british journal of diabetes & vascular disease-2010-frisher-267-73

THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 267

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Abstract

This paper reviews the role of cannabis in diabetes. Cannabis is by far the most commonly used illicit drug in Britain, though its use may be declining. There are an estimated 50,000100,000 people with dia-betes using cannabis, with an unknown number using the drug for self-medication. The evidence of the effects of cannabis on diabetes is complex, ranging from anec-dotal reports of benefits and harms to experimental research on cannabinoids. The endocannabinoid system appears to have a role in the regulation of body weight and food intake, and the development of hypergly-caemia, insulin resistance and dyslipidaemia. In experi-mental models, the main psychoactive constituent of herbal cannabis, 9-tetrahydrocannabinol, has been shown to interfere with both the action of insulin and its release. The paper also considers the effects of cannabis on complications of diabetes. Experimental work has suggested a mechanism to reduce neuropathy but the only double-blind clinical trial to date of a cannabis-based drug found no difference in the ability of the cannabis-based product to relieve neuropathic pain when compared with placebo. In conclusion, new insights into the role of cannabis and cannabinoids in diabetes are emerging from this developing field of research.Br J Diabetes Vasc Dis 2010;10:267-273.

Key words: cannabis, cannabinoid, diabetes, endocannabinoid.

IntroductionThere have been claims that cannabis and its derivative com-pounds have medicinal use including use for diabetes. However, cannabis (with some limited exceptions discussed below) has no current status as a medicine since it became illegal in the UK under the Dangerous Drugs Act 1925. Cannabis is now

classified as a class B drug under the Misuse of Drugs Act 1971. The aim of this paper is to review the literature on the relationship between cannabis and diabetes. The paper is divided into three sections: (1) epidemiology of cannabis and diabetes, (2) the effects of cannabis on diabetes and (3) the effects of cannabis on diabetic complications.

Although cannabis is by far the most commonly used illicit drug in the UK,1 the term cannabis applies to a wide range of substances. Cannabis refers to a genus of flowering plants that includes three species: cannabis sativa, cannabis indica and can-nabis ruderalis.2 The taxonomy of cannabis is somewhat in dispute, however most now regard the genus cannabis to belong to the Hemp family, Cannabacea.3 These plants that have grown wild throughout the world for centuries and have had various uses, such as to make rope and textiles, as a medicinal herb and as a recreational drug.4 Cannabis plants produce cannabinoids, although there are also synthetic cannabinoids which are not found in cannabis plants.5 To date, over 60 cannabinoids have been isolated, of which THC is considered to be the primary psy-choactive component of the plant.6 The amount of THC ingredient in herbal cannabis varies from 1% up to 15%, while skunk, can

The role of cannabis and cannabinoids in diabetesMARTIN FRISHER,1 SIMON WHITE,1 GABOR VARBIRO,1 CAROLYN VOISEY,1 DHAYA PERUMAL,1

ILANA CROME,2 NAZMEEN KHIDEJA,1 JAMES BASHFORD1

The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1474651410385860 267

1School of Pharmacy, Keele University, Keele, Staffordshire, UK.2Academic Psychiatry, Keele University, Keele, Staffordshire, UK.

Correspondence to: Martin FrisherSchool of Pharmacy and Medicines Management, Keele University, Keele, Staffordshire, ST5 5BG, UK.Tel: +44(0)1782 733 568; Fax: +44(0)1782 713 586E-mail: [email protected]

