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Endocannabinoid signaling and food addiction

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 Neuroscience and Biobehavioral Reviews 47 (2014) 203–224

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

Endocannabinoid signaling and food addiction

C. D’Addario a,e,∗ , M.V. Micioni Di Bonaventura b , M. Pucci a , A. Romano c , S. Gaetani c ,
R. Ciccocioppo b , C. Cifani b , M. Maccarrone d,f,∗∗
a
Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Piazza A Moro 45, 64100 Teramo, Italy
b
School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, MC, Italy
c
Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
d
School of Medicine and Center of Integrated Research, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy
e
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
f
European Center for Brain Research (CERC)/Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Overeating, frequently linked to an increasing incidence of overweight and obesity, has become epidemic
Received 3 May 2014 and one of the leading global health problems. To explain the development of this eating behavior, new
Received in revised form 28 July 2014 hypotheses involve the concept that many people might be addicted to food by losing control over their
Accepted 18 August 2014
ability to regulate food intake. Among the different neurotransmitter networks that partake in the reward
Available online 27 August 2014
circuitry within the brain, a large body of evidence supports the involvement of the endocannabinoid
system. Indeed, its dysfunctions might contribute to food addiction, by regulating appetite and food
Keywords:
preference through central and peripheral mechanisms. Here, we review and discuss the role of endo-
Endocannabinoid signaling
Food addiction
cannabinoid signaling in the reward circuitry, and the possible therapeutic exploitation of strategies
Food reward mechanisms based on its fine regulation.
Food intake regulation and energy balance © 2014 Elsevier Ltd. All rights reserved.

Contents

1. The endocannabinoid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

1.1. The endocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
1.2. eCBs metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
1.3. Molecular targets and signaling pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
2. Role of eCB system in food intake regulation and energy balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
3. Regulation of endocannabinoid levels by the diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

Abbreviations: 2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; ABA, activity-based anorexia; ACC1, acetyl coenzyme-A carboxylase-1; AEA, N-
arachidonoylethanolamine; AN, anorexia nervosa; ARC, arcuate nucleus; BBB, blood-brain barrier; BED, binge eating disorder; BN, bulimia nervosa; CB, cannabinoid; CB1, CB
receptor subtype 1; CB2, CB receptor subtype 2; CCK, colecistokinin; CRH, corticotrophin-releasing hormone; DA, dopamine; DAG, diacylglycerol; DAGL, diacylglycerol lipase;
DHA, docosahexanoic acid; DMH, dorsomedial hypothalamus; DMS-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; DOP, ␦-opioid receptor; eCB, endo-
cannabinoid; EDI-2, the Eating Disorder Inventory-2; EMA, European Medicines Agency; EMT, eCB membrane transporter; EPA, eicosapentaenoic paraventricular nucleus
acid; FAAH, fatty acid amide hydrolase; FAA, fatty acid amide; FAS, fatty acid synthase; Fa, fatty acid; FDA, Food and Drug Adminstration; GABA, ␥-aminobutyric acid; GI,
gastro-intestinal; GPR119, G protein coupled receptor 119; GPR55, G protein-coupled receptor 55; HFD, high fat diet; Icv, intracerebroventricular; LA, linoleic acid; LH, lateral
hypothalamus; MAGL, monoacylglycerol lipase; MAG, monoacylglycerol; MCH, melanin-concentrating hormone; MOP, ␮-opioid receptor; NAc, nucleus accumbens; NADA,
N-arachidonoyldopamine; NAE, N-acylethanolamine; NAPE, N-acylphosphatidyl-ethanolamines; NAT, N-acyltransferase; NPY, neuropeptide Y; OEA, N-oleoylethanolamine;
OP, obesity-prone; PE, phosphatidylethanolamine; PEA, palmitoylethanolamine; PET, positron emission tomography; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A;
PLC, phospholipase C; PLD, phospholipase D; POMC, proopiomelanocortin; PPAR, peroxisome proliferator-activated receptor; PUFA, polyunsaturated fatty acid; PYY, peptide
YY; SEA, N-stearoylethanolamine; THC, 9-tetrahydrocannabinol; TRPV1, transient receptor potential vanilloid 1; VTA, ventral tegmental area; WAT, white adipose tissue;
YFAS, Yale Food Addiction Scale.
∗ Corresponding author at: University of Teramo, Faculty of Bioscience and Technology for Food, Agriculture and Environment, Piazza A. Moro, 45, 64100 Teramo, Italy.
Tel.: +39 0861 266877; fax: +39 0737 403343.
∗∗ Corresponding author at: School of Medicine and Center of Integrated Research, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy.
Tel.: +39 06 2254 19169; fax: +39 06 2254 1456.
E-mail addresses: cdaddario@unite.it (C. D’Addario), m.maccarrone@unicampus.it (M. Maccarrone).

http://dx.doi.org/10.1016/j.neubiorev.2014.08.008
0149-7634/© 2014 Elsevier Ltd. All rights reserved.
204 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224

4. Neurobiology of food addiction and food reward mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

5. Cannabinoids and reward mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
6. eCB system-based drugs in eating disorders and obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
6.1. eCB system in eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
6.2. eCB system in obesity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

1. The endocannabinoid system (NAPE-PLD) hydrolyzes NAPEs to release NAEs (included AEA), and
phosphatidic acid (Okamoto et al., 2004).
Since the isolation and characterization of the active phyto- 2-AG is mainly synthesized from AA-containing membrane
cannabinoids in the cannabis (Cannabis sativa) plant, including phospholipids through the action of phospholipase C (PLC), lead-
the most psychoactive ingredient 9 -tetrahydrocannabinol (THC) ing to the formation of diacylglycerol (DAG), and then through one
(Mechoulam and Gaoni, 1965; Mechoulam, 1970), and after the of two diacylglycerol lipases (DAGLs), DAGL␣ and DAGL␤ (Bisogno
identification and cloning of the target of THC, the type-1 cannabi- et al., 2003).
noid receptor (Devane et al., 1988; Herkenham et al., 1991; Matsuda Inactivation of eCB signaling is achieved by two steps: a
et al., 1990), and of its endogenous counterparts, collectively rapid removal from molecular targets and subsequent hydroly-
termed “endocannabinoids” (Devane et al., 1992; Mechoulam et al., sis by specific enzymatic systems. eCBs rapid diffusion through
1995; Sugiura et al., 1995), many efforts have been profused to the plasma membrane has been shown to be mediated by a
study the different physiological functions modulated by what is selective and saturable transporter, the eCB membrane trans-
known as “endocannabinoid system”. porter (EMT), responsible for both AEA and 2-AG uptake by
several cells (Di Marzo et al., 1994; Hájos et al., 2004; Chicca
et al., 2012). Moreover, an intracellular accumulation of AEA
1.1. The endocannabinoids in adiposomes has been also reported (Oddi et al., 2008). Still
under debate is whether or not eCB transport and degra-
The endocannabinoids (eCBs) are derivatives of arachidonic acid dation are coupled or independent processes (Fegley et al.,
(AA), resembling other lipid transmitters such as prostaglandins or 2004).
leukotrienes. They are conjugated with ethanolamine to form fatty Once taken up by cells, AEA and 2-AG can be degraded by fatty
acid amides (FAAs), or with glycerol to form monoacylglycerols acid amide hydrolase (FAAH), which breaks the amide or ester
(MAGs), N-arachidonoylethanolamine (anandamide, AEA) and 2- bond, to release AA and ethanolamine or glycerol, respectively
arachidonoylglycerol (2-AG) so far representing the best studied (Cravatt et al., 1996). Yet, the main responsible for 2-AG metabolism
and most active members of each class, respectively (Devane et al., is monoacylglycerol lipase (MAGL) (Dinh et al., 2002). The degrada-
1992; Mechoulam et al., 1995). There are also other endoge- tion products are then recycled into the membrane phospholipids,
nous FAAs, like the appetite-suppressor N-oleoylethanolamine where they produce de novo the two eCBs (Bisogno et al., 2005).
(OEA) (Fu et al., 2008), the antiinflammatory, anticonvulsant and Moreover, AEA can be hydrolysed also by other enzymes with an
antiproliferative N-palmitoylethanolamine (PEA) (Lambert et al., “amidase signature”, like FAAH-2 (Wei et al., 2006), or that belong
2001), and the immunomodulator N-stearoylethanolamine (SEA) to the choloylglycine hydrolase family, like N-acylethanolamine-
(Maccarrone et al., 2002). The latter are called “eCB-like” com- hydrolysing acid amidase (Tsuboi et al., 2005). When MAGL or FAAH
pounds, since they do not activate cannabinoid receptors directly activity is suppressed, AEA and 2-AG might become substrates for
but have an “entourage effect” (Ben-Shabat et al., 1998; Lambert lipoxygenases (Van der Stelt et al., 2002), cyclooxygenase-2 (Rouzer
and Di Marzo, 1999; De Petrocellis et al., 2004). Moreover, 2- and Marnett, 2011) or cytochrome P450 (Snider et al., 2010), gen-
arachidonoylglycerolether (noladin ether) (Hanus et al., 2001), erating oxidative derivatives endowed with their own biological
N-arachidonoyldopamine (NADA) (Bisogno et al., 2000), and the activities. It has been also reported that AEA and possibly other
“inverted anandamide” virodhamine (Porter et al., 2002) also eCBs are transported intracellularly by distinct carriers, like fatty
belong to the ever-growing eCBs family. The chemical structures acid binding proteins (Kaczocha et al., 2009), albumin and heat
of these substances are shown in Fig. 1. shock protein 70 (Oddi et al., 2009), or a truncated FAAH termed
“FAAH-1-like AEA transporter” (Fu et al., 2011; Leung et al., 2013).
Therefore, the intracellular trafficking of eCBs might represent a
1.2. eCBs metabolism
new dimension to drive distinct signaling cascades of these com-
pounds in the CNS and at the periphery (Maccarrone et al., 2010a,b;
eCBs are produced by multiple synthetic pathways from lipid
Kaczocha et al., 2012).
precursors present in cell membranes “on demand”, that is when
and where needed following physiological or pathological stimuli.
However, AEA has been shown to have the potential to accumu- 1.3. Molecular targets and signaling pathways
late in intracellular stores called adiposomes (or lipid droplets)
(Oddi et al., 2008), whereas 2-AG might be pre-formed and AEA and 2-AG activate different signaling pathways by binding
sequestered in distinct intracellular pools until needed (Alger and to (with different affinities) and activating two well-characterized
Kim, 2011). 7-transmembrane G protein-coupled cannabinoid (CB) receptor
The best known biosynthetic pathway of AEA and other subtypes: type-1 (CB1 ) (Herkenham et al., 1991) and type-2 (CB2 )
N-acylethanolamines (NAEs) occurs in two steps: first a calcium- (Munro et al., 1993). In humans, CB1 is localized preferentially
dependent transacylase (NAT, N-acyltransferase) transfers an acyl in the terminals of central and peripheral neurons and glial cells
group from a membrane phospholipid to the N-position of (Egertová et al., 2003), but is also expressed in peripheral tis-
phosphatidylethanolamine (PE), to generate N-acylphosphatidyl- sues like heart, uterus, testis, liver and small intestine, as well
ethanolamines (NAPEs); then, a NAPE-selective phospholipase D as in immune cells (Maccarrone et al., 2001; Nong et al., 2001;
 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224
Fig. 1. Chemical structures of the major endocannabinoids and related compounds.
Klein et al., 2003) and adipose tissue (Spoto et al., 2006). Pheripheral
tissues also express CB2 (Roche et al., 2006), that is predominantly
found at high levels in leukocytes and spleen, and to a lower extent
in muscle, liver, intestine and testis (Liu et al., 2009). Interestingly,
CB2 is also present in the brain (Nunez et al., 2004; Van Sickle et al.,
2005), where it is markedly up-regulated upon various stressing
conditions (Viscomi et al., 2009).
Besides the well-characterized CB1 and CB2 receptors, pharma-
cological evidence suggests the existence of two additional GPCRs
as eCBs-binding receptors: G protein-coupled receptor 55 (GPR55),
and G protein coupled receptor 119 (GPR119). GPR55 is a purported
“type-3” (“CB3 ”) cannabinoid receptor, that shares low sequence
homology (10%–15%) with CB1 and CB2 (Ross, 2009), and has been
found in both CNS (Sawzdargo et al., 1999) and peripheral tissues
(Brown and Robin Hiley, 2009). Also GPR119 has been found in var-
ious mammalian species (Fredriksson et al., 2003), and in humans
is expressed in pancreas, liver and gastrointestinal tract (Overton
et al., 2008). AEA, but not 2-AG, also activates at an intracellular site
the transient receptor potential vanilloid 1 (TRPV1) ion channel (Di
Marzo and De Petrocellis, 2010), expressed in peripheral sensory
fibers and also in several nuclei of the CNS (Marinelli et al., 2003).
Finally, the peroxisome proliferator-activated receptor (PPAR) sub-
types ␣ and ␥ are also activated by eCBs for the regulation of
lipid and glucose metabolism, as well as of inflammatory responses
(Gasperi et al., 2007; Pagano et al., 2008). All the major elements of
the eCB system are schematically depicted in Fig. 2.
2. Role of eCB system in food intake regulation and energy
balance
The role of eCB system in maintaining energy balance has
received great attention since when synthetic compounds, like
the CB1 antagonist/inverse agonist SR141716A (rimonabant), also
known as Acomplia® and developed by Sanofi-Aventis, have shown
205
potential for the treatment of diet-induced obesity. Indeed, these
substances decrease food intake and body weight gain, not only
in animal models but also in humans (Cota, 2007; Di Marzo and
Desprès, 2009). Earlier studies had shown that pharmacological
stimulation of CB1 by systemic administration of plant-derived,
synthetic, or endogenous cannabinoids stimulate eating and pro-
duce anabolic effects (Williams et al., 1998; Williams and Kirkham,
1999; Hao et al., 2000). Moreover, using mice lacking CB1 , it was
documented that eCBs actions on food intake and body weight
depend on the functional expression and activity of CB1 (Cota et al.,
2003).
In the brain, eCB system tonically reinforces the motivation to
find and consume food, by interacting with the mesolimbic path-
ways engaged in reward mechanisms, whereas it is activated “on
demand” in the hypothalamus to transiently regulate levels and/or
actions of other orexigenic and anorexigenic mediators (Di Marzo
and Matias, 2005). eCBs levels in both hypothalamus and limbic
forebrain are highest during food deprivation and lowest during
food consumption (Kirkham et al., 2002). When directly injected
into the hypothalamus or the NAc shell, eCBs induce food intake
even in satiated animals (Kirkham et al., 2002; Jamshidi and Taylor,
2001). In agreement with this observation, local administration
of N-arachidonoylserotonin (an inhibitor of eCBs hydrolysis by
FAAH) in the NAc shell also stimulates food intake in parallel to
c-Fos expression in the arcuate nucleus (ARC) and paraventricular
nucleus (PVN), as well as in the dorsomedial (DMH) and lateral (LH)
hypothalamus (Soria et al., 2006).
Exogenous cannabinoids, via CB1 stimulation, inhibit gluta-
matergic signaling in pro-opiomelanocortin (POMC) neurons, thus
reducing the release of melanocortin, an anorexigenic media-
tor (Hentges et al., 2005). This finding is further supported by
additional evidence showing that intracerebroventricular (icv)
administration of CB1 antagonists can attenuate the orexigenic
effect of melanocortin antagonists (Verty et al., 2004). It seems
206 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224

