Association of cannabinoid receptor modulation with normal and abnormal skeletal remodelling: A systematic review and meta-analysis of in vitro, in vivo and human studies.

To address the inconsistent findings from studies that used different models to explore the role of classical cannabinoid type 1 (CB1) and 2 (CB2) receptors in skeletal remodelling, we searched Medline, Web of Science and Embase for relevant studies from inception to June 23, 2020. We identified 38 in vitro, 34 in vivo and 9 human studies. A meta-analysis of in vitro studies showed that exposure to the inverse-agonists AM251 (mean difference [MD]:-26.75, 95% confidence interval [CI]:-45.36,-8.14, p = 0.005), AM630 (standardised[std.] MD:-3.11, CI:-5.26,-0.97, p = 0.004; SR144528, std.MD:-4.88, CI -7.58,-2.18, p = 0.0004) and CBD (std.MD:-1.39, CI -2.64,-0.14, p = 0.03) is associated with reduced osteoclastogenesis, whereas the endocannabinoid 2-AG (std.MD:2.00, CI:0.11-3.89, p = 0.04) and CB2-selective agonist HU308 (MD:19.38, CI:11.75-27.01, p < 0.00001) were stimulatory. HU308 also enhanced osteoblast differentiation (std.MD:2.22, CI:0.95-3.50, p = 0.0006) and activity (std.MD:2.97, CI:1.22-4.71, p = 0.0008). In models of bone loss, CB1/2 deficiency enhanced peak bone volume (std.MD:3.70, CI:1.77-5.63, p = 0.0002) but reduced bone formation (std.MD:-0.54, CI:-0.90,-0.17, p = 0.004) in female mice. In male rats, CB1/2 deficiency (std.MD:2.31, CI:0.30-4.33, p = 0.02) and AM251 or CBD treatments (std.MD:2.19, CI:0.46-3.93, p = 0.01) enhanced bone volume. CB1/2 deficiency (std.MD:9.78, CI:4.96-14.61, p < 0.0001) and AM251 or AM630 treatments (std.MD:28.19, CI:19.13-37.25, p < 0.0001) were associated with osteoprotection. The CB2-selective agonists JWH133 and 4Q3C enhanced bone volume in arthritic rodents (std.MD:14.45, CI:2.08-26.81, p = 0.02). In human, CB2 SNPs (AA:rs2501431, MD:-0.28, CI:-0.55,-0.01, p = 0.04; CC:rs2501432, MD:-0.29, CI:-0.56,-0.02, p = 0.03) were associated with reduced bone mineral density, however the association of Marijuana use remains unclear. Thus, CB1/2 modulation is associated with altered bone metabolism, however findings are confounded by low study number and heterogenicity of models.

Epilepsy and cannabis: so near, yet so far.

Following media attention on children with refractory epilepsies reportedly deriving benefit from cannabis-based medicinal products (CBMPs), the UK government changed the law in 2018 so that CBMPs could be legally prescribed. Subsequently, a pure cannabidiol (CBD) product has been licensed for two epilepsy syndromes. However, despite pressure from campaign groups and allied politicians, almost no children have received unlicensed CBMPs under the UK NHS. This review explores the science behind CBMPs in paediatric epilepsies and highlights the areas that warrant further research. It identifies a lack of level I evidence for efficacy and safety as, currently, the major obstacle to prescribing. Unlicensed medicines are often used in paediatrics but almost all are used 'off-label', with supporting evidence of efficacy and safety derived either from other age-groups or from disease conditions. CBMPs, except for pure CBD, are unique in that they are currently both unlicensed and fall outside the 'off-label' category. The review acknowledges the treatment gap in refractory epilepsies and the potential use of CBMPs. However, it argues against exceptionally circumventing the usual standard of evidence required by regulatory prescribing authorities and warns against allowing vulnerable children to become the 'trojan horse' for deregulation of the commercial cannabis market.

Cannabis based medicines and cannabis dependence: A critical review of issues and evidence.

