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The role of cannabis and cannabinoids in

diabetes
MARTIN FRISHER,1 SIMON WHITE,1 GABOR VARBIRO,1 CAROLYN VOISEY,1 DHAYA PERUMAL,1
ILANA CROME,2 NAZMEEN KHIDEJA,1 JAMES BASHFORD1

Abstract

his 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 diabetes 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 anecdotal 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 experimental 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 cannabisbased 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.

Introduction
There have been claims that cannabis and its derivative compounds 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
1

School of Pharmacy, Keele University, Keele, Staffordshire, UK.

Academic Psychiatry, Keele University, Keele, Staffordshire, UK.

Correspondence to: Martin Frisher

School of Pharmacy and Medicines Management, Keele University,
Keele, Staffordshire, ST5 5BG, UK.
Tel: +44(0)1782 733 568; Fax: +44(0)1782 713 586
E-mail: m.frisher@keele.ac.uk

Abbreviations and acronyms

[Ca2+i]
CBD
GLUT
HDL
ICAM
IFN
IGF-I
IL
IP3
IRS
NOD
PPAR
RIO-Diabetes
RIO-Europe
STZ
Th
THC
TGF
TNF
TZD
VEGF

intracellular calcium transients

cannabidiol
glucose transporter gene
high-density lipoprotein
inter-cellular adhesion molecule
interferon
insulin-like growth factor-I
interleukin
inositol trisphosphate
insulin receptor substrate
non-obese diabetic
peroxisome-proliferator-activated receptor
Rimonabant in type 2 diabetes
Rimonabant In Obesity Europe
streptozotocin
T helper cell
9-tetrahydrocannabinol
transforming growth factor
tumour necrosis factor
thiazolidinedione/glitazone
vascular endothelial growth factor

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 cannabis 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 psychoactive component of the plant.6 The amount of THC ingredient
in herbal cannabis varies from 1% up to 15%, while skunk, can

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have up to 20% (skunk refers to a range of stronger types of cannabis, 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 psychiatric side effects (particularly depression and suicidal ideation).10

1. Epidemiology of cannabis and diabetes

In 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 2008
2009 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

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

agebands

Patterns of cannabis use

Surveys 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 consists 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

Diabetes
Prevalence (%) of cannabis

Prevalence (%) of

in England and Wales,

diagnosed diabetes

200820091

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

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

selected years 19932006

Self-reported diagnosis of either type 1 or type 2

diabetes.
Self-reported using cannabis in last year (aged 1659)
12.0
10.0
% of population

Cannabis

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 diabetic 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.

8.0
6.0
4.0
2.0
0.0

Note: agebands for cannabis and diabetes do not correspond.

1993

1994

1998

2003

2006

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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
patients. 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 cigarettes, 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 conclusions on cannabis-related harm. A recent review22 concludes,
cannabis use may be an independent risk factor for the development 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 cannabis 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 diabetes

The 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 references of uncertain quality. In other cases, claims are made that
appear to represent a partial but wholly misleading interpretation of study findings. An example of this is the claim that cannabis use can prevent diabetes, often supported (if referenced

at all) by citing experimental animal studies that used CBD (usually 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 websites 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 that
cannabis may cause decreased judgement and increased appetite, 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 receptors 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 diabetes the glucose uptake of cells is impaired due to insulin resistance. 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 expression 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 compound exhibits an insulin-sensitising effect.30 Endocannabinoid
receptors (CB1 and CB2 receptors as well as other yet unclassified 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 inositol
phospholipase-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 hydrochloride) inhibited insulin release in cells exposed to either glucose
or THC.40 THC was also shown to affect the expression of betatype TGF (TGF-b1, b2 and b3) 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 pancreatic b-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 diabetes 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 treatment 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 or
synthetic 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 example 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 pretreated 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

Reduction in fasting plasma glucose,

Rimonabant

CB1 antagonism (i.e. suppression of

RIO-Europe RCT: 20mg daily rimonabant vs.

endocannabinoid overactivity)

placebo in 1,507 obese patients (either BMI 30

fasting plasma insulin and insulin

or BMI 27 + dyslipidaemia or hBP or both)

resistance in non-diabetic patients

Reduces HbA1C in overweight or

Evidence

Rimonabant

obese diabetic patients

CB1 antagonism (i.e. suppression of

RIO-Diabetes RCT: 5 mg or 20mg daily

endocannabinoid overactivity)

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

Sativex (THC and CBD)

Insufficiently understood

than placebo) in painful DPN

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 dysfunction 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 diabetes 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.