Fig. 2. Overview of the eCB system indicating the most likely targets of eCBs, their anabolic and catabolic pathways, and intracellular localization. MAGs, Monoacylglycerol;
2-AG, 2-Arachidonoylglycerol; FAAs, Fatty acid amides; AEA, Anandamide; OEA, N-Oleoylethanolamine; SEA, N-stearoylethanolamine; PEA, N-Palmitoylethanolamine; AA,
Arachidonic acid; CB1/2 , type 1/2 cannabinoid receptors; GPR55/119, G protein-coupled receptor 55/119; TRPV1, transient receptor potential vanilloid 1 channel; EMT, endo-
cannabinoid membrane transporter; NAPE-PLD, N-acylphosphatidylethanolamine-selective phospholipase D; DAGL, diacylglycerol lipase; FAAH, fatty acid amide hydrolase;
NAAA, N-acylethanolamine-hydrolyzing acid amidase; MAGL, monoacylglycerol lipase; COX-2, cyclooxygenase-2; LOXs, lipoxygenases; eCBs, endocannabinoids; PPAR␥/␣,
Peroxisome proliferator-activated receptor ␥ and ␣; PG-G PG-EA See text for details.

that CB1 acts downstream of melanocortin receptors, because
melanocortin agonists administered icv do not alter hypothalamic
AEA nor 2-AG levels (Matias et al., 2008a,b), while central admin-
istration of melanocortin antagonists leads to a delayed increase
of hypothalamic eCBs (Matias et al., 2008a,b). In addition, AEA
was shown to increase the secretion of the orexigenic media-
tor neuropeptide Y (NPY) (Gamber et al., 2005). However, CB1
is not expressed by NPY-secreting neurons of the hypothalamus
(Cota et al., 2003), and rimonabant is able to reduce food intake
equally well in wild-type and NPY null-mice, making it unlikely
that eCBs can modulate food intake through NPY (Bermudez-Silva
et al., 2012). Within the PVN, eCBs can be released “on demand”
upon activation of the orexigenic substance glucocorticoid (Di
et al., 2003), which inhibits (among others) the anorexigenic medi-
ator corticotrophin-releasing hormone (CRH). In keeping with
these observations, CRH levels were found to be higher in CB1 -
deficient mice (Cota et al., 2003). Moreover, CB1 agonists inhibit
orexin neurons (Huang et al., 2007), while exciting the orexigenic
melanin-concentrating hormone (MCH) neurons in LH (Morrison
and Berthoud, 2007). Interestingly, in vitro studies have shown that
CB1 and orexin-1 receptors are present as heterodimers/oligomers
in intracellular vesicles, and that treatment with rimonabant blocks
the activation by orexin A of intracellular pathways under control
of the orexin receptor (Ellis et al., 2006). It has been also proposed a
bimodal regulation of food intake by eCB system involving the con-
trol by CB1 , on glutamatergic transmission, possibly responsible for
the well-known orexigenic role, and on ventrostriatal GABAergic
neurons, inducing a reduction in local inhibitory transmission and
thus mediating a hypophagic action (Bellocchio et al., 2010).
The modulation of the expression of several anorexigenic and
orexigenic peptides by eCB system in the hypothalamus is often
counterbalanced by opposite actions mediated by the adipose-
derived hormone leptin, another key player in the regulation of
energy intake and expenditure (included appetite and hunger,
metabolism and behavior). eCB levels in the hypothalamus seemed
to inversely correlate with leptin plasma levels (Di Marzo et al.,
2001). Moreover, leptin directly inhibits eCB synthesis by reducing
both intracellular calcium levels in MCH neurons (Jo et al., 2005)
and glucocorticoid-mediated eCB release in the PVN (Malcher-
Lopes et al., 2006). In the same context, it should be recalled that
in humans leptin can also promote eCBs hydrolysis by enhancing
FAAH gene expression and activity via binding to a distinct site
of the FAAH promoter (Maccarrone et al., 2003a,b). Such a tight
cross-talk between eCB system and leptin seems to affect also the
activity of the brain reward system. Obese rats with defective lep-
tin signaling show increased CB1 expression and binding activity
in reward brain structures (Thanos et al., 2008). The interaction
between eCB system and leptin seems noteworthy also outside
the CNS, in metabolically relevant organs like the white adipose
tissue (WAT). Indeed, it was shown that the administration of
leptin in the medio-basal hypothalamus can inhibit WAT lipoge-
nesis by engaging hypothalamic phosphoinositide 3-kinase (PI3K)
signaling, thus activating sympathetic innervations on the adipose
tissue and locally inhibiting AEA production (Buettner et al., 2008).
 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224
It has been reported that fatty acid (FA) sensing in the CNS
is associated with metabolic traits such as energy expenditure,
plasma glucose and substrate utilization in both rodents (Lam et al.,
2005) and humans (Jumpertz et al., 2012). Besides the hypothala-
mus and the reward system, eCB system regulates food intake and
energy balance also at the level of the vagus nerve, that connects the
gastro-intestinal (GI) tract to key brainstem nuclei and contributes
to the so called “gut-to-brain axis”, where a number of signals origi-
nating from the GI tract are implicated too. Among these, hormones
like colecistokinin (CCK), peptide YY (PYY), and ghrelin exert impor-
tant functions by regulating meal duration and termination, and by
inducing satiety (Strader and Woods, 2005). It has been shown that
CB1 expression in vagal afferent neurons is increased in fasting and
decreased after refeeding, under the control of CCK (Burdyga et al.,
2004). Interestingly, the down-regulation of CB1 expression during
refeeding is also prevented by the administration of ghrelin, sug-
gesting a role for the latter hormone in blocking CCK action on CB1
expression (Burdyga et al., 2006, 2010). Furthermore, the effects of
CCK on CB1 expression can also be blocked by co-administration of
AEA, while the fasting-induced increase of CB1 mRNA can be pre-
vented by the CB1 antagonist AM281 (Burdyga et al., 2010). Besides
CCK, there might also be a potential link between eCB system and
PYY, since expression of Y2R, the receptor subtype that mediates
the anorectic action of PYY (Batterham et al., 2002), and CB1 mRNAs
are oppositely regulated in the vagal afferent neurons (Burdyga
et al., 2010). In this context, Y2R mRNA expression is increased
by refeeding or CCK treatment, while high doses of AEA block CCK-
induced increase of Y2R expression (Burdyga et al., 2010).
Among gut hormones, ghrelin is known to exert an orexigenic
action (Wiedmer et al., 2007). In rats, a sub-anorectic dose of
rimonabant is able to abolish the orexigenic effect of an intra-PVN
injection of ghrelin, demonstrating for the first time a cross-talk
between ghrelin and eCB system (Tucci et al., 2004). A further study
showed that the release of ghrelin could depend on eCB system
activation, since systemic administration of rimonabant reduces
circulating ghrelin levels (Cani et al., 2004). Later on, further stud-
ies have demonstrated that ghrelin increases hypothalamic eCB
content (Kola et al., 2008), and that the administration of CB1 ago-
nists or of methanandamide (a non-hydrolyzable AEA analog) in
rats increases plasma ghrelin levels and ghrelin secretion from
gastric X/A-like cells (named X cells for their unknown functions
and A-like cells for the similarity with pancreatic A-cells) (Zbucki
et al., 2008). In addition to their role in food intake, forebrain eCBs
regulate energy homeostasis by modifying also the activity of the
sympathetic nervous system (Quarta et al., 2010; Jung et al., 2012).
Indeed, it has been recently reported that mice selectively lacking
CB1 expression in forebrain neurons, and showing a 60% reduction
of the expression of the same receptor in the cervical sympathetic
ganglia, have a lean phenotype and are resistant to diet-induced
obesity (Quarta et al., 2010). This is due to an increase in lipid oxi-
dation and thermogenesis caused by an enhanced sympathetic tone
(Quarta et al., 2010).
Conversely, it has been shown that activation of CB1 stimu-
lates fat deposition by facilitating adipocyte differentiation, and
by increasing expression of adipogenic enzymes and the activity
of lipoprotein lipase (Bensaid et al., 2003; Cota et al., 2003; Matias
et al., 2006; Muccioli et al., 2010).
In concert with the action of the eCB system in the adipose
tissue, it was described that activation of CB1 expressed by hepa-
tocytes can induce the expression of lipogenic enzymes, such as
acetyl coenzyme-A carboxylase-1 (ACC1) and fatty acid synthase
(FAS), which in turn increase de novo fatty acid synthesis and favor
the development of liver steatosis, during exposure to HFD (Osei-
Hyiaman et al., 2005, 2008).
Much less investigated is the specific role of the eCB system
within the skeletal muscle and the endocrine pancreas. In isolated
207
soleus muscle, pharmacological blockade of CB1 was shown to
improve both basal and insulin-stimulated glucose transport activ-
ity, while CB1 activation had the opposite effect (Lindborg et al.,
2010).
Several studies have demonstrated the presence of both CB1
and CB2 in rodent and human pancreatic islets (Li et al., 2011a),
where eCBs seem to play a role in the regulation of endocrine
secretion (Bermúdez-Silva et al., 2008). This hypothesis was ini-
tially suggested by in vitro studies, in which a down-regulation of
pancreatic basal insulin hypersecretion was observed when islets
cultured from obese Zucker rats were exposed to rimonabant for
24 h (Getty-Kaushik et al., 2009). As yet, conflicting results have
been obtained in human studies, where both activation and block-
ade of CB1 can modulate insulin secretion in pancreatic tissue (Li
et al., 2011b).
Apart from the role played by the eCB system in the modula-
tion of GI hormones and of peripheral organs involved in energy
metabolism, increasing evidence suggests that another key aspect
of the regulation of energy metabolism by eCB system might be
linked to gut microbiota, that is known to influence whole body
metabolism and energy balance (Turnbaugh et al., 2006). Mucci-
oli and colleagues have made observations in a colonic epithelial
monolayer cell model upon CB1 activation, demonstrating that gut
microbiota control intestinal eCB system tone, which in turn mod-
ulates gut permeability (Muccioli et al., 2010).
On a final note, it is known that orosensory positive feedback
mechanisms play a pivotal role in the rewarding properties of food
(Greenberg and Smith, 1996). Recent evidence demonstrated that
CB1 receptors are present in cells of the fungiform papillae of the
mouse tongue, where they mainly colocalize with type-1 taste
receptor 3, a putative sweet receptor (Montmayeur et al., 2001;
Max et al., 2001). Indeed, pharmacological activation of the latter
receptors enhances the neural responses to sweet foods, but not
by to bitter, umami, salty, or sour substances (Yoshida et al., 2010).
This effect was observed both in vivo and in vitro after application
of CB1 agonists to isolated taste cells (Yoshida et al., 2010). Inter-
estingly, recent observations demonstrated that the oral exposure
to dietary fats mobilizes eCBs in the rat proximal small intestine
(DiPatrizio et al., 2011), while intraduodenal infusion of rimona-
bant inhibit fat intake. Altogether, these findings support the view
that eCBs in the gut may play a major role in stimulating the intake
of fatty meals (DiPatrizio et al., 2011), thus acting as a crucial com-
ponent of the positive orosensory feedback mechanism that drives
fat intake. Finally, it was also observed that CB1 increases odor
detection and food intake in fasted mice through cortical feedback
projections to the main olfactory bulb (Soria-Gómez et al., 2014).
Table 1 summarizes the above-reported studies.
3. Regulation of endocannabinoid levels by the diet
Essential FAs, such as ␣-linolenic and linoleic acids, are con-
verted respectively to ␻-3 and ␻-6 polyunsaturated fatty acids
(PUFAs), that include the AEA and 2-AG moiety AA (Fig. 1). Since
dietary fats are the only source of PUFAs required for eCBs biosyn-
thesis, their intake clearly affects the modulation of eCB system
functions (Maccarrone et al., 2010a,b; Bisogno and Maccarrone,
2014). Moreover, eCBs distribution in different tissues depends on
the amounts of ingested PUFAs, also because diet per se is only a
minor source of preformed eCBs (Berger et al., 2003; Bisogno and
Maccarrone, 2014). Increased levels of eCBs have been found in spe-
cific brain regions of newborn piglets fed milk supplemented with
AA and docosahexanoic acid (DHA) (Berger et al., 2001). Similar
results have been observed in whole brain of newborn mice fed up
to day 58 an AA-rich diet (Berger et al., 2001; Berger and Roberts,
2005). A decrease in hypothalamic AEA levels has been reprtedin
208 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224

Table 1
link between CB1 activation, CB1 antagonism/deletion and central/peripheral signals involved in the control of food intake and metabolism.

Effects of CB1 activation Effects of CB1 antagosnim/genetic deletion Effects of other signals on eCB system elements

Melanocortin system
↓ Release of Hentges et al. (2005) ↓ orexigenic effect of Verty et al. (2004) melanocortin antagonists ↑ Matias et al. (2008a,b)
hypothalamic melanocortin hypothalamic eCBs synthesis
melanocortin antagonists

Leptin system
↑ Plasma leptin Monteleone et al. ↓ adipose tissue leptin Mastinu et al. (2012) Leptin ↑ eCBs synthesis both Di Marzo et al. (2001)
concentrations in (2005) expression centrally and peripherally Maccarrone et al.
patients with AN ↑ CB1 expression and binding (2003a,b)
activity in reward brain Buettner et al. (2008)
structures of obese rats with Thanos et al. (2008)
defective leptin signaling Di Marzo et al. (2001)
↑ hypothalamic eCBs levels in
ob/ob mice

CCK system
↓ CCK effects on CB1 Burdyga et al. (2010) ↓ fasting-induced Burdyga et al. (2010) CCK controls CB1 expression in Burdyga et al. (2004)
expression increase of CB1 mRNA vagal afferent neurons
↓CCK-induced increase Burdyga et al. (2010) expression of Y2R and CB1 Burdyga et al. (2010)
of Y2R expression mRNAs are oppositely
regulated in the vagal afferent
neurons

Other
↑ Plasma ghrelin levels Zbucki et al. (2008) ↓ orexigenic effect of Tucci et al. (2004) ghrelin ↑ hypothalamic eCB Kola et al. (2008)
and ghrelin secretion an intra-PVN injection Cani et al. (2004) content
from gastric X/A-like of ghrelin
cells. ↓ circulating ghrelin
levels
↑ CRH hypothalamic Glucocorticoid ↑ eCBs release Di et al. (2003)
levels in the PVN, while decreasing Maccarrone (2004)
CRH levels
↓ Activation of orexin Huang et al. (2007) ↓ activation of Ellis et al. (2006)
neurons in LH intracellular pathways
under control of the
orexin A receptor
↓ Activation of MCH Morrison and Berthoud
neurons in LH (2007)
↑ Hypothalamic Gamber et al. (2005) ↓ food intake equally Bermudez-Silva et al.
secretion of well in wild-type and (2012)
neuropeptide Y NPY null-mice

