Medicinal Cannabis (MedCan 3): a randomised, multicentre, double-blind, placebo-controlled trial to assess THC/CBD (1:20) to relieve symptom burden in patients with cancer-a study protocol for a randomised controlled trial.

BACKGROUND: Distressing symptoms are common in advanced cancer. Medicinal cannabinoids are commonly prescribed for a variety of symptoms. There is little evidence to support their use for most indications in palliative care. This study aims to assess a 1:20 delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) cannabinoid preparation in the management of symptom distress in patients with advanced cancer undergoing palliative care. METHODS AND DESIGN: One hundred and fifty participants will be recruited across multiple sites in Queensland, Australia. A teletrial model will facilitate the recruitment of patients outside of major metropolitan areas. The study is a pragmatic, multicenter, randomised, placebo-controlled, two-arm trial of escalating doses of an oral 1:20 THC/CBD medicinal cannabinoid preparation (10 mg THC:200 mg CBD/mL). It will compare the efficacy and safety outcomes of a titrated dose range of 2.5 mg THC/50mgCBD to 30 mg THC/600 mg CBD per day against a placebo. There is a 2-week patient-determined titration phase, to reach a dose that achieves symptom relief or intolerable side effects, with a further 2 weeks of assessment on the final dose. The primary objective is to assess the effect of escalating doses of a 1:20 THC/CBD medicinal cannabinoid preparation against placebo on change in total symptom distress score, with secondary objectives including establishing a patient-determined effective dose, the effect on sleep quality and overall quality of life. Some patients will be enrolled in a sub-study which will more rigorously evaluate the effect on sleep. DISCUSSION: MedCan-3 is a high-quality, adequately powered, placebo-controlled trial which will help demonstrate the utility of a THC:CBD 1:20 oral medicinal cannabis product in reducing total symptom distress in this population. Secondary outcomes may lead to new hypotheses regarding medicinal cannabis' role in particular symptoms or in particular cancers. The sleep sub-study will test the feasibility of using actigraphy and the Insomnia Severity Index (ISI) in this cohort. This will be the first large-scale palliative care randomised clinical trial to utilise the teletrial model in Australia. If successful, this will have significant implications for trial access for rural and remote patients in Australia and internationally. TRIAL REGISTRATION: ANZCTR ACTRN12622000083796 . Protocol number 001/20. Registered on 21 January 2022. Recruitment started on 8 August 2022.

Cannabis medicine for chronic pain.

In the last decade, patients with chronic pain have expressed increasing interest in cannabis-derived products for adjuvant therapy when treatment is deemed refractory to conventional analgesics. At present, clinical evidence to support this treatment approach appears to be sparse. Not because clinical studies as such are lacking, but rather as a result of methodological bias in relation to study design, patient populations, and treatment protocols. In this review, research in cannabis medicine for relief of chronic pain is reviewed, mainly with reference to published meta-analytic studies.

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.

Oral Delta-9-Tetrahydrocannabinol (THC) Increases Parasympathetic Activity and Supraspinal Conditioned Pain Modulation in Chronic Neuropathic Pain Male Patients: A Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Disordered autonomic nervous system regulation and supraspinal pain inhibition have been repeatedly described in chronic pain. We aimed to explore the effects of δ-9-tetrahydrocannabinol (THC), an emerging treatment option, on autonomic nervous system and central pain modulation measures in patients with chronic pain. METHODS: Twelve male patients with chronic radicular neuropathic pain participated in a randomized, double-blind, crossover, placebo-controlled, single-administration trial. Low/high frequency (LF/HF) heart rate variability (HRV) ratio and conditioned pain modulation (CPM) response were measured and resting-state functional magnetic resonance imaging (MRI) was performed at baseline and after sublingual administration of either 0.2 mg/kg oral THC or placebo. RESULTS: THC significantly reduced the LF/HF ratio compared with placebo (interaction effect F(1,11) = 20.5; p < 0.005) and significantly improved CPM responses (interaction effect F(1,9) = 5.2; p = 0.048). The THC-induced reduction in LF/HF ratio correlated with increased functional connectivity between the rostral ventrolateral medulla and the dorsolateral prefrontal cortex [T(10) = 6.4, cluster p-FDR < 0.005]. CONCLUSIONS: THC shifts the autonomic balance towards increased parasympathetic tone and improves inhibitory pain mechanisms in chronic pain. The increase in vagal tone correlates with connectivity changes in higher-order regulatory brain regions, suggesting THC exerts top-down effects. These changes may reflect a normalizing effect of THC on multiple domains of supraspinal pain dysregulation. CLINICAL TRIAL REGISTRY NUMBER: NCT02560545.

