Diabetes Studies

The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults

Of the participants in our study sample, 579 were current marijuana users and 1975 were past users. In multivariable adjusted models, current marijuana use was associated with 16% lower fasting insulin levels (95% confidence interval [CI], −26, −6) and 17% lower HOMA-IR (95% CI, −27, −6). We found significant associations between marijuana use and smaller waist circumferences. Among current users, we found no significant dose-response.
Elizabeth A. Penner, MD, MPH,a,b Hannah Buettner, BA,c Murray A. Mittleman, MD, DrPHb,c
a University of Nebraska College of Medicine, Omaha; b Department of Epidemiology, Harvard School of Public Health, Boston, Mass; c Cardiovascular Epidemiology Research Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Mass. The American Journal of Medicine
​ ​
Volume 126, Issue 7, Pages 583–589, July 2013 DOI: http://dx.doi.org/10.1016/j.amjmed.2013.03.002
 


Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-κB and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38α) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-α, markers of fibrosis (transforming growth factor-β, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation, and cell death in primary human cardiomyocytes.
 
J Am Coll Cardiol. 2010 Dec 14 ;56(25):2115-25. doi: 10.1016/j.jacc.2010.07.033.
Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-9413, USA.

Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes.

Diabetic retinopathy is characterized by blood-retinal barrier (BRB) breakdown and neurotoxicity. These pathologies have been associated with oxidative stress and proinflammatory cytokines, which may operate by activating their downstream target p38 MAP kinase. In the present study, the protective effects of a nonpsychotropic cannabinoid, cannabidiol (CBD), were examined in streptozotocin-induced diabetic rats after 1, 2, or 4 weeks. Retinal cell death was determined by terminal dUTP nick-end labeling assay; BRB function by quantifying extravasation of bovine serum albumin-fluorescein; and oxidative stress by assays for lipid peroxidation, dichlorofluorescein fluorescence, and tyrosine nitration. Experimental diabetes induced significant increases in oxidative stress, retinal neuronal cell death, and vascular permeability. These effects were associated with increased levels of tumor necrosis factor-alpha, vascular endothelial growth factor, and intercellular adhesion molecule-1 and activation of p38 MAP kinase, as assessed by enzyme-linked immunosorbent assay, immunohistochemistry, and/or Western blot. CBD treatment significantly reduced oxidative stress; decreased the levels of tumor necrosis factor-alpha, vascular endothelial growth factor, and intercellular adhesion molecule-1; and prevented retinal cell death and vascular hyperpermeability in the diabetic retina. Consistent with these effects, CBD treatment also significantly inhibited p38 MAP kinase in the diabetic retina. These results demonstrate that CBD treatment reduces neurotoxicity, inflammation, and BRB breakdown in diabetic animals through activities that may involve inhibition of p38 MAP kinase.
El-Remessy AB, Al-Shabrawey M, Khalifa Y, Tsai N-T, Caldwell RB, Liou GI. Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol in Experimental Diabetes. The American Journal of Pathology 2006;168(1):235-244. doi:  10.2353/ajpath.2006.050500 

Cannabidiol arrests onset of autoimmune diabetes in NOD mice.

CBD was administered i.p. to 11–14 week old female NOD mice. Treatment was continued for 4 weeks (5 days a week) at a dose of 5 mg/kg/day. Treatment was then withdrawn and the mice were observed until 24 weeks of age. A remarkable reduction of diabetes development was observed in CBD-treated mice, compared with vehicle-treated mice and untreated controls (p<0.001, log rank test). At the end of the 24 weeks, only 8 of 25 (32%) of the CBD-treated mice developed glucosuria, compared with 18 of 21 (86%) vehicle-treated mice and 100% (21 mice) of the untreated controls (Fig 1).
 
Weiss L, Zeira M, Reich S, et al. Cannabidiol Arrests Onset of Autoimmune Diabetes in NOD Mice. Neuropharmacology 2008;54(1):244-249. doi:10.1016/j.neuropharm.2007.06.029.
 