Neuropathy
Neuropathy is a commonly encountered complication of diabetes 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 neuropathy 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.

Retinopathy
Retinopathy in diabetic patients is the leading cause of preventable 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 adhesion 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 complications
Diabetic patients presenting with micro- and macro-vascular
complications reportedly show significant increases in serum

Key messages
There may be 50,000100,000 diabetic patients in the

UK who use cannabis

Herbal cannabis use has been linked to harms and

benefits 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

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 resulting 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 IFN, TNF 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.

Conclusions
This 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 spotlight 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 pathways associated with diabetes but it is too early to say whether
this will lead to new treatments.

References
1. Hoare J, Flatley J. Drug Misuse Declared: Findings from the 2007/08
British Crime Survey, England and Wales. London: Home Office, 2008.
2. Anonymous. Marijuana. www.a1b2c3.com/drugs/mjgrow9d.htm
(Accessed 20 August 2010)

THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

Downloaded from dvd.sagepub.com by guest on August 4, 2015

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REVIEW

3. Schultes RE, Hofmann A, Rtsch C. The nectar of delight. In: Plants of the
Gods, 2nd edn (Healing Arts Press, Rochester, Vermont, 2001) 92-101.
4. Royal College of Psychiatrists. Cannabis and mental health. www.
rcpsych.ac.uk/mentalhealthinfo/problems/alcoholanddrugs/cannabis.
aspx. (Accessed 20 August 2010)
5. Frank M. The Marijuana Growers Guide. London: Atlantic Books, 1988.
6. Downer EJ, Campbell, VA. Phytocannabinoids, CNS cells and development: A dead issue? Drug Alcohol Rev 2010;29:91-8.
7. Hardwick S, King L. Cannabis Potency Study. London: Home Office,
2008.
8. Medicines and Healthcare Products Regulatory Agency. Sativex
Oromucuscal spray. London: MHRA, 2010.
9. Fong TM, Heymsfield SB. Cannabinoid-1 receptor inverse agonists:
current understanding of mechanism of action and unanswered questions. Int J Obes (Lond) 2009;33:947-55.
10. European Medicines Agency. Acomplia (rimonabant): withdrawal of the
marketing authorization in the European Union. London: EMEA, 2009
11. Diment E, Harris J, Jotangia D et al. Smoking, drinking and drug use
among young people in England in 2008. London: NHS Information
Centre for Health and Social Care, 2009.
12. Hoare J. Drug Misuse Declared: Findings from the 2008/09 British
Crime Survey England and Wales. London: Home Office, 2010.
13. Independent Drug Monitoring Unit. www.idmu.co.uk/cannabis-use-inbritain.htm. (Accessed 20 August 2010).
14. Masso Gonzalez EL, Johansson S, Wallander MA , Garcia Rodriguez LA.
Trends in the prevalence and incidence of diabetes in the UK: 1996
2005. J Epidemiol Community Health 2009;63:332-6.
15. Koopman RJ, Mainous AG III, Diaz VA, Geesey ME. Changes in age at
diagnosis of type 2 diabetes mellitus in the United States, 1988 to
2000. Ann Fam Med 2005;3:60-3.
16. Nutt D, King LA, Saulsbury W, Blakemore C. Development of a rational
scale to assess the harm of drugs of potential misuse. Lancet 2007;
369:1047-53.
17. Craig R, Mindell J (eds). Health Survey for England 2006: Volume 1
Cardiovascular Disease and Risk Factors in Adults. London: The NHS
Information Centre for Health and Social Care, 2008.
18. Zinberg N. Drug, Set, and Setting. New Haven: Yale University, 1984.
19. Advisory Committee on the Misuse of Drugs. Cannabis: Classification
and Public Health. 2008. www.homeoffice.gov.uk/publications/drugs/.../
acmd-cannabis-report-2008. (Accessed 20 August 2010).
20. Anonymous. How many people in the US use medical marijuana?
http://medicalmarijuana.procon.org/view.answers.php?questionID=
001199 (Accessed 20 August 2010).
21. National Treatment Agency for Substance Misuse. NTA business plan
201011. London: NTA, 2010.
22. Amos A, Wiltshire S, Bostock Y, Haw S, McNeill A. You cant go without a fag...you need it for your hash: a qualitative exploration of
smoking, cannabis and young people. Addiction 2004;99:77-81.
23. Le Bec PY, Fatsas M, Denis C et al. Cannabis and psychosis: search of
a causal link through a critical and systematic review. Encephale 2009;
35:377-85.
24. McLaren J, Silins E, Hutchinson D et al. Assessing evidence for a causal
link between cannabis and psychosis: A review of cohort studies. Int J
Drug Policy 2010;21:10-19.
25. Hickman M, Vickerman P, Macleod J et al. Cannabis and schizophrenia:
model projections of the impact of the rise in cannabis use on historical
and future trends in schizophrenia in England and Wales. Addiction
2007;102:597-606.
26. Frisher M, Crome I, Martino O, Croft P. Assessing the impact of cannabis use on trends in diagnosed schizophrenia in the United Kingdom
from 1996 to 2005. Schizophr Res 2009 ;113:123-8.
27. Independent Drug Monitoring Unit. Cannabis and Stress Anxiety. http://
www.idmu.co.uk/canstressdepres.htm. (Accessed 20 August 2010).
28. Weiss L, Zeira M, Reich S, et al. Cannabidiol lowers incidence of diabetes in non-obese mice. Autoimmunity 2006;39:143-51.

