CRA-Z 

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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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)

(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-, 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-, 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.

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.

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)

Science a Go-go, 1st March 2006

FemaleFirst.co.uk, 28th February 2006

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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.

PMID: 17604177 [PubMed - indexed for MEDLINE]

 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.

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.

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.

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.