Chemical Senses

Cannabinoids, chemical senses and regulation of feeding behavior

Journal: Chemical Senses ManuscriptFor ID CS-18-104.R1 Review Only Manuscript Type: Review Article

Date Submitted by the Author: 27-Sep-2018

Complete List of Authors: Tarragon Cros, Ernesto; Universitat Jaume I, Psychobiology Moreno, Juan José; University of Barcelona, Dept. of Nutrition, Nutritional Sciences and Gastronomy

endocannabinoids, , sensory perception, flavor, synthetic Key Words:

Page 1 of 55 Chemical Senses

1 Cannabinoids, chemical senses and regulation of feeding behavior 1 2 3 2 Ernesto Tarragon1 and Juan José Moreno2 4 5 6 3 1 Department of Psychobiology, Faculty of Health Sciences, University Jaume I of 7 8 9 4 Castellon, Castellon, Spain 10 11 12 5 2 Department of Nutrition, Food Sciences and Gastronomy, Institute of Nutrition and 13 14 6 Food Safety, University of Barcelona, Barcelona Spain. CIBEROBN Fisiopatologia de 15 16 7 la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain 17 18 19 8 Correspondence to Forbe sent to: Review Ernesto Tarragon, DepartmentOnly of Psychobiology, Faculty 20 21 22 9 of Health Sciences, University Jaume I of Castellon, Av Sos Baynat s/n, 12071, 23 24 10 Castellon de la Plana, Spain 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 60 Chemical Senses Page 2 of 55

1 Abstract1 1 2 3 12 The herb sativa has been traditional used in many cultures and all over the 4 5 13 world for thousands of years as medicine and recreation. However, since it was brought 6 7 14 to the Western world in the late 19th century, its use has been a source of controversy 8 9 15 respect to its physiological effects as well as the generation of specific behaviors. In this 10 11 12 16 regard, the CB1 represents the most relevant target molecule of 13 14 17 components on nervous system and wholebody energy homeostasis. Thus, the 15 16 18 promotion of CB1 signaling can increase appetite and stimulate feeding, while blockade 17 18 19 of CB1 suppresses hunger and induces hypophagia. Taste and flavor are sensory 19 For Review Only 20 20 experiences involving the oral perception of foodderived chemicals and drive a primal 21 22 21 sense of acceptable or unacceptable for what is sampled. Therefore, research within the 23 24 25 22 last decades focused on deciphering the effect of cannabinoids on the chemical senses 26 27 23 involved in food perception and consequently in the pattern of feeding. In this review, 28 29 24 we summarize the data on the effect of cannabinoids on chemical senses and their 30 31 25 influences on food intake control and feeding behavior. 32 33 34 26 Keywords: endocannabinoids , obesity , sensory perception , flavor , synthetic 35 36 27 cannabinoids 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 2 60 Page 3 of 55 Chemical Senses

2 1.8 Introduction 1 2 3 29 For more of 10,000 years, (C. sativa) has been used medically and 4 5 30 recreationally for its diverse pharmacological actions and psychotropic properties in 6 7 31 many cultures and all over the world. However, its use has been a source of controversy 8 9 32 since it was brought to the Western world in the late 19th century due to its specific 10 11 12 33 effects on physiology and behaviors. The study of C. sativa components has nonetheless 13 14 34 contributed to discover various key elements of the (ECS). At 15 16 35 the same time, the insight gathered about the ECS has helped to understand the 17 18 36 mechanisms involved in the physiological/pharmacological effects of the bioactive 19 For Review Only 20 37 components of C. sativa. 21 22 23 38 Central regulation of feeding behavior is indispensable to energy homeostasis and to 24 25 39 maintain essential daily functions (Gao and Horvath 2016)⁠ . The ECS is one of the 26 27 40 most prominent actors in the complex neural circuitry involved in this central regulation 28 29 30 41 of energy homeostasis. Several studies revealed that endocannabinoids (eCBs), a highly 31 32 42 conversed group of autacoids, play a role in central and peripheral regulation of energy 33 34 43 balance (Nogueiras et al. 2010; O’Keefe et al. 2014)⁠ . Specifically, it has been shown 35 36 44 that stimulating CB1 signalling can induce adipogenesis (Vettor and Pagano 2009) and 37 38 45 increase pancreatic insulin secretion (JuanPico et al. 2006), indicating that circulating 39 40 46 eCBs may act as modulators of endocrine signals in peripheral organs (Hillard 2018). 41 42 43 47 At the same time, energy status modulates eCB levels. For instance, it was shown that 44 45 48 2arachidonoylglycerol (2AG), a representative eCB, increases specifically after acute 46 47 49 food deprivation and decreases during feeding (Kirkham et al. 2002)⁠ . There is as well 48 49 50 a compelling amount of evidence suggesting that the dysregulation of the ECS 50 51 51 contributes to obesity (Bluher et al. 2006)⁠ . 52 53 54 52 However, energy balance is not the only way through which the ECS influences 55 56 53 feeding. An increasing number of studies in the last decade have shown that eCBs and 57 58 59 3 60 Chemical Senses Page 4 of 55