pups until weaning, but not in adults, when dams where under food
restriction during gestation and/or lactation (Matias et al., 2003).
In another study, 4 week-old mice fed an ␻-3 PUFA-deficient diet
showed higher brain levels of 2-AG when compared to the ␻-3
PUFA-sufficient diet group, whereas a 6 weeks supplementation of
DHA-rich fish oil reduced brain 2-AG levels. These data suggested
that in the developing mice manipulation of dietary ␻-3 PUFAs reg-
ulates CNS physiological functions of eCBs (Watanabe et al., 2003).
Consistently, a 2 weeks diet with DHA supplementation induced
alterations in the eCB metabolome in adult mice plasma and brain,
plasma being more responsive than brain to dietary manipulation
(Wood et al., 2010). It can be anticipated that longer times are
required to affect brain eCBs, because FA composition of brain is
more stable than other tissues to changes in the diet (Lauritzen
et al., 2001; Hulbert, 2003). Since adult humans do not have a high
intake of fish oil for a prolonged time, it is unlikely that brain levels
of 2-AG and AEA could be affected.
Many studies have documented an eCB system overactivity in
animals fed a high fat diet (HFD), as well as in obese patients
(Monteleone et al., 2005; Engeli et al., 2005; Osei-Hyiaman et al.,
2005; Matias et al., 2006; Bluher et al., 2006; Cota, 2007), at multiple
levels: plasma, hypothalamus, organs with endocrine function or
involved in energy expenditure or affected by the consequences of
metabolic disorders (e.g., heart and kidney) (Matias et al., 2008a,b).
In human studies, an increase in AEA levels was observed in the
blood of women with anorexia nervosa (AN) and binge eatind dis-
order (BED) (Monteleone et al., 2005), along with an increase of AEA
and 2-AG levels and a reduction of FAAH and CB1 gene expression
in adipose tissue of obese women (Engeli et al., 2005). Incidentally,
human adipose tissue has been shown to possess a fully functional
eCB system (Spoto et al., 2006). In addition, HFD induced an increase
of AEA in liver, due to reduced degradation by FAAH (Osei-Hyiaman
et al., 2005). Another study reported higher eCB levels from mice
with diet-induced obesity, compared to lean mice, in epididymal fat
and pancreas (Matias et al., 2006). In visceral adipose tissue, strong
expression of FAAH and CB1 receptors was observed when com-
pared to subcutaneous adipose tissue, leading to the suggestion of
potential beneficial effects of CB1 blockade on metabolic syndrome
(Bluher et al., 2006). In the same study, an increase in circulating
2-AG was reported in visceral fat of obese subjects (Bluher et al.,
2006). Consistently, another investigation showed that only plasma
2-AG levels, among all the eCBs measured, markedly increased
in subjects with intra-abdominal adiposity accumulation (Cota,
2007).
It was also reported that circulating eCBs resulted to be unaf-
fected by isocaloric changes in dietary fat intake do not affect in
lean and in obese subjects. However, HFD selectively reduced CB1
and MAGL genes expression in skeletal muscle (Engeli et al., 2014).
Moreover, the same authors also observed the up-regulation of
DAGL␣ mRNA and the down-regulation of FAAH and MAGL mRNAs
in obese subjects in subcutaneous adipose tissue (Engeli et al.,
2014). In the stomach of HFD mice, OEA levels increased, in parallel
with an up-regulation of NAPE-PLD and a down-regulation of FAAH
gene expression (Aviello et al., 2008). Interestingly, alterations of
eCB system elements were found in adipose tissue, pancreas, liver
and skeletal muscle of HFD-induced obese mice, and thus eCB
 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224
system overactivation was supposed to contribute to the reduced
nutrient oxidation and oxygen consumption that sustain obesity
development in this model (Osei-Hyiaman et al., 2005; Pagotto
et al., 2006; Starowicz et al., 2008).
As mentioned in the previous section, just as yet one clinical
study investigated the regulation of eCB levels after hedonic eating
(Monteleone et al., 2012). The authors observed that, in satiated
normal-weight healthy subjects, consumption of food for pleasure,
increased plasma levels of 2-AG and ghrelin, but not of AEA, OEA
and PEA (Monteleone et al., 2012). In agreement with these data, 2-
AG resulted increased in the hypothalamic reward system of mice
showing HFD preference (Higuchi et al., 2011). Later on, the same
research group showed that there are two different stages, induc-
tion and maintenance, that involve a transient and a long-lasting
increase of 2-AG, respectively (Higuchi et al., 2012). In the cen-
tral amygdala of rats during abstinence from palatable food, an
elevation of 2-AG and CB1 levels was observed, and was possi-
bly needed to counteract the negative emotional state produced
by withdrawal (Blasio et al., 2013). Lower expression of CB1 and
FAAH were observed in the hippocampus of Fischer rats, when
compared to Wistar rats, the first strain expressing a lower reward
sensitivity than the second toward a palatable food reward (Brand
et al., 2012). CB1 mRNA levels were also found to be differentially
regulated depending on the access to high palatable food: they
increased in the nucleus of the solitary tract of rats with contin-
uous access to highly palatable sweet for 6 weeks, and decreased
in the cingulate cortex of rats with intermittent feeding schedules.
Moreover, CB1 binding densities were reduced in NAc shell of rats
with access to a highly palatable sweet-fat food (Bello et al., 2012).
Down-regulation of CB1 expression was observed also in the NAc of
rats fed a highly palatable chow for 10 weeks (Harrold et al., 2002),
as well as in other rat brain regions (cingulate cortex, ventromedial
hypothalamic nucleus, descending/autonomic divisions of the par-
vocellular hypothalamic nucleus, ventrolateral parvocellular, and
dorsomedial parvocellular) of animals fed a high palatable, high
energy food for 13 weeks (Timofeeva et al., 2009).
Selective alterations of eCB levels have been reported in liver
and small intestine, but also in the brain, of adult rats fed 5 differ-
ent dietary fats for only 1 week (Artmann et al., 2008). For instance,
DHA and eicosapentaenoic acid (EPA) administration reduced PEA
levels in rats (Artmann et al., 2008), even though PEA levels are
not yet believed to be affected by nutrient intake, nor by starva-
tion/refeeding protocols (Fu et al., 2007).
EPA/DHA supplementation induced a decrease in 2-AG (Banni
et al., 2011; Batetta et al., 2009; Di Marzo et al., 2010) and AEA
(Batetta et al., 2009; Balvers et al., 2012; Wood et al., 2010) levels in
obese subjects (both humans and animals) at peripheral and central
levels, paralleled by a reduction in NAPE-PLD, FAAH and CB2 gene
expression (Hutchins et al., 2011). Overall, these data indicate a
reduction in eCB system signaling linked to decreased appetite and
food intake.
The primary FA in olive oil, oleic acid, is the precursor of
OEA that, when administered orally as part of a HFD, increases
gene expression of FAAH (Thabuis et al., 2010) and PPAR␣ (Cluny
et al., 2009). OEA levels are, instead, reduced by a ketogenic diet,
that is a HFD used for the treatment of refractory epilepsy in
children (Freeman et al., 2007). Because of its effects on OEA
and congeners, such a diet could also lead to overconsump-
tion and obesity (Hansen et al., 2009). The role of OEA in the
induction of satiety is well-established (Fu et al., 2007), and it
has been proposed that at the periphery, OEA increase due to
NAPE-PLD overexpression, reduces across-meal satiety in rats
(Fu et al., 2008). Consistently, high intake of any type of fats
reduces intestinal levels of OEA and congeners (Artmann et al.,
2008). At the peripheral level, it has also been observed that a
HFD (60% energy) for 14 weeks increased AEA levels in mice
209
liver, an effect that is possibly related to the observed diet-
induced obesity via hepatic CB1 activation (Osei-Hyiaman et al.,
2005).
Dietary guidelines recommend the shift from saturated to
polyunsaturated fat, in order to reduce the incidence of cardio-
vascular diseases (Harris et al., 2009). This recommendation has
led to increased consumption of vegetable oils. Soybean oil is one
of the major dietary sources of linoleic acid (LA), an AA precur-
sor that is able to modulate eCBs biosynthesis (Salem et al., 1999).
Human and animal studies showed that high LA diets promote obe-
sity (Massiera et al., 2003, 2010; Alvheim et al., 2012), and in mice
induce an increase of 2-AG and AEA levels (Alvheim et al., 2012).
More recently, Alvehim and colleagues also observed that replac-
ing fish oil with soyabean oil in feed for Atlantic salmon evokes
high dietary levels of LA and elevates AA, eCB activity and fat accu-
mulation in the salmon liver. Moreover, mice consuming Atlantic
salmon fed soyabean oil have higher weight gain, adipose tissue
inflammation and liver levels of AA, AEA and 2-AG, when compared
to mice fed fish oil salmon diet (Alvheim et al., 2013). In a recent
investigation, rats receiving LA diet showed a 2-fold accumulation
of jejunal eCBs, as well as a strong preference to this type of food
when compared to other unsaturated fats (DiPatrizio et al., 2013).
All the studies described so far support a regulatory role for
eCB system in modulation of appetite, control of food consumption
and regulation of the hedonic aspects of eating (see summary in
Table 2). However, eCB system is also implicated in the homeostatic
regulation of eating, as described in the next section.
4. Neurobiology of food addiction and food reward
mechanisms
The concept of food addiction has been suggested for the first
time by Randolph in 1956 (Randolph, 1956), but only recently it
has received due attention, mainly because of its correlation to the
increasing rate of obesity; a condition that has reached pandemic
proportions, and that is increasing exponentially if considering that
overweight/obese people are estimated to become ∼58% of the
world population by the year 2030 (Skidmore and Yarnell, 2004;
Kelly et al., 2008).
Obesity is a complex multifactorial disease, not limited to
genetic or environmental factors, nor to an unbalanced energy
uptake and expenditure. Current knowledge supports a relation-
ship with neurobiological as well as psychological aspects of
overeating, including mood disturbances, altered reward percep-
tion and motivation, and possibly addictive behavior (Jauch-Chara
and Oltmanns, 2014).
Hence obesity should no longer be viewed only as a metabolic
disease but also as result of eating behavior disturbances charac-
terized by a significant CNS component, with important impact not
only on physical health but also on psychosocial functioning (APA,
2013).
Binge eating is a proto-typical eating-related maladaptive
behavior that may determine fluctuations in body weight and in
some instance may cause obesity (Hudson et al., 2007; Swanson
et al., 2011). It also represents a central feature of bulimia nervosa
(BN) and BED and as described by the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DMS-5) (APA, 2013) it
is a condition in which the subject consumes an amount of food
that is definitely larger than what most individuals would eat in
a similar period and it is characterized by a subjective sense of
loss of control over food consumption. Over the recent years it
has been recognized that BN and BED share important common-
alities with substance abuse. In fact, like substance abuse, these
eating disorders are characterized by an uncontrollable urge to
seek the reward and to cosume it in excessive amounts despite the
perceived negative consequences (Gold et al., 2003). Additionally,
210 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224

Table 2
Overview of studies examining the regulation of eCB levels by the diet.