Medicinal Use of Different Cannabis Strains: Results from a Large Prospective Survey in Germany.

BACKGROUND: Up to now, it is unclear whether different medicinal cannabis (MC) strains are differently efficacious across different medical conditions. In this study, the effectiveness of different MC strains was compared depending on the disease to be treated. METHODS: This was an online survey conducted in Germany between June 2020 and August 2020. Patients were allowed to participate only if they received a cannabis-based treatment from pharmacies in the form of cannabis flowers prescribed by a physician. RESULTS: The survey was completed by n=1,028 participants. Most participants (58%) have used MC for more than 1 year, on average, 5.9 different strains. Bedrocan (pure tetrahydrocannabinol to pure cannabidiol [THC:CBD]=22:<1) was the most frequently prescribed strain, followed by Bakerstreet (THC:CBD=19:<1) and Pedanios 22/1 (THC:CBD=22:1). The most frequent conditions MC was prescribed for were different pain disorders, psychiatric and neurological diseases, and gastrointestinal symptoms. Overall, the mean patient-reported effectiveness was 80.1% (range, 0-100%). A regression model revealed no association between the patient-reported effectiveness and the variety. Furthermore, no influence of the disease on the choice of the MC strain was detected. On average, 2.1 side effects were reported (most commonly dry mouth (19.5%), increased appetite (17.1%), and tiredness (13.0%)). However, 29% of participants did not report any side effects. Only 398 participants (38.7%) indicated that costs for MC were covered by their health insurance. CONCLUSIONS: Patients self-reported very good efficacy and tolerability of MC. There was no evidence suggesting that specific MC strains are superior depending on the disease to be treated.

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.

Does medicinal cannabis affect depression, anxiety, and stress in people with cancer? A systematic review and meta-analysis of intervention studies.

INTRODUCTION: Medicinal cannabis might have a role in supporting the mental health of people with cancer. This systematic review and meta-analysis examined the efficacy and safety of medicinal cannabis, compared with any control, as an intervention for depression, anxiety, and stress symptoms in people living with cancer. A secondary aim was to examine the effect of low versus high Δ9-tetrahydrocannabinol (THC) dose on these outcomes. METHODS: Five databases were systematically searched, and complemented with a snowball search from inception to May 2023, for any type of interventional study that included humans of any age with any cancer type. Primary outcomes were incidence and severity of depression, anxiety, and stress symptoms. Secondary outcomes were mood, cognition, quality of life, appetite, nutrition status, gastrointestinal symptoms, and adverse events. Data were pooled using Review Manager. Evidence was appraised using Cochrane risk of bias tools. Confidence in the estimated effect of pooled outcomes was assessed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE). RESULTS: Fifteen studies (n = 11 randomized trials, n = 4 non-randomized trials) of 18 interventions (N = 1898 total participants; 100 % ≥18 years of age) were included. Ten studies examined THC (70 % synthetic), two synthetic cannabidiol with or without THC, and six whole-plant extracts. No clinically significant effects of medicinal cannabis were found on primary outcomes. The likelihood of anxiety events increased with higher-dose synthetic THC compared with a lower dose (OR: 2.0; 95 % CI: 1.4, 2.9; p < 0.001; Confidence: very low). Medicinal cannabis (THC, cannabidiol, and whole-plant extract) increased the likelihood of improved appetite (OR: 12.3; 95 % CI: 3.5, 45.5; p < 0.001; n = 3 interventions; Confidence: moderate) and reduced severity of appetite loss (SMD: -0.4; 95 % CI: -0.8, -0.1; p = 0.009; Confidence: very low). There was very low confidence that higher doses of synthetic THC increased the likelihood of any adverse event (OR: 0.5; 95 % CI: 0.3, 0.7; p < 0.001). Medicinal cannabis had no effect on emotional functioning, mood changes, confusion, disorientation, quality of life, and gastrointestinal symptoms. Confidence in findings was limited by some studies having high or unclear risk of bias and imprecise pooled estimates. CONCLUSIONS: There was insufficient evidence to determine the efficacy and safety of medicinal cannabis as a therapeutic intervention for depression, anxiety, or stress in people with active cancer. Further research should explore whether medicinal cannabis might improve and maintain appetite and if high-dose synthetic THC might increase the incidence of side-effects, including anxiety. To inform clinical practice, well-powered and rigorously designed trials are warranted that evaluate the effects of medicinal cannabis prescribed to target anxiety, depression, and stress.

