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The British Journal of Diabetes & Vascular
The online version of this article can be found at:
2010 10: 267British Journal of Diabetes & Vascular Disease
Martin Frisher, Simon White, Gabor Varbiro, Carolyn Voisey, Dhaya Perumal, Ilana Crome, Nazmeen Khideja and James
The role of cannabis and cannabinoids in diabetes
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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 267
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 50,000–100,000 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, Δ9-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.
There 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,
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-
The taxonomy of cannabis is somewhat in dispute,
however most now regard the genus cannabis to belong to the
Hemp family, Cannabacea.
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.
Cannabis plants produce cannabinoids,
although there are also synthetic cannabinoids which are not
found in cannabis plants.
To date, over 60 cannabinoids have
been isolated, of which THC is considered to be the primary psy-
choactive component of the plant.
The amount of THC ingredient
in herbal cannabis varies from 1% up to 15%, while skunk, can
The role of cannabis and cannabinoids in
© The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1474651410385860 267
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
Abbreviations and acronyms
i] intracellular calcium transients
GLUT glucose transporter gene
HDL high-density lipoprotein
ICAM inter-cellular adhesion molecule
IGF-I insulin-like growth factor-I
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
Th T helper cell
TGF transforming growth factor
TNF tumour necrosis factor
VEGF vascular endothelial growth factor
268 VOLUME 10 ISSUE 6
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).
Despite concerns about increased
potency, the evidence is mixed, with recent studies indicating
broadly similar ranges of potency over the last 10 years.
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.
Rimonabant (an inverse agonist for the cannabinoid receptor
), 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).
1. Epidemiology of cannabis and diabetes
In England, 9.0% of school pupils in 2007 aged 11–15 used
cannabis in the last year, down from 13.4% in 2001.
adults aged 16–59 use in the last year was 7.9% in 2008–
2009 compared with 10.6% in 2001–2002.
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.
The prevalence of diabetes in the UK in 2005 was 4.3%
(type 1, 0.4%; type 2, 3.9%) among people aged 10–79.
Prevalence is linearly related to age and most type 2 diabetic
patients are diagnosed in their mid-40s.
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 use
Surveys only provide data on frequency of cannabis use, but as
pointed out in the classic book, Drug Set and Setting,
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.
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.
Table 1. Prevalence of self reported cannabis use and diabetes by
Prevalence (%) of cannabis
in England and Wales,
Prevalence (%) of
in England, 2006
16–19 18.3 16–24 0.8
20–24 19.1 25–34 1.2
25–29 12.1 35–44 1.8
30–34 8.2 45–54 4.8
35–44 4.6 55–64 7.2
45–54 2.4 65–74 12.9
55–59 1.1 75+ 11.7
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 1993–2006
1993 1994 1998 2003 2006
% of population
Self-reported diagnosis of either type 1 or type 2
Self-reported using cannabis in last year (aged 16–59)
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 269
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 18–24-year group in
the UK. Indeed over 90% of young people who access specialist
drug/alcohol services have problems with alcohol or cannabis.
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.
Cannabis harm and schizophrenia: lessons for
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 review
‘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.
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.’
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-
However, between 1996 and 2005 the incidence
and prevalence of schizophrenia and psychoses were either
stable or declining in the UK,
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.
There are well-documented
reports of cannabis use leading to reduced headache, migraine
and post-surgery pain.
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,
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.
report adverse effects, such as Stark,
who comments that
cannabis may cause ‘decreased judgement’ and increased appe-
tite, but offers no additional information about these effects
(e.g. whether ‘judgement’ includes awareness of impending
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.
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.
It was also
shown that TNFa affects the effectiveness of insulin on glucose
uptake by interfering with insulin signalling,
and the expres-
sion of GLUT4 in adipocytes.
THC has been demonstrated to
decrease the level of TNFa in various experimental models.
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.
receptors (CB1 and CB2 receptors as well as other yet unclassi-
fied receptors) stimulate intracellular calcium transients [Ca
leading to the release of insulin.
In a study using RINm5F rat
insulinoma β-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.
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
ride) inhibited insulin release in cells exposed to either glucose
THC was also shown to affect the expression of beta-
type TGF (TGF-β1, β2 and β3) as well as the expression of IGF-I
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 β-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.
270 VOLUME 10 ISSUE 6
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.
CBD treatment of mice
with latent diabetes or with initial symptoms of diabetes showed
improvement in disease manifestation.
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.
Recently, therapeutic actions of cannabinoids on the nuclear
receptor superfamily ,the PPARs, have also been suggested.
PPARs regulate cell differentiation and lipid metabolism.
in particular, plays a role in the regulation of adipocyte formation,
insulin sensitivity and inflammation.
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)
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.
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
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.
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 colleagues
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 argues
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
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
This is potentially important since CHD
causes almost 60% of deaths among diabetic patients.
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
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)
in overweight or
obese diabetic patients
Rimonabant CB1 antagonism (i.e. suppression of
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; HbA
= glycosylated haemoglobin;
RCT = randomised controlled trial; RIO-Diabetes = Rimonabant in type 2 diabetes; RIO-Europe = Rimonabant In Obesity – Europe;
THC = Δ9-tetrahydrocannabinol
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 271
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.
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.
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 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
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.
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 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.
Research in rat models of
diabetes has demonstrated that the cannabinoid CBD exerts
protection against damage to the blood–brain 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,
in common with the immunomodulatory functions previously
attributed to CBD where a switch from Th1 to Th2 dominance
was observed in NOD mice.
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.
Diabetic 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.
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.
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
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.
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.
Taken together, these results suggest an immunomodulatory
role for cannabinoids in addition to their previously documented
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 spot-
light since the publication in The Lancet of ‘development of a
rational scale to assess the harm of drugs of potential misuse’
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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