Cannabis Health Science Studies Index

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DIABETES & Cannabis studies completed

Overview

Wikipedia Diabetes mellitus, or simply diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the pancreas does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).

There are three main types of diabetes mellitus (DM).

  • Type 1 DM results from the body's failure to produce insulin, and presently requires the person to inject insulin or wear an insulin pump. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes".
  • Type 2 DM results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. This form was previously referred to as non insulin-dependent diabetes mellitus (NIDDM) or "adult-onset diabetes".
  • The third main form, gestational diabetes occurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level. It may precede development of type 2 DM.
Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes.

Recommended Cannabis Strains That Benefit Diabetics

Science & Research

2006 - Study ~ Regulation, Function, and Dysregulation of Endocannabinoids in Models of Adipose and ß-Pancreatic Cells and in Obesity and Hyperglycemia.

2006 - Study ~ Weight Control in Individuals With Diabetes.

2006 - Study ~ Changes in endocannabinoid and palmitoylethanolamide levels in eye tissues of patients with diabetic retinopathy and age-related macular degeneration.

2006 - Study ~ Expression of the Gene for a Membrane-bound Fatty Acid Receptor in the Pancreas and Islet Cell Tumours in Humans: Evidence for Gpr40 Expression in Pancreatic Beta Cells and Implications for Insulin Secretion.

2006 - Study - Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol.

2006 - Study - The Cannabinergic System as a Target for Anti-inflammatory Therapies.

2006 - News -  Non-Psychoactive Cannabinoid Reduces Incidence Of Diabetes, Study Says.

2006 - News - Marijuana Compound May Help Stop Diabetic Retinopathy.

2006 - News - Cannabidiol reduces the development of diabetes in an animal study.

2006 - News - Getting Eye On Cannabinoids.

2006 - News - Marijuana compound could prevent eye damage in diabetics.

2007 - Patent ~ US Patent Application 20070099987 - Treating or preventing diabetes with cannabidiol.

2007 - Study - Anticoagulant Effects of a Cannabis Extract in an Obese Rat Model.

2007 - Study - The synthetic cannabinoid HU-210 attenuates neural damage in diabetic mice and hyperglycemic pheochromocytoma PC12 cells.

2007 - Study - Cannabidiol arrests onset of autoimmune diabetes in NOD mice.

2007 - Study - Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption.

2007 - Study ~ Expression of Cannabinoid CB1 Receptors in Models of Diabetic Neuropathy.

2007 - Study ~ Role of cannabinoid CB2 receptors in glucose homeostasis in rats.

2007 - Study ~ The synthetic cannabinoid HU-210 attenuates neural damage in diabetic mice and hyperglycemic pheochromocytoma PC12 cells.

2007 - Study ~ Anticoagulant Effects of a Cannabis Extract in an Obese Rat Model.

2008 - Study ~ Mediation of Cannabidiol anti-inflammation in the Retina by Equilibrative Nucleoside Transporter and A2A Adenosine Receptor.

2008 - Study ~ The Role of Adipocyte Insulin Resistance in the Pathogenesis of Obesity-Related Elevations in Endocannabinoids.

2008 - Study ~ GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity.

2008 - Study ~ Endogenous and synthetic agonists of GPR119 differ in signalling pathways and their effects on insulin secretion in MIN6c4 insulinoma cells.

2008 - Study ~ Endocannabinoid Dysregulation in the Pancreas and Adipose Tissue of Mice Fed With a High-fat Diet.

2008 - Study ~ Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: critical role of p38 MAPK activation.

2008 - Study ~ Endocannabinoids and the Control of Energy Homeostasis.

2008 - Study ~ Mediation of Cannabidiol Anti-inflammation in the Retina by Equilibrative Nucleoside Transporter and A2A Adenosine Receptor.

2008 - Study ~ Presence of functional cannabinoid receptors in human endocrine pancreas.

2009 - Study ~ Cannabidiol As a Putative Novel Therapy for Diabetic Retinopathy: A Postulated Mechanism of Action as an Entry Point for Biomarker-Guided Clinical Development.

2009 - Study ~ Cannabinoids as novel anti-inflammatory drugs.

2009 - Study ~ Cannabinoid CB2 Receptor Potentiates Obesity-Associated Inflammation, Insulin Resistance and Hepatic Steatosis.

2009 - Study ~ The endocanabinnoid system and diabetes - critical analyses of studies conducted with rimonabant.

2009 - Study ~ Anti-inflammatory effect of palmitoylethanolamide on human adipocytes.

2009 - Study - Biological effects of THC and a lipophilic cannabis extract on normal and insulin resistant 3T3-L1 adipocytes.

2009 - Study - Beneficial effects of a Cannabis sativa extract on diabetes induced neuropathy and oxidative stress.

2009 - News ~ Cannabis plant extracts could potentially form the basic ingredients for a market-leading diabetes drug.

2010 - Study ~ Medical Marijuana and Diabetes, Adult Onset.