Patient-reported benefits from nabiximols treatment in multiple sclerosis-related spasticity exceed conventional measures.

Aim: This prospective, multicenter, open-label, noninterventional 12-week study investigated the effectiveness and tolerability of add-on nabiximols oromucosal spray (Sativex®) in the real-world setting in Germany. Patients & methods: The main analysis set comprised 51 adult patients (49 nabiximols responders) with multiple sclerosis (MS) spasticity. Results: The mean overall goal attainment scale score (primary outcome measure) increased by 46% from baseline to week 12 (35.2 vs 51.4; p < 0.001). Mean gait speed was improved by 23% at 4 and 12 weeks. Clinically meaningful improvements in mean 0-10 numerical rating scale scores for spasticity, pain, sleep quality and urinary bladder dysfunction were recorded at 4 and 12 weeks. Conclusion: Nabiximols is a useful therapeutic option for patients with MS spasticity.

People with multiple sclerosis (MS) spasticity experience a variety of symptoms and have individual expectations about a new treatment. This study investigated patients' perceptions about the effectiveness and tolerability of nabiximols oromucosal spray (Sativex^®) when added to current medications for spasticity. Common treatment goals for patients (n = 51) were less pain, better walking and improved sleep. After 12 weeks of treatment, 62% of selected treatment goals were achieved 'as expected' or 'better than expected' and 65% of patients considered their spasticity to be 'much improved'. Meaningful improvements were recorded in spasticity-related symptoms of pain, sleep quality and bladder problems. Few side effects were reported. Nabiximols may be useful for MS patients with a poor response to usual spasticity medications.

Potential to use cannabinoids as adjunct therapy for dexamethasone: An in vitro study with canine peripheral blood mononuclear cells.

Dexamethasone (dex) is a potent glucocorticoid used to treat a variety of diseases. It is widely used in veterinary medicine in many species; for instance, in dogs, it can be used for emergent cases of anaphylaxis or trauma, management of immune-mediated hemolytic anemia or thrombocytopenia, certain cancers, allergic reactions, and topically for skin or eye inflammation. Dex is not without its side effects, especially when administered systemically, which might compromise compliance and effective treatment. Thus, adjunct therapies have been suggested to allow for decreased dex dosing and reduction in side effects while maintaining immunosuppressive efficacy. The goal of this study was to evaluate the potential for cannabinoids to serve as adjunct therapies for dex. Immune function was assessed in canine peripheral blood mononuclear cells (PBMCs) after treatment with dex with and without cannabidiol (CBD) and/or Δ9-tetrahydrocannabinol (THC). Dex suppressed IFN-γ protein secretion in a concentration-dependent manner and this suppression by low concentrations of dex was enhanced in the presence of CBD, THC, or the combination of CBD and THC. Similar effects were found with INFG and TNFA mRNA expression. These findings provide a rationale for using CBD or THC in vivo to reduce dex dosing and side effects.

Phytocannabinoids for the Treatment of Neuropathic Pain: A Scoping Review of Randomised Controlled Trials Published Between 2012 and 2023.

