Cannabis Science and Therapeutics: An Overview for Clinicians.

Cannabis-based therapeutics have garnered increasing attention in recent years as patients seek alternative treatments for various medical conditions. This narrative review provides a comprehensive overview of the science behind the medical use of cannabis, focusing on the medical evidence for commonly treated conditions. In addition, the review addresses the practical considerations of using cannabis as a therapeutic agent, offering insights into dosing strategies, variations in cannabinoid formulation, and individual patient responses. Precautions, adverse consequences, and drug interactions are also discussed, with a focus on patient safety and the potential risks associated with cannabis use.

Cannabis constituents interact at the drug efflux pump BCRP to markedly increase plasma cannabidiolic acid concentrations.

Cannabis is a complex mixture of hundreds of bioactive molecules. This provides the potential for pharmacological interactions between cannabis constituents, a phenomenon referred to as "the entourage effect" by the medicinal cannabis community. We hypothesize that pharmacokinetic interactions between cannabis constituents could substantially alter systemic cannabinoid concentrations. To address this hypothesis we compared pharmacokinetic parameters of cannabinoids administered orally in a cannabis extract to those administered as individual cannabinoids at equivalent doses in mice. Astonishingly, plasma cannabidiolic acid (CBDA) concentrations were 14-times higher following administration in the cannabis extract than when administered as a single molecule. In vitro transwell assays identified CBDA as a substrate of the drug efflux transporter breast cancer resistance protein (BCRP), and that cannabigerol and Δ9-tetrahydrocannabinol inhibited the BCRP-mediated transport of CBDA. Such a cannabinoid-cannabinoid interaction at BCRP transporters located in the intestine would inhibit efflux of CBDA, thus resulting in increased plasma concentrations. Our results suggest that cannabis extracts provide a natural vehicle to substantially enhance plasma CBDA concentrations. Moreover, CBDA might have a more significant contribution to the pharmacological effects of orally administered cannabis extracts than previously thought.

Efficacy of cannabinoids against glioblastoma multiforme: A systematic review.

INTRODUCTION: The increased incidence of Glioblastoma Multiforme, the most aggressive and most common primary brain tumour, is evident worldwide. Survival rates are reaching only 15 months due to its high recurrence and resistance to current combination therapies including oncotomy, radiotherapy and chemotherapy. Light has been shed in the recent years on the anticancer properties of cannabinoids from Cannabis sativa. OBJECTIVE: To determine whether cannabinoids alone or in combination with radiotherapy and/or chemotherapy inhibit tumour progression, induce cancer cell death, inhibit metastasis and invasiveness and the mechanisms that underlie these actions. METHOD: PubMed and Web of Science were used for a systemic search to find studies on the anticancer effects of natural cannabinoids on glioma cancer cells in vitro and/or in vivo. RESULTS: A total of 302 papers were identified, of which 14 studies were found to fit the inclusion criteria. 5 studies were conducted in vitro, 2 in vivo and 7 were both in vivo and in vitro. 3 studies examined the efficacy of CBD, THC and TMZ, 1 study examined CBD and radiation, 2 studies examined efficacy of THC only and 3 studies examined the efficacy of CBD only. 1 study examined the efficacy of CBD, THC and radiotherapy, 2 studies examined the combination of CBD and THC and 2 more studies examined the efficacy of CBD and TMZ. CONCLUSION: The evidence in this systematic review leads to the conclusion that cannabinoids possess anticancer potencies against glioma cells, however this effect varies with the combinations and dosages used. Studies so far were conducted on cells in culture and on mice as well as a small number of studies that were conducted on humans. Hence in order to have more accurate results, higher quality studies mainly including human clinical trials with larger sample sizes are necessitated urgently for GBM treatment.

Therapeutic and Cosmetic Uses of Cannabis: Cannabinoids for Acne Treatment and Skin -Rejuvenation.

Cannabinoids can be endogenous (endocannabinoids), plant-derived (phytocannabinoids), or synthesized (synthetic cannabinoids). They are being used for the management of several medical conditions. Laboratory and preliminary clinical studies suggest that topical cannabinoids may be beneficial for the treatment of acne and for skin rejuvenation. (SKINmed. 2021;19:-0).

Cannabinoid treatment for autism: a proof-of-concept randomized trial.