Abbreviations and acronyms

[Ca2+i] intracellular calcium transients

CBD cannabidiol

GLUT glucose transporter gene

HDL high-density lipoprotein

ICAM inter-cellular adhesion molecule

IFN interferon

IGF-I insulin-like growth factor-I

IL interleukin

IP3 inositol trisphosphate

IRS insulin receptor substrate

NOD non-obese diabetic

PPAR peroxisome-proliferator-activated receptor

RIO-Diabetes Rimonabant in type 2 diabetes

RIO-Europe Rimonabant In Obesity Europe

STZ streptozotocin

Th T helper cell

THC 9-tetrahydrocannabinolTGF transforming growth factor

TNF tumour necrosis factor

TZD thiazolidinedione/glitazone

VEGF vascular endothelial growth factor

by guest on August 4, 2015dvd.sagepub.comDownloaded from

268 VOLUME 10 ISSUE 6 . NOVEMBER/DECEMBER 2010

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have up to 20% (skunk refers to a range of stronger types of can-nabis, grown either under artificial lights or in a greenhouse, often using hydroponic techniques).4 Despite concerns about increased potency, the evidence is mixed, with recent studies indicating broadly similar ranges of potency over the last 10 years.7

The only cannabinoids available as medicines in the UK are nabilone (a synthetic cannabinoid) and Sativex (cannabis plant extract containing THC and CBD) but neither are licensed for use in diabetes. Nabilone is licensed for nausea and vomiting caused by cytotoxic chemotherapy that is unresponsive to conventional antiemetics, while Sativex was granted a product licence in June 2010 as an add-on treatment for symptom improvement in multiple sclerosis patients with moderate to severe spasticity.8 Rimonabant (an inverse agonist for the cannabinoid receptor CB19), which had been licensed as an appetite suppressant, was withdrawn from the market in 2009 over concerns about psychi-atric side effects (particularly depression and suicidal ideation).10

1. Epidemiology of cannabis and diabetesIn England, 9.0% of school pupils in 2007 aged 1115 used cannabis in the last year, down from 13.4% in 2001.11 Among adults aged 1659 use in the last year was 7.9% in 20082009 compared with 10.6% in 20012002.12 Despite these reductions, cannabis is by far the most widely used illicit drug in the UK. On the basis of these figures, 2.5 million people are estimated to have used cannabis in the last year in the UK. The Independent Drug Monitoring Unit estimated there to be over 3 million regular users in 2004.13

The prevalence of diabetes in the UK in 2005 was 4.3% (type 1, 0.4%; type 2, 3.9%) among people aged 1079.14

Prevalence is linearly related to age and most type 2 diabetic patients are diagnosed in their mid-40s.15 Table 11,16 shows that most cannabis users are in their 20s and 30s while most diabetic patients are 45 and over. Extrapolating these trends would suggest there to be between 50,000 and 100,000 dia-betic patients in the UK who have used cannabis in the last year (assuming that diabetic patients use of cannabis is similar to use reported by the general population).

Figure 1 shows that diabetes has increased between 2003 and 2006 when cannabis use in England was declining. At a population level, there does not appear to be any connection between use of cannabis and diabetes. However, as discussed below (in sections 2 and 3), it is possible that there could be some link that is not revealed by the crude prevalence rates shown in figure 1.

Patterns of cannabis useSurveys only provide data on frequency of cannabis use, but as pointed out in the classic book, Drug Set and Setting,17 both the set, that is, the personality of the user, and the setting in which the drug is used are of central importance. Dutch researchers have proposed three main types of cannabis use.18 Cluster 1 consists mainly of young males (mean age 22.7 years) who use cannabis frequently and are seeking high levels of intoxication. Cluster II consists mainly of older people (mean age 27.7 years) of both sexes who seek moderate levels of intoxication. They adjust their smoking behaviour in response to the potency of the cannabis they are using. Cluster III con-sists of mature cannabis smokers (mean age 37.5 years) whose consumption is consistently high and whose pattern of use is largely unaffected by the strength of the product. There is also a possible fourth cluster of medicinal cannabis users. Although there are many issues surrounding the definition of medicinal cannabis use, a Canadian study suggested that 2% of the general population use marijuana for medical purposes.19 At

Table 1. Prevalence of self reported cannabis use and diabetes by

agebands

Cannabis Diabetes

Prevalence (%) of cannabis

in England and Wales,

200820091

Prevalence (%) of

diagnosed diabetes

in England, 200616

Ageband Ageband

1619 18.3 1624 0.8

2024 19.1 2534 1.2

2529 12.1 3544 1.8

3034 8.2 4554 4.8

3544 4.6 5564 7.2

4554 2.4 6574 12.9

5559 1.1 75+ 11.7

Sex Sex

Men 10.6 Men 5.6

Women 5.2 Women 4.2

Note: agebands for cannabis and diabetes do not correspond.