29. Grinspoon L, Bakalar J. Shared experiences. Diabetes by Anonymous.

www.rxmarijuana.com/shared_comments/index.htm (Accessed 14 July
2010).
30. Stark G. Cannabis and Diabetes. www.glenstark.net/2009/06/cannabis-diabetes. (Accessed 14 July 2010).
31. Nogueiras R, Veyrat-Durebex C, Suchanek P et al. Peripheral, but not
central, CB1 antagonism provides food intake-independent benefits in
diet-induced obese rats. Diabetes 2008;57:2977-91.
32. Matias I, Gonthier M, Orlando P et al. Regulation, function and dysregulation of endocannabinoids in models of adipose and -pancreatic
cells in obesity and hyperglycaemia. J Clin Endocrinol Metab 2006;91:
3171-80.
33. Roth M. Marijuana and your heart. Nature 2005;434:708-09.
34. Scherer T, Buettner C. The dysregulation of the endocannabinoid
system in diabesity: a tricky problem. J Molec Med 2009;87:663-8.
35. Gallanta M, Odei-Addoa F, Frosta CL, Levendal R-A. Biological effects
of THC and a lipophilic cannabis extract on normal and insulin resistant
3T3-L1 adipocytes. Phytomedicine 2009;16:942-9.
36. Solomon SS, Odunusi O, Carrigan D et al. TNF-alpha inhibits insulin
action in liver and adipose tissue: A model of metabolic syndrome.
Horm Metab Res 2010;42:115-21.
37. Stephens JM, Lee J, Pilch PF. Tumor necrosis factor-alpha-induced
insulin resistance in 3T3-L1 adipocytes is accompanied by a loss
of insulin receptor substrate-1 and GLUT4 expression without a
loss of insulin receptor-mediated signal transduction. J Biol Chem
1997;272:971-6.
38. Klein TW, Lane B, Newton CA, Friedman H. The cannabinoid system
and cytokine network. Exp Biol Med 2000;225:1-8.
39. Matias I, Gonthier M, Orlando P et al. Regulation, function and dysregulation of endocannabinoids in models of adopise and -pancreatic
cells in obesity and hyperglycaemia. J Clin Endocrinol Metab 2006;91:
3171-80.
40. De Petrocellis L, Marini P, Matias I et al. Mechanisms for the coupling
of cannabinoid receptors to intracellular calcium mobilization in rat
insulinoma beta-cells. Exp Cell Res 2007;313:2993-3004.
41. Laychock SG, Hoffman JM, Meisel E, Bilgin S. Pancreatic islet arachidonic acid turnover and metabolism and insulin release in response to
delta-9-tetrahydrocannabinol. Biochem Pharmacol 1986;35:2003-8.
42. Das SK, Paria BC, Andrews GK, Dey SK. Effects of 9-enetetrahydrocannabinol on expression of beta-type transforming growth
factors, insulin-like growth factor-I and c-myc genes in the mouse
uterus. J Steroid Biochem Mol Biol 1993;45:459-65.
43. Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Cannabidiol:
recent advances. Chem Biodivers 2007;4:1678-92.
44. Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with
wide spectrum of action. Rev Bras Psiquiatr 2008;30: 271-80.
45. Bouaboula M, Hilairet S, Marchand J et al. Anandamide induced
PPARgamma transcriptional activation and 3T3-L1 preadipocyte
differentiation. Eur J Pharmacol 2005;517:174-81.
46. OSullivan SE. Cannabinoids go nuclear: evidence for activation of
peroxisome proliferator-activated receptors. Br J Pharmacol 2007;152:
576-82.
47. Fievet C, Fruchart JC, Staels B. PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome.
Curr Opin Pharmacol 2006;6:606-14.
48. Gelman L, Feige JN, Desvergne B. Molecular basis of selective
PPARgamma modulation for the treatment of type 2 diabetes. Biochim
Biophys Acta 2007;1771:1094-107.
49. Van Gaal L, Rissanen A, Scheen A et al. Effects of the cannabinoid-1
receptor blocker rimonabant on weight reduction and cardiovascular
risk factors in overweight patients: 1 year experience from the RIOEurope study. Lancet 2005;365:1389-97.
50. Scheen A, Finer N, Hollander P et al. Efficacy and tolerability of
rimonabant in overweight or obese patients with type-2 diabetes: a
randomised controlled trial. Lancet 2006;368:1660-72.