BACKGROUND: Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5-21 years) with ASD. METHODS: We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and Δ9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and Δ9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI). RESULTS: Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results. CONCLUSIONS: This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226.

Intoxication by a synthetic cannabinoid (JWH-018) causes cognitive and psychomotor impairment in recreational cannabis users.

BACKGROUND: Smoking mixtures containing synthetic cannabinoids (SCs) have become very popular over the last years but pose a serious risk for public health. Limited knowledge is, however, available regarding the acute effects of SCs on cognition and psychomotor performance. Earlier we demonstrated signs of impairment in healthy volunteers after administering one of the first SCs, JWH-018, even though subjective intoxication was low. In the current study, we aimed to investigate the acute effects of JWH-018 on several cognitive and psychomotor tasks in participants who are demonstrating representative levels of acute intoxication. METHODS: 24 healthy cannabis-experienced participants took part in this placebo-controlled, cross-over study. Participants inhaled the vapor of 75 µg JWH-018/kg body weight and were given a booster dose if needed to induce a minimum level of subjective high. They were subsequently monitored for 4 h, during which psychomotor and cognitive performance, vital signs, and subjective experience were measured, and serum concentrations were determined. RESULTS: Maximum subjective high (average 64%) was reached 30 min after administration of JWH-018, while the maximum blood concentration was shown after 5 min (8 ng/mL). JWH-018 impaired motor coordination (CTT), attention (DAT and SST), memory (SMT), it lowered speed-accuracy efficiency (MFFT) and slowed down response speed (DAT). CONCLUSION: In accordance with our previous studies, we demonstrated acute psychomotor and cognitive effects of a relatively low dose of JWH-018.

Therapeutic potential of cannabinoids in combination cancer therapy.

Derivatives of the plant Cannabis sativa have been used for centuries for both medical and recreational purposes, as well as industrial. The first proof of its medicinal use comes from ancient China, although there is evidence of its earlier utilization in Europe and Asia. In the 19th century, European practitioners started to employ cannabis extracts to treat tetanus, convulsions, and mental diseases and, in 1851, cannabis made its appearance in the Pharmacopoeia of the United States as an analgesic, hypnotic and anticonvulsant. It was only in 1937 that the Marijuana Tax Act prohibited the use of this drug in the USA. The general term Cannabis is commonly used by the scientific and scholar community to indicate derivatives of the plant Cannabis sativa. The word cannabinoid is a term describing chemical compounds that are either derivate of Cannabis (phytocannabinoids) or artificial analogues (synthetic) or are produced endogenously by the body (endocannabinoids). A more casual term "marijuana" or "weed", a compound derived from dried Cannabis flower tops and leaves, has progressively superseded the term cannabis when referred to its recreational use. The 2018 World health organisation (WHO) data suggest that nearly 2.5% of the global population (147 million) uses marijuana and some countries, such as Canada and Uruguay, have already legalised it. Due to its controversial history, the medicinal use of cannabinoids has always been a centre of debate. The isolation and characterisation of Δ9 tetrahydrocannabinol (THC), the major psychoactive component of cannabis and the detection of two human cannabinoid receptor (CBRs) molecules renewed interest in the medical use of cannabinoids, boosting research and commercial heed in this sector. Some cannabinoid-based drugs have been approved as medications, mainly as antiemetic, antianorexic, anti-seizure remedies and in cancer and multiple sclerosis patients' palliative care. Nevertheless, due to the stigma commonly associated with these compounds, cannabinoids' potential in the treatment of conditions such as cancer is still largely unknown and therefore underestimated.

Psychiatric Disorders and Cannabinoid Receptors.

With the increasing global use of medical and adult recreational use of cannabis and cannabinoids, this chapter provides overview of evidence from animal and human studies on psychiatric disorders and cannabinoid receptors. We review and present evaluation of the relationship between changes in the ECS and psychiatric disorders. Evidence suggests the existence of a relationship between changes in components of the ECS, and some of the symptoms present in psychiatric disorders. Both CB1Rs and CB2Rs are components of the endocannabinoid system with different cellular and tissue localization patterns that are differentially expressed in the CNS and PNS and are emerging targets for the treatment of number psychiatric disorders. As cannabis preparations are widely used for recreation globally, it is predictable that cannabis use disorders (CUDs) will increase and there is currently no available treatment for CUDs. Although major advances have been reported from cannabinoid and ECS research, there are gaps in scientific knowledge on long-term consequences of cannabis use. Adolescent and cannabis use during pregnancy presents further challenges, and more research will uncover the signaling pathways that couple the gut microbiota with the host ECS. Development of cannabis and cannabinoid nanomedicine for nanotherapy will certainly overcome some of the shortcomings and challenges in medicinal and recreational use of cannabis and cannabinoids. Thus, nanotechnology will allow targeted delivery of cannabinoid formulations with the potential to elevate their use to scientifically validated nanotherapeutic applications as the field of cannabis nanoscience matures.