Figure 1. Self-reported rates of cannabis use and diabetes in England, selected years 19932006

0.0

2.0

4.0

6.0

8.0

10.0

12.0

1993 1994 1998 2003 2006

% o

f pop

ulat

ion

Self-reported diagnosis of either type 1 or type 2diabetes.Self-reported using cannabis in last year (aged 1659)



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present there are no data to indicate if this figure applies to diabetic patients in Canada only, or elsewhere. As noted in this paper, there are anecdotal reports of medicinal use by diabetic pati ents. Another factor that may be important is the increase in cannabis dependency particularly in the 1824-year group in the UK. Indeed over 90% of young people who access specialist drug/alcohol services have problems with alcohol or cannabis.20

Although this paper is concerned with cannabis, the vast majority of cannabis use in the UK is in combination with tobacco, which is known to be especially harmful to people with diabetes. In a qualitative study of young cannabis users several reported how smoking joints had been a gateway to smoking cigarettes. While most wanted to quit smoking ciga-rettes, cannabis use reinforced their cigarette smoking and few wanted to stop using cannabis.21

Cannabis harm and schizophrenia: lessons for diabetes research?The debate surrounding the role of cannabis as a cause of schizophrenia illustrates the complexities of drawing firm con-clusions on cannabis-related harm. A recent review22 concludes, cannabis use may be an independent risk factor for the devel-opment of psychotic disorders. Increasing cannabis use in the 1990s has been linked to increased incidence of psychoses.20 However, others have concluded that the contentious issue of whether cannabis use can cause serious psychotic disorders that would not otherwise have occurred cannot be answered from the existing data.21 It has been suggested that rising cannabis use in the UK over the 30 years between 1970 and 2000, would have led to an increase in the schizophrenia prevalence of 19% between 1990 and 2010, assuming increased risk among can-nabis users.22 However, between 1996 and 2005 the incidence and prevalence of schizophrenia and psychoses were either stable or declining in the UK,23 casting doubt on the causal model. However, the issue remains controversial with different methodologies, populations and exposures (e.g. type and frequency of cannabis) producing a range of interpretations.

2. Effects of cannabis on diabetesThe previous section raises the issue of patients using cannabis to self-medicate for certain conditions.24 There are well-documented reports of cannabis use leading to reduced headache, migraine and post-surgery pain.7 However, in relation to diabetes, there are only anecdotal reports of cannabis use reducing stress levels and blood sugar levels.

There are also numerous websites that advocate or support medical uses of cannabis, often as part of wider campaigns concerning cannabis use. In the majority of cases the claims that are made about the beneficial effects in diabetes appear to be unsubstantiated, disingenuous or inaccurate. Claims are often not supported by references at all, or are supported by refer-ences of uncertain quality. In other cases, claims are made that appear to represent a partial but wholly misleading interpreta-tion of study findings. An example of this is the claim that can-nabis use can prevent diabetes, often supported (if referenced

at all) by citing experimental animal studies that used CBD (usu-ally only present in small quantities in herbal cannabis). Such animal studies, for example those by Weiss and colleagues,27 make no such claims for cannabis.

The evidence for whether herbal cannabis has beneficial or adverse effects in diabetes remains inconclusive. Various web-sites make anecdotal reports about cannabis having beneficial effects, such as stabilising or lowering blood sugar.28,29 Some also report adverse effects, such as Stark,25 who comments thatcannabis may cause decreased judgement and increased appe-tite, but offers no additional information about these effects (e.g. whether judgement includes awareness of impending hypoglycaemia).25 However, physiological and pharmacological studies do not provide unequivocal support for anecdotal reports and claims of benefit of herbal cannabis in diabetes; rather, if anything, they point to the situation being highly complex.