2010 - Study ~ Expression and function of cannabinoid receptors in mouse islets.

2010 - Study ~ Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain.

2010 - Study ~ Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression.

2010 - Study ~ Cannabinoid Receptor 1 Blockade Ameliorates Albuminuria in Experimental Diabetic Nephropathy.

2010 - Study ~ Cannabinoid Receptors are Coupled to Stimulation of Insulin Secretion from Mouse MIN6 β-cells.

2010 - Study ~ Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients.

2010 - Study ~ Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways.

2010 - Study ~ Cannabidiol protects retinal neurons by preserving glutamine synthetase activity in diabetes.

2010 - Study ~ Cannabidiol Attenuates Cardiac Dysfunction, Oxidative Stress, Fibrosis, and Inflammatory and Cell Death Signaling Pathways in Diabetic Cardiomyopathy.

2010 - Study ~ Rehashing endocannabinoid antagonists: can we selectively target the periphery to safely treat obesity and type 2 diabetes?

2010 - Study ~ Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients.

2010 - Study ~ Diabetic retinopathy: Role of inflammation and potential therapies for anti-inflammation.

2010 - Study ~ Novel GPR119 agonist AS1535907 contributes to first-phase insulin secretion in rat perfused pancreas and diabetic db/db mice.

2010 - Study ~ AS1907417, a novel GPR119 agonist, as an insulinotropic and β-cell preservative agent for the treatment of type 2 diabetes.

2010 - Study ~ Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age.

2010 - Study ~ G1359A polymorphism in the cannabinoid receptor-1 gene is associated with metabolic syndrome in the Chinese Han population.

2010 - Study ~ GPR119 agonists for the potential treatment of type 2 diabetes and related metabolic disorders.

2010 - News ~ Pot Compound Mitigates Diabetic Cardiomyopathy.

2010 - News ~ Cannabinoids inhibit and may prevent neuropathic pain in diabetes.

2010 - News ~ Lab Notes: Pot Has Benefits for Diabetic Hearts.

2011 - Study ~ Cannabinoid receptor 2 signaling does not modulate atherogenesis in mice.

2011 - Study ~ Role for cannabinoid receptors in human proximal tubular hypertrophy.

2011 - Study ~ Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

2011 - Study ~ Central Endocannabinoid Signaling Regulates Hepatic Glucose Production and Systemic Lipolysis.

2011 - Study ~ Cannabinoids Inhibit Insulin Receptor Signaling in Pancreatic β-Cells.

2011 - Study ~ Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice.

2011 - Study ~ Cannabinoid receptor agonists and antagonists stimulate insulin secretion from isolated human islets of Langerhans.

2011 - Study ~ A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans.

2011 - Study ~ Protective Role of Cannabinoid Receptor Type 2 in a Mouse Model of Diabetic Nephropathy.

2011 - Study ~ Cannabinoids and Endocannabinoids in Metabolic Disorders with Focus on Diabetes.

2011 - Study ~ Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress.

2011 - Study ~ Win 55,212-2 reduces cardiac ischaemia-reperfusion injury in zucker diabetic fatty rats: role of cb2 receptors and cardiac inos/enos expression.

2011 - Study ~ GPR119 Regulates Murine Glucose Homeostasis Through Incretin Receptor-Dependent and Independent Mechanisms.

2011 - Study ~ Cannabidiol Dampens Streptozotocin-Induced Retinal Inflammation by Targeting of Microglial Activation.

2011 - Study ~ The cytoprotective effects of oleoylethanolamide in insulin-secreting cells do not require activation of GPR119.

2011 - Study ~ The Endocannabinoid System: Plant-Derived Cannabinoids in Diabetes and Diabetic Complications.

2011 - Study ~ TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats.

2011 - News ~ Takeda moves potential first-in-class diabetes drug into phase III.

2012 - Study ~ Optimization of (2,3-dihydro-1-benzofuran-3-yl)acetic acids: discovery of a non-free fatty acid-like, highly bioavailable G protein-coupled receptor 40/free fatty acid receptor 1 agonist as a glucose-dependent insulinotropic agent.

2012 - Study ~ A Multiple-Ascending-Dose Study to Evaluate Safety, Pharmacokinetics, and Pharmacodynamics of a Novel GPR40 Agonist, TAK-875, in Subjects With Type 2 Diabetes.

2012 - Study ~ G1359A polymorphism in the cannabinoid receptor-1 gene is associated with the presence of coronary artery disease in patients with type 2 diabetes.

2012 - Study ~ The Novel Reversible Fatty Acid Amide Hydrolase Inhibitor ST4070 Increases Endocannabinoid Brain Levels and Counteracts Neuropathic Pain in Different Animal Models.

2012 - Study ~ A Randomized, Double-Blind, Placebo Controlled, Parallel Assignment, Flexible Dose, Efficacy Study of Nabilone as Adjuvant in the Treatment of Diabetic Peripheral Neuropathic Pain Using an Enriched Enrollment Randomized Withdrawal Design (S38.003).

