Tag Archives: Cannabinoids

Medical Cannabinoids in Children and Adolescents: A Systematic Review

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AAP Gateway

“CONTEXT: Legalization of medical marijuana in many states has led to a widening gap between the accessibility and the evidence for cannabinoids as a medical treatment.

OBJECTIVE: To systematically review published reports to identify the evidence base of cannabinoids as a medical treatment in children and adolescents.

RESULTS: Evidence for benefit was strongest for chemotherapy-induced nausea and vomiting, with increasing evidence of benefit for epilepsy.”  http://pediatrics.aappublications.org/content/early/2017/10/19/peds.2017-1818

“Limited data on medical cannabis use in children. Strongest evidence supports use to reduce seizures, side effects of chemotherapy.”  https://www.sciencedaily.com/releases/2017/10/171023094606.htm

“Marijuana Can Help Children with Seizures, Cancer Nausea”   https://www.healthline.com/health-news/marijuana-can-help-children-with-seizures-cancer-nausea

“Medical Marijuana Reduces CINV, Seizures in Children”  https://www.medscape.com/viewarticle/887616

Sativex in the management of multiple sclerosis-related spasticity: An overview of the last decade of clinical evaluation.

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Multiple Sclerosis and Related Disorders Home

“Spasticity is a common symptom of multiple sclerosis (MS) affecting about 80% of MS patients. Numerous lines of evidence suggest that spasticity due to its complexity is not adequately managed with conventional anti-spastic therapies. Therefore, in order to improve the outcomes for the majority of MS patients, alternative approaches are needed to be discovered. Over the last years, the use of cannabinoid compounds as a potential treatment for MS-related symptoms has aroused great interest, owing to encouraging preclinical and clinical studies. To date, Sativex, an oromucosal spray containing tetrahydrocannabinol and cannabidiol in approximately 1:1 ratio, is the only commercially available formulation containing cannabinoids used as add-on therapy for treatment of spasticity in adult MS patients who are not responding to conventional antispastic therapies.

METHODS:

Here, by performing a literature search, we provided an overview of the last decade of clinical evaluations as well as post-marketing studies about effectiveness and safety of Sativex in the management of MS-related spasticity.

RESULTS:

Sativex was proven effective in treating spasticity and also in improving the patient’s quality of life. In addition, a low incidence of adverse reactions Sativex-related supports the good safety profile and its tolerability.

CONCLUSION:

This review by recognizing the clinical effectiveness of Sativex in spasticity management, opened a new opportunity for many patients with spasticity resistant to common antispastic drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/29055461

http://www.msard-journal.com/article/S2211-0348(17)30148-7/fulltext

THC/CBD oromucosal spray in patients with multiple sclerosis overactive bladder: a pilot prospective study.

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“Lower urinary tract dysfunctions (LUTDs) are commonly reported in multiple sclerosis (MS) patients and are mainly related to neurogenic overactive bladder (OAB).

The aim of this observational study was to assess the effect of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray on resistant OAB by means of clinical and instrumental tools.

The THC/CBD treatment successfully reduced the OAB symptoms.

THC/CBD oromucosal spray has shown to be effective in improving overactive bladder symptoms in MS patients demonstrating a favorable impact on detrusor overactivity.”

https://www.ncbi.nlm.nih.gov/pubmed/29052091

Inverse association of marijuana use with nonalcoholic fatty liver disease among adults in the United States.

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“The impact of marijuana on nonalcoholic fatty liver disease (NAFLD) is largely unknown. We studied the association between marijuana and NAFLD utilizing cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) from 2005-2014 and NHANES III (1988-1994).

RESULTS:

Of the 14,080 (NHANES 2005-2014) and 8,286 (NHANES III) participants, prevalence of suspected NAFLD and ultrasonographically-diagnosed NAFLD were inversely associated with marijuana use (p < 0.001). Compared to marijuana-naïve participants, marijuana users were less likely to have suspected NAFLD (odds ratio [OR]: 0.90, 95% confidence interval [CI]: 0.82-0.99 for past user; OR: 0.68, 95% CI: 0.58-0.80 for current user) and ultrasonographically-diagnosed NAFLD (OR: 0.75, 95% CI: 0.57-0.98 for current user) in the age, gender, ethnicity-adjusted model. On multivariate analysis, the ORs for suspected NAFLD comparing current light or heavy users to non-users were 0.76 (95% CI 0.58-0.98) and 0.70 (95% CI 0.56-0.89), respectively (P for trend = 0.001) with similar trends in ultrasonographically-diagnosed NAFLD (OR: 0.77, 95% CI: 0.59-1.00 for current user; OR: 0.71, 95% CI: 0.51-0.97 for current light user). In insulin resistance-adjusted model, marijuana use remained an independent predictor of lower risk of suspected NAFLD.