Experimental system Diet ECS elements Reference

Newborn piglets and Milk supplemented with AA and ↑ eCBs Berger et al. (2001)
mice AA-rich diet
Mice ␻ 3-PUFA-deficient diet ↑ 2-AG Watanabe et al. (2003)
DHA-rich fish oil ↓ 2-AG
Adult mice Diet DHA-rich (for 6 weeks) Alteration eCB metabolome Wood et al. (2010)
CNS Mice HFD (414 kcal/100 g) ↑ 2-AG Higuchi et al. (2011,
2012)
Mice obese Diet supplemented with EPA/DHA ↓ AEA Balvers et al. (2012),
Wood et al. (2010)
Mice and Rats Highly palatable and high-energy food ↓ CB1 gene expression Timofeeva et al. (2009)
(13 weeks)
Rats Abstinence from palatable food ↑ 2-AG Blasio et al. (2013)
↑CB1 gene expression
Rats Continuous access to highly palatable ↑ CB1 gene expression Bello et al. (2012)
sweet-fat food for 6 weeks) ↓ CB1 gene expression
Intermittent feeding schedules ↓ CB1 gene expression
Highly palatable sweet-fat food
Rats Highly palatable chow (10 weeks) ↓ CB1 binding Harrold et al. (2002)
Adult rats 5 different dietary fats (1 weeks) ↓ PEA Artmann et al. (2008)
↓ OEA
Obese Zucker rats Diet supplemented with EPA/DHA ↓ 2-AG Di Marzo et al. (2010)
Women with AN and HFD ↑ AEA Monteleone et al.
BED (2005)
Obese women HFD ↑ AEA and 2-AG Engeli et al. (2005)
↓ FAAH and CB1 gene
expression
Obese humans Diet supplemented with EPA/DHA ↓ 2-AG Banni et al. (2011)
Adult mice Diet DHA-rich (for 6 weeks) Alteration eCB metabolome Wood et al. (2010)
Pheripheral
Mice HFD (33.5% fat) ↑ AEA Osei-Hyiaman et al.
↓ FAAH activity (2005)
Mice Diet-induced obesity ↑ eCB Matias et al. (2006)
Mice HFD (25.5% fat) ↑ OEA Aviello et al. (2008)
↑ NAPE-PLD and ↓ FAAH
activity
Mice obese Diet supplemented with EPA/DHA ↓ AEA Balvers et al. (2012);
Wood et al. (2010)
Mice Diet supplemented with EPA/DHA ↓ NAPE-PLD, FAAH and CB2 Hutchins et al. (2011)
gene expression
Mice HFD enriched with oleic acid (the ↑ FAAH and PPAR␣ gene Thabuis et al. (2010)
precursor of OEA) expression Cluny et al. (2009)
Mice Diet supplemented with Atlantic ↑ AEA, 2-AG and AA Alvheim et al. (2013)
salmon fed a high LA diet
Adult rats 5 different dietary fats (1 weeks) ↓ PEA Artmann et al. (2008)
↓ OEA
Obese Zucker rats Diet supplemented with EPA/DHA ↓ 2-AG Batetta et al. (2009)
Rats LA diet ↑ eCB DiPatrizio et al. (2013)