VOLUME 10 ISSUE 6 . NOVEMBER/DECEMBER 2010

272

Downloaded from dvd.sagepub.com by guest on August 4, 2015

REVIEW

51. Steffens S, Veillard N, Arnaud C et al. Low dose oral cannabinoid

therapy reduces progression of atherosclerosis in mice. Nature 2005;
434:782-6.
52. Winstock AR, Ford C, Witton J. Assessment and management of
cannabis use disorders in primary care. BMJ 2010;340:c1571.
53. Tan MH. Diabetes and coronary heart disease. Diabetes Spectrum
1999;12:80-3.
54. Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the
Framingham study. Circulation 1979;59:8-13.
55. Takeda M, Mori F, Yoshida A et al. Constitutive nitric oxide synthase
is associated with retinal vascular permeability in early diabetic rats.
Diabetologia 2001;44:1043-50.
56. Adamis AP, Miller JW, Bernal MT et al. Increased vascular endothelial
growth factor levels in the vitreous of eyes with proliferative diabetic
retinopathy. Am J Ophthalmol 1994; 18:445-50.
57. Comelli F, Bettoni I, Colleoni M et al. Beneficial effects of a Cannabis
sativa extract treatment on diabetes-induced neuropathy and oxidative
stress. Phytother Res 2009;23:1678-84.

58. Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized placebocontrolled double-blind clinical trial of cannabis-based medicinal
product (Sativex) in painful diabetic neuropathy: depression is a major
confounding factor. Diabetes Care 2010;33:128-30.
59. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet 2010;
376:124-36.
60. Rajesh M, Mukhopadhyay P, Batkai S et al. Cannabidiol attenuates
high glucose-induced endothelial cell inflammatory response
and barrier disruption. Am J Physiol Heart Circ Physiol 2007;293:
H610-9.
61. El-Remessy AB, Al-Shabrawey M, Khalifa Y et al. Neuroprotective and
blood-retinal barrier-preserving effects of cannabidiol in experimental
diabetes. Am J Pathol 2006;168:235-44.
62. Weiss L, Zeira M, Reich S et al. Cannabidiol lowers incidence of diabetes
in non-obese mice. Autoimmunity 2006;39:143-51.
63. Mahdy RA, Nada WM, Hadhoud KM, El-Tarhony SA. The role of vascular endothelial growth factor in the progression of diabetic vascular
complications. Eye (Lond) 2010 May 28. [Epub ahead of print].

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