THC, the major active component of herbal cannabis, appears to principally exert its pharmacological action by stimulating the endocannabinoid system, via the cannabinoid cell-surface recep-tors CB1 and CB2. This system appears to have a role in the regulation of body weight and food intake, and the development of hyperglycaemia, insulin resistance and dyslipidaemia.30-33

In various experimental models THC was shown to interfere with both the action of insulin and its release. In type 2 diabe-tes the glucose uptake of cells is impaired due to insulin resis-tance. THC can increase insulin-induced glucose uptake, as demonstrated in a study in cultured adipocytes.34 It was also shown that TNFa affects the effectiveness of insulin on glucose uptake by interfering with insulin signalling,35 and the expres-sion of GLUT4 in adipocytes.36 THC has been demonstrated to decrease the level of TNFa in various experimental models.30,37 Studies have also demonstrated the increased gene expression of IRS-1, IRS-2 and GLUT4 by THC, suggesting that this com-pound exhibits an insulin-sensitising effect.30 Endocannabinoid receptors (CB1 and CB2 receptors as well as other yet unclassi-fied receptors) stimulate intracellular calcium transients [Ca2+]i leading to the release of insulin.38 In a study using RINm5F rat insulinoma -cells, it was shown that CB1 and CB2 receptor agonists stimulate insulin secretion via the phosphatidyl inositolphospholipase-C pathway and the mobilisation of [Ca2+]i through IP3 receptors.39 Furthermore, THC stimulated the release of insulin from rat pancreatic islet cells by increasing the activity of lipooxygenase and by accelerating the metabolism of arachidonic acid. Inhibition of lipooxygenase (with inhibitor 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline hydrochlo-ride) inhibited insulin release in cells exposed to either glucose or THC.40 THC was also shown to affect the expression of beta-type TGF (TGF-1, 2 and 3) as well as the expression of IGF-I in mice.41 It is also likely that THC enhances insulin action. Although these data suggest that cannabis could impact on glucose metabolism and the diabetic patient by simultaneously increasing the expression and release of insulin from the pan-creatic -cells and also by sensitising the peripheral tissues to enhance glucose uptake, the supporting evidence is based on studies carried out in cultured cells and not in diabetic patients.



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Other mechanisms have also been proposed. In a study using CBD, a non-psychoactive cannabinoid, the development of dia-betes in NOD mice was prevented.42,43 CBD treatment of mice with latent diabetes or with initial symptoms of diabetes showed improvement in disease manifestation.23 While no direct effect of CBD on glucose levels in the blood were found, CBD treat-ment inhibited IL-12 production by splenocytes. This cytokine plays a major role in autoimmunity including diabetes. Also shown in a prior study, pro-inflammatory cytokines, IFN-g and TFNa were reduced and destruction of pancreatic islets inhibited. These data point possibly to an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.23

Recently, therapeutic actions of cannabinoids on the nuclear receptor superfamily ,the PPARs, have also been suggested.44 The PPARs regulate cell differentiation and lipid metabolism.45 PPARg in particular, plays a role in the regulation of adipocyte formation, insulin sensitivity and inflammation.46 The TZDs, ligands of PPARg, are used clinically in the management of type 2 diabetes to improve insulin sensitivity. The side-effect profile of the TZDs (weight gain, oedema and increased plasma lipoproteins)46 has led to suggestions that partial or weak agonists may be beneficial for low-level PPARg activation. Endogenous, phytoderived orsynthetic cannabinoids that do not activate PPARs to the same degree as the current TZDs may therefore prove successful.