2012 - Study ~ Stimulating beta cell replication and improving islet graft function by GPR119 agonists.

2012 - Study ~ TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial.

2012 - Study ~ Induction of Glucose Intolerance by Acute Administration of Rimonabant.

2012 - Study ~ Overexpression of cannabinoid CB2 receptor in the brain induces hyperglycaemia and a lean phenotype in adult mice.

2012 - Study ~ Characterization of cannabinoid-induced relief of neuropathic pain in rat models of type 1 and type 2 diabetes.

2012 - Study ~ Islet protection and amelioration of diabetes type 2 in Psammomys obesus by treatment with cannabidiol.

2012 - Study ~ The L-α-lysophosphatidylinositol/GPR55 system and its potential role in human obesity.

2012 - Study ~ The cytoprotective effects of oleoylethanolamide in insulin-secreting cells do not require activation of GPR119.

2012 - Study ~ A Multiple-Ascending-Dose Study to Evaluate Safety, Pharmacokinetics, and
Pharmacodynamics of a Novel GPR40 Agonist, TAK-875, in Subjects With Type 2 Diabetes.

2012 - Study ~ Optimization of (2,3-dihydro-1-benzofuran-3-yl)acetic acids: discovery of a non-free fatty acid-like, highly bioavailable G protein-coupled receptor 40/free fatty acid receptor 1 agonist as a glucose-dependent insulinotropic agent.

2012 - Study ~ An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain.

2012 - Study ~ The role of the endocannabinoid system in skeletal muscle and metabolic adaptations to exercise: potential implications for the treatment of obesity.

2012 - Study ~ Reports of the death of CB1 antagonists have been greatly exaggerated: recent preclinical findings predict improved safety in the treatment of obesity.

2012 - Study ~ Peripheral antinociceptive effect of anandamide and drugs that affect the
endocannabinoid system on the formalin test in normal and streptozotocin-diabetic rats.

2012 - Study ~ New vistas for treatment of obesity and diabetes? Endocannabinoid signalling and metabolism in the modulation of energy balance.

2012 - Study ~ Chronic activation of cannabinoid receptors in vitro does not compromise mouse islet function.

2012 - News ~ Cannabis Use Associated With Decreased Prevailence Of Diabetes

2012 - News ~ Synthetic cannabinoid could treat pain in diabetes patients

2012 - News ~ Synthetic THC Analogue Mitigates Diabetic Neuropathy, Is ‘Well Tolerated’ In
Patients

2012 - News ~ Encouraging anti-diabetic results for new cannabinoid drug

2012 - News ~ New drug offers novel pain management therapy for diabetics.

2012 - News ~ Drug offers new pain management therapy for diabetics

2013 - Study ~ The impact of marijuana use on glucose, insulin, and insulin resistance among US adults

2013 - Study ~ Developmental Role for Endocannabinoid Signaling in Regulating Glucose Metabolism and Growth.

2013 - Study ~ Influence of G1359A polimorphysm of the cannabinoid receptor gene (CNR1) on insulin resistance and adipokines in patients with non alcoholic fatty liver disease.

2013 - Study ~ Modulating the endocannabinoid system in human health and disease: successes and failures

2013 - Study ~ Reduced Food Intake is the Major Contributor to the Protective Effect of Rimonabant on Islet in Established Obesity-Associated Type 2 Diabetes.

2013 - Study ~ Is the cardiovascular system a therapeutic target for cannabidiol?

2013 - Study ~ Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids

2013 - Study ~ The complex effects of cannabinoids on insulin secretion from rat isolated islets of Langerhans.

2013 - Study ~ Effects of CB1 receptor blockade on monosodium glutamate induced hypometabolic and hypothalamic obesity in rats.

2013 - Study ~ Circulating endocannabinoids in insulin sensitive vs. Insulin resistant obese
postmenopausal women. A MONET group study.

2013 - Study ~ Synergetic Insulin Sensitizing Effect of Rimonabant and BGP-15 in Zucker-Obes Rats.

2013 - Study ~ The cannabinoid Δ(9)-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity.

2013 - Study ~ Activation of type 2 cannabinoid receptors (CB2R) promotes fatty acid oxidation through the SIRT1/PGC-1α pathway.

2013 - Study ~ Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action.

2013 - Study ~ Activation of spinal cannabinoid cb2 receptors inhibits neuropathic pain in
streptozotocin-induced diabetic mice.

2013 - Study ~ Evaluation of the insulin releasing and antihyperglycaemic activities of GPR55 lipid agonists using clonal beta-cells, isolated pancreatic islets and mice.

2013 - Study ~ Common polymorphism in the cannabinoid type 1 receptor gene (CNR1) is associated with microvascular complications in type 2 diabetes.

2013 - Study ~ Cannabinoids alter endothelial function in the Zucker rat model of type 2 diabetes.

