British Journal of Nutrition (2003), 90, 729–734
The cannabinoid system: a role in both the homeostaticand hedonic control of eating?
Neuroendocrine and Obesity Biology Unit, Department of Medicine, University of Liverpool,University Clinical Departments, Liverpool L69 3GA, UK
(Received 16 May 2003 – Revised 19 May 2003 – Accepted 20 May 2003)
Knowledge of the cannabinoid system and its components has expanded greatly over the past decade. There is increasing evidence for itsrole in the regulation of food intake and appetite. Cannabinoid system activity in the hypothalamus is thought to contribute to the homeo-static regulation of energy balance, under the control of the hormone leptin. A second component of cannabinoid-mediated food intakeappears to involve reward pathways and the hedonic aspect of eating. With the cannabinoid system contributing to both regulatory path-ways, it presents an attractive therapeutic target for the treatment of both obesity and eating disorders.
Anandamide: Endocannabinoids: 2-Arachidonoyl glycerol: SR 141716: Food intake: Obesity: Reward
The regulation of energy homeostasis and feeding beha-
viour is highly complex. It depends on the brain beingable to read, interpret and integrate a wide range of signals
The cannabinoid system consists of two receptors (termed
and to make appropriate changes in food intake and energy
CB1 and CB2), their endogenous ligands (the endocannabi-
expenditure as a result of the information. Responsibility
noids) and the uptake mechanisms and hydrolysing
for this control is shared between several brain regions,
enzymes that regulate ligand levels.
spanning both higher and lower centres (cortex to brain-
The cannabinoid receptors belong to the 7-transmembrane
stem), within which are located numerous neurochemical
G-protein coupled receptor family. CB1 is known as the
transmitters. Regulatory activities of this complexity are
central receptor subtype and is expressed at particularly
likely to be controlled by a number of transmitters operat-
high levels in brain regions including the cortex, basal
ing at a variety of levels. Novel information regarding the
ganglia, cerebellum and hippocampus (Glass et al. 1997;
neuronal circuits that control food intake continues to
Harrold et al. 2002). However, the distribution of CB1 is
extend our understanding of energy homeostasis. The
not limited to brain circuitry, with receptors recently ident-
present review will focus on one neuronal system, the
ified on nerve terminals innervating the gastrointestinal
tract (Croci et al. 1998; Hohmann & Herkenham, 1999).
In the past decade, cannabinoid receptors and their puta-
By contrast, expression of CB2, the peripheral receptor, is
tive ligands have been discovered within the central nervous
restricted to sites at the periphery, mostly within immune
system and linked to a number of aspects of feeding
cells. There is evidence for the existence of a further centrally
behaviour, including a potential role in the regulation of
located cannabinoid receptor, as certain effects of centrally
food intake. Recently, interest has revived in the effects on
administered cannabinoid ligands are not inhibited by the
appetite of the plant-derived cannabinoids and analogous
CB1-specific antagonist SR 141716 (Welch et al. 1998). It
molecules. The present article will discuss current advances
is also possible that the endocannabinoids may exert some
in this area and will also consider the potential of the
of their pharmacological actions by non-receptor-mediated
cannabinoid system as a therapeutic target in the control of
mechanisms, e.g. membrane perturbations and gap junction
Abbreviations: AG, arachidonoyl glycerol; CB, cannabinoid receptor; FAAH, fatty acid amide hydoxylase; THC, tetrahydrocannabinol.
* Corresponding author: Dr Joanne A. Harrold, fax þ 44 151 706 5797, email firstname.lastname@example.org
The psychoactive ingredient of marijuana, D9-tetrahy-
exogenous cannabinoids, e.g. D9-THC and the endogenous
drocannabinol (THC) is known to interact with CB1 recep-
cannabinoids, anandamide and 2-AG, are reliably reported
tors (Ledent et al. 1999). It mimics the effects of the
to stimulate feeding (Williams et al. 1998; Williams &
endogenous cannabinoids, the first of which was identified
Kirkham, 1999; Hao et al. 2000). The hyperphagia
in porcine brain in 1992 and termed anandamide from
‘ananda’ meaning ‘bliss’ (Devane et al. 1992; Di Marzo
D9-THC stimulates feeding as potently as central injection
et al. 1998a). To date, three endocannabinoids have been
of neuropeptide Y (Corp et al. 1990). As the hyperphagia
identified, with the inclusion of 2-arachidonoyl glycerol
is selectively blocked by the CB1 receptor antagonist SR
(AG) and very recently nolodin ether (Hanus et al.