In human studies stimulation of CB1 receptors (e.g. by THC, see table 2) has been shown to cause increased food intake, as well as mediating the psychoactive effects of cannabis.29 Blockade of these receptors, such as by treatment with the selective CB1 receptor antagonist rimonabant, has been shown to have beneficial effects on diabetes, as well as causing weight loss. In the RIO-Europe trial, which involved 1,507 obese but non-diabetic patients, rimonabant significantly reduced waist

circumference, triglycerides and insulin resistance, and increased HDL-cholesterol.48 The RIO-Diabetes trial found that in obese or type 2 diabetic patients inadequately controlled on metformin and sulphonylureas, rimonabant also reduced glycosylated haemoglobin, as well as body weight.49 However, as noted above rimonabant was withdrawn from the UK market in 2009 and there are now no CB1 receptor antagonists commercially available for human use in the UK.

In contrast to CB1 receptor stimulation, CB2 receptors are thought to have an anti-inflammatory effect (mediated by the modulation of cytokine production) when stimulated, for exam-ple by THC. Steffens and colleagues50 found that low-dose administration of THC reduced the progression of atherosclerosis (which is characterised by inflammation) in an experimental mouse model. This effect appeared to have been mediated by CB2 receptors, as it was not seen in mice that had been pre-treated with a CB2 receptor antagonist and the dose of THC used was less than would usually stimulate central CB1 receptors. However, as Roth argues28 it would be very hard to achieve this effect by smoking cannabis, since the blood concentration of THC required was found to be within a very narrow range (higher and lower concentrations were ineffective). It is also unknown whether this effect could be replicated in humans, given that there are differences between the mouse model and human atherosclerosis.28 Similarly, it is not known what effect this may have on the development of coronary heart disease or type 2 diabetes in humans. However, these findings should also be seen in the light of a recent review on cannabis harm, which did not specifically mention diabetes, but noted that cannabis use may be a risk for coronary events, especially in those with pre-existing cardiovascular disease.51 This is potentially important since CHD causes almost 60% of deaths among diabetic patients.52

Table 2. Summary of reported clinical effects of cannabinoids on type 2 diabetes in humans

Clinical effect Cannabinoid Proposed mechanism of action Evidence

Reduction in fasting plasma glucose,

fasting plasma insulin and insulin

resistance in non-diabetic patients

Rimonabant CB1 antagonism (i.e. suppression of

endocannabinoid overactivity)

RIO-Europe RCT: 20 mg daily rimonabant vs.

placebo in 1,507 obese patients (either BMI 30

or BMI 27 + dyslipidaemia or hBP or both)

Reduces HbA1C in overweight or

obese diabetic patients

Rimonabant CB1 antagonism (i.e. suppression of

endocannabinoid overactivity)

RIO-Diabetes RCT: 5 mg or 20 mg daily

rimonabant vs placebo in 1,047 overweight or

obese type 2 diabetic patients on metformin or

sulphonylurea monotherapy and hypocaloric diet

Analgesia (but no more efficacious

than placebo) in painful DPN

Sativex (THC and CBD) Insufficiently understood RCT of Sativex vs placebo in 30 patients with DPN

found significant change in pain score in both

groups but difference in quality of life assessments

Depression appeared to be a major confounder

Key: BMI = body mass index; BP = blood pressure; CBD = cannabidiol; DPN = diabetic peripheral neuropathy; HbA1C = glycosylated haemoglobin;RCT = randomised controlled trial; RIO-Diabetes = Rimonabant in type 2 diabetes; RIO-Europe = Rimonabant In Obesity Europe; THC = 9-tetrahydrocannabinol



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In short, there is mounting evidence pointing to dysfunc-tion of the endocannabinoid system having an important role in the development of type 2 diabetes and obesity.29 However, effectively targeting this system to treat or prevent type 2 dia-betes appears to be far more likely with individual cannabinoids than herbal cannabis. This equally appears to be the case with cannabinoids being used in the treatment and prevention of the complications of diabetes, as this review will now consider.