Diabetic retinopathy: Role of inflammation and potential therapies for anti-inflammation.

The best-known cannabinoids from marijuana are (-)-Δ9-tetrahydrocannabinol (THC), cannabinol (CBN), and (-)-cannabidiol (CBD) (Figure (Figure11)[66]. THC, but not CBN or CBD, is known to exert psychotropic effects[67,68]. Cannabinoids are also known to be therapeutic with properties of anti-inflammation[69,70] and anti-oxidation[71]. Cannabinoids produce their biological effects by acting through at least two receptors. Receptor CB1 (cloned) is responsible for psychoactivity and is expressed in the brain[72] and retinal neurons[73,74]. Receptor CB2 (cloned) is expressed in immune cells[75] and cerebral microglial cells[76], but also in the retina[77]. These receptors are coupled to Gi/o proteins to inhibit adenylyl cyclase activity and immediate early gene signaling pathway(s)[78]. Receptor CB1 is also coupled through Gi/o proteins to inhibit voltage-sensitive calcium channels[79] and activate potassium channels[80].
Liou GI. Diabetic retinopathy: Role of inflammation and potential therapies for anti-inflammation. World Journal of Diabetes 2010;1(1):12-18. doi:10.4239/wjd.v1.i1.12.

The endocannabinoid system in obesity and type 2 diabetes.

Endocannabinoids (ECs) are defined as endogenous agonists of cannabinoid receptors type 1 and 2 (CB1 and CB2). ECs, EC anabolic and catabolic enzymes and cannabinoid receptors constitute the EC signalling system. This system participates in the control of lipid and glucose metabolism at several levels, with the possible endpoint of the accumulation of energy as fat. Following unbalanced energy intake, however, the EC system becomes dysregulated, and in most cases overactive, in several organs participating in energy homeostasis, particularly, in intra-abdominal adipose tissue. This dysregulation might contribute to excessive visceral fat accumulation and reduced adiponectin release from this tissue, and to the onset of several cardiometabolic risk factors that are associated with obesity and type 2 diabetes. This phenomenon might form the basis of the mechanism of action of CB1 antagonists/inverse agonists, recently developed by several pharmaceutical companies as adjuvants to lifestyle modification for weight reduction, glycaemic control and dyslipidaemia in obese and type 2 diabetes patients. It also helps to explain why some of the beneficial actions of these new therapeutics appear to be partly independent from weight loss.
 
The endocannabinoid system in obesity and type 2 diabetes.  Di Marzo V.
Diabetologia. 2008 Aug ;51(8):1356-67. doi: 10.1007/s00125-008-1048-2. Epub 2008 Jun 18 .


The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications.

Endocannabinoids (ECs) are endogenous, bioactive lipid mediators that exert their effects mainly through specific G protein–coupled (primarily Gi/o) receptors: cannabinoid-1 (CB1) receptor and cannabinoid-2 (CB2) receptor. The signaling of these receptors is complex and, depending on the cell type, may involve inhibition (also activation in certain cases) of adenyl cyclase activity, activation of various mitogen-activated protein kinases (MAPKs) (eg, p38- and p44/42-MAPKs, c-Jun N-terminal kinase, and extracellular signal–regulated kinase), protein kinases A and C, and modulation of various Ca2+ and K+ channels.1–3 Previously, it was thought that the CB1 receptor was predominantly expressed in the central nervous system, mediating undesirable psychoactive effects, whereas the CB2 receptor was expressed mainly in immune and hematopoietic cells, modulating immune activities. However, recent studies also have demonstrated the expression of these receptors in various other cell types, both centrally and in the peripheral organs, implicating these receptors in a wide range of physiologic and pathologic functions and activities.1,4,5 In addition to their primary target cannabinoid receptors, ECs and possibly their metabolites may also activate multiple receptor-dependent and -independent mechanisms.3
 
Horváth B, Mukhopadhyay P, Haskó G, Pacher P. The Endocannabinoid System and Plant-Derived Cannabinoids in Diabetes and Diabetic Complications. The American Journal of Pathology 2012;180(2):432-442. doi:10.1016/j.ajpath.2011.11.003.

Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain.

Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state.
 
Toth CC, Jedrzejewski NM, Ellis CL, Frey WH. Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. Molecular Pain 2010;6:16. doi:10.1186/1744-8069-6-16.

DIABETES​

The impact of marijuana use on glucose, insulin, and insulin resistance among US adults

http://www.amjmed.com/article/S0002-9343%2813%2900200-3/abstract

(American Journal of Medicine)

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy 

http://www.ncbi.nlm.nih.gov/pubmed/21144973

(PubMed)


Cannabidiol lowers incidence of diabetes in non-obese diabetic mice

http://www.ncbi.nlm.nih.gov/pubmed/16698671 

(PubMed)


Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes 

http://www.ncbi.nlm.nih.gov/pubmed/16400026

(PubMed)

 

Cannabidiol arrests onset of autoimmune diabetes in NOD mice

http://www.ncbi.nlm.nih.gov/pubmed/17714746 

(PubMed)


Diabetic retinopathy: Role of inflammation and potential therapies for anti-inflammation

http://www.ncbi.nlm.nih.gov/pubmed/21537423

 (PubMed)


Cannabinoids alter endothelial function in the Zucker rat model of type 2 diabetes

http://www.ncbi.nlm.nih.gov/pubmed/24120371 

(PubMed)


The endocannabinoid system in obesity and type 2 diabetes

http://www.ncbi.nlm.nih.gov/pubmed/18563385

 (PubMed)


Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes

http://www.ncbi.nlm.nih.gov/pubmed/21484568

 (PubMed)


The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications

http://www.ncbi.nlm.nih.gov/pubmed/22155112

​ (PubMed)

Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain

http://www.ncbi.nlm.nih.gov/pubmed/20236533

 (PubMed)

Biochemical and immunohistochemical changes in delta-9-tetrahydrocannabinol-treated type 2 diabetic rats

http://www.ncbi.nlm.nih.gov/pubmed/23845579

 (PubMed)

 


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Cancer Studies

Cannabis - Brain Cancer
http://www.nature.com/bjc/journal/v95/n2/abs/6603236a.html
http://www.ncbi.nlm.nih.gov/pubmed/11479216
http://www.jneurosci.org/content/21/17/6475.abstract
http://jpet.aspetjournals.org/content/308/3/838.abstract
http://mct.aacrjournals.org/content/10/1/90.abstract

Cannabis - Mouth and Throat Cancer
http://www.ncbi.nlm.nih.gov/pubmed/20516734

Cannabis - Breast Cancer
http://www.ncbi.nlm.nih.gov/pubmed/20859676
http://www.ncbi.nlm.nih.gov/pubmed/18025276
http://www.ncbi.nlm.nih.gov/pubmed/21915267
http://jpet.aspetjournals.org/content/early/2006/05/25/jpet.106.105247.full.pdf+html
http://www.molecular-cancer.com/content/9/1/196
http://www.ncbi.nlm.nih.gov/pubmed/22776349
http://www.pnas.org/content/95/14/8375.full.pdf+html

Cannabis - Lung Cancer
http://www.ncbi.nlm.nih.gov/pubmed/22198381?dopt=Abstract
http://www.ncbi.nlm.nih.gov/pubmed/21097714?dopt=Abstract
http://www.nature.com/onc/journal/v27/n3/abs/1210641a.html

Cannabis - Uterine, Testicular, and Pancreatic Cancers
http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page4
http://cancerres.aacrjournals.org/content/66/13/6748.abstract