141716, but not by an antagonist of the peripheral CB2
2001). Anandamide is widely distributed within the brain.
receptors (SR 144258), this suggests that the actions are
However, its basal levels are low compared with most neu-
mediated by the central receptors. This is further sup-
rotransmitters, with the lipophilic compound being syn-
ported by the observation that mice with genetically
thesised on demand and immediately released from nerve
impaired CB1 receptors eat less than their wild type litter-
terminals by a Ca2þ dependent mechanism. Anandamide
mates in response to food deprivation (Di Marzo et al.
is inactivated by reuptake via the anandamide membrane
transporter (Day et al. 2001) and rapid degradation by
These observations suggest that tonic cannabinoid
fatty acid amide hydroxylase (FAAH)-mediated hydrolysis
release may be crucial to the normal regulation of feed-
(Giuffrida et al. 2001). 2-AG is thought to be similarly
ing. Direct measurements of brain endocannabinoid
regulated by the anandamide membrane transporter and
levels in response to fasting, feeding and satiation further
FAAH, both of which are distributed in brain areas in a
support this observation. Fasting increases levels of ana-
pattern corresponding to that of CB1 receptors. It is too
damide and 2-AG in the nucleus accumbens, and to a
early to apply these principles to nolodin ether.
lesser extent the hypothalamus, where 2-AG levels also
Endocannabinoids are implicated in a variety of physio-
declined with feeding (Kirkham et al. 2002). No changes
logical functions including pain reduction, motor regulation,
were detected in satiated rats and levels in the cerebellum,
learning and memory, appetite stimulation and reward. In
a control region not directly involved in the control of
some of these functions the cannabinoids play a modulatory
feeding, were unaffected regardless of nutritional state
role, whilst in others they are essential system components.
The mechanisms of cannabinoid-induced hyperphagia
remain to be elucidated. However, there is a body of evi-dence that points towards an involvement of both reward
processes and established homeostatic pathways, many of
There is increasing evidence for a role of the cannabinoid
which are regulated by the hormone leptin and operate
system in the regulation of food intake and appetite. Both
Table 1. Summary of the cannabinoid system-mediated regulation of energy homeostasis, indicating the known influence of perturbations of
energy balance and drug administration on receptor density and endocannabinoid levels
CNS, central nervous system; VMH, ventromedial hypothalamic nucleus.
1 Subpopulations of cannabinoid receptor containing neurones appear to exist, playing roles in both the hedonic and homeostatic control of food intake. Whether
these represent functional independent populations is unclear. It has been shown that cannabinoid receptor-containing neurones in the hypothalamus are allintrinsic to this brain region (Romero et al. 1998). However, modulation of brain reward circuitry by leptin has also been reported (Fulton et al. 2000).
2 Peripheral anandamide may promote feeding by acting on specific hypothalamic areas important in the control of food intake. However, endocannabinoids are
rapidly hydrolysed in the intestine and may not reach the brain in sufficient quantities to interact with central CB1 receptors (Di Marzo et al. 1998b). Alternatively,signals from the viscera indicating cannabinoid-mediated alterations of gastric activity may converge on the nucleus of the solitary tract in the medulla, fromwhere inputs are relayed to the hypothalamus.
Hedonic mechanisms for regulating food intake
satiated rats induces significant hyperphagia (Jamshidi &Taylor, 2001). Finally, defective leptin signalling in ob/ob
Brain reward systems allow the reinforcement of responses
and db/db mice and fa/fa Zucker rats is associated with elev-
that have no homeostatic value. Motivation and reward
ated hypothalamic endocannabinoid levels, with these levels
have been studied most extensively in the context of
being reduced in ob/ob mice following leptin treatment
drug addiction. However, a number of studies suggest
that food reward and drug reward pathways may share
Genetically obese rodents exhibit a continuous motivation
some common components, including evidence that the
to eat and thus demonstrate extreme hyperphagia. The
cannabinoid system plays roles in both feeding and
evidence presented earlier implicates the endocannabinoid
system in this mechanism, possibly acting as a component
Association of the cannabinoid system with reward pro-
of a leptin-sensitive regulatory pathway. Interestingly, a
cesses is indicated by a number of lines of evidence.
