoids significantly downregulated Ki-67 and PCNA expression levels. Interestingly, cannabinoids upregulated BAX, BAX/BCL-2 ratio, and Caspase-3, meanwhile, downregulated BCL-2 expression level and could not change Caspase-8 expression level. These findings suggest that cannabinoid solution (THC:CBD at 1:6) could inhibit proliferation and induce apoptosis in human PDAC xenograft models. Cannabinoids, including THC:CBD, should be further studied for use as the potent PDCA therapeutic agent in humans.

Toll-like receptor signalling as a cannabinoid target.

Toll-like receptors (TLRs) have become a focus in biomedicine and biomedical research given the roles of this unique family of innate immune proteins in immune activation, infection, and autoimmunity. It is evident that TLR dysregulation, and subsequent alterations in TLR-mediated inflammatory signalling, can contribute to disease pathogenesis, and TLR targeted therapies are in development. This review highlights evidence that cannabinoids are key regulators of TLR signalling. Cannabinoids include component of the plant Cannabis sativa L. (C. sativa), synthetic and endogenous ligands, and overall represent a class of compounds whose therapeutic potential and mechanism of action continues to be elucidated. Cannabinoid-based medicines are in the clinic, and are furthermore under intense investigation for broad clinical development to manage symptoms of a range of disorders. In this review, we present an overview of research evidence that signalling linked to a range of TLRs is targeted by cannabinoids, and such cannabinoid mediated effects represent therapeutic avenues for further investigation. First, we provide an overview of TLRs, adaptors and key signalling events, alongside a summary of evidence that TLRs are linked to disease pathologies. Next, we discuss the cannabinoids system and the development of cannabinoid-based therapeutics. Finally, for the bulk of this review, we systematically outline the evidence that cannabinoids (plant-derived cannabinoids, synthetic cannabinoids, and endogenous cannabinoid ligands) can cross-talk with innate immune signalling governed by TLRs, focusing specifically on each member of the TLR family. Cannabinoids should be considered as key regulators of signalling controlled by TLRs, and such regulation should be a major focus in terms of the anti-inflammatory propensity of the cannabinoid system.

Cannabidiol Exerts Anticonvulsant Effects Alone and in Combination with Δ9-THC through the 5-HT1A Receptor in the Neocortex of Mice.

Cannabinoids have shown potential in drug-resistant epilepsy treatment; however, we lack knowledge on which cannabinoid(s) to use, dosing, and their pharmacological targets. This study investigated (i) the anticonvulsant effect of Cannabidiol (CBD) alone and (ii) in combination with Delta-9 Tetrahydrocannabinol (Δ9-THC), as well as (iii) the serotonin (5-HT)1A receptor's role in CBD's mechanism of action. Seizure activity, induced by 4-aminopyridine, was measured by extracellular field recordings in cortex layer 2/3 of mouse brain slices. The anticonvulsant effect of 10, 30, and 100 µM CBD alone and combined with Δ9-THC was evaluated. To examine CBD's mechanism of action, slices were pre-treated with a 5-HT1A receptor antagonist before CBD's effect was evaluated. An amount of ≥30 µM CBD alone exerted significant anticonvulsant effects while 10 µM CBD did not. However, 10 µM CBD combined with low-dose Δ9-THC (20:3 ratio) displayed significantly greater anticonvulsant effects than either phytocannabinoid alone. Furthermore, blocking 5-HT1A receptors before CBD application significantly abolished CBD's effects. Thus, our results demonstrate the efficacy of low-dose CBD and Δ9-THC combined and that CBD exerts its effects, at least in part, through 5-HT1A receptors. These results could address drug-resistance while providing insight into CBD's mechanism of action, laying the groundwork for further testing of cannabinoids as anticonvulsants.

Cannabinoids for Cancer-related Pain Management: An Update on Therapeutic Applications and Future Perspectives.

Pain is a debilitating phenomenon that dramatically impairs the quality of life of patients. Many chronic conditions, including cancer, are associated with chronic pain. Despite pharmacological efforts that have been conducted, many patients suffering from cancer pain remain without treatment. To date, opioids are considered the preferred therapeutic choice for cancer-related pain management. Unfortunately, opioid treatment causes side effects and inefficiently relieves patients from pain, therefore alternative therapies have been considered, including Cannabis Sativa and cannabinoids. Accumulating evidence has highlighted that an increasing number of patients are choosing to use cannabis and cannabinoids for the management of their soothing and non-palliative cancer pain and other cancer-related symptoms. However, their clinical application must be supported by convincing and reproducible clinical trials. In this review, we provide an update on cannabinoid use for cancer pain management. Moreover, we tried to turn a light on the potential use of cannabis as a possible therapeutic option for cancer-related pain relief.