Cannabis - Prostate Cancer
http://www.ncbi.nlm.nih.gov/pubmed/12746841?dopt=Abstract
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339795/?tool=pubmed
http://www.ncbi.nlm.nih.gov/pubmed/22594963

Cannabis - Colorectal Cancer
http://www.ncbi.nlm.nih.gov/pubmed/22231745

Cannabis - Ovarian Cancer
http://www.aacrmeetingabstracts.org/cgi/content/abstract/2006/1/1084

Cannabis - Blood Cancer
http://www.ncbi.nlm.nih.gov/pubmed/12091357
http://www.ncbi.nlm.nih.gov/pubmed/16908594
http://onlinelibrary.wiley.com/doi/10.1002/ijc.23584/abstract
http://molpharm.aspetjournals.org/content/70/5/1612.abstract

Cannabis - Skin Cancer
http://www.ncbi.nlm.nih.gov/pubmed/12511587

Cannabis - Liver Cancer
http://www.ncbi.nlm.nih.gov/pubmed/21475304

Cannabis - Biliary Tract Cancer
http://www.ncbi.nlm.nih.gov/pubmed/19916793

Cannabis - Various Cancers
http://www.ncbi.nlm.nih.gov/pubmed/12514108
http://www.ncbi.nlm.nih.gov/pubmed/15313899
http://www.ncbi.nlm.nih.gov/pubmed/14570037
http://www.ncbi.nlm.nih.gov/pubmed/16682966
http://www.ncbi.nlm.nih.gov/pubmed/12648025
http://www.ncbi.nlm.nih.gov/pubmed/19914218


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Please support our charitable and educational work by making a generous tax deductible donation.


 

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Back Pain & Spinal Cord Injuries

Cannabis Research - Back Pain/Spinal Cord Injuries
Back Pain due to degenerated disk - Therapeutic role of Cannabis (2005)
http://www.bjjprocs.boneandjoint.org...

Investigational pharmacology for low back pain (2010)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004649/?tool=pmcentrez

Cannabinoids and muscular pain. Effectiveness of the local administration in rat. (2012) 
http://www.ncbi.nlm.nih.gov/pubmed/22354705

 

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Arthritis Studies

Electroacupuncture Inhibition of Hyperalgesia in Rats with Adjuvant Arthritis: Involvement of Cannabinoid Receptor 1 and Dopamine Receptor Subtypes in Striatum

Both western blot assays and FQ-PCR analysis results showed that the levels of CB1 expression in the repeated-EA group were much higher than those in any other group (P = 0.001). The CB1-selective antagonist AM251 inhibited the effects of repeated EA by attenuating the increases in CB1 expression. The two kinds of dopamine receptors imparted different actions on the EA-induced CB1 upregulation in AA rat model. These results suggested that the strong activation of the CB1 receptor after repeated EA resulted in the concomitant phenomenon of the upregulation of D1 and D2 levels of gene expression.
 
Shou Y, Yang Y, Xu M-S, Zhao Y-Q, Ge L-B, Zhang B-M. Electroacupuncture Inhibition of Hyperalgesia in Rats with Adjuvant Arthritis: Involvement of Cannabinoid Receptor 1 and Dopamine Receptor Subtypes in Striatum.Evidence-based Complementary and Alternative Medicine : eCAM2013;2013:393460. doi:10.1155/2013/393460.

Cortisol-mediated adhesion of synovial fibroblasts is dependent on the degradation of anandamide and activation of the endocannabinoid system
In rheumatoid arthritis (RA) synovial fluid, levels of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol are elevated. Since synovial fibroblasts (SFs) possess all of the enzymes necessary for endocannabinoid synthesis, it is likely that these cells contribute significantly to elevated endocannabinoid levels. While glucocorticoids initiate endocannabinoid synthesis in neurons, this study was undertaken to test whether cortisol also regulates endocannabinoid levels in mesenchymal cells such as SFs, and whether this interferes with integrin-mediated adhesion.
 