54 cannabinoid (CB) receptors participate in relevant processes of eating behavior, 1 2 55 including reinforcement and reward processes (D’Addario et al. 2014; GattaCherifi and 3 4 56 Cota 2016), and food preference (Di Patrizio et al. 2013)⁠ . In a recent review, we 5 6 57 summarized much of the evidence on the role of the ECS on sweet taste perception, 7 8 ⁠ 9 58 food preference and obesity (Tarragon and Moreno 2018) . In this review, we will try 10 11 59 to expand the coverage to how the ECS and especially exogenous cannabinoids (CBs) 12 13 60 are involved in chemosensory perception (olfaction, gustation) and its influence on 14 15 61 eating behavior and food intake control. 16 17 18 62 19 For Review Only 20 21 63 2. The endocannabinoid system. 22 23 24 64 The ECS comprises the eCBs, the /proteins that regulate their synthesis and 25 26 65 degradation, and the receptors through which they signal. The identification of the 27 28 66 tetrahydrol structure of (, THC) was discovered in 29 30 67 Cannabis sativa (C. sativa) in the 1940s (Adams et al. 1941). Years later, Gaoni and 31 32 9 33 68 Mechoulam (1964) were able to identify the positioning of the , which confers THC 34 9 35 69 ( THC) its main psychoactive properties . However, it was not until 1988 that the 36 37 70 CB1 receptor was characterized (Devane et al. 1988; Gerard et al. 1991)⁠ . The 38 39 71 discovery of specific CB receptors implied the existence of endogenous ligands capable 40 41 72 of activating these receptors, leading to propose the concept of an ECS (Howlett et al. 42 43 73 1990)⁠ . This was rapidly confirmed by the isolation of the first endogenous CB , 44 45 ⁠ 46 74 (AEA) (Devane et al. 1992) , the identification and characterization of the 47 48 75 CB2 receptor (Munro et al. 1993)⁠ , and the identification of a second endogenous 49 50 76 ligand, 2arachidonoylglycerol (2AG) a few years later (Mechoulam et al. 1995; Stella 51 52 77 et al. 1997; Sugiura and Waku 2000). These and other lipid mediators capable of 53 54 78 activating the CB receptors were named eCBs. Interestingly, these compounds were 55 56 79 shown to activate several other receptors in addition to CB receptors, including the 57 58 59 4 60 Page 5 of 55 Chemical Senses