Cannabis has been legalised for medical use in an ever-increasing number of countries. A growing body of scientific evidence supports the use of medical cannabis for a range of therapeutic indications. In parallel with these developments, concerns have been expressed by many prescribers that increased use will lead to patients developing cannabis use disorder. Cannabis use disorder has been widely studied in recreational users, and these findings have often been projected onto patients using medical cannabis. However, studies exploring medical cannabis dependence are scarce and the appropriate methodology to measure this construct is uncertain. This article provides a narrative review of the current research to discern if, how and to what extent, concerns about problems of dependence in recreational cannabis users apply to prescribed medical users. We focus on the main issues related to medical cannabis and dependence, including the importance of dose, potency, cannabinoid content, pharmacokinetics and route of administration, frequency of use, as well as set and setting. Medical and recreational cannabis use differs in significant ways, highlighting the challenges of extrapolating findings from the recreational cannabis literature. There are many questions about the potential for medical cannabis use to lead to dependence. It is therefore imperative to address these questions in order to be able to minimise harms of medical cannabis use. We draw out seven recommendations for increasing the safety of medical cannabis prescribing. We hope that the present review contributes to answering some of the key questions surrounding medical cannabis dependence.

Cannabis in patients with Parkinson's disease in Argentina. A cross sectional study.

We made an observational cross-sectional study to evaluate the prevalence of cannabis use, characteristics and results perceived by a group of PD patients. Semi-structured questionnaire was applied to patients. Until obtaining more information we suggest to incorporate into regular medical practice the question about the use of cannabis.

Adverse Effects of Cannabis Use on Neurocognitive Functioning: A Systematic Review of Meta- Analytic Studies.

Objective: As the perceived risk of cannabis use continues to decline among youths and access continues to increase, it has become more important to synthesize the rapidly growing literature on the effects of cannabis on neurocognition. Hundreds of studies examining associations between cannabis use and neurocognitive functioning have been published in recent decades. However, results often differ across individual studies, particularly when sample sizes are small. Meta-analytic methods help to make sense of this literature and have been increasingly applied to studies on cannabis use and neurocognition. Methods: A systematic literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted to identify peer-reviewed meta-analyses of neurocognitive or functional neuroimaging data that examined associations between cannabis use and non-acute effects on neurocognitive functioning (n = 8). Results: Current findings suggest that regular healthy cannabis users, regardless of age, display poorer neurocognitive functioning relative to nonusers of small to medium effect sizes across many neurocognitive domains, as well as functional brain alterations when compared to non-users. Adverse effects are not uniform across neurocognitive domains and evidence for adolescent-onset users having poorer neurocognitive outcomes remains equivocal based on these studies. However, less is known about cannabis effects on neurocognition among clinical samples, as findings from specific clinical samples revealed mixed results. Conclusions: Meta-analyses have played an important role in helping to grasp the totality of results from a large body of literature on cannabis effects on neurocognition, yet more research (particularly large-scale longitudinal studies) is needed to identify critical periods or patterns of use that are more likely to result in negative outcomes.

Cannabis Use and the Risk for Psychosis and Affective Disorders.

Objective: This review discusses the relationship between cannabis use and psychotic, bipolar, depressive, and anxiety disorders, as well as suicide. It summarizes epidemiological evidence from cross-sectional and long-term prospective studies and considers possible etiological mechanisms. Methods: Systematic reviews and methodologically robust studies in the field (from inception to February 2019) were identified using a comprehensive search of Medline, PsychINFO, and Embase and summarized using a narrative synthesis. Results: Consistent evidence, both from observational and experimental studies, has confirmed the important role of cannabis use in the initiation and persistence of psychotic disorders. The size of the effect is related to the extent of cannabis use, with greater risk for early cannabis use and use of high-potency varieties and synthetic cannabinoids. Accumulating evidence suggests that frequent cannabis use also increases the risk for mania as well as for suicide. However, the effect on depression is less clear and findings on anxiety are contradictory with only a few methodologically robust studies. Furthermore, the relationship with common mental disorders may involve reverse causality, as depression and anxiety are reported to lead to greater cannabis consumption in some studies. Pathogenetic mechanisms focus on the effect of tetrahydrocannabinol (THC, the main psychoactive ingredient of cannabis) interacting with genetic predisposition and perhaps other environmental risk factors. Cannabidiol (CBD), the other important ingredient of traditional cannabis, ameliorates the psychotogenic effects of THC but is absent from the high-potency varieties that are increasingly available. Conclusions: The evidence that heavy use of high-THC/low-CBD types of cannabis increases the risk of psychosis is sufficiently strong to merit public health education. Evidence of similar but smaller effects in mania and suicide is growing, but is not convincing for depression and anxiety. There is much current interest in the possibility that CBD may be therapeutically useful.