Lowin, T., Zhu, W., Dettmer-Wilde, K. and Straub, R. H. (2012), Cortisol-mediated adhesion of synovial fibroblasts is dependent on the degradation of anandamide and activation of the endocannabinoid system. Arthritis & Rheumatism, 64: 3867–3876. doi: 10.1002/art.37684

Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system.

Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of cannabinoid receptor-mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour.
 
Okine BN, Norris LM, Woodhams S, et al. Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system. British Journal of Pharmacology 2012;167(3):627-640. doi:10.1111/j.1476-5381.2012.02028.x.

Cannabinoids: novel therapies for arthritis?

A key feature of osteoarthritis and rheumatoid arthritis is the loss of articular cartilage. Cartilage breakdown is mediated by complex interactions of proinflammatory cytokines, such as IL-1, inflammatory mediators, including nitric oxide and prostaglandin E(2), and proteases, including matrix metalloproteinases and aggrecanases, such as ADAMTS-4 and -5. Cannabinoids have been shown to reduce joint damage in animal models of arthritis. They have also been shown to prevent IL-1-induced matrix breakdown of collagen and proteoglycan, indicating that cannabinoids may mediate chondroprotective effects. Cannabinoids produce their effects via several cannabinoid receptors and it is important to identify the key cannabinoids and their receptors that are involved in chondroprotection. This review aims to outline the current and future prospects of cannabinoids as anti-arthritic therapeutics, in terms of their ability to prevent cartilage breakdown.
 
Robert I Scheinman. (2012) Rheumatology Mini Focus. Future Medicinal Chemistry 4:6, 697-699. Online publication date: 1-Apr-2012.

Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice.

Fatty acid amide hydrolase (FAAH) is the primary degradative enzyme of the endocannabinoid anandamide (N-arachidonoylethanolamine), which activates cannabinoid CB(1) and CB(2) receptors. FAAH disruption reduces nociception in a variety of acute rodent models of inflammatory pain. The present study investigated whether these actions extend to the chronic, collagen-induced arthritis (CIA) model. We investigated the anti-arthritic and anti-hyperalgesic effects of genetic deletion or pharmacological inhibition of FAAH in the CIA model. FAAH (-/-) mice, and FAAH-NS mice that express FAAH exclusively in nervous tissue, displayed decreased severity of CIA and associated hyperalgesia. These phenotypic anti-arthritic effects were prevented by repeated daily injections of the CB(2) receptor antagonist, SR144528, but not the CB(1) receptor antagonist rimonabant. Similarly, repeated administration of the FAAH inhibitor URB597 reduced CIA severity, and acute administration of rimonabant, but not SR144528, blocked the anti-hyperalgesic effects of prolonged FAAH inhibition, suggesting that prolonged CB(2) receptor activation reduces the severity of CIA, whereas acute CB(1) receptor activation reduces CIA-induced hyperalgesia. In contrast, acute administration of URB597 elicited a CB(1) receptor-dependent anti-hyperalgesic effect. The observed anti-arthritic and anti-hyperalgesic properties of FAAH inhibition, coupled with a lack of apparent behavioral alterations, suggest that endocannabinoid modulating enzymes offer a promising therapeutic target for the development of novel pharmacological approaches to treat rheumatoid arthritis and associated hyperalgesia.
 
Kinsey SG, Naidu PS, Cravatt BF, Dudley DT, Lichtman AH. Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice. Pharmacology, biochemistry, and behavior 2011;99(4):718-725. doi:10.1016/j.pbb.2011.06.022.

Is lipid signaling through cannabinoid 2 receptors part of a protective system?

The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB2) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, auto-immune, lung disorders to pain and cancer, and modulating CB2 receptor activity holds tremendous therapeutic potential in these pathologies. While CB2 receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB2 receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB2 receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects.
 
Pacher P, Mechoulam R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Progress in lipid research 2011;50(2):193-211. doi:10.1016/j.plipres.2011.01.001.
pdf3pngsm.png Full Text http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062638/

Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials.