Targeting the Endocannabinoid System Present in the Glioblastoma Tumour Microenvironment as a Potential Anti-Cancer Strategy.

The highly aggressive and invasive glioblastoma (GBM) tumour is the most malignant lesion among adult-type diffuse gliomas, representing the most common primary brain tumour in the neuro-oncology practice of adults. With a poor overall prognosis and strong resistance to treatment, this nervous system tumour requires new innovative treatment. GBM is a polymorphic tumour consisting of an array of stromal cells and various malignant cells contributing to tumour initiation, progression, and treatment response. Cannabinoids possess anti-cancer potencies against glioma cell lines and in animal models. To improve existing treatment, cannabinoids as functionalised ligands on nanocarriers were investigated as potential anti-cancer agents. The GBM tumour microenvironment is a multifaceted system consisting of resident or recruited immune cells, extracellular matrix components, tissue-resident cells, and soluble factors. The immune microenvironment accounts for a substantial volume of GBM tumours. The barriers to the treatment of glioblastoma with cannabinoids, such as crossing the blood-brain barrier and psychoactive and off-target side effects, can be alleviated with the use of nanocarrier drug delivery systems and functionalised ligands for improved specificity and targeting of pharmacological receptors and anti-cancer signalling pathways. This review has shown the presence of endocannabinoid receptors in the tumour microenvironment, which can be used as a potential unique target for specific drug delivery. Existing cannabinoid agents, studied previously, show anti-cancer potencies via signalling pathways associated with the hallmarks of cancer. The results of the review can be used to provide guidance in the design of future drug therapy for glioblastoma tumours.

Pharmacological management of fragile X syndrome: a systematic review and narrative summary of the current evidence.

INTRODUCTION: Fragile X syndrome (FXS) is the most common inherited cause of Intellectual Disability. There is a broad phenotype that includes deficits in cognition and behavioral changes, alongside physical characteristics. Phenotype depends upon the level of mutation in the FMR1 (fragile X messenger ribonucleoprotein 1) gene. The molecular understanding of the impact of the FMR1 gene mutation provides an opportunity to target treatment not only at symptoms but also on a molecular level. METHODS: We conducted a systematic review to provide an up-to-date narrative summary of the current evidence for pharmacological treatment in FXS. The review was restricted to randomized, blinded, placebo-controlled trials. RESULTS: The outcomes from these studies are discussed and the level of evidence assessed against validated criteria. The initial search identified 2377 articles, of which 16 were included in the final analysis. CONCLUSION: Based on this review to date there is limited data to support any specific pharmacological treatments, although the data for cannabinoids are encouraging in those with FXS and in future developments in gene therapy may provide the answer to the search for precision medicine. Treatment must be person-centered and consider the combination of medical, genetic, cognitive, and emotional challenges.

Effect of cannabinoids in mild-to-moderate cases of Crohn's disease as compared to placebo: a systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: In view of limited treatment options (those too may fail) for Crohn's disease, cannabinoids have been tried as a therapeutic. However, their efficacy is not unequivocally established. This systematic review and meta-analysis was planned to pool data from randomised controlled trials (RCTs) evaluating effect of cannabinoids in Crohn's disease with an intention to take this uncertainty away. CONTENT: Following literature search in Medline, EMBASE, Scopus and Google Scholar databases, RCTs assessing the effect of cannabinoids on mild-to-moderate Crohn's disease in adults were included. Crohns' disease activity index (CDAI), QoL (Quality of life), number participants achieving full remission and serum CRP at eight weeks of treatment were the outcomes considered for meta-analysis. Quality of studies was assessed using Cochrane's RoB2 tool. Random effect model was applied for meta-analysis. Heterogeneity was assessed by Cochrane 'Q' statistics and I2 test. Sensitivity analysis was performed to identify the major contributor(s) to heterogeneity and assess robustness of the results. SUMMARY: Risk of bias for the four included studies varied from 'low' to 'some concern'. Overall effect estimate (SMD -0.92; 95 % CI -1.80, -0.03) indicated a statistically significant effect of cannabinoids as compared to control (p<0.05) on CDAI score. Effect of cannabinoids on rest of the outcome parameters was comparable to that of placebo. Magnitude of heterogeneity for different outcome parameters ranged from 'low' to 'substantial'. OUTLOOK: Cannabinoids were superior to placebo for favourably affecting the disease severity in terms of CDAI score. However, no statistically significant difference was found between the two for improving QoL, causing full disease-remission and reducing inflammatory markers. The results must be interpreted with caution in view of relatively high heterogeneity among the studies.

CB2 Cannabinoid Receptor as a Potential Target in Myocardial Infarction: Exploration of Molecular Pathogenesis and Therapeutic Strategies.

The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1ß. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-ß/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.