2013 - Study ~ Monounsaturated fatty acids generated via stearoyl CoA desaturase-1 are endogenous inhibitors of fatty acid amide hydrolase.

2013 - Study ~ Biochemical and immunohistochemical changes in delta-9-tetrahydrocannabinol  treated type 2 diabetic rats.

2013 - Study ~ Long-term supplementation of honokiol and magnolol ameliorates body fat
accumulation, insulin resistance, and adipose inflammation in high-fat fed mice.

2013 - Study ~ Cannabinoid Receptor 2 Expression in Human Proximal Tubule Cells is Regulated by Albumin Independent of ERK1/2 Signaling.

2013 - Study ~ Role of Genetic Variation in the Cannabinoid Receptor Gene (CNR1) (G1359A
Polymorphism) on Weight Loss and Cardiovascular Risk Factors After Liraglutide
Treatment in Obese Patients With Diabetes Mellitus Type 2.

2013 - Study ~ Vascular targets for cannabinoids: animal and human studies.

2013 - Study ~ A potential role for GPR55 in the regulation of energy homeostasis.

2013 - Study ~ Effects of C358A polymorphism of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH) on weight loss, adipocytokines levels, and insulin resistance
after a high polyunsaturated fat diet in obese patients.

2013 - News ~ Marijuana: The next diabetes drug?

2013 - News ~ Regular Marijuana Use is Associated With Favorable Indices to Diabetic Control, Say Investigators

2013 - News ~ Marijuana Users Have Better Blood Sugar Control

2013 - News ~ Study: Why Pot Smokers Are Skinnier

2013 - News ~ Cannabis linked to prevention of diabetes

2013 - News ~ Marijuana Extract Holds Promise as Diabetes Treatment

2013 - News ~ Marijuana Smokers Are Thinner And Healthier Than Non-Users

2014 - Study ~ A Role for Trans-caryophyllene in the Moderation of Insulin Secretion.

2014 - Study ~ Effect of intermittent cold exposure on brown fat activation, obesity, and energy
homeostasis in mice.

Marijuana Compound May Help Stop Diabetic Retinopathy

TScienceDaily (Feb. 27, 2006) — A compound found in marijuana won’t make you high but it may help keep your eyes healthy if you’re a diabetic, researchers say.

Early studies indicate cannabidiol works as a consummate multi-tasker to protect the eye from growing a plethora of leaky blood vessels, the hallmark of diabetic retinopathy, says Dr. Gregory I. Liou, molecular biologist at the Medical College of Georgia.

“We are studying the role of cannabinoid receptors in our body and trying to modulate them so we can defend against diabetic retinopathy,” Dr. Liou says. Diabetic retinopathy is the leading cause of blindness in working-age adults and affects nearly 16 million Americans.

High glucose levels resulting from unmanaged diabetes set in motion a cascade ultimately causing the oxygen-deprived retina to grow more blood vessels. Ironically, the leaky surplus of vessels can ultimately destroy vision.

Dr. Liou, who recently received a $300,000 grant from the American Diabetes Association, wants to intervene earlier in the process, as healthy relationships inside the retina first start to go bad.

Cannabinoid receptors are found throughout the body and endogenous cannabinoids are produced to act on them. “Their function is very different from organ to organ but in the central nervous system, cannabinoid receptors are responsible for the neutralization process that should occur after a nerve impulse is finished,” says Dr. Liou.

Nerves come together at a point of communication called a synapse. Glutamate is a neurotransmitter that excites these nerves to action at their point of communication. “There are also inhibitory neurotransmitters such as GABA,” Dr. Liou says. Endogenous cannabinoids help balance the excitation and inhibition, at least until oxygen gets scarce.

In the face of inadequate oxygen, or ischemia – another hallmark of diabetes – nerve endings start producing even more glutamate, setting in motion an unhealthy chain of events. Pumps that keep the right substances inside or outside of cells start to malfunction. Excess nitric oxide and superoxides are produced, which are toxic to the cells. Another irony is the heightened activity increases the retina’s need for oxygen. “We are talking about nerve cell death,” Dr. Liou says. “In the retina, if a lot of our nerve cells die, our vision is directly affected.”

And that’s not all that goes wrong in the nerve-packed retina. Glial cells, which support nerve cells by supplying nutrients and oxygen, are closely attuned to their charges. When they sense something is amiss, microglia, one type of glial cells, start eating the dying nerve cells.

“Microglial cells become voracious. They eat dying nerve cells, making the whole thing irreversibly bad,” says Dr. Liou. Interestingly, the body start producing more endogenous cannabinoids to stop the role reversal, then produces an enzyme to destroy the cannabinoids because of concern there are too many of them. The same thing happens in the brain after a stroke. “Long before all these blood vessels start growing, the partnership between glial cells and nerve cells starts breaking down,” says Dr. Liou.

That’s why cannabidiol, an antioxidant, may help save the retina. Test-tube studies by others, as well as Dr. Liou’s pilot studies in diabetic animal models show cannabidiol works to interrupt essentially all these destructive points of action.