Opioid-sparing effects of cannabinoids: Myth or reality?

A converging line of evidence is indicating that cannabinoids may have an opioid-sparing effect. This property, well validated in preclinical studies, allow when both drugs are co-administered to reduce the dose of opioids without loss of analgesic effects. A meta-analysis of pre-clinical studies indicated in 2017 that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower than the ED50 of morphine alone (Nielsen et al., 2017). However, very few studies have been conducted in humans to validate this effect. This narrative review provides an update on whether or not cannabinoid drugs can be used to produce an opioid sparing effect. For this, various lines of evidence ranging from preclinical, epidemiological and human studies will be summarized. Overall, this review indicates that the preclinical results are strongly and consistently supportive of the presence of an opioid sparing effect of cannabinoid drugs. However, to date the clinical studies have been mostly negative; and, the evidence collected in humans so far is so limited that it is premature to conclude. Therefore, prospective high quality controlled clinical trials are still required to validate this. Priorities for future research are also discussed.

Cannabidiol - therapeutic and legal aspects.

Cannabidiol (CBD) is an alkaloid present in Cannabis sativa, along with tetrahydrocannabinol (THC) and more than 100 other substances belonging to a group of compounds called cannabinoids. Whereas the legal status and medical use of Cannabis is a controversial issue in many countries, inconsistent legislation makes CBD status even more complicated. Some CBD products are legal in some countries, while banned in other countries, further compounding the confusion. In 2018, the Food and Drug Administration (FDA) approved the first CBD containing medical product, Epidiolex®, for the treatment of paediatric seizures. Currently, several clinical trials are in progress for the potential treatment of neurologic and behavioural disorders. CBD's current legal and regulatory status is a continuously evolving issue; the current review is presenting historical and present information regarding the use of CBD products worldwide.

The legalization of cannabinoid products and standardizing cannabis-drug development in the United States: a brief report
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This brief report covers recent advances in cannabis and cannabinoid regulation and drug approval. The popularity of cannabis and cannabinoid products continues to rise, and these products are available for the majority of the population in the United States to purchase as easily as alcohol. Although many states have approved programs and research licenses, these activities and products all remain federally illegal. The solution may be for the United States to offer multiple pathways for product approval that adapt to the diversity of the products and the needs of the consumer. Multiple pathways for market approval would protect public health, whether the public is using cannabis and cannabinoids as a medicine, a wellness product, or as a recreational substance.
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Este breve informe cubre los avances recientes en la regulación del cannabis y los cannabinoides y en la aprobación de medicamentos. La popularidad del cannabis y de los productos cannabinoides continúa aumentando. Estos productos están disponibles para la mayoría de la población en los Estados Unidos y se pueden comprar tan fácilmente como el alcohol. Aunque muchos estados han aprobado programas y licencias de investigación, estas actividades y productos siguen siendo ilegales a nivel federal. La solución para Estados Unidos sería ofrecer múltiples vías para la aprobación de productos que se adaptarían a la diversidad de los productos y las necesidades del consumidor. Estas múltiples vías para la aprobación del mercado protegerían la salud pública, ya sea que el público esté utilizando cannabis y cannabinoides como medicamento, producto de bienestar o o sustancia recreativa.

Ce rapport couvre les progrès récents dans la réglementation du cannabis et des cannabinoïdes et l'approbation des médicaments. La popularité du cannabis et des dérivés cannabinoïdes continue d'augmenter, et ces produits sont disponibles pour la majorité de la population aux États-Unis, où ils s'achètent aussi facilement que l'alcool. Bien que de nombreux états aient approuvé des programmes et les licences de recherche, ces activités et produits demeurent tous illégaux au niveau fédéral. La solution pourrait être pour les États-Unis d'offrir plusieurs voies d'approbation qui s'adaptent à la diversité des produits et aux besoins du consommateur. Plusieurs voies d'approbation du marché protégeraient la santé publique, que le cannabis et les cannabinoïdes soient consommés en tant que médicament, produit de bien-être ou substance récréative.