deficient leptin function has been reported in dietary-obese
SR 141716 antagonises the hunger induced by anandamide
animals, with the development of leptin resistance
and 2-AG. However, the compound also produces changes
(Widdowson et al. 1997a), which could modulate the
in ingestive behaviour when administered alone. SR 141716
relationship between plasma leptin levels and cannabinoid
selectively inhibits consumption of palatable food and drink,
system activity. It is tempting to speculate that the
with decreased intake of sucrose, alcohol and a sweet diet
hyperphagia demonstrated by dietary obese animals may
observed in rats, mice and marmosets respectively (Arnone
also arise from an increased hypothalamic endocannabinoid
et al. 1997; Simiand et al. 1998). However, it has little
system activity occurring as a consequence of reduced leptin
effect on bland food consumption. These results suggest
regulation. However, evidence has recently come to light that
that the central cannabinoid system may act to amplify
refutes this argument. Hypothalamic 2-AG levels have been
found to increase with food deprivation and decline with
This is further supported by the observation that CB1
feeding (Kirkham et al. 2002), suggesting that once initiated,
receptors are expressed particularly in areas of the brain
eating no longer depends on hypothalamic endocannabinoids
such as the nucleus accumbens, the hippocampus and the
for maintenance. Furthermore, no relationship has been
entopeduncular nucleus; these areas are either directly
identified between CB1 receptor binding density and leptin
involved in hedonic aspects of eating or are connected to
in dietary obese animals (as discussed later).
reward-related brain areas (Finkelstein et al. 1996; Gorba-chevskaia, 1999; Pecina & Berridge, 2000). In addition, thecannabinoids appear to interact with known opioidergic
A role for the cannabinoid system in common human
reward pathways, indicated by synergistic actions of SR
141716 and the opioid receptor antagonist, naloxone, on
Unselected Wistar rats given a palatable diet overeat to a
food intake (Welch & Eads, 1999; Kirkham & Williams,
variable degree, with approximately half the animals
becoming significantly obese (Harrold et al. 2000). This
Evidence in human subjects also supports specific
dietary-induced obesity, attributable to voluntary hyperpha-
cannabinoid involvement in food (orosensory) reward.
gia, is the closest approximation to common lifestyle-related
For example, hyperphagic effects of marijuana in human
obesity in man, in which overconsumption of palatable food
volunteers were principally attributed to an increase in
is an important contributing factor. Recent evidence points
the consumption of highly palatable sweet foods such as
to the conclusion that the endogenous cannabinoids, acting
chocolate and biscuits (Iverson, 2000).
on discrete extrahypothalamic populations of CB1 receptors,may drive appetite for palatable food and thus lead to thedevelopment of dietary-induced obesity. Rats fed a palatable
Cannabinoids, leptin and the hypothalamus
diet for 10 weeks demonstrated reduced CB1 receptor den-
Several lines of evidence suggest that the cannabinoids are
sity in the forebrain and hippocampus, consistent with
modulated by leptin and this may be involved in the control
increased activation of the receptors by endogenous cannabi-
of feeding First, leptin administration decreases
noids. By contrast, CB1 receptor binding in the hypothala-
hypothalamic levels of anandamide and 2-AG; endogenous
mus was low and unaltered. Furthermore a lack of
cannabinoid levels in the only extrahypothalamic site exam-
correlation between receptor density and plasma leptin
ined, the cerebellum, were reportedly unaffected (Di Marzo
suggests that this receptor activity is not regulated by the
et al. 2001). Curiously, CB1 receptor density, as determined
circulating hormone (Harrold et al. 2002).