PURPOSE OF REVIEW: Neuropathic pain (NP) remains a challenge to treat, with 50% of patients experiencing limited efficacy from current treatments. Medicinal cannabis, which contains tetrahydrocannabinol (THC), cannabidiol (CBD) and other minor cannabinoids, is garnering attention as an alternative treatment for NP. This paper reviews the clinical evidence for phytocannabinoid treatment of NP. RECENT FINDINGS: Seventeen randomised controlled trials (RCT) were identified for inclusion in this review. Of these, ten studies using phytocannabinoid preparations containing THC alone had the most evidence for pain relief. Four studies investigating THC/CBD combinations showed some reductions in pain scores, although not all findings were statistically significant, whereas studies investigating CBD (two studies) or cannabidivarin (one study) showed no analgesic effect over placebo. However, CBD studies were of small sample size when compared to other studies in the review and short duration. Results for treatment of diabetic peripheral neuropathy patients with THC showed better improvements over those for NP induced by chemotherapy and multiple sclerosis, with these trials using vaporised whole plant cannabis. This formulation may have trace amounts of other minor cannabinoids, compared with synthetic cannabinoids such as dronabinol or nabilone that were investigated in other studies. This review provides an overview of RCTs that have investigated phytocannabinoid use for the treatment of NP. There appears to be evidence to necessitate further high quality RCTs into novel formulations of phytocannabinoids for the treatment of NP.

Dosing of Cannabinoids Associated with an Opioid-Sparing Effect: A Systematic Review of Longitudinal Studies.

OBJECTIVE: To assess cannabinoid dosing that could be associated with a reduction in opioid use. DESIGN: Systematic review conducted according to the PRISMA statement. DATA SOURCES: PubMed, Embase, Web of Science, and PsycINFO were searched up to December 10, 2022. REVIEW/ANALYSIS METHODS: We included randomized controlled trials (RCT) and longitudinal observational studies assessing cannabinoids effect on opioid use in patients with acute or chronic pain. Two reviewers independently assessed the studies for inclusion and extracted the data. Tetrahydrocannabinol (THC), Cannabidiol (CBD), and other cannabinoids with dosing were the exposures. Change in opioid doses and opioid discontinuation were the outcomes. RESULTS: Fifteen studies (including seven RCTs) were included. Eight studies (six observational and two RCTs) were conducted among patients with chronic pain including three with cancer-related pain. Seven studies involved patients with acute pain (five RCTs).In chronic non-cancer pain patients, two observational studies that assessed THC and CBD in combination (average daily dose 17mg/15mg), and one that assessed a CBD-rich extract (31.4 mg/day), showed a significant reduction in opioid use. Of the three studies conducted on patients with cancer, only the observational study that assessed nabilone (average 1.7 mg/day) showed a significant reduction in opioid use. In patients with acute pain, only two observational studies that assessed dronabinol (5mg and 5-10 mg/day for four days) showed a significant reduction in opioid use. CONCLUSION: The opioid-sparing effect of cannabinoids remains uncertain based on current evidence. However, attention could be paid to cannabinoid doses associated with opioid reduction in included observational studies.

Impacts of delta 9-tetrahydrocannabinol against myocardial ischemia/reperfusion injury in diabetic rats: Role of PTEN/PI3K/Akt signaling pathway.

Despite the current optimal therapy, patients with myocardial ischemia/reperfusion (IR) injury still experience a high mortality rate, especially when diabetes mellitus is present as a comorbidity. Investigating potential treatments aimed at improving the outcomes of myocardial IR injury in diabetic patients is necessary. Our objective was to ascertain the cardioprotective effect of delta 9-tetrahydrocannabinol (THC) against myocardial IR injury in diabetic rats and examine the role of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in mediating this effect. Diabetes was induced in male Wistar rats (8-10 weeks old, 200-250 g; n = 60) by a single injection of streptozotocin. The duration of the diabetic period was 10 weeks. During the last 4 weeks of diabetic period, rats were treated with THC (1.5 mg/kg/day; intraperitoneally), either alone or in combination with LY294002, and then underwent IR intervention. After 24 h of reperfusion, infarct size, cardiac function, lactate dehydrogenase (LDH) and cardiac-specific isoform of troponin-I (cTn-I) levels, myocardial apoptosis, oxidative stress markers, and expression of PTEN, PI3K, and Akt proteins were evaluated. THC pretreatment resulted in significant improvements in infarct size and cardiac function and decreases in LDH and cTn-I levels (P < 0.05). It also reduced myocardial apoptosis and oxidative stress, accompanied by the downregulation of PTEN expression and activation of the PI3K/Akt signaling pathway (P < 0.05). LY294002 pretreatment abolished the cardioprotective action of THC. This study revealed the cardioprotective effects of THC against IR-induced myocardial injury in diabetic rats and also suggested that the mechanism may be associated with enhanced activity of the PI3K/Akt signaling pathway through the reduction of PTEN phosphorylation.