Cannabinoids in the Treatment of Insomnia Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Insomnia is associated with significant comorbidity, disability and impact on quality of life and, despite advances in pharmacotherapy and psychotherapy, remains a significant burden to society. Cannabinoids are gaining acceptance for use as medicines in the treatment of insomnia disorder. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the efficacy of cannabinoids in the treatment of insomnia disorder. METHODS: We performed a systematic review of the PubMed, Cochrane Library, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature Complete databases from inception to 5 December 2019, and again prior to data abstraction, for studies of cannabis-based products for the treatment of insomnia disorder in adults. Inclusion criteria were (1) clinical studies, (2) participants aged ≥ 18 years, (3) insomnia disorder either formally diagnosed against contemporaneous diagnostic criteria or quantified with validated instruments and (4) compared cannabis-based products with the standard of care, placebo or a sedative. No language restrictions were imposed. Non-primary research, animal studies and studies of cannabis-induced insomnia were excluded. Risk of bias was assessed using the RoB 2 tool for randomised controlled trials (RCTs) and Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool for non-randomized trials. Heterogeneity was assessed with the I2 statistic. RESULTS: A total of five studies (two RCTs and three non-randomised studies) with 219 study participants were included, of which three could be combined. The three non-randomised studies contributed data on the Pittsburgh Sleep Quality Index Questionnaire score, showing a favourable effect of cannabinoids at ≤ 4 weeks of follow-up (mean difference - 1.89 [95% confidence interval {CI} - 2.68 to - 1.10]; n = 176) and at 8 weeks of follow-up (mean difference - 2.41 [95% CI - 3.36 to - 1.46]; n = 166). One double-blind crossover RCT (n = 32) reported that, compared with amitriptyline, nabilone-a synthetic analogue to tetrahydrocannabinol (THC)-improved Insomnia Severity Index scores after 2 weeks of treatment (adjusted difference - 3.25 [95% CI - 5.26 to - 1.24]) and resulted in a more restful sleep as a sub-measure of the Leeds Sleep Evaluation Questionnaire (LSEQ) (difference 0.48 [95% CI 0.01-0.95]) but with no effect on overall sleep quality as measured by the LSEQ. In a single ascending-dose RCT (n = 9), THC reduced sleep-onset latency compared with placebo at 10 mg, 20 mg and 30 mg doses (mean difference - 43.00 min [95% CI - 82.76 to - 3.24], - 62.00 [95% CI - 103.60 to - 20.40] and - 54.00 [95% CI - 103.93 to - 4.07], respectively). All the included studies were assessed as poor quality, mainly due to small sample sizes, short treatment periods, uncertain clinical significance and high risk of bias. CONCLUSIONS: Few studies have examined the efficacy of cannabinoids in the treatment of insomnia disorder. Despite some possible signals for efficacy, the heterogeneity of participants, interventions, efficacy outcomes and results, and the high risk of bias across included trials, do not reliably inform evidence-based practice. This review highlights shortcomings in the existing literature, including lack of diagnostic clarity, poorly defined participant groups, non-standardised interventions and studies of inappropriate design, duration and power to detect clinically meaningful outcomes. Further research in the form of high-quality RCTs are required before drawing any conclusions about the efficacy of cannabinoids in the treatment of insomnia disorder. TRIAL REGISTRATION: PROSPERO registration number, CRD42020161043.

Flavonoid and cannabinoid impact on the ocular surface.