The Changing Legal Landscape of Cannabis Use and Its Role in Youth-onset Psychosis.

The rapidly changing landscape of cannabis in terms of availability, potency, and routes of administration, as well as the decrease in risk perception and changing norms, have contributed to an increase in the popularity of cannabis. Cannabis use is associated with a poorer recovery from a psychotic disorder, increasing the risk of relapse, rehospitalization, and lower social functioning. Data are mixed regarding cannabis use as a component cause of psychosis in people at risk for psychotic disorder. Care providers, parents, and schools must educate youth and adolescents about the risks of cannabis use.

Cannabis-based products for pediatric epilepsy: An updated systematic review.

PURPOSE: To provide an up-to-date summary of the benefits and harms of cannabis-based products for epilepsy in children. METHODS: We updated our earlier systematic review, by searching for studies published up to May 2019. We included randomized controlled trials (RCTs) and non-randomized studies (NRS) involving cannabis-based products administered to children with epilepsy. Outcomes were seizure freedom, seizure frequency, quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and emergency room visits. RESULTS: Thirty-five studies, including four RCTs, have assessed the benefits and harms of cannabis-based products in pediatric epilepsy (12 since April 2018). All involved cannabis-based products as adjunctive treatment, and most involved cannabidiol. In the RCTs, there was no statistically significant difference between cannabidiol and placebo for seizure freedom (relative risk 6.77, 95 % confidence interval [CI] 0.36-128.38), quality of life (mean difference [MD] 0.6, 95 %CI -2.6 to 3.9), or sleep disruption (MD -0.3, 95 %CI -0.8 to 0.2). Data from both RCTs and NRS suggest that cannabidiol reduces seizure frequency and increases treatment response; however, there is an increased risk of gastrointestinal adverse events. CONCLUSION: Newly available evidence supports earlier findings that cannabidiol probably reduces the frequency of seizures among children with drug-resistant epilepsy. PROSPERO: CRD42018084755.

A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is characterized by a range of developmental, neuropsychiatric, and behavioral symptoms that cause significant impairment in those with the disorder. Cannabidiol (CBD) holds promise as a potential treatment for FXS symptoms due to its safety profile and positive effects on a number of emotional and behavioral symptoms associated with FXS. The aim of the current study was to evaluate the safety, tolerability, and initial efficacy of ZYN002, a transdermal CBD gel, in a pediatric population with FXS. METHODS: Twenty children and adolescents (aged 6-17 years) with a diagnosis of FXS (confirmed through molecular documentation of FMR1 full mutation) were enrolled in an open-label, multi-site, trial of ZYN002. Transdermal CBD gel was administered twice daily for 12 weeks, titrated from 50 mg to a maximum daily dose of 250 mg. The primary efficacy endpoint was change from screening to week 12 on the Anxiety, Depression, and Mood Scale (ADAMS). Secondary endpoint measures included the Aberrant Behavior Checklist-Community for FXS (ABC-CFXS), Pediatric Anxiety Rating Scale (PARS-R), Pediatric Quality of Life Inventory (PedsQL™), three Visual Analogue Scales (VAS), and the Clinical Global Impression Scale-Severity (CGI-S) and Improvement (CGI-I). RESULTS: The majority of treatment-emergent AEs (reported by 85% of participants) were mild in severity (70%), and no serious adverse events were reported. There was a statistically significant reduction in ADAMS total score from screening to week 12 and significant reductions on nearly all other secondary endpoints, including all ADAMS subscales (except depressed mood), all ABC-CFXS subscale scores (e.g., social avoidance, irritability), PARS-R total severity score, and PedsQL total score. CONCLUSIONS: ZYN002 was well tolerated and produced clinically meaningful reductions in anxiety and behavioral symptoms in children and adolescents with FXS. These findings support further study of ZYN002 in a randomized, well-controlled trial for the treatment of behavioral symptoms of FXS. TRIAL REGISTRATION: ANZCTR, ACTRN12617000150347 Registered 27 January 2017.