Unlocking the Healing Potential: Cannabinoids in Spine Surgery for Pain Relief and Recovery.

¼ Cannabinoids, such as D9-tetrahydrocannabinol and cannabidiol, interact with endocannabinoid receptors in the central nervous system and immune system, potentially offering pain relief. The entourage effect, resulting from the interaction of multiple cannabis components, may enhance therapeutic impact and efficacy, making them promising candidates for exploring pain relief in spine operations, known to be among the most painful operative procedures.¼ The use of cannabinoids in pain management requires careful consideration of safety, including their cognitive and psychomotor effects, potential cardiovascular risks, risk of dependence, mental health implications, and drug interactions.¼ Few studies have analyzed cannabinoid use in relation to spine surgery, with variable results reported, indicating possible effects on reoperation rates, mortality, complications, postoperative opioid use, and length of hospital stay.¼ Current knowledge gaps exist in the understanding of cannabinoid effects on spine surgery, including the exploration of different administration routes, timing, dosage, and specific outcomes. In addition, mechanistic explanations for the observed results are lacking.¼ Ethical considerations related to informed consent, medical expertise, societal impact, and legal compliance must also be thoroughly addressed when considering the utilization of cannabinoids in spinal pathologies and back pain treatment.

A Semi-Naturalistic, Open-Label Trial Examining the Effect of Prescribed Medical Cannabis on Neurocognitive Performance.

BACKGROUND AND OBJECTIVES: Medical cannabis use is increasing in Australia and other jurisdictions, yet little is known about the effects of medical cannabis on cognitive function. Findings from studies of non-medical ('recreational') cannabis may not be applicable to patients using prescribed medical cannabis to manage a health condition. METHODS: In this semi-naturalistic, open-label trial, patients with various health conditions attended a single laboratory session in which they self-administered a standard dose of prescribed medical cannabis as per instructions on the pharmacy label. We assessed cognitive performance using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and Druid application (app) prior to and following (CANTAB: + 3 h; Druid: + 3 and 5.5 h) medical cannabis self-administration. We also assessed subjective drug effects prior to and following (1, 2 and 4 h) medical cannabis self-administration using a range of 0-10 cm visual analogue scales ('stoned', 'sedated', 'relaxed', 'comfortable', 'anxious' and 'confident'). Data were analyzed using linear fixed-effect models. RESULTS: Participants (N = 40; 22 females) were prescribed a range of products including orally administered oils (n = 23) and flower for vaporization (n = 17). Participants had a mean (standard deviation [SD]) age of 41.38 (12.66) years and had been using medical cannabis for a mean (SD) of 10.18 (8.73) months. Chronic non-cancer pain was the most common indication for medical cannabis use (n = 20), followed by sleep disorder (n = 18) and anxiety (n = 11). The mean (SD) delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) dose administered by participants was 9.61 (8.52) mg/9.15 (10.11) mg among those using an oil, and 37.00 (24.53) mg/0.38 (1.58) mg among those who vaporized flower, respectively. Participants' performance improved over time on the CANTAB Multitasking Test and Rapid Visual Information Processing test (both p-values <0.001). All other changes in cognitive performance measures over time were non-significant (p > 0.05). Vaporization of flower was associated with significantly stronger subjective feelings of 'stoned' and 'sedated' relative to oils (both p < 0.001). CONCLUSIONS: These findings suggest that prescribed medical cannabis may have minimal acute impact on cognitive function among patients with chronic health conditions, although larger and controlled trials are needed.

Efficacy and safety of medical cannabinoids in children with cerebral palsy: a systematic review.