80 transient receptor potential cation channel, subfamily V, member 1 (TPRV1) (Sartim et 1 2 81 al. 2017)⁠ and a novel orphan CB receptor GPR55 (Ryberg et al. 2007)⁠ . 3 4 5 82 Today we know that eCBs serve as retrograde synaptic messengers within the central 6 7 83 nervous system (CNS) (Pertwee and Ross 2002)⁠ . This suggests that eCBs act as both 8 9 84 neuromodulators and immunomodulators. The ECS functions have been characterized 10 11 ⁠ 12 85 as “relax, eat, sleep, forget and protect” (Di Marzo 1998) , but the number of processes 13 14 86 in which the ECS participates increases each year with additional research discoveries. 15 16 87 17 18 19 88 For Review Only 20 21 22 89 2.1. Cannabinoid receptors 23 24 25 90 CB1 and CB2 receptors were first cloned by Matsuda et al. (1990)⁠ and Munro et al. 26 27 91 (1993)⁠ , respectively. Both receptors are members of the Gproteincoupled receptors 28 29 92 (GPCR) superfamily and are widely expressed in the brain (Moldrich and Wenger 2000; 30 31 93 Gong et al. 2006). CB1 is one of the most abundant GPCR in the brain. 32 33 94 Autoradiographic studies demonstrated that high levels of CB are expressed in the 34 1 35 36 95 cortex, hippocampus, cerebellum, basal ganglia, and the spinal cord (Herkenham et al. 37 38 96 1990; Tsou et al. 1998; Freund et al. 2003), correlating with the wellknown effects of 39 40 97 CBs on cognition, memory, motor control, and spinal signaling, respectively. The 41 42 98 functional effects of the CB1 expression in the hypothalamus with respect feeding 43 44 99 related patterns was described few years later (Breivogel et al. 1997; Elmquist et al. 45 46 100 1999)⁠ . This was further supported by in situ hybridation studies that confirmed that 47 48 101 CB receptors are found on axon terminals (Matsuda et al. 1993)⁠ , and by electron 49 50 51 102 microscope studies which also confirmed that cellsurface CB1 receptors are found 52 53 103 almost exclusively on presynaptic terminals (Tsou et al. 1998; Katona et al. 2000)⁠ . 54 55 104 CB1 is also expressed in numerous peripheral tissues including heart, lung, prostate, 56 57 58 59 5 60 Chemical Senses Page 6 of 55

105 liver, ovaries and testis (Galiegue et al. 1995)⁠ , whereas CB2 is abundantly expressed 1 2 106 in peripheral organs with immune function (Galeigue et al. 1995) and upregulated in 3 4 107 response to immune cell activation and inflammation (Stella 2010)⁠ . Although it is 5 6 108 considered that the majority of the effects on the CNS are related with CB (Freund et 7 1 8 ⁠ 9 109 al. 2003) , recent work has reported some functional expression of CB2 receptor in the 10 11 110 brain (Onaivi et al. 2006)⁠ and that these may also be involved in eating behavior 12 13 111 (Onaivi et al. 2008)⁠ . 14 15 16 112 Although CB1 and CB2 receptors are the most relevant CB receptors, it is likely that 17 18 113 CBs can also act upon other GPCR, such as GPR18, GPR55 and GPR119. GPR55 was 19 For Review Only 20 114 identified in the human brain by Sawzdargo et al. (1999)⁠ and it can be considered a 21 22 115 third CB receptor. 9THC (Lauckner et al. 2005)⁠ as well as synthetic CB ligands 23 1 24 ⁠ activate GPR 25 116 such as AM251 or SR141716A (Kapur et al. 2009) 55, an “enigmatic” 26 27 117 receptor that recent studies have linked to anorexia nervosa (Ishiguro et al. 2010)⁠ . In 28 29 118 addition, although GPR119 was not initially linked to ECS, Overton et al. (2006)⁠ 30 31 119 showed that N (OEA), an analogue of AEA, also binds to this 32 33 120 receptor. Interestingly, stimulating GPR119 with OEA suppresses feeding in rats 34 35 121 (Rodríguez De Fonseca et al. 2001)⁠ ,.despite this receptor not being directly involvedin 36 37 122 central eCBmediated feeding (Overton et al. 2006, 2008)⁠ 38 39 40 123 There is still much to clarify about how CBs produce their endogenous effects, and how 41 42 ⁠ 43 124 these effects and other systems might interact with each other (Ben Amar 2006) . For 44 45 125 instance, the cross talk between the ECS and others such as the opioid system seems to 46 47 126 modulate energy balance and food intake to a greater extent than either system alone 48 49 127 (Morley and Levine 1982; Solinas and Goldberg 2005)⁠ . 50 51 52 128 53 54 55 129 2.2. Endogenous cannabinoids 56 57 58 59 6 60 Page 7 of 55 Chemical Senses