3. Effects of cannabis on complications of diabetes.Key complications observed in diabetic patients result from micro- and macro-vasculature changes, leading to problems such as cardiovascular disease, retinopathy and nephropathy.53-55 In this section, we aim to review the literature regarding each of these three complications and, where appropriate, make links between animal and human data.

NeuropathyNeuropathy is a commonly encountered complication of diabe-tes and can manifest in any of the body systems, resulting in numbness, pain and weakness. Protection against oxidative stress has been implicated as being important in reducing neu-ropathy in experimental settings. In STZ-induced diabetic rats, C. sativa extract increased the level of reduced glutathione in the liver, resulting in a significant reduction in liver lipid peroxidation, in addition to relieving mechanical allodynia, when administered repeatedly.56 In direct contrast to these findings, a double-blind clinical trial of Sativex (which contains THC and CBD) found no difference in the ability of the cannabis-based product to relieve neuropathic pain when compared with placebo.57 Of note were the observations that depression influenced the baseline pain scores and that patients showed improvement of symptoms regardless of the treatment regimen, which demonstrates the strong association of depression with pain perception.

RetinopathyRetinopathy in diabetic patients is the leading cause of prevent-able blindness in people of working age and is associated with an increased risk of other vascular complications including coronary heart disease and stroke.58 Research in rat models of diabetes has demonstrated that the cannabinoid CBD exerts protection against damage to the bloodbrain barrier during the initial stages of diabetes. This protection appears to be linked to a reduction in expression of inflammatory and adhe-sion molecules including TNF and ICAM-1, among others,59,60 in common with the immunomodulatory functions previously attributed to CBD where a switch from Th1 to Th2 dominance was observed in NOD mice.61 It is essential to note, however, that the levels of CBD found in herbal cannabis are very low so its relevance to the clinical management of retinopathy remains unclear at this time.

Cardiovascular complicationsDiabetic patients presenting with micro- and macro-vascular complications reportedly show significant increases in serum

VEGF concentration, compared with those patients who did not present with these symptoms.56 In addition, increased serum levels of VEGF are observed in diabetic patients compared with controls, and also in diabetic patients suffering with proliferative retinopathy compared with those without this complication.62 Cannabinoid treatment decreased serum VEGF levels, the result-ing reduction in VEGF leading to an improvement of symptoms for the patient. VEGF is one of a profile of cytokines/inflammatory mediators whose expression is attenuated by treatment with CBD,56 other cytokines showing a significant reduction in serum level on CBD treatment include IFNg, TNFa and Th1-associated cytokines produced by activated T-lymphocytes in vitro.56 Indeed, CBD treatment appeared to induce a cytokine bias away from the Th1 type, favouring Th2 cytokines such as IL-10. In parallel with this change in cytokine profile, insulitis was reduced in the pancreatic islets of treated NOD mice compared with controls.57 Taken together, these results suggest an immunomodulatory role for cannabinoids in addition to their previously documented anti-inflammatory effects.

ConclusionsThis review has demonstrated that the evidence relating cannabis to diabetes is highly complex and of variable quality. Some evidence is anecdotal, while some is experimental (i.e. in vitro) and difficult to extrapolate to humans. The issue of standardisation of the illicit drug harms has been in the spot-light since the publication in The Lancet of development of a rational scale to assess the harm of drugs of potential misuse63 in which cannabis is ranked at the lower end of the harm spectrum. With regard to herbal cannabis, the potential risks and benefits for diabetic patients remain unquantified at the present time. Cannabinoids appear to affect biochemical path-ways associated with diabetes but it is too early to say whether this will lead to new treatments.

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Key messages

There may be 50,000100,000 diabetic patients in the UK who use cannabis

Herbal cannabis use has been linked to harms andbenefits for diabetic patients

Experimental research indicates that the endocannabinoid system has a role in mechanisms central to diabetes

New insights into the relationship between cannabis, cannabinoids and diabetes are emerging



REVIEW

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