INTRODUCTION: The increasing popularity of cannabinoids for treating numerous neurological disorders has been reported in various countries. Although it reduces tetrahydrocannabinol psychoactivity, it helps patients tolerate higher doses and complements the anti-spasmodic effects of tetrahydrocannabinol. One of the most important potential of cannabinoids are related to its potential to help children with cerebral palsy, a contributor of lifelong disability. Therefore, this systematic review aimed to assess the efficacy and safety of medical cannabinoids in children with cerebral palsy. METHODS: This review adhered to The Preferred Reporting Items for Systematic Reviews and Meta-analysis 2020 guidelines. Seven databases, namely, Scopus, PubMed, EBSCO Host, ProQuest, Google Scholar, Semantic Scholar, and JSTOR, were used to identify relevant studies. Studies examining pediatric patients with cerebral palsy and reporting the efficacy and safety of medical cannabinoids through clinical trials, observational cross-sectional studies, or cohort designs were included. The outcomes of the studies included the efficacy of medical cannabinoids administered for spasticity, motor components, pain control, sleep difficulties, adverse effects, and seizure control. RESULTS: Of 803 identified articles, only three met the inclusion criteria for data synthesis. One study exhibited a moderate risk-of-bias. A total of 133 respondents, mainly from Europe, were investigated. Overall effectiveness and safety were considered good. However, the results are inconsistent, especially regarding spasticity treatment variables. CONCLUSION: The anti-spasticity, anti-inflammatory, and anti-seizure properties of cannabinoids might be beneficial for patients with cerebral palsy, although their effectiveness has not been widely studied. Further studies with larger sample sizes and various ethnicities are warranted. Prospero database registration: (www.crd.york.ac.uk/prospero) under ID CRD42022358383.

Pharmacohistory of Cannabis Use-A New Possibility in Future Drug Development for Gastrointestinal Diseases.

Humans have employed cannabis for multiple uses including medicine, recreation, food, and fibre. The various components such as roots, flowers, seeds, and leaves have been utilized to alleviate pain, inflammation, anxiety, and gastrointestinal disorders like nausea, vomiting, diarrhoea, and inflammatory bowel diseases (IBDs). It has occupied a significant space in ethnomedicines across cultures and religions. Despite multi-dimensional uses, the global prohibition of cannabis by the USA through the introduction of the Marijuana Tax Act in 1937 led to prejudice about the perceived risks of cannabis, overshadowing its medicinal potential. Nevertheless, the discovery of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and the endocannabinoid system renewed scientific interest in understanding the role of cannabis in modulating different conditions, including gastrointestinal disorders. Preparations combining cannabidiol and THC have shown promise in mitigating gut symptoms through anti-inflammatory and motility-enhancing effects. This review revisits the ethnomedicinal use of cannabis in gastrointestinal diseases and emphasizes the need for further research to determine optimal dosages, formulations, and safety profiles of cannabis-based medicines. It also underscores the future potential of cannabinoid-based therapies by leveraging the role of the expanded endocannabinoid system, an endocannabinoidome, in the modulation of gastrointestinal ailments.

The Main Therapeutic Applications of Cannabidiol (CBD) and Its Potential Effects on Aging with Respect to Alzheimer's Disease.

The use of cannabinoids (substances contained specifically in hemp plants) for therapeutic purposes has received increased attention in recent years. Presently, attention is paid to two main cannabinoids: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). With respect to the psychotropic effects and dependence potential of THC (though it is very mild), its use is associated with certain restrictions, and thus the therapeutic properties of CBD are frequently emphasized because there are no limitations associated with the risk of dependence. Therefore, this review covers the main pharmacodynamic and pharmacokinetic features of CBD (including characteristics of endocannabinoidome) with respect to its possible beneficial effects on selected diseases in clinical practice. A substantial part of the text deals with the main effects of CBD on aging, including Alzheimer's disease and related underlying mechanisms.

A systematic review of cannabidiol trials in neurodevelopmental disorders.