by autoradiography, is relatively sparse within the hypo-
The anatomical localisation of these changes is notable,
thalamus (Harrold et al. 2002), although studies using
drawing attention away from the hypothalamus. The unal-
[35S]guanylyl 50-[g-[35S]thio]-triphosphate binding indicate
tered hypothalamic receptor density argues against a role
that receptor coupling to G proteins is more efficient in the
for hypothalamic cannabinoids in driving appetite in dietary
hypothalamus than in areas with a higher receptor density
obesity. It is possible that hypothalamic cannabinoids act to
(Breivogel et al. 1997). In addition, studies have shown
stimulate feeding under particular circumstances, e.g. star-
that anandamide increases Fos expression in the paraventric-
vation, when falling leptin and insulin levels are known to
ular nucleus of the rat hypothalamus, which plays an import-
activate other orexigenic systems such as neuropeptide
ant role in the regulation of energy balance (Wenger et al.
Y. Unlike the cannabinoid system, these pathways are
1997; Patel et al. 1998). Furthermore, anandamide adminis-
reported to be switched off under conditions of excess
tration into the ventromedial hypothalamic nucleus of
intake of palatable food (Widdowson et al. 1997b).
Therefore, pharmacological targeting of the cannabinoid
oleoylethanolamide (the oleic acid analogue of ananda-
system may prove particularly useful in the treatment of
human obesity. This is supported by the recent observation
increases after a meal in conjunction with reductions in ana-
that SR 141716-treated dietary obese mice demonstrate tran-
ndamide (Rodrı´guez de Fonseca et al. 2001; Go´mez et al.
sient reductions in food intake. Sustained falls in body
2002). It is possible that both act in a coordinated way to
weight and adiposity were also reported. These were attrib-
control food intake and gastric motility via opposing actions
uted to the hypophagia, potentially in conjunction with a
thermogenic or metabolic effect, as treated animals demon-
Recently, a peripheral role for CB1 receptors in meta-
strated significantly greater weight loss following a 24 h fast
bolic regulation has been indicated by the observation
than vehicle-treated controls (Ravinet Trillou et al. 2003).
that SR 141716 increases Acrp30 (more commonlyknown as adiponectin) mRNA expression in adiposetissue of obese fa/fa rats and in cultures of adipocytes
(Bensaid et al. 2003). Adiponectin induces non-esterified
Despite the existence of central mechanisms for the regu-
fatty acid oxidation, decreases hyperglycaemia and hyper-
lation of food intake by the endocannabinoids, evidence
insulinaemia and reduces body weight. This regulation
suggests that they may also promote feeding by acting at per-
may play a role in the body weight reduction induced by
ipheral sites Indeed, CB1 receptors are located on
SR 141716, with metabolic regulation contributing to its
nerve terminals innervating the gastrointestinal tract, which
are involved in mediating gut-derived satiety signals (Crociet al. 1998; Hohmann & Herkenham, 1999). In addition, cap-
saicin-induced deafferentation prevents changes in feedingelicited by the administration of cannabinoid drugs (Go´mez
The ability of marijuana to increase hunger has been
et al. 2002). Moreover, the peripheral administration of
noticed for centuries. Despite the public concern related
CB1 agonists and antagonists and the acute administration
to the abuse of marijuana and its derivatives, scientific
of peripherally acting satiety factors or feeding inhibitors,
studies have highlighted their ability to stimulate appetite,
such as gastrointestinal hormones and the non-cannabinoid
especially for sweet and palatable food, and point to the
anandamide analogue oleamide, induce similar patterns of
future therapeutic potentials of cannabinoid compounds
c-fos expression in hypothalamic and brainstem areas regu-
in the treatment of obesity and eating disorders.
lating food intake (Rodrı´guez de Fonseca et al. 1997).
Finally, central administration of SR 141716 has no effect
on food intake in food-deprived animals. SR 141716 isactive only after intraperitoneal or oral administration, but
Application of cannabinoid effects include the treatment of
not after subcutaneous injection, further supporting the
wasting diseases in which patients are unable or unwilling
hypothesis of peripheral actions of cannabinoids on food
to eat. Indeed, D9-THC is used clinically for this purpose,
particularly in AIDS and cancer patients (Mechoulam &
There is some controversy as to whether peripheral
Fride, 2001). Anorexia also develops with old age in
anandamide also promotes feeding by acting on specific
man. This is analogous to the decline in food intake
hypothalamic areas involved in energy homeostasis. For
observed in old mice. An age-dependent decline in alcohol
example, diets containing polyunsaturated non-esterified
preference has also been observed (Wang et al. 2003). This
fatty acids are known to enhance anandamide levels in
is absent in CB1 receptor knockout mice, independent of
some brain structures of newborn pigs and mice (Berger
their age, suggesting that the decline is related to loss of
et al. 2001). Furthermore, food deprivation for 24 h increases
cannabinoid signalling in relevant brain areas (Wang et al.