Effective therapeutic options for patients living with chronic pain are limited. The pain relieving effect of cannabinoids remains unclear. A systematic review of randomized controlled trials (RCTs) examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to the PRISMA statement update on the QUORUM guidelines for reporting systematic reviews that evaluate health care interventions. Cannabinoids studied included smoked cannabis, oromucosal extracts of cannabis based medicine, nabilone, dronabinol and a novel THC analogue. Chronic non-cancer pain conditions included neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain. Overall the quality of trials was excellent. Fifteen of the eighteen trials that met the inclusion criteria demonstrated a significant analgesic effect of cannabinoid as compared with placebo and several reported significant improvements in sleep. There were no serious adverse effects. Adverse effects most commonly reported were generally well tolerated, mild to moderate in severity and led to withdrawal from the studies in only a few cases. Overall there is evidence that cannabinoids are safe and modestly effective in neuropathic pain with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis. The context of the need for additional treatments for chronic pain is reviewed. Further large studies of longer duration examining specific cannabinoids in homogeneous populations are required.
 
Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British Journal of Clinical Pharmacology 2011;72(5):735-744. doi:10.1111/j.1365-2125.2011.03970.x.

Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress.

Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB₁ and CB₂ G-protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.
 
Booz GW. Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress. Free radical biology & medicine2011;51(5):1054-1061. doi:10.1016/j.freeradbiomed.2011.01.007.
pdf3pngsm.png Full Text http://www.ncbi.nlm.nih.gov/pmc/articles/PMC308554

Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression

Cannabinoids are a group of compounds present in Cannabis plant (Cannabis sativa L.). They mediate their physiological and behavioral effects by activating specific cannabinoid receptors. With the recent discovery of the cannabinoid receptors (CB1 and CB2) and the endocannabinoid system, research in this field has expanded exponentially. Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide range of immune-mediated diseases such as multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma. Cannabinoid receptor 1 (CB1) is mainly expressed on the cells of the central nervous system as well as in the periphery. In contrast, cannabinoid receptor 2 (CB2) is predominantly expressed on immune cells. The precise mechanisms through which cannabinoids mediate immunosuppression is only now beginning to be understood and can be broadly categorized into four pathways: apoptosis, inhibition of proliferation, suppression of cytokine and chemokine production and induction of T regulatory cells (T regs). Studies from our laboratory have focused on mechanisms of apoptosis induction by natural and synthetic cannabinoids through activation of CB2 receptors. In this review, we will focus on apoptotic mechanisms of immunosuppression mediated by cannabinoids on different immune cell populations and discuss how activation of CB2 provides a novel therapeutic modality against inflammatory and autoimmune diseases as well as malignancies of the immune system, without exerting the untoward psychotropic effects.
 
Rieder SA, Chauhan A, Singh U, Nagarkatti M, Nagarkatti P. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression.Immunobiology 2010;215(8):598-605. doi:10.1016/j.imbio.2009.04.001.

Tonic Modulation of Spinal Hyperexcitability by the Endocannabinoid Receptor System in a Rat Model of Osteoarthritis Pain

Our findings provide new evidence for altered spinal nociceptive processing indicative of central sensitization and for adaptive changes in the spinal cord endocannabinoid system in an experimental model of OA. The novel control of spinal cord neuronal responses by spinal cord CB2 receptors suggests that this receptor system may be an important target for the modulation of pain in OA.
Sagar DR, Staniaszek LE, Okine BN, et al. Tonic Modulation of Spinal Hyperexcitability by the Endocannabinoid Receptor System in a Rat Model of Osteoarthritis Pain. Arthritis and Rheumatism 2010;62(12):3666-3676. doi:10.1002/art.27698.

Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain.