CONCLUSIONS:

In this nationally representative sample, active marijuana use provided a protective effect against NAFLD independent of known metabolic risk factors. The pathophysiology is unclear and warrants further investigation.”

https://www.ncbi.nlm.nih.gov/pubmed/29049354

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186702

Reprint of: survey of medicinal cannabis use among childbearing women: patterns of its use in pregnancy and retroactive self-assessment of its efficacy against ‘morning sickness’.

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Complementary Therapies in Clinical Practice

“A majority of women experience some nausea and/or vomiting during pregnancy. This condition can range from mild nausea to extreme nausea and vomiting, with 1-2% of women suffering from the life-threatening condition hyperemesis gravidarum.

Cannabis (Cannabis sativa) may be used therapeutically to mitigate pregnancy-induced nausea and vomiting.

This paper presents the results of a survey of 84 female users of medicinal cannabis, recruited through two compassion societies in British Columbia, Canada. Of the seventy-nine respondents who had experienced pregnancy, 51 (65%) reported using cannabis during their pregnancies. While 59 (77%) of the respondents who had been pregnant had experienced nausea and/or vomiting of pregnancy, 40 (68%) had used cannabis to treat the condition, and of these respondents, 37 (over 92%) rated cannabis as ‘extremely effective’ or ‘effective.’

Our findings support the need for further investigations into cannabis therapy for severe nausea and vomiting during pregnancy.”

https://www.ncbi.nlm.nih.gov/pubmed/19880090

“Marijuana use is common in pregnancy but may not be an independent risk factor for poor neonatal outcomes in term pregnancies.”  http://www.sciencedirect.com/science/article/pii/S000293781500527X

http://www.sciencedirect.com/science/article/pii/S1744388109000796?via%3Dihub

Cannabis in fat: high hopes to treat obesity.

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“Cannabinoid receptor type-1 (CB1s) is known to have a substantial impact on the regulation of energy metabolism via central and peripheral mechanisms. In this issue of the JCI, Ruiz de Azua and colleagues provide important insights into the regulation of adipocyte physiology by CB1. Mice with adipocyte-specific deletion of the CB1-encoding gene had an overall improved metabolic profile in addition to reduced body weight and total adiposity. These changes were associated with an increase in sympathetic tone of the adipose tissue and expansion of activated macrophages, both of which occurred prior to changes in body weight, lending support to a causal relationship between loss of CB1 in adipocytes and systemic metabolic changes. This work identifies adipocyte CB1s as a potential novel peripheral target for affecting systemic metabolism with diminished CNS effects.”

https://www.ncbi.nlm.nih.gov/pubmed/29035279

https://www.jci.org/articles/view/97042

Cannabinoid Receptor 1 Participates in Liver Inflammation by Promoting M1 Macrophage Polarization via RhoA/NF-κB p65 and ERK1/2 Pathways, Respectively, in Mouse Liver Fibrogenesis.

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“Macrophage M1/M2 polarization mediates tissue damage and inflammatory responses. Cannabinoid receptor (CB) 1 participated in liver fibrogenesis by affecting bone marrow (BM)-derived monocytes/macrophages (BMMs) activation. However, the knowledge of whether CB1 is involved in the polarization of BMMs remains limited.

Here, we found M1 gene signatures (including CD86, MIP-1β, tumor necrosis factor, IL-6, and inducible nitric oxide synthase) and the amount of M1 macrophages (CD86+ cells, gated by F4/80) were significantly elevated in carbon tetrachloride (CCl4)-induced mouse injured livers, while that of M2 type macrophages had little change by RT-qPCR and fluorescence-activated cell sorting (FACS).

Our preceding study confirmed CB1 was involved in CCl4-induced liver fibrogenesis. Our results noted CB1 expression showed positive correlation with CD86. Blockade of CB1 by its antagonist or siRNA in vivo downregulated the mRNA and protein levels of M1 markers using RT-qPCR, western blot, and Cytometric Bead Array (CBA) assays, and reduced the proportion of M1 macrophages. Moreover, chimera mouse models, which received BM transplants from EGFP-transgenic mice or clodronate liposome injection mouse models, in which Kupffer cells were depleted, were performed to clarify the role of CB1 on the polarization of Kupffer cells and BMMs.