Beyond stimulants: a systematic review of randomised controlled trials assessing novel compounds for ADHD.

Introduction: Despite stimulants being highly efficacious in short-term randomized controlled trials (RCTs), not all patients respond or can successfully tolerate them. A number of novel non-stimulant options are currently in the pipeline for the treatment of attention-deficit/hyperactivity disorder (ADHD). Areas covered: The authors conducted a systematic review of RCTs registered in ClinicalTrials.gov in the past 5 years (January 2014 and February 2019), supplemented by searches in PubMed, Web of Science, and drug manufacturer websites to find recent RCTs on novel non-stimulant ADHD medications. Expert opinion: The authors found 28 pertinent RCTs of compounds acting on a variety of biological targets, including Dasotraline, Viloxazine (SPN-812), Centanafadine SR (CTN SR), OPC-64005, Fasoracetam (NFC-1, AEVI-001), Metadoxine (MDX), Vortioxetine, Tipepidine Hibenzate, Oxytocin, Sativex (delta-9-tetrahydrocannabinol (THC) plus cannabidiol), Mazindol, and Molindone hydrochloride (SPN-810). Given the high effect size found in RCTs of stimulants in terms of efficacy on ADHD core symptoms, it is unlikely that these novel agents will show better efficacy than stimulants, at the group level. However, they may offer comparable or better tolerability. Additionally, agents acting on etiopathophysiological targets disrupted in specific subgroups of patients with ADHD will move forward the pharmacotherapy of ADHD from a 'one size fits all' to a 'precision medicine' approach.

How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders. Five data bases were systematically searched (2006-August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a  meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists. THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.

Cannabis use behaviors and prevalence of anxiety and depressive symptoms in a cohort of Canadian medicinal cannabis users.

Cannabis is commonly used recreationally for its euphoric and relaxing effects, while its medical use is permitted in several jurisdictions. With only low-quality evidence suggesting anxiolytic effects of cannabis and strong public sentiment surrounding such purported effects, the purpose of this study was to examine the prevalence of cannabis for medicinal purposes (CMP) use for anxiety symptoms. An online survey was disseminated to CMP users registered with a Canadian licensed producer. Respondents completed demographic and validated self-report questionnaires (GAD-7, PHQ-9, MINI-SPIN, and panic disorder/agoraphobia DSM-5 criteria). Cannabis use behaviors were also discussed. Overall, 2032 completed responses with a verified user number were collected. Of the total sample, 888 (43.7%) reported CMP authorization to treat anxiety symptoms and completed all psychometric screening instruments. Rates of probable disorders were high (Generalized Anxiety Disorder: 45.6%, Social Anxiety Disorder: 42.4%, Major Depressive Disorder: 25.7%, Panic Disorder/Agoraphobia: 25.7%); 63.4% met screening criteria for ≥1 disorder. Most (92%) reported that cannabis improved their symptoms, despite continuing to endorse moderate-level severity. Nearly half (49%) reported replacing a non-psychiatric (53.7%) or psychiatric medication (46.3%) prescribed to them by their physician with CMP. Respondents endorsed daily CMP use and severity of anxiety (GAD-7, p < 0.001) and depressive (PHQ-9, p < 0.001) symptoms were positively associated with the amount of cannabis used/day. The vast majority perceived symptom improvement with CMP use and did not believe CMP use was associated with impairment or an inability to control use. Nevertheless, the possibility of cannabis use disorder cannot be ruled out as well as the possibility that improvements in non-psychiatric conditions were attributed to improvements in anxiety. These results highlight the need to systematically evaluate CMP use for mental illness.