binge eating episodes usually occur in secrecy, involve intense crav-
ings associated with stress and sense of guilt (Jastreboff et al., 2013;
McAleavey, 2001), and are associated with high rate of recidivism
(Bergh et al., 2002; Fairburn et al., 2000).
Unlike drugs of abuse, food is necessary for survival and humans
have developed evolutionary mechanisms to select and prefer
calory reach highly palatable food. The constant and easy access
to these foods leads to their unnatural consumption that is no
longer aimed at maintaining health and satiety but rather to
achieve reward. Moreover, refined carbohydrate, fat and salt rich
of highly palatable food has an important impact on the regulation
of mood and some individuals may overconsume these nutrients
to self-medicate from negative affective conditions such as anxi-
ety, depression, mental fatigue (Ifland et al., 2009). In this respect
highly palatable foods may evoke alterations in the CNS in ways
similar to drugs of abuse and reinforce behaviors with mechanisms
resembling addiction (Spring et al., 2008; Gearhardt et al., 2011a,b;
Kenny, 2011), and through regulation of common neurobiological
substrates (Avena et al., 2008a; Oswald et al., 2011; Rossetti et al.,
2013).
This view is indirectly supported by pharmacological evidence
showing that binge eating and excessive food consumption are
attenuated by drugs that influence also the intake of drugs of abuse;
these include naloxone (Boggiano et al., 2005), naltrexone, baclofen
(Buda-Levin et al., 2005; Corwin et al., 2012), topiramate (Cifani
et al., 2009), Rhodiola rosea and Hypericum perforatum extracts
(Cifani et al., 2010; Micioni Di Bonaventura et al., 2012a), adeno-
sine A2A receptor agonists (Micioni Di Bonaventura et al., 2012b),
orexin 1 receptor antagonists (Piccoli et al., 2012) and CRF1 recep-
tor antagonists (Micioni Di Bonaventura et al., 2014). The effecicacy
of some of these drugs on binge eating have been described also in
clinical studies (Broft et al., 2007; Meyer, 2008; Arbaizar et al., 2008;
McElroy et al., 2004).
In addition to these pharmacological data, molecular and neu-
rochemical evidence suggest that overconsumption of palatable
foods is accompained by the stimulation of brain reward dopa-
minergic and opioid systems. Notably, in binge eaters and in
the obese population these systems are subjected to a profound
readaptation leading to a state of reward hyposensitivity and to
the development of compulsive-like eating (Volkow et al., 2009a;
Avena et al., 2008b; Kenny et al., 2013; Thamotharan et al.,
2013). Evidence also suggests that the reward deficit observed
in obese patients and in rodents fed with high fat food may be
linked to dysregulation of striatal D2 receptors signaling (Volkow
et al., 2008; De Weijer et al., 2011; Geiger et al., 2009; Johnson
and Kenny, 2010). In overweight rats it has been proposed that
 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224
Fig. 3. Main features of food addiction.
reward deficit, associated with blunted D2 mediated activity may
reflect counteradaptive decreases in the baseline sensitivity of
brain reward circuitries to oppose their overstimulation by palat-
able food (Johnson and Kenny, 2010). In another study, Alsio
et al. (2010) showed that D1 and D2 receptors expression in the
nucleus accumbens (NAc) is downregulated in obesity-prone (OP)
rats, in comparison to obesity-resistant rats, under high-fat and
high-sugar diets. These findings strongly involve both dopamine
(DA) and opioid receptors in the OP phenotype, but they also
suggest longer term changes for the DA circuitry. Interestingly,
similar disruption occurs after intravenous cocaine or heroin self-
administration (Ahmed et al., 2002; Markou and Koob, 1991; Kenny
et al., 2006), and supports other studies suggesting that obesity
and drug addiction share neuroadaptive responses in brain reward
circuitries, to alleviate the persistent state of reduced reward
(Stice et al., 2008; Teegarden and Bale, 2007; Avena et al., 2008a;
Volkow et al., 2006; Volkow and Wise, 2005; Volkow and O’Brien,
2007).
Human brain imaging data showed compromised striatal DA
signaling, particularly in subjects carrying genetic polymorphisms
associated with long-term weight gain (Stice et al., 2008). Imag-
ing studies also showed that increased DA in addicted subjects
predicts the intensity of cue-induced cravings (Volkow et al.,
2006) and similarly, in obese individuals with BED, higher DA
release upon exposure to food cues was associated with the sever-
ity of the disorder (Wang et al., 2011). Functional neuroimaging
has also demonstrated in obese individuals that pleasant looking,
smelling, and tasting foods have reinforcing properties similar to
drugs of abuse (Zhang et al., 2011). Positron emission tomographic
(PET) imaging studies have further provided evidence that reduced
211
levels of DA receptors are related to both obesity and drug depend-
ence (Volkow et al., 2009a).
Furthermore, individuals with a variety of eating disturbances
report craving and symptoms they percieve as withdrawal, and
escalating patterns of eating that might be viewed as evidence
for tolerance and dependence (Pelchat, 2002). Likewise, binge
eating patients report withdrawal-like feelings of panic and dis-
tress and a sense of abstinence when their binge eating behaviors
were delayed (Huebner, 1993). In other studies, removal of certain
foods from diet triggered some symptoms of withdrawal such as
headaches, sweats, irritability, and panic (McAleavey, 2001). Rats
fed sucrose solution and lab chow on a schedule that induced bing-
ing, after several weeks exhibited behaviors similar to those found
in addicted individuals, like symptoms resembling tolerance, with-
drawal, and craving (Avena et al., 2008b). Accordingly, Parylak
et al. (2011) suggested that the “side” of addiction, described by
Koob and Le Moal (2005) and Le Moal and Koob (2007) as devel-
opment of the aversive emotional state that drives the negative
reinforcement of addiction, occurred also in food addiction under
certain instances of obesity or eating disorders. According to this
view, like for drug addiction (Koob and Le Moal, 1997), stress
and negative moods (depression, anxiety) can trigger compulsive
food intake in humans, through a three-stage cycle characterized
by binge/intoxication, withdrawal/negative affect and preoccupa-
tion/anticipation.
Although excessive consumption of different nutrients can
induce behaviors associated with addiction, caution is still neces-
sary before drawing conclusions. Many groups, first of all those led
by the pioneers Bartley G. Hoebel (Hoebel and Teitelbaum, 1962)
and Nicole M. Avena (Avena et al., 2008a), have interrogated the
212 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224
Fig. 4. Interactions between the endocannabinoid, opioid and dopaminergic systems in the mesolimbic reward circuit. VTA, ventral tegmental area; NAc, Nucleus Accumbens;
AM, amygdala; FC, Frontal cortices; GABA, GABAergic neurons, GLU, glutamatergic neurons; DA, dopaminergic neurons; Opioid; Opioid neurons; CB1 , type 1 cannabinoid
receptors.
validity of the food addiction construct (Avena et al., 2011, 2012) and
investigated different angles of this phenomenon also by dissecting
the neurobiology of appetite from hedonic overeating (Bocarsly
et al., 2011; Avena and Gold, 2011).
It has been noted that food addiction behavior is related to the
nutritional composition of the food consumed under certain envi-
ronmental conditions (Corwin, 2011). Rats with a fat-rich food did
not show signs of opiate-like withdrawal when precipitated by the
opiate antagonist naloxone or during fasting, as previously shown
with sugar (Avena et al., 2008b; Colantuoni et al., 2002), suggesting
that the brain opioid system can be differently affected by overeat-
ing fat foods versus sugar. Moreover, neither obesity (Blundell and
Finlayson, 2011) nor BED (Gearhardt et al., 2011b) should be con-
sidered synonymous of food addiction, that is neither necessary nor
sufficient for obesity. Indeed, among adults with BED, the preva-
lence of obesity is 42%, that is only ∼8% higher than that seen in the
general population (Wonderlich et al., 2009).
In order to further validate the construct of food addiction, and
to explore its prevalence, the Yale Food Addiction Scale (YFAS)
has been designed in college students and binge eaters (Gearhardt
et al., 2009), and then used in eating disorder patients (Gearhardt
et al., 2011b) and obese subjects (Davis et al., 2011). YFAS is a
systematic tool to distinguish between individuals with or with-
out addictive-like eating patterns. This scale may be a useful tool
for the detection of “food addiction” in humans, using the cri-
teria identified for substance dependence in the fifth edition of
the Diagnostic and Statistical Manual of Mental Disorders (DSM-
V).
In BED patients with high prevalence of food addiction (51%),
a relationship between diagnosis of this trait and more severe
depression, emotion dysregulation, eating disorder psychopathol-
ogy and lower self-esteem it has been observed, when compared
to subjects that were not diagnosed with food addiction (Gearhardt
et al., 2011b). Similarly, Davis et al. (2011) showed that food addic-
tion was linked to higher levels of depression and trait impulsivity
in obese adults. More recently, Gearhardt et al. (2013) indicated
that ∼42% of obese patients with BED met the food addiction
threshold, whereas Pedram et al. (2013) reported that ∼80–89%
of subjects, recruited in a population of food-addicted individuals,
were overweight/obese, further providing evidence that food addic-
tion contributes to obesity. Finally, in patients undergoing weight
loss surgery, more than 40% met the criteria for food addiction
(Meule, 2011).
Although the concept of food addiction remains highly debated
(Ziauddeen et al., 2012; Salamone and Correa, 2013), these find-
ings call for additional investigations to identify clinically relevant
subgroups within obesity or eating disorder, that show features (or
symptoms) described in Fig. 3. The ultimate goal is to define more
personalized prevention and treatment strategies.
The proposal, originally made by Holden (2001, 2010), and then
the inclusion of food addiction in the DSM-V strongly suggest that
the status of some individuals with eating disorders resembles that
typically endorsed for individuals with substance use disorders.
This observation might reflect the engagement of the same neu-
ral systems, including those implicated in regulatory self-control
and reward (APA, 2013).
On a final note, it should be recalled that human and animal
studies are pivotal to further our understanding of the factors that
contribute to the escalating rates of obesity, and to develop effective
approaches not only to restrain hunger and eating behavior, but also
 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224
to study the next generation of obesity treatments, as suggested by
Avena et al. (2013). Among potential neuropathways and neuro-
transmitters involved in the reinforcement and reward associated
with food intake, this review focuses on the eCB system.
5. Cannabinoids and reward mechanisms
eCBs affect the release of various neurotransmitters, including
GABA (␥-aminobutyric acid), glutamate, and DA (Pertwee, 2008;
Lüscher and Malenka, 2011; Szabo et al., 2002) and plays an
important function in the neuroplasticity associated with chronic
exposure to drug of abuse (Fig. 4).
High density of eCB receptors is found in several regions of the
basal ganglia (Ameri et al., 1999; Gardner, 2005) and their impor-
tant role in the regulation of the cortico-mesolimbic DA system
that originates from the ventral tegmental area (VTA), and project