We found that CB1 was especially involved in BMM polarization toward M1 phenotype but have no effect on that of Kupffer cells. The reason might due to the lower CB1 expression in Kupffer cells than that of BMMs. In vitro, we discovered CB1 was involved in the polarization of BMMs toward M1. Furthermore, CB1-induced M1 polarization was apparently impaired by PTX [G(α)i/o protein inhibitor], Y27632 (ROCK inhibitor), and PD98059 [extracellular signal-regulated kinase (ERK) inhibitor], while SB203580 (p38 inhibitor) and compound C (AMPK inhibitor) had no such effect. ACEA (CB1 agonist) activated G(α)i/o coupled CB1, then enlarged GTP-bound Rho and phosphor-ERK1/2, independently. NF-κB p65 nuclear translocation is also a marker of M1 phenotype macrophages. We found that CB1 switched on NF-κB p65 nuclear translocation only depending on G(α)i/o/RhoA signaling pathway.

CONCLUSION:

CB1 plays a crucial role in regulating M1 polarization of BMMs in liver injury, depending on two independent signaling pathways: G(α)i/o/RhoA/NF-κB p65 and G(α)i/o/ERK1/2 pathways.”

 https://www.ncbi.nlm.nih.gov/pubmed/29033935
https://www.frontiersin.org/articles/10.3389/fimmu.2017.01214/full

Control of myogenic tone and agonist induced contraction of intramural coronary resistance arterioles by cannabinoid type 1 receptors and endocannabinoids.

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“It was tested whether intrinsic CB1R activation modifies myogenic and agonist induced contraction of intramural coronary resistance arteries of the rat. CB1R protein was detected by immuno-histochemistry and by Western blot, its mRNA by qRT-PCR in their wall. Microsurgically prepared cylindrical coronary segments (∼100-150μm) developed myogenic contraction (∼20% of relaxed luminal diameter), from which a substantial relaxation (∼15%) in response to WIN55212 (a specific agonist of the CB1Rs) has been found. CB1R-mediated relaxation was blocked by O2050 and AM251 (neutral antagonist and inverse agonist of the CB1R, respectively) and was partially blocked by the NO synthase blocker LNA. CB1R blockade enhanced myogenic tone and augmented AngII-induced vasoconstriction (from 17,8±1,2 to 29,1±2,9%, p <0,05). Inhibition of diacylglycerol lipase by tetrahydrolipstatin, (inhibitor of endogenous 2-AG production) also augmented coronary vasoconstriction. These observations prove that vascular endocannabinoids are significant negative modulators of the myogenic and agonist-induced tone of intramural coronary arterioles acting through CB1Rs.”

https://www.ncbi.nlm.nih.gov/pubmed/29031792

http://www.sciencedirect.com/science/article/pii/S1098882317300047

Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling.

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Molecular Metabolism

“In visceral obesity, an overactive endocannabinoid/CB1 receptor (CB1R) system promotes increased caloric intake and decreases energy expenditure, which are mitigated by global or peripheral CB1R blockade. In mice with diet-induced obesity (DIO), inhibition of food intake by the peripherally restricted CB1R antagonist JD5037 could be attributed to endogenous leptin due to the rapid reversal of hyperleptinemia that maintains leptin resistance, but the signaling pathway engaged by leptin has remained to be determined.

METHODS:

We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037.

RESULTS:

Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY+ than with POMC+ ARC neurons. The hypophagic effect of JD5037 was absent in melanocortin-4 receptor (MC4R) deficient obese mice or DIO mice treated with a MC4R antagonist, but was maintained in NPY-/- mice kept on a high-fat diet.

CONCLUSIONS:

Peripheral CB1R blockade in DIO restores sensitivity to endogenous leptin, which elicits hypophagia via the re-activation of melanocortin signaling in the ARC.”

https://www.ncbi.nlm.nih.gov/pubmed/29031713

http://www.molmetab.com/article/S2212-8778(17)30327-7/fulltext

Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy.

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“Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.”

https://www.ncbi.nlm.nih.gov/pubmed/29030466

http://jasn.asnjournals.org/content/early/2017/10/12/ASN.2017040371