Cannabis-derived compounds, such as cannabidiol (CBD) and delta-9-trans-tetrahydrocannabinol (THC), are increasingly prescribed for a range of clinical indications. These phyto-cannabinoids have multiple biological targets, including the body's endocannabinoid system. There is growing scientific interest in the use of CBD, a non-intoxicating compound, to ameliorate symptoms associated with neurodevelopmental disorders. However, its suitability as a pharmaceutical intervention has not been reliably established in these clinical populations. This systematic review examines the nine published randomised controlled trials (RCTs) that have probed the safety and efficacy of CBD in individuals diagnosed with attention deficit hyperactivity disorder, autism spectrum disorder, intellectual disability, Tourette Syndrome, and complex motor disorders. Studies were identified systematically through searching four databases: Medline, CINAHL complete, PsycINFO, and EMBASE. Inclusion criteria were randomised controlled trials involving CBD and participants with neurodevelopmental disorders. No publication year or language restrictions were applied. Relevant data were extracted from the identified list of eligible articles. After extraction, data were cross-checked between the authors to ensure consistency. Several trials indicate potential efficacy, although this possibility is currently too inconsistent across RCTs to confidently guide clinical usage. Study characteristics, treatment properties, and outcomes varied greatly across the included trials. The material lack of comparable RCTs leaves CBD's suitability as a pharmacological treatment for neurodevelopmental disorders largely undetermined. A stronger evidence base is urgently required to establish safety and efficacy profiles and guide the ever-expanding clinical uptake of cannabis-derived compounds in neurodevelopmental disorders. Prospero registration number: CRD42021267839.

Nabiximols is Efficient as Add-On Treatment for Patients with Multiple Sclerosis Spasticity Refractory to Standard Treatment: A Systematic Review and Meta-Analysis of Randomised Clinical Trials.

BACKGROUND: Spasticity affects 54% of multiple sclerosis (MS) patients at disease onset, but this rate gradually increases with disease progression. Spasticity does not fully respond to standard treatment in one-third of the patients. OBJECTIVE: Our systematic review and meta-analysis assessed whether add-on nabiximols, can improve MS-associated refractory spasticity. METHODS: The systematic literature search was performed in Web of Science, MEDLINE, Scopus, CENTRAL, and Embase, on 15/10/2021, without restrictions. We included in the review blinded, randomized, placebo-controlled trials evaluating the efficacy of nabiximols in adult MS patients with refractory spasticity, by comparison with placebo. The primary outcome was responder rate by spasticity numerical rating scale (NRS). Secondary outcomes were spasticity-related parameters. We used random effect models to calculate odds ratios (OR) or mean differences and the corresponding 95% CI. Bias-factors were assessed with Cochrane risk of bias tool (RoB2). (PROSPERO ID: CRD42021282177). RESULTS: We identified 9 eligible articles, of which 7 (1128 patients) were included in the meta-analysis. The spasticity numerical rating scale (NRS) was significantly higher in the nabiximols group than in the placebo group (OR 2.41 (95% CI 1.39; 4.18)). Secondary outcomes were in accordance with our primary results. At least some concerns were detected in the risk of bias analysis. CONCLUSION: Our results indicate that nabiximols is efficient in MS associated spasticity, refractory to standard treatment and it may be considered as add-on symptomatic therapy. Nevertheless, further studies are needed to establish the optimal treatment protocol - dose, duration, moment of initiation, disease type.

Cannabis: Drug of Abuse and Therapeutic Agent, Two Sides of the Same Coin.

The consumption of Cannabis sativa plant, known as marijuana in the Western world, for different purposes (therapeutic, intoxicating, and spiritual) due to its psychoactive effects, can be traced back to ancient times. Cannabis is the most used illicit drug worldwide; however, its legal status is changing rapidly. Cannabis regulation will allow a better understanding of its effects as a misused drug, including new challenges, such as the availability of highly potent Cannabis extracts. Furthermore, scientific research is making significant efforts to take advantage of the potential therapeutic uses of Cannabis active compounds. The science of Cannabis derivatives started with the identification of the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), allowing the formal study of the complex set of effects triggered by Cannabis consumption and the deciphering of its pharmacology. Δ9-THC is recognized as the compound responsible for the psychoactive and intoxicating effects of Cannabis. Its study led to the discovery of the endocannabinoid system, a neuromodulatory system widespread in the human body. CBD does not induce intoxication and for that reason, it is the focus of the search for cannabinoid potential clinical applications. This review examines the current state of knowledge about contrasting perspectives on the effects of Cannabis, Δ9-THC, and CBD: their abuse liability and potential therapeutic use; two sides of the same coin.