“What we believe cannabidiol does is go in here as an antioxidant to neutralize the toxic superoxides. Number two, it inhibits the self-destructive system and allows the self-produced endogenous cannabinoids to stay there longer by inhibiting the enzyme that destroys them.” Cannabidiol also helps keep microglial cells from turning on nerve cells by inhibiting cannabinoid receptors on microglial cells that are at least partially responsible for their ability to destroy rather than support the cells.

“Cannabinoids are trying to ease the situation on both sides. They help save the neuron and, at the same time, make sure the microglial cells stay in microglial form. How good do you want a drug to be?” Dr. Liou says.

His earliest studies in animal models, published in the January issue of the American Journal of Pathology, indicate it may be very good.

Co-authors on the study include Dr. Azza B. El-Remessy, MCG Department of Pharmacology and Toxicology; Drs. Mohamed Al-Shabrawey, Nai-Tse Tsai and Ruth B. Caldwell, MCG Vascular Biology Center; and Dr. Yousuf Khalifa, MCG Department of Ophthalmology.

“We are very pleased,” he says of studies in which cannabidiol is injected into the stomachs of diabetic rats and mice.

He hopes the compound in marijuana may one day be given along with insulin to stop the early changes that set the stage for damaged or destroyed vision.

 

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Anticoagulant Effects of a Cannabis Extract in an Obese Rat Model

Coetzee C, Levendal RA, van de Venter M, Frost CL

Department of Biochemistry and Microbiology, Nelson Mandela Metropolitan University, PO Box 77000, Port Elizabeth 6031, South Africa.

 Blood coagulation studies were conducted to determine the possible anti-/prothrombotic effect of an organic cannabis extract and the three major cannabinoids, THC, CBD and CBN.

The in vitro effect of the cannabis extract on thrombin activity produced an IC50 value of 9.89 mg/ml, compared to THC at 1.79 mg/ml. It was also found that the extract, THC and CBN showed considerable inhibition of thrombin-induced clot formation in vitro with IC50 values of 600, 87 and 83 microg/ml for the extract, THC and CBN respectively.

In an in vivo model used to determine clotting times of lean and obese rats treated with a cannabis extract, 50% clotting times were found to be 1.5 and 2 fold greater than their respective control groups, supporting the results obtained in the in vitro model.

The study thus shows that Cannabis sativa and the cannabinoids, THC and CBN, display anticoagulant activity and may be useful in the treatment of diseases such as type 2 diabetes in which a hypercoagulable state exists.

Published 30 April 2007 in Phytomedicine, 14(5): 333-7.
Full-text of this article is available online (may require subscription)

 

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Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol

(American Journal of Pathology. 2006;168:235-244.)
© 2006 American Society for Investigative Pathology

Azza B. El-Remessy, Mohamed Al-Shabrawey, Yousuf Khalifa, Nai-Tse Tsai, Ruth B. Caldwell, and Gregory I. Liou

From the Departments of Pharmacology and Toxicology* and Ophthalmology, the Vascular Biology Center, Cellular Biology and Anatomy, and the Medical College of Georgia; and the Veterans Affairs Medical Center, Augusta, Georgia

 

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.

 

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The Cannabinergic System as a Target for Anti-inflammatory Therapies

Authors: Lu, Dai; Kiran Vemuri, V.; Duclos, Richard I.; Jr.; Makriyannis, Alexandros

Source: Current Topics in Medicinal Chemistry, Volume 6, Number 13, July 2006 , pp. 1401-1426(26)

Publisher: Bentham Science Publishers

 

Abstract:

Habitual cannabis use has been shown to affect the human immune system, and recent advances in endocannabinoid research provide a basis for understanding these immunomodulatory effects.

Cell-based experiments or in vivo animal testing suggest that regulation of the endocannabinoid circuitry can impact almost every major function associated with the immune system. These studies were assisted by the development of numerous novel molecules that exert their biological effects through the endocannabinoid system.
 
Several of these compounds were tested for their effects on immune function, and the results suggest therapeutic opportunities for a variety of inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, allergic asthma, and autoimmune diabetes through modulation of the endocannabinoid system.
 
 
 
 
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Effect of tetrahydrocurcumin on blood glucose, plasma insulin and hepatic key enzymes

Pari L, Murugan P

J Basic Clin Physiol Pharmacol 2005; 16(4):257-74.

The enzymes of glucose and lipid metabolism are markedly altered in experimental diabetes. In the present study, we investigated the effect of tetrahydrocurcumin (THC), one of the active metabolites in curcumin, on the key hepatic metabolic enzymes involved in carbohydrate metabolism in streptozotocin-induced diabetic rats. Different doses of THC (20, 40, and 80 mg\kg body weight) were orally administered to diabetic rats for 45 days.