PURPOSE OF REVIEW: To evaluate the impact of flavonoids and cannabinoids as anti-inflammatory and antiallergic treatments on the anterior surface of the eye. RECENT FINDINGS: Allergic conjunctivitis and dry eye syndrome are common ocular surface diseases that have been treated with traditional pharmacological measures, e.g. corticosteroids, antihistamines. Given the side-effect profiles of these medications and the growing interest in complementary treatment modalities as part of integrative medical interventions, well known flavonoids, such as quercetin and catechin, are under investigation for topical and systemic application methods for relief. As flavonoid derivatives, pycnogenol and epigallocatechin gallate have alleviated dry eye symptoms, including lacrimal gland inflammation, tear secretion, and the stability of the tear film. Research on ocular cannabinoid receptors and response to synthetic cannabinoids are also being considered for therapy of anterior ocular disorders. The expansion of herbal formulations provides a framework for future treatment regimens for ocular surface disorders. SUMMARY: Flavonoids and cannabinoids show promise as potential complementary treatment for allergic diseases because of their anti-inflammatory and antiallergic properties. Several studies implementing ocular and systemic application of these compounds show potential in becoming adjuvant treatment strategies for improving quality of life while also managing ocular surface disease processes.

Pharmacotherapeutic management of lower urinary tract symptoms in Multiple Sclerosis patients.

INTRODUCTION: Multiple Sclerosis (MS) manifests with a plethora of signs and symptoms affecting brain structures and spinal pathways. The multitude of lesions in MS patients makes difficult to establish the relative role of each of them to lower urinary tract symptoms (LUTS). Generally, the subcortical white-matter lesions result in detrusor overactivity, whilst lesions of the spinal cord result in the combined occurrence of detrusor overactivity and detrusor-sphincter dyssynergia (DSD). It has been estimated that 80-90% of patients with MS will suffer from some form of LUTS over the course of the disease. Among LUTS, the most reported is detrusor overactivity which includes urinary urgency, frequent urination, nocturia, and urge urinary incontinence. AREAS COVERED: The authors review the management of lower urinary tract symptoms in MS patients providing their expert opinions on the subject matter. EXPERT OPINION: LUTS affect the quality of life substantially and are associated with a significantly increased mortality. The adequate management is an important challenge for both patients and caregivers with a multidisciplinary approach likely necessary.

Use of cannabinoid-based medicine among older residential care recipients diagnosed with dementia: study protocol for a double-blind randomised crossover trial.

BACKGROUND: Dementia is a neurological condition that affects the cognitive and functional ability of the brain and is the leading cause of disability among those aged 65 years and above. More effective ways to manage dementia symptoms are needed because current treatment options (antidepressants and antipsychotics) can be ineffective and are associated with substantial side effects, including increased rate of mortality. Cannabinoid-based medicine (CBM) has shown an ability to inhibit some symptoms associated with dementia, and the adverse effects are often minimal; yet, little research has explored the use of CBM among this population. AIM: To monitor the safety of a purified dose of CBM oil (3:2 delta-9-tetrahydrocannabinol:cannabidiol) on behaviour symptoms, quality of life and discomfort caused by pain. METHODS/DESIGN: We will carry out an 18-week, randomised, double-blind crossover trial that consists of a 2-week eligibility period, two 6-week treatment cycles, and two 2-week washout periods (between both cycles and after the second treatment cycle). We aim to recruit 50 participants with dementia who are living in residential aged-care facilities. The participants will be randomised into two groups and will receive a dose of either CBM oil or placebo for the first treatment cycle and the opposite medication for the second. Data will be collected using the Neuropsychiatric Inventory Questionnaire, the Cohen-Mansfield Agitation Inventory, the Quality of Life in Alzheimer's Disease questionnaire, and the Abbey Pain Scale on seven occasions. These will be completed by the participants, aged-care staff, and nominated next of kin or family members. The participants' heart rate and blood pressure will be monitored weekly, and their body composition and weight will be monitored fortnightly by a research nurse, to assess individual dose response and frailty. In addition, pre- and post-surveys will be administered to aged-care staff and family members to understand their perceptions of CBM and to inform proposed focus groups consisting of the aged-care staff and next of kin. DISCUSSION: The study design has been informed by medical professionals and key stakeholders, including those working in the residential aged-care industry to ensure patient safety, collection of non-invasive measures, and methodological rigor and study feasibility. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12619000474156. Registered on 21 March 2019.

