Medical cannabis & diabetes: a review of the evidences

http://growcompare.eu/cannabis-the-future-of-preventing-insulin-resistance/
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With diabetes being one of the leading disease burdens in the Western world, it is important to understand whether cannabis may provide protection from the development of this disorder, or if it can ease symptoms, leading towards a cure altogether.

Self-medicating patients have been known to relieve their diabetic ulcers with topical application of cannabis extracts (also commonly known as “Simpson Oil”). Interestingly, cannabis ingestion is suggested to allow for a safe reduction of prescription insulin, and in some cases it may be stopped entirely.

Cannabis users in general are thought to show a lower risks of developing diabetes.

Several epidemiological studies, observing large population cohorts have investigated a possible correlation between cannabis use and diabetic incidence.

The results reported by researchers at the University of California, Los Angeles, showed that from 10,896 US adults, past and present cannabis consumers possessed a lower prevalence of adult onset diabetes, even after authors adjusted for social variables (ethnicity, level of physical activity, age etc.), despite all groups possessing a similar family history of diabetes.

The authors concluded, ʺOur analysis (NHANES, National Health and Nutrition Examination Survey data from 2005 to 2010) showed that participants who used marijuana had a lower prevalence of Diabetes Mellitus and lower odds of Diabetes Mellitus relative to non‐marijuana users.ʺ [1]

These studies were matched by results obtained from two independent trials run by Harvard Medical School and the Beth Israediabetesl Deaconess Medical Center in Boston, investigating the consequences of cannabis consumption on fasting insulin, glucose and insulin resistance in a large male population (4,657 subjects).

High fasting insulin levels are considered evidence of insulin resistance — the inability of the body to respond properly to insulin, which is a risk factor for pre-diabetes. Amongst the cannabis users there were 16% lower fasting insulin levels and plasma glucose and 17 % lower levels of insulin resistance.

What did they find?

They found that cannabis use was positively associated with lower body mass index, lower waist circumference and higher levels of HDL‐C [high‐density lipoprotein or ʹgoodʹ cholesterol].

These associations were attenuated among those who reported using marijuana at least once, but not in the past 30 days, suggesting that the impact of marijuana use on insulin and insulin resistance exists during periods of recent use.

Previous observational data has similarly reported that the prevalence of obesity in the general population is sharply lower among cannabis consumers than among non-users, and that cannabis users posses smaller waist circumferences than non-users. [2, 3, 4]

http://beforeitsnews.com/mediadrop/uploads/2015/08/3707d4fdff02b0c9234d69638d507dcbc284428b.jpgThese claims, as well as the preclinical data, may seem contradictory with the canonic association of cannabis and increased appetite and caloric intake.

Yet, the “munchies” are triggered by acute rather than chronic doses. 

This is due to effects of cannabis altering the activity of appetite controlling hormones (like ghrelin) in the liver as well as in the adipose tissue, which provoke a range of effects on expression of glucose and insulin in the blood.

Specifically, cannabis increases the levels of AMPK in the heart, whilst decreasing AMPK activity in the liver and adipose (fatty) tissue.

http://selfhacked.com/wp-content/uploads/2014/11/F3.large-2.jpg

AMPK (AMP-activated protein kinase)

AMPK integrates nutritional and hormonal signals to maintain cellular energy balance and execute appropriate metabolic functions. It is also implicated in the central regulation of food intake and energy expenditure in response to hormonal cues including leptin, ghrelin and adiponectin.

There is a strong correlation between low AMPK activation state, mainly due to over-nutrition and lack of exercise, and metabolic disorders associated with insulin resistance, obesity and sedentary lifestyle. [4,5].

https://fandm.spoonuniversity.com/wp-content/uploads/sites/73/2015/03/tumblr_n69o5nGjHb1rp8dyco1_1280-1024x679.jpgThus, cannabis lowers blood glucose, which is evident to inexperienced users, who may feel dizziness or weakness after dosing; Despite the appetite-stimulating effects generated by lower plasma glucose and possibly some intrinsic effects of cannabis on leptin-ghrelin signalling, it is a plant that plays an important role in body weight and fat maintenance, protecting against diabetes onset. [5]

Cannabis itself, when administered to obese rats, was associated with weight reduction and an increase in pancreatic weight, implying β-cell protection (insulin-producing cells) [8].

Rodent models of Type 1 Diabetes (early onset) demonstrated how THC treatment decreased inflammatory mediators (such as interferon-γ, TNF-α) in the pancreatic islets, which was associated with improved insulin content and blood glucose levels. [17, 18].

Moreover, a study in rodents showed that the endogenous activator for CB-2 receptors, (2- arachidonoylglycerol or 2-AG in short), is significantly lower in diabetic mice, suggesting impaired CB2 receptor regulation in metabolic syndrome. [21, 22] This data was confirmed from a very recent publication, that observed 501 obese children in Italy, and found out their less functional CB2 receptors. The children treated with a CB2 selective agonist were found to reverse the obesity-related inflammatory effects. [25]

Learn more about cannabinoid receptors and their involvement in maintaining human health in our article Caution: understanding the Endocannabinoid System might change your life!