The activities of hexokinase, glucose-6-phosphate dehydrogenase (G6PD), glucose-6-phosphatase, fructose-1,6-bisphosphatase, and sorbitol dehydrogenase in liver, and glycogen content in liver and muscle were assayed.

In untreated diabetic control rats, the activities of the gluconeogenic enzymes were significantly increased, whereas hexokinase and G6PD activity and glycogen levels were significantly decreased.

Both THC and curcumin were able to restore the altered enzyme activities to near normal levels. Tetrahydrocurcumin was more effective than curcumin. Our results indicate that the administration of THC to diabetic animals normalizes blood glucose and causes a marked improvement of altered carbohydrate metabolic enzymes.

 

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Cannabidiol reduces the development of diabetes in an animal study

Science: Cannabidiol reduces the development of diabetes in an animal study

Researchers of the Hadassah University Hospital of Jerusalem investigated the effects of the plant cannabinoid cannabidiol (CBD) on the development of diabetes in mice, which develop diabetes due to genetic causes. So-called NOD mice develop insulitis within 4 to 5 weeks of age followed by diabetes within a median of 14 weeks. Insulitis is an inflammation of the cells in the pancreas that produce insulin, and diabetes is a result of a destruction of these cells.

NOD mice aged 6 to 12 weeks that were treated with 10 to 20 injections of CBD (5 mg per kilogram body weight) presented with a significantly reduced incidence of diabetes of 30 per cent compared to 86 per cent in untreated control mice.

In addition, in the mice that developed diabetes in the treated group disease onset was a significantly delayed. Blood levels of two cytokines that promote inflammation, IFN-gamma and TFN-alpha, are usually increased in NOD mice. A treatment with CBD caused a significant reduction (more than 70 per cent) in levels of both cytokines. In another experiment CBD-treated mice were observed for 26 weeks. While the 5 control mice all developed diabetes, 3 of 5 of the CBD-treated mice remained diabetes-free at 26 weeks.

Researchers concluded that confirmation of the observed immunomodulatory effects of CBD "may lead to the clinical application of this agent in the prevention of type 1 diabetes" and possibly other autoimmune diseases. They note that many patients diagnosed with type 1 diabetes have sufficient residual cells that produce insulin at the time of diagnosis, and may be candidates for immunomodulation therapy.

(Source: Weiss L, Zeira M, Reich S, Har-Noy M, Mechoulam R, Slavin S, Gallily R. Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity 2006;39(2):143-51)

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Getting Eye On Cannabinoids

 

Science a Go-go, 1st March 2006

With the multitude of chemical compounds contained in cannabis, odds are that at least a few of them are going to be beneficial to humans. In current research on how to modulate cannabinoid receptors in the human body, Dr. Gregory I. Liou, a molecular biologist at the Medical College of Georgia, has found that cannabidiol (a cannabis compound) could prevent the overabundance of leaky eye blood vessels associated with diabetic retinopathy.

As the leading cause of blindness in the United States, diabetic retinopathy is a major health concern for more than 16 million American adults. Diabetic retinopathy occurs when high levels of glucose, stemming from unmanaged diabetes, trigger the oxygen-deprived retina to grow more blood vessels. Far from remedying the situation, the abundance of excess blood vessels can eventually lead to blindness.

Dr. Liou hopes that he can nip the body's damaging response in the bud by focusing on early interactions within the retina prior to its deterioration. "We are studying the role of cannabinoid receptors in our body and trying to modulate them so we can defend against diabetic retinopathy," he explained.

The human body comes naturally equipped with cannabinoid receptors and endogenous (DNA receiving) cannabinoids are formed to act upon them. "Their function is very different from organ to organ but in the central nervous system, cannabinoid receptors are responsible for the neutralization process that should occur after a nerve impulse is finished," said Liou.

Nerves are known to terminate at a single point of communication (a synapse), which is then excited into action by a neurotransmitter called glutamate. Endogenous cannabinoids help balance the excitation and inhibition, at least until oxygen gets scarce.

Under circumstances such as inadequate oxygen (ischemia), these nerve endings produce unhealthy amounts of glutamate, excess nitric oxide and other toxic superoxides that lead to diabetic retinopathy. The injurious cycle is exacerbated further as all the increased activity means that the retina requires even more oxygen. "We are talking about nerve cell death," Dr. Liou said. "In the retina, if a lot of our nerve cells die, our vision is directly affected."

As if matters weren't bad enough, the glial cells that closely monitor nutrient and oxygen levels in the retina's densely packed nerve cells send out microglial cells to destroy and clean up the dying nerve cells. The microglial cells become voracious, eating dying nerve cells and making the whole thing irreversibly bad.

During his research Dr. Liou observed that the body produced more endogenous cannabinoids to stop the destructive role reversal, but their release triggered the production of an enzyme to destroy the cannabinoids as they grew in number. "Long before all these blood vessels start growing, the partnership between glial cells and nerve cells starts breaking down," says Dr. Liou.