These data indicate that GW405833 reduces the mechanosensitivity of afferent nerve fibres in control joints but causes nociceptive responses in OA joints. The observed pro-nociceptive effect of GW405833 appears to involve TRPV1 receptors.
 

Cannabinoids as novel anti-inflammatory drugs 

Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. The discovery of Δ9-tetrahydrocannabinol (THC) as the major psychoactive principle in marijuana, as well as the identification of cannabinoid receptors and their endogenous ligands, has led to a significant growth in research aimed at understanding the physiological functions of cannabinoids. Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression. In addition, several studies showed that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunoregulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endocannabinoids, led to immunosuppression and recovery from immune-mediated injury to organs such as the liver. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders. This review will focus on the potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T cells or other cellular immune components.
 
Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future medicinal chemistry 2009;1(7):1333-1349. doi:10.4155/fmc.09.93.

Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis

Cannabis-based medicines have a number of therapeutic indications, including anti-inflammatory and analgesic effects. The endocannabinoid receptor system, including the cannabinoid receptor 1 (CB1) and receptor 2 (CB2) and the endocannabinoids, are implicated in a wide range of physiological and pathophysiological processes. Pre-clinical and clinical studies have demonstrated that cannabis-based drugs have therapeutic potential in inflammatory diseases, including rheumatoid arthritis (RA) and multiple sclerosis. The aim of this study was to determine whether the key elements of the endocannabinoid signalling system, which produces immunosuppression and analgesia, are expressed in the synovia of patients with osteoarthritis (OA) or RA.
 
Richardson D, Pearson RG, Kurian N, et al. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Research & Therapy2008;10(2):R43. doi:10.1186/ar2401.

In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee joints

Cannabinoids (CBs) are known to be vasoactive and to regulate tissue inflammation. The present study examined the in vivo vasomotor effects of the CB2 receptor agonists JWH015 and JWH133 in rat knee joints. The effect of acute and chronic joint inflammation on CB2 receptor-mediated responses was also tested.
 
McDougall JJ, Yu V, Thomson J. In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee joints. British Journal of Pharmacology 2008;153(2):358-366. doi:10.1038/sj.bjp.0707565.

ARTHRITIS

Cannabis Research - Rheumatoid Arthritis
Clinical Candidate for the Treatment of Osteoarthritic Pain. (2013) 
http://www.ncbi.nlm.nih.gov/pubmed/23...

Electroacupuncture inhibition of hyperalgesia in rats with adjuvant arthritis. (2013)
http://www.ncbi.nlm.nih.gov/pmc/artic...

Neuromodulators for pain management in rheumatoid arthritis (2012)
http://onlinelibrary.wiley.com/doi/10...

CB1 and CB2 contribute to antinociceptive and anti-inflammatory effects of electroacupuncture on experimental arthritis of the rat temporomandibular joint.(2013) 
http://www.ncbi.nlm.nih.gov/pubmed/23...

Role of CB1 and CB2 cannabinoid receptors in the development of joint pain induced by monosodium iodoacetate. (2012) 
http://www.ncbi.nlm.nih.gov/pubmed/23...

Cortisol-mediated adhesion of synovial fibroblasts is dependent on the degradation of anandamide and activation of the endocannabinoid system (2012)
http://onlinelibrary.wiley.com/doi/10...

Platelet-rich plasma loaded hydrogel scaffold enhances chondrogenic differentiation and maturation with up-regulation of CB1 and CB2. (2012)
http://www.ncbi.nlm.nih.gov/pubmed/22...

Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system. (2012) 
http://www.ncbi.nlm.nih.gov/pubmed/22...

Cannabinoids: novel therapies for arthritis? (2012)
http://www.ncbi.nlm.nih.gov/pubmed/22...

The abnormal cannabidiol analogue O-1602 reduces nociception in a rat model of acute arthritis via the putative cannabinoid receptor GPR55. (2011)
http://www.ncbi.nlm.nih.gov/pubmed/21...

Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice. (2011)
http://www.ncbi.nlm.nih.gov/pubmed/21...

Is lipid signaling through cannabinoid 2 receptors part of a protective system? (2011) 
http://www.ncbi.nlm.nih.gov/pmc/artic...

Cannabinoids for Treatment of Chronic Non-Cancer Pain; a Systematic Review of Randomized Trials. (2011) 
http://www.ncbi.nlm.nih.gov/pubmed/21...

Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. (2011)
http://www.ncbi.nlm.nih.gov/pubmed/21...

Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression.(2010) 
http://www.ncbi.nlm.nih.gov/pmc/artic...

Tonic modulation of spinal hyperexcitability by the endocannabinoid receptor system in a rat model of osteoarthritis pain. (2010)
http://www.ncbi.nlm.nih.gov/pmc/artic...

Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis. (2010)
http://www.ncbi.nlm.nih.gov/pubmed/21...

Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain. (2010) 
http://www.ncbi.nlm.nih.gov/pubmed/20...

Cannabinoids as novel anti-inflammatory drugs. (2009)
http://www.ncbi.nlm.nih.gov/pmc/artic...

Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells. (2008)
http://www.ncbi.nlm.nih.gov/pubmed/18...

Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononuclear precursor cells and induces apoptosis in mature osteoclast-like cells.(2008) 
http://www.ncbi.nlm.nih.gov/pubmed/17...

Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. (2008)
http://www.ncbi.nlm.nih.gov/pmc/artic...

In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee joints (2008)
http://www.pubmedcentral.nih.gov/arti...

In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee joints (2007)
http://www.ncbi.nlm.nih.gov/pmc/artic...

Arthritis and pain. Future targets to control osteoarthritis pain. (2007)
http://www.ncbi.nlm.nih.gov/pmc/artic...

Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid. (2007) 
http://www.ncbi.nlm.nih.gov/pubmed/16...


This Research and Resources page is sponsored by the Ohio Rights Group Education Fund.
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Endocannabinoid System Wiki

The endocannabinoid system is a group of neuromodulatory lipids and their receptors in the brain that are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory; it mediates the psychoactive effects of cannabis and, broadly speaking, includes:

The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators[2][3][4] for a variety of physiological processes, including motor learning,[5]synaptic plasticity,[6]appetite,[7] and pain sensation.[8]

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Care and Feeding of the Endocannabinoid System

Background

The “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.

Methodology/Principal Findings

We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the eCB system.

Conclusions/Significance

Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

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How to Fill out a Circulator Statement

Steps for filling out the OCRA's Circulator Statement

Other than the individual signature pages, this may be the most important part of the petition for the Ohio Cannabis Rights Amendment (OCRA). Please carefully read these instructions before filling out this statement. If you have any questions whatsoever, please ask by calling 614-300-0529 or sending an e-mail message to contact@ohiorights.org.

The OCRA's Circulator Statement can be found on the very last page 12 of the petition. You will see five lines surrounded by text. Fill in these lines sequentially as follows:

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Vote like your future depends on it

VOTE like your future depends on it. Because it does.

What if you could go back in time and change bad laws? No parent or child would have to endure so much pain. No patient would fear arrest for a mere plant. No family member would lose a job or educational opportunity because of it. Why? Because those who made the laws that resulted in these injustices would never have been voted into office in the first place.

You may not be able to change the past, or even the present, but YOUR VOTE can change the future. Don't vote for people who will make laws that you disagree with. Don't vote a straight ticket because it is easy. And for gosh sake, don't sit home and not vote at all!

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Election Day Rules

Attention all Election Day Petition Circulators!

The Ohio Rights Group has asked volunteers to collect signatures for the Ohio Cannabis Rights Amendment (OCRA) at their county's early voting location and at their polling place on Election Day, November 4th. The signatures gathered at such locations are of high value since all potential signers will be both registered voters and residents of that county.

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Governor Hypocrite?

Governor Hypocrite?

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