Non-psychotropic cannabinoids prevent diabetes

There is a robust body of evidence indicating that cannabinoids are agents capable of modifying energy metabolism and diabetes progression, providing support for symptomatic relief for those suffering from it. [6,7]

Cannabidiol (CBD) & diabetes prevention / reduction

CBD is a non-psychotropic molecule contained in the cannabis plant at different concentrations, depending from strain to strain. Many CBD extracts are now viable on the market (although we recommend to check this article to make sure you are purchasing a safely produced extract).

A 2006 study published in the Journal of Autoimmunity, reported that daily injections of 5 mg /per kg of the non‐psychoactive cannabinoid CBD, significantly reduced the incidence of hereditary diabetes in mice. Investigators reported that amongst the genetically diabetic (NOD) mice, 86% of untreated control rodents developed diabetes. By contrast, only 30% of CBD‐treated mice developed the disease. [9]

Not only was the incidence of diabetes lower with the use of CBD, but also the overall onset occurred markedly later, as shown in a separate study. Indeed, researchers found that in an induced high fat diet model, (in order to investigate diabetes Type 2), all control mice 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. [10]

http://icanhasscience.com/wp-content/uploads/2010/10/Rat-dads-and-their-diets-e1287977097515.jpgOther data confirmed these findings, reporting that CBD prevents the initiation of diabetes in non obese diabetic (NOD) mice and, importantly, ameliorates the manifestations of the disease in NOD mice, which are either in a latent diabetes stage or with only initial symptoms of diabetes. [4, 11, 12]

CBD protective effects induced qualitative modification of the pancreatic islets infiltrated by mononuclear cells, and inhibited the specific destruction of the islets, ultimately preventing further degeneration of the cells deputed to insulin release. [4]

CBD ameliorates symptoms

CBD exerts beneficial actions against diabetes and some of its complications.

Some of the complications that can arise from Type 1 and Type 2 diabetes are neuropathy, glaucoma, high blood pressure, and peripheral vascular disease.

Medical marijuana has been studied to see its effects on each of these conditions, with positive outcomes, you can click on the links to read more about each of these conditions & cannabinoid therapy.

– Cardiomyopathy

Activation of the cannabinoid system was reported to protect against the pro-inflammatory pathways (ROS-MAPK), which play a key role in the development of diabetic cardiovascular dysfunction. [19]

More recently, researchers from the United States, Switzerland and Israel reported in the Journal of the American College of Cardiology that the administration of CBD reduces various symptoms of diabetic cardiomyopathy (weakening of the heart muscle) in a mouse model of type 1 diabetes.

The authors concluded, “these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications.ʺ [20]

http://www.cormedicalgroup.com/wp-content/uploads/2013/02/dilated-cardiomyopathy-diagram.jpg

– Blindness

Writing in the March 2006 issue of the American Journal of Pathology, researchers at the Medical College of Virginia reported that rats treated with CBD for periods of one to four weeks experienced significant protection from diabetic retinopathy, one the leading cause of blindness in working‐age adults. [13]

CBD therapy was found to exert significant therapeutic benefits against diabetic complications such as retinopathy also by other investigators, who showed how CBD significantly reduces oxidative stress and prevents retinal cell death and vascular hyperpermeability in the diabetic retina in an experimental model of diabetic retinopathy [11,12];

http://www.improveeyesighthq.com/images/Diabetic-Retinopathy.jpg

In addition, CBD exerts anti-inflammatory and neuroprotective effects in retinal microglial cells (the immune cells of the brain).[14]

For the curious readers, the proposed mechanism by which CBD exerts a protective effect against diabetes-induced retinal damage, may be linked to inhibition of adenosine uptake. [15]pablo-8-copy-3

– Nephropathy

CBD, a molecule capable to bind Cannabinoid-2 Receptors, was found to ameliorate kidney problems in patients with advanced diabetic nephropathy; This effect was also suggested for other non-psychotropic CB2 activators, THCV and β-Caryophyllene.

Tetrahydrocannabivarin (THCV) & diabetes prevention / reduction

– Improves insulin sensitivity

The lesser known cannabinoid THCV, seems to be another promising agent in the fight against diabetes.

A 2013 study assessing the effect of THCV in genetically modified obese mice, reported that the cannabinoid’s administration produced several metabolically beneficial effects relative to diabetes, including reduced glucose intolerance, increase energy expenditure, improved glucose tolerance, improved liver triglyceride levels, and increased insulin sensitivity.