Cannabis for pain in orthopedics: a systematic review focusing on study methodology

Background: Medical cannabis use is an emerging topic of interest in orthopedics. Although there is a large amount of literature on medical cannabis use for managing various types of pain, few studies have focused on orthopedic conditions. There is little high-quality evidence in core orthopedic areas. The objective of this study was to summarize the literature on the efficacy of cannabis use for pain related to orthopedic conditions. Methods: We conducted a systematic review of the literature on the use of cannabinoids for pain management in core orthopedic conditions. Two independent reviewers extracted information on reporting quality, risk of bias, drugs, population, control, duration of study, pain outcomes and the authors' conclusions regarding efficacy for pain outcomes. Results: We identified 33 orthopedic studies, including 21 primary studies and 12 reviews. Study quality was generally low to moderate. Six of the included studies had a control group and 15 were noncontrolled studies. Methodologies, drugs and protocols of administration varied greatly across studies. Study conclusions were generally positive in noncontrolled studies and mixed in controlled studies. Studies using higher doses tended to conclude that cannabis use was effective, but the potential for harmful effects may also be increased with higher doses. Conclusion: Variability in the methodologies used in cannabis research makes it challenging to draw conclusions about dosing, routes and frequency of administration. Most of the existing evidence suggests that medical cannabis use is effective, but this efficacy has been demonstrated only when either there is no comparator or cannabis is compared with placebo. Studies using an active comparator have not demonstrated efficacy. Future research should focus on improving study reporting and methodologic quality so that protocols that optimize pain control while minimizing harmful effects can be determined.

Contexte: La consommation de cannabis à des fins médicales est un sujet d'intérêt émergent en orthopédie. Malgré l'existence d'un important corpus de littérature médicale sur l'utilisation du cannabis pour traiter divers types de douleurs, peu d'études ont porté sur les problèmes orthopédiques. On dispose de peu de données probantes de grande qualité relatives aux principaux domaines de l'orthopédie. L'objectif de cette étude était de résumer la littérature sur l'efficacité du cannabis à soulager les douleurs orthopédiques. Méthodes: Nous avons réalisé une revue systématique de la littérature sur l'utilisation des cannabinoïdes pour la prise en charge de la douleur associée aux principaux problèmes orthopédiques. Deux examinateurs indépendants ont extrait l'information sur la qualité des rapports, le risque de biais, les médicaments, les populations et groupes témoins, la durée des études, les scores de douleur et les conclusions des auteurs quant à l'efficacité au plan des scores de douleur. Résultats: Nous avons recensé 33 études orthopédiques, dont 21 études primaires et 12 revues. La qualité des études était généralement de faible à moyenne. Six des études incluses étaient contrôlées et 15 ne l'étaient pas. Les méthodologies, les médicaments et les protocoles d'administration variaient grandement d'une étude à l'autre. Les conclusions étaient généralement positives dans les études non contrôlées, et mixtes dans les études contrôlées. Les études qui utilisaient des doses plus fortes avaient tendance à conclure que le cannabis était efficace, mais le risque d'effets négatifs pouvait également être proportionnel à la dose. Conclusion: En raison de la variabilité des méthodologies utilisées dans la recherche sur le cannabis, il est difficile de tirer des conclusions sur la posologie, les voies et la fréquence d'administration. La plupart des preuves disponibles donnent à penser que le cannabis médical est efficace, mais cette efficacité n'a été démontrée que s'il n'y avait pas de comparateur ou si le cannabis était comparé à un placebo. Les études ayant utilisé un comparateur actif n'ont pas fait état d'efficacité. La recherche future devrait veiller à améliorer les rapports et la qualité méthodologique des études afin de déterminer quels protocoles améliorent la maîtrise de la douleur tout en réduisant les effets négatifs.

Involvement of CB2 Receptors in the Neurobehavioral Effects of Catha Edulis (Vahl) Endl. (Khat) in Mice.

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene. The results show sub-acute administration of khat extract alone increased locomotor activity in mice and co-administration of the CB2R agonist, JWH133, reduced khat extract induced hyperlocomotor activity. The data revealed that cell type specific deletion of CB2Rs on dopaminergic neurons increased the hyperlocomotor behavior of khat extract. Furthermore, the results revealed that khat extract attenuated MPTP induced motor deficits, which is enhanced by JWH133. Khat extract also increased expression of tyrosine hydroxylase positive cells and expression of dopamine transporter mRNA gene in wild type mice. Nevertheless, JWH133 did not alter the effect of khat extract on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat extract. Taken together, the results suggest that the CB2Rs selectively interact with khat extract-mediated locomotor effects and could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation.