to the NAc, the amygdala and the frontal and limbic cortices has
been described (Solinas et al., 2006; Oleson et al., 2014; Massi et al.,
2008; Melis et al., 2004, 2012).
For instance, eCBs modulate the glutamatergic excitatory and
GABAergic inhibitory synaptic inputs into the dopaminergic neu-
rons of the VTA and the glutamate transmission in the NAc, acting
as retrograde messengers on CB1 . The latter is the primary tar-
get of eCBs to control emotional reactivity, motivated behaviors
and energy homeostasis (Fride, 2002; Piomelli, 2005; Steiner and
Wotjak, 2008).
The activation of CB1 , present on axon terminals of GABAergic
neurons in the VTA, inhibits GABA transmission and removing this
inhibitory input on DA neurons, it leads to an increase in the fir-
ing patterns of these cells (Riegel and Lupica, 2004). With similar
mechanism, the activation of CB1 decrease excitatory glutamater-
gic transmission in the VTA and NAc, mainly regulating the activity
of neurons projecting from the prefrontal cortex (Melis et al., 2004).
Therefore, the final effect of eCBs on the modulation of DA activity
depends on the functional balance between the inhibitory GABAer-
gic and excitatory glutamatergic inputs to the VTA, with the latter
that predominates (Maldonado et al., 2006). Hence, eCBs do not
directly depolarize DA neurons but acting indirectly via pre- and
post-synaptic inhibition of interneurons (Szabo et al., 2002), they
may ultimately activate mesolimbic DA transmission (Gessa et al.,
1998).
Although DA is not a direct measure of reward, it is considered an
important neurochemical correlate of rewarding effects of abused
drugs, and a potential mechanism for these effects. All addictive
drugs display ability to increase DA, particularly in the NAc, under-
ling their rewarding effects (Koob, 1992; Wise, 2004). Like for other
addictive drugs, animal (Gardner et al., 2005; Solinas et al., 2007)
and human (Glass et al., 1997; Terry et al., 2009; Van Hell et al.,
2012) studies have indicated that cannabinoids affect brain reward
processes and reward-related behaviors, through their ability to
enhance extracellular DA levels in the NAc (Fadda et al., 2006; Lecca
et al., 2006).
For instance, Gardner et al. (2005) were the first to report
that cannabinoids enhance extracellular DA overflow in brain
reward axon terminal loci (Ng Cheong Ton and Gardner, 1986);
whereas direct agonism at CB1 leads to rewarding effects in ani-
mals (Gardner, 2005; Solinas et al., 2007). Consistent with a role
of CB1 in reward modulation other studies have shown that recep-
tor antagonists like rimonabant reduce the reinforcing effects of all
major drugs of abuse (Economidou et al., 2006; De Vries et al., 2003;
Cohen et al., 2002). Reduction in substance of abuse self adminis-
tration has been also reported following the selective inhibition of
the AEA transporter (Gamaleddin et al., 2013; Cippitelli et al., 2007).
In line with preclinical evidence, human PET studies have shown
that like other addictive substances, cannabis increase DA levels in
213
the dorsal and ventral striatum, and that these increases are asso-
ciated with the subjective rating of drug reward (Bossong et al.,
2009).
Moreover, in a study on healthy voluntiers it has been shown
that treatment with rimonabant reduces striatal brain activity dur-
ing reward processing (Horder et al., 2010).
THC, is the major psychoactive ingredient of cannabis and is
the main responsible of cannabis effects on the reward system
(Pertwee, 2008).
For example in Wistar rats it has been shown that THC stimu-
lates reward as measured by either conditioned place preference
or intracranial operant self-administration in a free-choice proce-
dure, yet only within a limited dose range (Braida et al., 2004).
Squirrel monkeys lever-press for intravenous injections of THC
(Justinova et al., 2005). Moreover, THC decreases electrical brain-
stimulation reward thresholds (Gardner, 2005), and increases
the firing rate of VTA dopaminergic neurons that project to the
NAc (French et al., 1997; Gifford et al., 1997). A PET study in
humans in which glucose metabolism was monitored it has been
shown that, after chronic THC, marijuana abusers have increased
orbitofrontal cortex, medial superior prefrontal cortex and striatum
metabolic activation compared to controls, whereas cerebellar
metabolism resulted increased in both abusers and controls. Also
tactile marijuana-related cues versus neutral cues were shown
to increase fMRI activation in VTA, supporting the involvement
of striatal networks in abstinent marijuana users (Filbey et al.,
2009). Finally, 69% of the abnormal activation clusters in studies
on marijuana effects on brain function were located in regions
functionally connected to the striatum (Tomasi and Volkow, 2013).
These findings suggest that striatal networks are involved in mari-
juana addiction (Volkow et al., 1996).
Besides DA, other neurochemicals reciprocally modulate
cannabinoid-induced reward, like noradrenaline, serotonine,
acetylcholine, adenosine and opioids (for a review, see Maldonado
et al., 2011). The best studied cross-talk occurs with the brain opi-
oid peptide system (Gardner, 1997, 2000; Robledo et al., 2008;
Parolaro et al., 2010). For example, it has been also shown that
␦-opioid (DOP) and CB1 receptor agonists synergistically activate
the mesolimbic DA system, increasing intracellular cAMP and pro-
moting protein kinase A (PKA)-dependent C␣ translocation (Yao
et al., 2003). Moreover, in a microdialysis study in the rat it has
been shown that THC stimulates DA release in the shell of the NAc
through mechanisms involving VTA MOP receptors (Tanda et al.,
1997). Noteworthy the interaction the opioid systems seem to be
important not only for the reinforcing and rewarding effects of
cannabinoids (Tanda et al., 1997) but also for the expression of
withdrawal (Navarro et al., 1998; for reviews, see Justinova et al.,
2005; Scavone et al., 2013).
More recently, the hypocretin (Flores et al., 2013) has also
been linked to cannabinoid-induced reward. The link between
cannabinoid system with this neuropeptidergic circuitry playing a
central role in caloric homeostasis, food consumption and reward
processing (Martin-Fardon et al., 2010; Aston-Jones et al., 2010;
Piccoli et al., 2012) may be suggestive of potential mechanisms
through wich the eCB system may impact on food reward and may
regulate its non-homeostatic consumption (Di Marzo et al., 2009).
Foods that are rich in sugars and fat are potent reward stimuli,
and can promote over-eating (Lenoir et al., 2007). As discussed
above, they activate brain reward circuits with release of DA, eCBs
and opiates, while inhibiting that of satiety mediators. Indeed,
limbic levels of DA and eCBs correlate with craving for tasty
food, indicating their involvement in reward-driven palatable food
eating behavior (Tanda and Goldberg, 2003; DiPatrizio, 2014). Con-
sistent with a role of cannabinoid neurotransmission in food reward
pharmacological data with rimonabant have shown that its admin-
istration leads to a reduction in the conditioned place preference for
214 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224
palatable food, such as sucrose or chocolate (Chaperon et al., 1998).
Moreover, they dose-dependently reduce the motivation for food
in a progressive ratio schedule of food self-administration in rats
(Gallate and Mc Gregor, 1999). CB1 antagonism has been shown also
to counteract the increase of extracellular DA release, induced by
novel and highly palatable foods (Melis and Pistis, 2007); while CB1
agonists do the opposite (Higgs et al., 2005; Solinas and Goldberg,
2005; Wakley and Rasmussen, 2009; Ward and Dykstra, 2005). For
instance, THC increases sucrose-induced hedonic activity and DA
release into the NAc (De Luca et al., 2012). Furthermore, CB1 and
MOP blockade synergize to reduce food intake and body weight
in rodents (Lockie et al., 2011; Tallett et al., 2009). Accordingly,
CB1 knock-out mice show a reduced motivation to work for food,
compared to wild-type mice (Sanchis-Segura et al., 2004). In addi-
tion, intra-NAc injections of AEA enhance reward associated with
food palatability (Mahler et al., 2007). Thus, CB1 appears to be an
important component of the neural substrate that mediates the
reinforcing and motivational properties of a highly palatable food
(Maccioni et al., 2008). In line with this, CB1 mRNA expression
is down-regulated in areas of the limbic forebrain of rats fed a
palatable diet (Harrold et al., 2002), an effect that can be consid-
ered as part of a compensatory mechanism aimed at counteracting
increased levels of eCBs resulting from the consumption of a fat-
rich palatable food. On the other hand it has been also shown that
fasting leads to an increase of limbic of AEA and 2-AG levels, that
return to normal after refeeding. This effect occurs selectively in
brain areas that are not involved in the regulation of feeding behav-
ior (Kirkham et al., 2002). This overactivation of the eCBs systems
during fasting may be part of a physiological mechanism aimed at
enhancing the motivation for food. Furthermore, injection of 2-AG
directly in the NAc shell, which shows high CB1 expression, trigg-
ers increased feeding also in satiated rodents, via CB1 activation
(Kirkham et al., 2002).
Interestingly, in healthy volunteers consumption of favorite
food, as compared to normal food, is accompanied by elevated
plasma 2-AG levels, which correlate positively with plasma ghrelin
levels (Monteleone et al., 2012). Altogether these evidence demon-
strate that the eCBs system plays a major role in regulating
reward related mechanisms in response to not only substances of
abuse but also calory reach highly palatable food. This strongly
supports its role in the regulation of food-related addictive-like
behaviors.
6. eCB system-based drugs in eating disorders and obesity
6.1. eCB system in eating disorders
The widespread role of the eCB system as a modulator of both
homeostatic and hedonic aspects of eating prompted intensive
investigations into possible defects of this system in eating disor-
ders. In particular, increased blood levels of AEA (with unaltered
levels of 2-AG) were found in patients with AN or BE disorder,
but not in women affected by BN (Monteleone et al., 2005). In
both healthy controls and AN women, blood AEA levels appeared
inversely correlated with plasma leptin concentrations. Since a
negative modulation of leptin on eCB mobilization was previously
demonstrated (Di Marzo et al., 2001), this observation suggested
that the decreased leptin signaling of underweight AN patients
could be at least in part involved in the increase of AEA lev-
els. A subsequent study demonstrated that AEA is not the only
acylethanolamide altered in eating disorders. Indeed, also OEA was
associated with eating disorders. In particular, both plasma and
cerebrospinal fluid levels of this endogenous lipid were increased
in bulimic-anorexic women, with respect to restrictor anorexic and
control women (Gaetani et al., 2008). Differently from the previous
studies on AEA levels, these observations were made on patients
who were classified as recovered from the pathology, thus possibly
excluding the limit that the altered nutritional status might have
affected the plasma levels of the investigated lipids (Gaetani et al.,
2008).
Higher blood levels of CB1 mRNA were detected in women suf-
fering from AN and BN (Frieling et al., 2009), whereas decreased
peripheral CB1 mRNA expression was observed in patients with
more severe forms of the disorders, such as those with self-
injurious behaviors (Schroeder et al., 2012). Further observations
on altered CB1 expression came from PET studies, demonstrating