The authors concluded, ʺBased on these data, it can be suggested that THCV may be useful for the treatment of the metabolic syndrome and/or type 2 diabetes (adult onset diabetes), either alone or in combination with existing treatments.ʺ [16]

– Weight loss

D9-THCV, at doses as low as 3 mg/kg, shares the ability of synthetic CB1 antagonists to reduce food intake and body weight both in fasted and non fasted mice, which granted this compound the appellative of “hypophagic” [23]

http://cannamagazine.com/wp-content/uploads/2015/01/bowl.jpg

Cannabis as a unique functional food

Cannabis is the sole source of a patented lipophillic antioxidants and neuroprotectants, a broad terpenoid profile with complementary immunologic activity as well as altering CB2 binding affinity through allosteric modulation.
In addition cannabis is the unique source of the essential cannabinoid acids that aid in down regulation of the inflammatory arm of the immune system, mitigating oxidative associated diseases, ranging from diabetes, cancer, CNS and myocardial degenerative and ischemic conditions and autoimmune disorders.

Says Dr W. Courtney, recommending raw, unadulterated cannabis in form of juices and smoothies.

If you are interested to know more on raw Cannabis we suggest you to check here.

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References:

[1] Rajavashisth TB, Shaheen M, Norris KC, et al. Decreased prevalence of diabetes in marijuana users: cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) III. BMJ Open.2012;2:e000494.

[2] Penner et al. 2013. Marijuana use on glucose, insulin, and insulin resistance among US adults. American Journal of Medicine 126: 583‐589

[3] Strat and Foll. 2011. American Journal of Epidemiology 174: 929‐933. ʺMarijuana users have better blood sugar control.ʺ

[4] Weiss, L. et al. (2008) Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacology 54, 244–249

[5] AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome.Ruderman N, Prentki M Nat Rev Drug Discov. 2004 Apr;3(4):340-51.

[6] Croxford and Yamamura. 2005. Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases. Journal of Neuroimmunology 166: 3‐18.

[7] Lu et al. 2006. The cannabinergic system as a target for anti‐inflammatory therapies. Current Topics in Medicinal Chemistry 13: 1401‐1426.

[8] Levendal R, Schumann D, Donath M, Frost C. Cannabis exposure associated with weight reduction and b -cell protection in an obese rat model. Phytomedicine. 2012;19:575-582.

[9] Weiss et al. 2006. Cannabidiol lowers incidence of diabetes in non‐obese diabetic mice. Autoimmunity 39:2

[10]Ibid

[11] Zuardi, A.W. (2008) Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev. Bras. Psiquiatr. 30, 271– 280

[12] Mechoulam, R. et al. (2007) Cannabidiol recent advances. Chem. Biodivers. 4, 1678–1692

[13] El‐Remessy et al. 2006. Neuroprotective and blood‐retinal barrier preserving effects of cannabidiol in experimental diabetes. American Journal of Pathology 168: 235‐244.

[14] El-Remessy, A.B. et al. (2008) Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: critical role of p38 MAPK activation. Mol. Vis. 14, 2190–2203

[15] Liou, G.I. et al. (2008) Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor. Invest. Ophthalmol. Vis. Sci. 49,5526–5531

[16] Wargent et al. 2013. The cannabinoid Δ9‐tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutrition & Diabetes 3

[17] Li, X.,Kaminski, NE and Fischer, LJ (2001). Examination of the immunosoppressive effect of D9-tetrahydrocannabinol in streptozotocin-induced autoimmune diabetes. International immunopharmacology, 1, 699-712

[18] Coskun, Z.M and Bolkent, S. (2013) Biochemical and immunohistochemical changes in D-9 tetrahydrocannabinol-treated type 2 diabetic rats. Acta Histochemica. S0065-1281(13), 112-118

[19] Rajesh, M Pan, H Mukhopadhyay, P. et al. (2007) Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis. Journal of Luokocyte Biology. 82, 1382-1389

[20] Rajesh et al. 2010. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. Journal of the American College of Cardiology 56: 2115‐2125.

[21] Barutta, F Piscitelli, F Pinach, S et al. (2011) Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. Diabetes, 60, 2386-2396

[22] Pertwee, R G (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philosophical Transactions of the Royal Society. Series B, Biological Sciences, 367, 3353-3363

[23] Riedel, G. et al. (2009) Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br. J. Pharmacol. 156, 1154–1166

[24] Cannabis as a unique functional food, Courtney, W (2010) Treating Yourself Issue, 24

[25] F Rossi,G Bellini,L Luongo et al. (2016) Cannabinoid receptor 2 as anti-obesity target: inflammation, fat storage and browning modulation. The Journal of Clinical Endocrinology & Metabolism 0 0:0

Viola Brugnatelli

Viola Brugnatelli is a Neuroscientist specialised in Cannabinoid circuitry & GPCRs signalling. Her academy and research training let her gain extensive experience on medical cannabis and terpenes both from preclinical as well as clinical perspective. In her vision, collective human knowledge behold the power for overall improvement of life, thus, it should be accessible and shareable. Viola is Founder of the science online magazine Nature Going Smart, and works as a consultant for companies & individual patients, as a speaker at seminars and workshops and as a lecturer in a CME course on Medical Cannabis in Italy, at the University of Padua.

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