Distinct inflammatory profiles in HIV-infected individuals under antiretroviral therapy using cannabis, cocaine or cannabis plus cocaine.

OBJECTIVES: To evaluate the effects of cannabis and/or cocaine use on inflammatory, oxidative stress status and circulating monocyte subsets in HIV-infected individuals under antiretroviral therapy. DESIGN: Soluble CD14 (sCD14), intestinal fatty acid-binding protein (IFABP), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP) and oxidative stress markers were examined. The monocyte subsets and their activation and cytokine production by peripheral blood mononuclear cells (PBMCs) of HIV-1 infected individuals upon lipopolysaccharide (LPS)-stimulation were also investigated. METHODS: sCD14, IFABP, TNF-α, IL-6, IL-8 and IL-10 levels were evaluated using ELISA, CRP by turbidimetry; lipid peroxidation (TBARS) spectrofluometrically and total thiol levels by using 5-5'-dithio-bis (2-nitrobenzoic acid) reagent. Monocyte subsets and activation were assessed by flow cytometry. RESULTS: All HIV-infected drug user groups showed higher sCD14 levels compared with HIV+ nondrug users. IFABP was increased in HIV+ drug-users in relation to healthy individuals. Cannabis use lowered the percentages of inflammatory, nonclassical, activated-classic and activated-inflammatory monocytes. Cocaine users showed increased plasmatic TNF-α and TBARS levels, decreased thiols content and lower activated-classic and inflammatory-monocyte percentages. Cannabis-plus-cocaine use increased CRP, IL-8 and IL-6/IL-10 ratio, but decreased thiol content, and inflammatory and activated-classic monocyte percentages. PBMCs of cannabis and cannabis-plus-cocaine users showed low-potential cytokine production either spontaneously or under LPS-stimulation. CONCLUSION: In HIV infection, the use of cannabis induces predominantly an anti-inflammatory profile. The use of cocaine and cannabis-plus-cocaine showed a mixed pro-inflammatory and anti-inflammatory profile, with predominance of inflammatory status. Further studies are required to better understand the action of these drugs in HIV infection.

Therapeutic impact of orally administered cannabinoid oil extracts in an experimental autoimmune encephalomyelitis animal model of multiple sclerosis.

There is a growing surge of investigative research involving the beneficial use of cannabinoids as novel interventional alternatives for multiple sclerosis (MS) and associated neuropathic pain (NPP). Using an experimental autoimmune encephalomyelitis (EAE) animal model of MS, we demonstrate the therapeutic effectiveness of two cannabinoid oil extract formulations (10:10 & 1:20 - tetrahydrocannabinol/cannabidiol) treatment. Our research findings confirm that cannabinoid treatment produces significant improvements in neurological disability scoring and behavioral assessments of NPP that directly result from their ability to reduce tumor necrosis factor alpha (TNF-α) production and enhance brain derived neurotrophic factor (BDNF) production. Henceforth, this research represents a critical step in advancing the literature by scientifically validating the merit for medical cannabinoid use and sets the foundation for future clinical trials.

On healthcare by popular appeal: critical assessment of benefit and risk in cannabidiol based dietary supplements.

Introduction: In recent decades, federal legislation in the U.S. has recognized a new paradigm of pharmacotherapy in which ideology and popular demand, as opposed to sound clinical evidence, drives the marketing of ostensible herbal therapeutics as 'dietary supplements'. This vogue of democratizing medicine has more recently manifested in the ongoing legalization of cannabis products at the state level, where an arbitrary variety of definitions, restrictions, and assumed therapeutic uses are applied to a family of phytochemicals with no definitive evidence of efficacy or safety. With the recent publication of clinical trials submitted to the FDA in efforts to gain approval of the cannabidiol based therapeutic Epidiolex, a rare opportunity exists to examine high-quality data for a drug which has in recent years been marketed as a greatly unregulated dietary supplement. Areas covered: A critical analysis is offered of data regarding efficacy, dosing, exposure, adverse events, drug-drug interactions, and non-specific effects associated with CBD - all of which raise questions regarding the wisdom of assuming the safety and efficacy of cannabinoids in particular and dietary supplements in general. Expert opinion: Ongoing lack of meaningful regulation of cannabinoid supplements continues to put consumers at undue risk without clear evidence of therapeutic value.