Dr. Liou's work, published in the January issue of the American Journal of Pathology, is encouraging and indicates that cannabidiol can interrupt the destructive points of action in diabetic animals.

"What we believe cannabidiol does is go in here as an antioxidant to neutralize the toxic superoxides. Number two, it inhibits the self-destructive system and allows the self-produced endogenous cannabinoids to stay there longer by inhibiting the enzyme that destroys them," Dr. Liou explained. Even more promising, his experiments have also shown that the microglial cells are prevented from destroying the retina's toxin ravaged nerve cells.

Dr. Liou believes that cannabinoids act as a type of negotiator, trying to keep peace, harmony and balance between a host of potentially volatile and dangerous factions of cells. "Cannabinoids are trying to ease the situation on both sides. They help save the neuron and, at the same time, make sure the microglial cells stay in microglial form. How good do you want a drug to be?" he mused.

 

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Marijuana compound could prevent eye damage in diabetics

 

FemaleFirst.co.uk, 28th February 2006

Scientists have discovered a compound in marijuana that could protect against eye damage in diabetics.

Diabetic retinopathy is a leading cause of blindness in working-age adults and affects nearly 16 million Americans. It occurs when diabetes damages the tiny blood vessels inside the retina, the light-sensitive tissue at the back of the eye.

Gregory I. Liou and other researchers of molecular biology at the Medical College of Georgia studied the role of cannabinoid receptors and said the compound they had found could defend against diabetic retinopathy.

Liou studied the compound in diabetic animal models and found that it works to interrupt essentially all destructive points of action that cause vision loss in a diabetic patient, reported the science portal EurekAlert.

He hoped the compound in marijuana may one day be given along with insulin to stop the early changes that set the stage for damaged or destroyed vision.

 

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The synthetic cannabinoid HU-210 attenuates neural damage in diabetic mice and hyperglycemic pheochromocytoma PC12 cells

Diabetes

Neurobiol Dis. 2007 Aug;27(2):174-81. Epub 2007 May 21

 

Dagon Y, Avraham Y, Link G, Zolotarev O, Mechoulam R, Berry EM.

Department of Human Nutrition and Metabolism, Braun School of Public Health, Faculty of Medicine Hebrew University, Hadassah Medical School, Israel.

Abstract

Diabetic neuropathy (DN) is a common complication of diabetes mellitus resulting in cognitive dysfunction and synaptic plasticity impairment.

Hyperglycemia plays a critical role in the development and progression of DN, through a number of mechanisms including increased oxidative stress. Cannabinoids are a diverse family of compounds which can act as antioxidative agents and exhibit neuroprotective properties.

We investigated the effect of the synthetic cannabinoid HU-210 on brain function of streptozotocin (STZ)-induced diabetic mice.

These animals exhibit hyperglycemia, increased cerebral oxidative stress and impaired brain function. HU-210, through a receptor independent pathway, alleviates the oxidative damage and cognitive impairment without affecting glycemic control. To study the neuroprotective mechanism(s) involved, we cultured PC12 cells under hyperglycemic conditions. Hyperglycemia enhanced oxidative stress and cellular injuries were all counteracted by HU-210-in a dose dependent manner.

These results suggest cannabinoids might have a therapeutic role in the management of the neurological complications of diabetes.

PMID: 17604177 [PubMed - indexed for MEDLINE]

 

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Cannabidiol arrests onset of autoimmune diabetes in NOD mice

 Lola Weiss, Michael Zeira, Shoshana Reich, Shimon Slavin, Itamar Raz, Raphael Mechoulam, Ruth Gallily

Abstract - We have previously reported that cannabidiol (CBD) lowers the incidence of diabetes in young non-obese diabetes-prone (NOD) female mice.

In the present study we show that administration of CBD to 11e14 week old female NOD mice, which are either in a latent diabetes stage or with initial symptoms of diabetes, ameliorates the manifestations of the disease. Diabetes was diagnosed in only 32% of the mice in the CBDtreated group, compared to 86% and 100% in the emulsifier-treated and untreated groups, respectively.

In addition, the level of the proinflammatory cytokine IL-12 produced by splenocytes was significantly reduced, whereas the level of the anti-inflammatory IL-10 was significantly elevated following CBD-treatment. Histological examination of the pancreata of CBD-treated mice revealed more intact islets than in the controls. Our data strengthen our previous assumption that CBD, known to be safe in man, can possibly be used as a therapeutic agent for treatment of type 1 diabetes.

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Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption

 
Am J Physiol Heart Circ Physiol. Author manuscript; available in PMC 2008 February 4.
Published in final edited form as:
PMCID: PMC2228254
NIHMSID: NIHMS38117
Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption
Mohanraj Rajesh,1 Partha Mukhopadhyay,1 Sándor Bátkai,1 György Haskó,2 Lucas Liaudet,3 Viktor R. Drel,4 Irina G. Obrosova,4 and Pál Pacher1
1 Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
2 Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey
3 Department of Intensive Care Medicine, University Hospital, Lausanne, Switzerland
4 Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana

Biological effects of THC and a lipophilic cannabis extract on normal and insulin resistant 3T3-L1 adipocytes

Gallant M, Odei-Addo F, Frost CL, Levendal RA

 Phytomedicine 2009 Apr 1.