increased receptor levels in the insula and inferior frontal and tem-
poral cortex of underweight AN patients, as well as in the insula
of symptomatic BN subjects (Gérard et al., 2011). Finally, human
genetic studies reported a positive association between eating dis-
orders and specific polymorphisms of genes encoding for different
components of the eCB system, such as CB1 (Siegfried et al., 2004;
Monteleone et al., 2008), CB2 (Ishiguro et al., 2010) and FAAH
(Monteleone et al., 2009), although previous contrasting findings
showing no association were also reported (Muller et al., 2008).
It has been hypothesized that the deregulated eCB tone of AN
and BN patients may represent an adaptive response aimed at
maintaining energy balance by potentiating internal orexigenic
signals, and hence stimulating food ingestion. Yet, it might also con-
tribute to facilitate the rewarding properties of the aberrant eating
behaviors (Monteleone and Maj, 2013).
Given the appetite-stimulating and antiemetic properties of
THC, research has focused on its role in patients with AN. How-
ever, two small trials exploring the effects of THC in underweight
AN patients did not give the expected positive results (Gross et al.,
1983; Berry, 2006). In particular, five years before the discovery of
CB1 receptors, Gross et al. (1983) evaluated the effects of synthetic
THC treatment in 11 patients with primary AN, that caused a 25%
loss of their body weight. The study was conducted in a 4-week
crossover trial, testing quite high doses of THC (from 7.5 mg/day
to a maximum dose of 30 mg/day), against diazepam as an active
placebo. Moreover, the medication was discontinued during the
weekend, possibly to avoid addiction. The daily caloric intake was
controlled, and occasionally tube feeding was used. THC treatment
corresponded to a slightly higher weight gain (about 1 kg), as com-
pared to that observed during diazepam treatment; three patients
(27%) withdrew after experiencing severe dysphoric reactions and
the authors concluded that THC was not an effective drug for the
treatment of primary AN. This study raised several concerns, mainly
due to the use of high doses of THC and of diazepam as a con-
trol, despite the evidence from both animal (Naruse et al., 1991)
and human (Hein and Huyser, 2010) studies that benzodiazepines
may also increase food intake. Several years later a pilot study was
conducted by Berry (2006) in 9 ambulatory AN patients treated
with THC, who did not show any effect on body weight gain, but a
significant improvement of depression and perfectionism scores.
A very recent publication reported the results of an add-on,
prospective, randomized, double blind, controlled cross-over study,
aimed at testing the effects of dronabinol (a synthetic THC for oral
administration, 2.5 mg twice a day for 4 weeks) on body weight
gain, as well as on the Eating Disorder Inventory-2 (EDI-2) score
and leptin plasma levels (Andries et al., 2014). The results of this
study demonstrated that dronabinol therapy induced a small yet
significant weight gain in the absence of severe adverse events.
Conversely, no effects were noticed on EDI-2 score change dur-
ing treatment, while leptin levels rose to 15% above placebo, but
returned to baseline after the last dose of dronabinol. In addition,
weight records collected up to one year after the end of the trial
indicated a persistent improvement of patient nutritional status
without signs of addiction or withdrawal, suggesting that dron-
abinol effects were longlasting and safe in these patients, thus
 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224
encouraging more research on the positive effects of cannabinoids
in eating disorders.
A certain degree of positive effects induced by THC treat-
ment was also reported in a recent preclinical study that used
the activity-based anorexia (ABA) model of AN. In this model,
THC treatment attenuated the weight loss associated with the
development of ABA, by increasing high-palatable food intake and
moderately decreasing running wheel activity (Verty et al., 2011).
The stimulation of eCB system actiivity has been clearly shown to be
of success in diseases in which weight gain is needed (i.e., cachexia
in AIDS patients), however only a few studies claim so far the effi-
cacy in ED and the development of new clinical trials will be of
relevance (Marco et al., 2012).
6.2. eCB system in obesity
Several preclinical and clinical observations (reviewed by
Matias and Di Marzo, 2007; Bermudez-Silva et al., 2010) sug-
gest that there is a close positive association between obesity
and the hyperactivity of the eCB system manifested as either/both
an overproduction of eCBs or/and an upregulation of cannabi-
noid receptors in central and peripheral tissues involved in energy
homeostasis. At the central level, the first evidence for the hyper-
activity of the eCB system came from studies on genetically obese
mice (ob/ob), whose hypothalamic eCBs levels were higher with
respect to lean animals, and were significantly reduced by the
exogenous administration of leptin (Di Marzo et al., 2001). Sub-
sequently, an elevated CB1 expression was observed in the white
adipose tissue of another rodent model of obesity, caused by
defective leptin signaling as compared to lean controls (Bensaid
et al., 2003). An up-regulation of CB1 was observed also dur-
ing the differentiation of mouse 3T3-F442A (Bensaid et al., 2003)
and 3T3-L1 (Gasperi et al., 2007) fibroblasts into adipocytes, and
increased 2-AG levels were found in mature and hypertrophic
adipocytes, as well as in the epididymal fat pads of obese animals
compared with those of lean mice (Matias et al., 2006). Remark-
ably, in differentiated 3T3-L1 adipocytes AEA increased by ∼2-fold
insulin-stimulated glucose uptake, according to a CB1 -dependent
mechanism that involves nitric oxide synthase (Gasperi et al.,
2007). Elevated levels of both 2-AG and AEA were detected in pan-
creatic ␤-cells cultured under high glucose conditions, and were
further increased by insulin application, suggesting that hyper-
glycemia and insulinemia may cause an overactivation of the eCB
system in obesity-related type 2 diabetes (Matias et al., 2007). Dys-
regulation of the eCB system in obese human subjects has also
been reported, and the first evidence came from studies in over-
weight/obese women with a BED (Monteleone et al., 2005) and in
obese postmenopausal women (Engeli et al., 2005). In clinical stud-
ies obesity-related elevations of eCBs were coupled to a decreased
activity of FAAH, and consistently specific polymorphisms of the
faah gene were associated with overweight and obesity (Sipe et al.,
2005) or with lower insulin sensitivity (de Luis et al., 2010a,b; de
Luis et al., 2012).
When obese subjects were classified on the basis of fat distri-
bution by Blüher et al. (2006), higher levels of 2-AG in adipose
tissue samples were found in patients with elevated abdominal fat
distribution, as compared to those observed in patients with sub-
cutaneous fat or in lean controls. Such an increase was shown to
positively correlate with major cardiometabolic risk factors, such as
visceral fat mass and fasting plasma insulin levels, and to correlate
negatively with glucose infusion rates during the clamp procedure,
a method for assessing insulin sensitivity in humans (Blüher et al.,
2006; Côté et al., 2007).
A recent report by Matias et al. (2012) has shown that AEA lev-
els increased in the saliva of obese subjects, and directly correlate
with Body Mass Index, waist circumference and fasting insulin.
215
Interestingly, body weight loss in these patients after a 12-weeks
lifestyle program, significantly decreased salivary AEA levels. Based
on their findings, the authors suggest that salivary AEA might rep-
resent a useful biomarker in obesity.
Similar alterations in the blood and adipose tissues of obese sub-
jects and in different animal models of obesity were also reported
for other eCB-related acylethanolamides, such as OEA and PEA.
In particular, the latter compounds increased in the blood and
subcutaneous adipose tissue of subjects with both obesity and
type 2 diabetes (Annuzzi et al., 2010), and in the saliva of obese
subjects (Matias et al., 2012). Conversely, the intestinal levels of
OEA appeared to follow an opposite deregulation in obese ani-
mals, being down-regulated by the prolonged exposure to HFD. The
latter observation raised the possibility that excessive fat consump-
tion might promote overeating, by suppressing (at least in part)
the satiating effects of gut-derived OEA (Hansen et al., 2012; Diep
et al., 2011; Artmann et al., 2008; Tellez et al., 2013; Aviello et al.,
2008).
Based on the observations of a pathological overactivation of the
eCB system in overweight and obese subjects, restoring a normal
eCB tone by drugs that interfere with eCB signaling was considered
as a potential therapeutic approach to arrest both the development
and the maintenance of obesity and obesity-related co-morbidities.
Initial preclinical studies conducted with rimonabant found evi-
dence to support this hypothesis (Cota et al., 2003).
Several clinical trials followed the initial experimental findings
and they were grouped in the four rimonabant in Obesity (RIO)
studies (Van Gaal et al., 2005; Després et al., 2005; Pi-Sunyer et al.,
2006; Scheen et al., 2006).
The very promising therapeutic benefits of rimonabant seemed
to extend even beyond obesity and obesity co-morbidities, as
it turned to be efficacious also for addictive disorders such as
alcoholism (Gutierrez-Lopez et al., 2010; Getachew et al., 2011;
Economidou et al., 2006), and nicotine dependence (Rigotti et al.,
2009; Diergaarde et al., 2008; Shoaib, 2008; Bhatti et al., 2009).
The latter aspect was considered particularly interesting because
of its negative effect on weight gain (that is often associated with
smoking cessation).
Rimonabant was approved and introduced into the market as
an anti-obesity agent in several countries, including the European
Union. However, the USA Food and Drug Adminstration (FDA) asked
further evidence about the safety of rimonabant before approving
its marketing in the United States. Even though psychiatric disor-
ders were used as exclusion criteria, a meta-analysis of these four
RIO studies suggested that patients treated with Rimonabant were
2.5- and 3.0-times more likely to experience psychiatric adverse
effects, such as anxiety and depression or depressive symptoms,
than patients receiving placebo (Christensen et al., 2007).
Further investigations were conducted on rimonabant, in which
psychiatric disorders were not regarded as exclusion criteria
(Rosenstock et al., 2008; Rigotti et al., 2009; Nissen et al., 2008;
Després et al., 2009). The authors showed that adverse psychiatric
effects were more pronounced in patients treated with rimon-
abant versus placebo controls. The European Union Committee
for Medicinal Products for Human Use definitely concluded that
rimonabant doubled the risk of psychiatric disorders, and the Euro-
pean Medicines Agency (EMA) suspended the license of this drug.
Sanofi-Aventis withdrew the product from sale worldwide, and also
stopped clinical development.
These events profoundly influenced the pharmaceutical indus-
try. The development of several other CB1 antagonists that were
being tested in clinical trials, such as otenabant (Pfizer), ibipin-
abant (Solvay/Bristol-Myers Squibb), surinabant (Sanofi-Aventis),
and taranabant (Merck) were interrupted and their further devel-
opment was not supported because of adverse psychiatric side
effects (Addy et al., 2008a,b; Kipnes et al., 2010).
216 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224