A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects.

Access to cannabis and cannabinoid products is increasing worldwide for recreational and medicinal use. Two primary compounds within cannabis plant matter, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are both psychoactive, but only THC is considered intoxicating. There is significant interest in potential therapeutic properties of these cannabinoids and of CBD in particular. Some research has suggested that CBD may ameliorate adverse effects of THC, but this may be dose dependent as other evidence suggests possible potentiating effects of THC by low doses of CBD. We conducted a randomised placebo controlled trial to examine the acute effects of these compounds alone and in combination when administered by vaporisation to frequent and infrequent cannabis users. Participants (n = 36; 31 male) completed 5 drug conditions spaced one week apart, with the following planned contrasts: placebo vs CBD alone (400 mg); THC alone (8 mg) vs THC combined with low (4 mg) or high (400 mg) doses of CBD. Objective (blind observer ratings) and subjective (self-rated) measures of intoxication were the primary outcomes, with additional indices of intoxication examined. CBD showed some intoxicating properties relative to placebo. Low doses of CBD when combined with THC enhanced, while high doses of CBD reduced the intoxicating effects of THC. The enhancement of intoxication by low-dose CBD was particularly prominent in infrequent cannabis users and was consistent across objective and subjective measures. Most effects were significant at p < .0001. These findings are important to consider in terms of recommended proportions of THC and CBD in cannabis plant matter whether used medicinally or recreationally and have implications for novice or less experienced cannabis users.Trial registration: ISRCTN Registry Identifier: ISRCTN24109245.

Cannabis and psychosis: what do we know and what should we do?

It is now incontrovertible that heavy use of cannabis increases the risk of psychosis. There is a dose-response relationship and high potency preparations and synthetic cannabinoids carry the greatest risk. It would be wise to await the outcome of the different models of legalisation that are being introduced in North America, before deciding whether or not to follow suit. Declaration of interest None.

Sex-Dependent Effects of Cannabis and Cannabinoids: A Translational Perspective.

Recent policy changes have led to significant increases in the use of cannabis for both medical and recreational purposes. Although men are more likely to endorse past month cannabis use and are more frequently diagnosed with Cannabis Use Disorder relative to women, a growing proportion of medical cannabis users are reported to be women. The increased popularity of cannabis for medical purposes and the narrowing gap in prevalence of use between men and women raises questions regarding sex-dependent effects related to therapeutic efficacy and negative health effects of cannabis and cannabinoids. The objective of this review is to provide a translational perspective on the sex-dependent effects of cannabis and cannabinoids by synthesizing findings from preclinical and clinical studies focused on sex comparisons of their therapeutic potential and abuse liability, two specific areas that are of significant public health relevance. Hormonal and pharmacological mechanisms that may underlie sex differences in the effects of cannabis and cannabinoids are highlighted.

Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure.

Cannabis use has become increasingly accepted socially and legally, for both recreational and medicinal purposes. Without reliable information about the effects of cannabis, people cannot make informed decisions regarding its use. Like alcohol and tobacco, cannabis can have serious adverse effects on health, and some people have difficulty discontinuing their use of the drug. Many cannabis users progress to using and becoming addicted to other drugs, but the reasons for this progression are unclear. The natural cannabinoid system of the brain is complex and involved in many functions, including brain development, reward, emotion, and cognition. Animal research provides an objective and controlled means of obtaining information about: (1) how cannabis affects the brain and behavior, (2) whether medications can be developed to treat cannabis use disorder, and (3) whether cannabis might produce lasting changes in the brain that increase the likelihood of becoming addicted to other drugs. This review explains the tactics used to address these issues, evaluates the progress that has been made, and offers some directions for future research.