intestinal anandamide concentrations 7-fold, reaching levels
2003). No age-dependent change in anandamide, 2-AG or
that are 3-fold greater than those needed to half-maximally
CB1 receptor density have been detected in wild type
activate CB1 receptors (Devane et al. 1992). However, as
mice, suggesting that a decrease in ligand or receptor
only 1·6 – 5·0 % of orally administered cannabinoids survive
number is unlikely to account for the decline. In fact, a
their passage through the digestive system and enter the
reduction in agonist stimulated guanylyl 50-[g-[35S]thio]-
bloodstream (Di Marzo et al. 1998b), probably due to the
triphosphate labelling in old mice suggests that a localised
high levels of the enzyme that degrades the compounds in
decline in the coupling of CB1 receptors to G-proteins may
the gastrointestinal tract (FAAH), this suggests that levels
account for reductions in food intake and alcohol prefer-
are too low to cause considerable central effects. This is sup-
ence. Accordingly, treatment with low doses of ananda-
ported by the observation that no increases in brain levels of
mide is able to cause a small but significant increase in
anandamide occur after 24 h of food deprivation (Go´mez
voluntary alcohol intake in old mice (Wang et al. 2003).
Although anandamide binds and activates the CB1
It is hypothesised that the raised gut anandamide levels
receptor in vitro, the compound produces only weak and
following food deprivation may serve as a short-range
transient cannabinoid effects in vivo, thus limiting its effec-
hunger signal to promote feeding. Elevated anandamide
tiveness as a means of treatment. This probably arises as a
may also play a role in regulating gastric emptying and
result of anandamide’s rapid catabolism (Adams et al.
intestinal peristalsis, both processes being inhibited by the
1998). Indeed, the half-life of anandamide appears to
endocannabinoids (Calignano et al. 1997; Izzo et al.
be in the order of minutes (Willoughby et al. 1997). One
1999). Interestingly, intestinal levels of anandamide and
candidate enzyme for regulating anandamide activity is
FAAH. Mice lacking FAAH are severely impaired in their
The location of the anorectic actions of SR 141716 is
ability to degrade anandamide, and when treated with the
not clear. As the receptor antagonist is able to cross the
CB1 receptor ligand exhibit intense CB1 mediated effects
blood – brain barrier, it has been assumed that the effects
that are inhibited by SR 141716 (Cravatt et al. 2001).
have a central origin. However, CB1 receptors are not
Thus, FAAH may represent an attractive pharmacological
exclusive to the brain. High effectiveness of intraperitoneal
target, with inhibitors of the enzyme (whose actions
and oral administration suggests that further studies of gut
would only be evident as sites where endocannabinoid pro-
mechanisms of action are warranted. Furthermore, it may
duction and release is taking place) serving as therapeutic
prove useful to combine cannabinoid antagonists with
agents for the treatment of cachexia. To this end, several
agents acting at other neurotransmitter systems implicated
exceptionally potent inhibitors of FAAH are being investi-
in the control of food intake, e.g. opioid systems.
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Stevens Johnson Syndrome Foundation OnLine Newsletter Stevens Johnson Syndrome Foundation Newsletter September 17, 2004 Our Prayers To: SJS F oundation B oard of D irector L eroy C alvert, from Glenhead, Long Island, diagnosed with bladder and liver cancer. Our love and support are with him and his family at this difficult time. D r. S tephen B yrnes suffered
Johannes Kepler Univ. of Linz & Inst. of Problems of Chemical Physics of Russian: Fabrication of “green” organic field-effect transistors N. Marjanovic M. Irimia-Vladu and colleagues from the Johannes Kepler University of Linz & Institute of Problems of Chemical Physics of Russian present this work in the frame of the “green potentiality” of organic electr