Type 2 diabetes, a chronic disease, affects about 150 million people world wide. It is characterized by insulin resistance of peripheral tissues such as liver, skeletal muscle, and fat. Insulin resistance is associated with elevated levels of tumor necrosis factor alpha (TNF-alpha), which in turn inhibits insulin receptor tyrosine kinase autophosphorylation.

It has been reported that cannabis is used in the treatment of diabetes. A few reports indicate that smoking cannabis can lower blood glucose in diabetics.

Delta(9)-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. This study aimed to determine the effect of a lipophilic cannabis extract on adipogenesis, using 3T3-L1 cells, and to measure its effect on insulin sensitivity in insulin resistant adipocytes. Cells were cultured in Dulbecco's modified eagle medium (DMEM) with 10% fetal bovine serum (FBS) and differentiated over a 3 day period for all studies. In the adipogenesis studies, differentiated cells were exposed to the extract in the presence and absence of insulin. Lipid content and glucose uptake was subsequently measured.

Insulin-induced glucose uptake increased, while the rate of adipogenesis decreased with increasing THC concentration. Insulin-resistance was induced using TNF-alpha, exposed to the extract and insulin-induced glucose uptake measured. Insulin-induced glucose was increased in these cells after exposure to the extract. Semiquantitative real time polymerase chain reaction (RT-PCR) was performed after ribonucleic acid (RNA) extraction to evaluate the effects of the extract on glucose transporter isotype 4 (GLUT-4), insulin receptor substrate-1 (IRS-1) and IRS-2 gene expression.

 

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Beneficial effects of a Cannabis sativa extract on diabetes induced neuropathy and oxidative stress

Comelli F, Bettoni I, Colleoni M, Giagnoni G, Costa B

Phytother Res 2009 May 13.

Neuropathy is the most common complication of diabetes and it is still considered to be relatively refractory to most of the analgesics.

The aim of the present study was to explore the antinociceptive effect of a controlled cannabis extract (eCBD) in attenuating diabetic neuropathic pain. Repeated treatment with cannabis extract significantly relieved mechanical allodynia and restored the physiological thermal pain perception in streptozotocin (STZ)-induced diabetic rats without affecting hyperglycemia.

In addition, the results showed that eCBD increased the reduced glutathione (GSH) content in the liver leading to a restoration of the defence mechanism and significantly decreased the liver lipid peroxidation suggesting that eCBD provides protection against oxidative damage in STZ-induced diabetes that also strongly contributes to the development of neuropathy.

Finally, the nerve growth factor content in the sciatic nerve of diabetic rats was restored to normal following the repeated treatment with eCBD, suggesting that the extract was able to prevent the nerve damage caused by the reduced support of this neurotrophin.

These findings highlighted the beneficial effects of cannabis extract treatment in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and a specific action upon nerve growth factor. Copyright (c) 2009 John Wiley & Sons, Ltd.

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Non-Psychoactive Cannabinoid Reduces Incidence Of Diabetes, Study Says

May 18, 2006 - Jerusalem, Israel

Jerusalem, Israel: Administration of the non-psychoactive cannabinoid cannabidiol (CBD) lowers incidence of diabetes in animals and may one day play a role in the prevention of human type 1 diabetes, according to preclinical findings published in the March issue of the journal Autoimmunity.

Researchers at Hadassah University Hospital in Jerusalem reported that injections of 5 mg per day of CBD significantly reduced the prevalence of diabetes in mice from an incidence of 86 percent in non-treated controls to an incidence of only 30 percent. In a separate experiment, investigators reported that control mice all developed diabetes at a median of 17 weeks (range 15-20 weeks) while a majority (60 percent) of CBD-treated mice remained diabetes-free at 26 weeks.

Investigators also reported that CBD significantly lowered plasma levels of the pro-inflammatory cykotines (proteins), INF-gamma and TNF-alpha, and significantly reduced the severity of insulitis (an infiltration of white blood cells resulting in swelling) compared to non-treated controls.

"Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory ... cykotine production in ... mice resulting in decreased incidence of diabetes," authors concluded.

Preclinical trial data published earlier this year found that CBD prevents diabetic retinopathy in animals. The condition, which is characterized by retinal oxygen deprivation, is the leading cause of blindness in working-age adults.

Cannabinoids have also been demonstrated to alleviate certain types of neuropathic pain associated with diabetes, and to reduce glucose levels in animal models of the disease.

For more information, please contact Paul Armentano, NORML Senior Policy Analyst, at (202) 483-5500. Full text of the study, "Cannabidiol lowers incidence of diabetes in non-obese diabetic mice," appears in the March issue of Autoimmunity.

 

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