Table 3
modulators of the eCB system for the treatment of obesity.

Drug Mechanism Reduction of Reduction of Reduction References

food intake body weight of liver fat

Synthetic cannabinoid antagonist/inverse agonist

AM6545 Selective CB1 Yes Yes Yes Tam et al. (2012)
peripheral antagonist
LH21 Peripheral CB1 Yes Yes No Alonso et al. (2012),
antagonist Pavón et al. (2008)
JD5037 CB1 antagonist/inverse Yes Yes Yes Tam et al. (2012)
agonist
URB447 Mixed CB1 Yes Yes Not yet LoVerme et al. (2009)
antagonist/CB2 agonist assessed
PSNCBAM-1 CB1 allosteric Yes Yes Not yet Horswill et al. (2007)
antagonist assessed

Polyphenols
Catechins Antagonists/inverse Yes Yes Yes Korte et al. (2009,
(epigallocatechin-3-O- agonists of human 2010) and Bose et al.
gallate cannabinoid receptors (2008)
(EGCG))

Inhibitors of 2-AG biosynthesis

O-5596 di- acylglycerol lipase Yes Not yet Not yet Bisogno et al. (2009,
(DAGL) inhibitors assessed assessed 2012)

Compounds alternative to cannabinoid receptor antagonists

OEA PPAR-␣ Yes Yes Yes Piomelli (2013)

New neutral CB1 antagonists and/or peripherally restricted CB1
antagonists or inverse agonists unable to cross the blood–brain
barrier (BBB) have been developed, in the attempt to preserve
rimonabant positive effects and to avoid the unwanted psy-
chiatric side-effects (for a review, see Silvestri and Di Marzo,
2012). Many of these new compounds have already provided
very promising results at the preclinical level (Tam et al., 2010,
2012) and are reported schematically in Table 3. Examples of
this kind of drugs are AM4113, AM6545, LH-21, JD5037, or
URB447 (for a review, see O’Keefe et al., 2014; Bermudez-Silva
et al., 2010). AM4113 (N-piperidin-1-yl-2,4-dichlorophenyl-1
h-pyrazole-3-carboxamide analog) in Sprague-Dawley rats fed
either a normal diet or a diet high in carbohydrates or HFD,
reinforced positive appetite control crossing the BBB and binding
to neural CB1 (Sink et al., 2008). AM6545 (5-(4-(4-cyanobut-
1-ynyl)phenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1,1-dioxo-
thiomorpholino)-1H-pyrazole-3-carboxamide) is a high affinity
and selective CB1 peripheral antagonist, that showed high BBB
permeability resistance (Tam et al., 2012). In diet-induced obese
mice it displayed the same effects as rimonabant, by ameliorating
the fatty liver and improving lipid profile (Tam et al., 2012). LH-21
(5-(4-Chlorophenyl)-1-(2,4-Dichlorophenyl)-3-Hexyl-1H-1,2,4-
Triazole) displays poor brain penetration and peripheral CB1
targeting in in vitro studies (Alonso et al., 2012). Diet-induced
obese rats showed reduced food intake, body weight gain and gene
expression of leptin, FAS and Stearoyl-CoA desaturase 1 (Alonso
et al., 2012), following subchronic treatment with LH-21. The same
drug, however, did not inhibit fatty acid accumulation in the liver,
nor it improved metabolic parameters in Zucker rats, suggesting
that lack of inverse agonism, or poor penetration in the brain,
might limit the metabolic benefits of CB1 blockade (Pavón et al.,
2008).
JD5037 is aCB1 antagonist/inverse agonist able to block
peripheral CB1 upon both acute and chronic administration in diet-
induced obese mice, where it reduced body weight and food intake,
reversed hepatic steatosis and improved insulin sensitivity (Tam
et al., 2012).
URB447 has been identified as a mixed CB1 antagonist/CB2 ago-
nist with anorectic actions and devoid of CNS effects (LoVerme et al.,
2009).
Among the peripherally targeted CB1 antagonists, only LH-21
has been investigated with regards to psycho-behavioral effects
(Griebel et al., 2005). Therefore, the potential adverse behavioral
effects of these new peripherally targeted CB1 antagonists should
be addressed in future studies.
Finally, it is noteworthy that some natural dietary antioxidant
polyphenols display significant affinity for human cannabinoid
receptors, acting as antagonists/inverse agonists (Gertsch et al.,
2008; Korte et al., 2009, 2010).
Blockade of CB1 may induce a feedback loop that drives eCB
levels even higher than those derived from the activation of other
cannabinoid receptors (Bermudez-Silva et al., 2010). Moreover,
pharmacological modulation of eCBs synthesis, rather than CB1
blockade, may provide a more physiological approach to treat
obesity, since excessive eCB levels, rather than excessive CB1
expression, appear to be the primary alteration associated with
obesity (Matias and Di Marzo, 2007). Evidence for the efficacy of this
strategy was obtained by the manipulation of 2-AG levels in two dif-
ferent ways: the systemic administration of DAGL inhibitors, that
was able to inhibit palatable or HFD intake in mice (Bisogno et al.,
2009, 2012); the overexpression of MAGL, that increased energy
expenditure and decreased weight gain on a HFD regimen (Jung
et al., 2012).
Another potential strategy is related to the allosteric modulation
of CB1 , suggested by the finding that PSNCBAM-1, a novel allosteric
antagonist of this receptor, inhibited appetite and produced weight
loss in rats (Horswill et al., 2007). Finally, other pharmacological
opportunities for the development of new therapies linked to the
eCB system may derive from the involvement of other receptor-
sand/or other eCB congeners, such as OEA.
For example, Deveaux et al. (2009) showed that CB2 potentiates
obesity-associated inflammation, insulin resistance and fatty liver
in mice fed a HFD. Therefore, CB2 antagonism may open a novel
therapeutic approach for the management of obesity-associated
metabolic disorders. Furthermore, the pharmacological blockade
of TRPV1 receptor was reported to enhance insulin release from
islet ␤ cells, and to improve glucose tolerance in diabetic Zucker
rats (Suri and Szallasi, 2008). In mice, a similar effect was linked
also to the activation of GPR119 receptors, that caused an increase
in insulin secretion as well as a decrease in food intake and body
 C. D’Addario et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 203–224
weight gain (Overton et al., 2008). In this context, it should be
recalled that GPR119 has been recently proposed as a preferen-
tial fat sensor (Hansen et al., 2012). OEA has also emerged as a
possible pharmacological alternative to CB1 antagonists for the
treatment of obesity, and for limiting excessive food intake in
rodents (Romano et al., 2014). OEA is a gut-derived satiety signal
(for a review, see Dipasquale et al., 2010; Piomelli, 2013), released
from enterocytes and acting on local PPAR-␣ receptor to modulate
absorption and oxidation of dietary fats. OEA also induces satiety by
prolonging the inter-meal interval and activating brain oxytociner-
gic and histaminergic neurons (Gaetani et al., 2010; Romano et al.,
2013a,b; Provensi et al., 2014). Decreased intestinal content of OEA
was observed in rodent models of obesity (Artmann et al., 2008;
Aviello et al., 2008; Diep et al., 2011), where exogenous adminis-
tration of OEA decreased hyperphagia and body weight gain, by
increasing lipolysis, and decreasing hypertriglyceridemia, hyper-
cholesterolemia and liver steatosis (Rodriguez de Fonseca et al.,
2001; Lo Verme et al., 2005; Fu et al., 2005; Newberry et al., 2012;
Thabuis et al., 2010; Serrano et al., 2008). It also re-established a
normal response of the brain reward system to an intraduodenal
infusion of lipids, which seemed to be altered in diet-induced obese
animals (Tellez et al., 2013).
7. Conclusions
Accumulated evidence places eCB system components at the
heart of communications between the brain and peripheral organs
and tissues. Based on its widespread role in the multifaceted aspects
of food intake and energy balance, the eCB system appears as a
unique modulatory system that integrates different neurotrans-
mitter and hormonal signals. As such, it offers an array of novel
therapeutic opportunities to combat pathologies linked to aberrant
feeding patterns and/or altered metabolic pathways, such as eating
disorders and obesity, as well as disorders related to altered moti-
vation, hedonic value perception and/or activation of the reward
system In particular, peripherally restricted CB1 antagonists might
be useful in controllong overeating of fatty foods, thus possibly
opening the avenue to next-generation therapeutics able to con-
trol excessive food intake and energy balance. The mechanisms
engaged span from those involving the hedonic aspects of food
consumption, to those depending on storage of its energy content.
Acknowledgements
The work was supported by the Italian Ministry of Education,
University and Research under grants FIRB-RBFR12DELS to CDA,
CC and SG and PRIN2010-11 to MM.
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