130 eCBs are derivatives of arachidonic acid (AA), resembling other lipid mediators such as 1 2 131 . AA is conjugated with ethanolamine to form fatty acid amides such as 3 4 132 AEA, or with glycerol to form monoacylglycerols, like 2AG. AEA biosynthesis occurs 5 6 133 in two steps. First, a calciumdependent transacylase transfers an acyl group to 7 8 9 134 membrane phospholipids in the Nposition of phosphatidyletanolamine. This 10 11 135 transference generates the Nacylphosphatidylethanolamines that selective 12 13 136 phospholipases D hydrolyze to release AEA and phosphatidic acid (Okamoto et al. 14 15 137 2004). 2AG is mainly synthetized from AAcontaining membrane phospholipids 16 17 138 through the action of phospholipase C, leading to the formation of diacylglycerol 18 19 139 hydrolyzed by diacylglycerolFor Review lipase (DAGL) (Bisogno Only et al. 2005)⁠ . Finally, AEA is 20 21 22 140 degraded by fatty acid amide hydrolase (FAAH), whereas 2AG is degraded by 23 24 141 (MGL) or the α β serine hydrolase domain (ABHD) (Fig. 1). 25

26 9 27 142 AEA resembles THC in acting as a partial agonist at CB1 receptor. 2AG is an 28 29 143 agonist at both CB1 and CB2 receptors. However, other eCBs have been identified more 30 31 144 recently, such as noladin (2arachidonylglyceryl ether, 2AGE) (Hanus et al. 2001)⁠ , 32 33 145 virhodamine (Oarachidonoylethanolimine) (Porter 2002)⁠ , Narachidonyldopamine 34 35 146 (Bisogno et al. 2000)⁠ , and (Cis9,10octadecanoamide) (Leggett et al. 36 37 147 2004)⁠ to name some. 38 39 40 148 41 42 43 149 2.3. Exogenous cannabinoids 44 45 46 150 Exogenous CBs are natural molecules, mainly derived from plants (phytocannabinoids), 47 48 151 and synthetic compounds that are able to bind to CB receptors and consequently 49 50 51 152 interfere with the ECS functions, offering insights into the mechanisms of eCBs as well 52 53 153 as bearing potential for future treatments. Depending on the source, they are defined as 54 55 154 phytocannabinoids or synthetic CBs. 56 57 58 59 7 60 Chemical Senses Page 8 of 55

1 55 1 2 3 156 2.3.1. Phytocannabinoids 4 5 6 157 The cannabis plant contains more than 200 chemical compounds, including 120 7 8 158 different phytocannabinoids, in addition to other constituents such as terpenoids and 9 10 159 flavonoids (Radhakrishnan et al. 2014)⁠ . Together with cannabidiol (Russo 2013) , 11 12 160 9THC is the beststudied CB, responsible for most of the pharmacological and 13 14 161 psychoactive effects of C. sativa preparations. However, components of other plants 15 16 17 162 besides cannabis have been reported to interact with CB receptors, binding to these and 18 19 163 other CBaffine receptors,For promotingReview diverse physiologicalOnly effects as well. These 20 21 164 components are named phytocannabinoids, a chemical class substance of C21 22 23 165 terpenophenolic compounds (Mechoulam and Gaoni 1967)⁠ that were considered “a 24 25 166 medicinal treasure trove which waits to be discovered” (Mechoulam 2007)⁠ . 26 27 28 167 Examples of phytocannabinoids are also found in bark extract of Magnolia officinalis 29 30 168 (Lee et al. 2011)⁠ as well as in Echinacea spp. (Gertsch et al. 2008)⁠ . On the other 31 32 33 169 hand, sesquiterpene and , present in essential oils of Origarum vulgare, 34 35 170 Cinnamomum spp., Piper nigrum, and C. sativa, are CB2 receptor agonists; some of 36 37 171 them showing promising antiinflammatory properties in recent, preliminary studies 38 39 172 (Gertsch et al. 2008). Another phytocannbinoid newly discovered is , 40 41 173 which has shown effective anticonvulsant properties (Hill et al. 2012)⁠ and efficacy as 42 43 174 an antiepileptic agent through activation of CB receptors (Whalley et al. 2015)⁠ . Other 44 45 46 175 nonlipid derivatives, such as βcaryophyllene also present binding affinity for CB2 47 48 176 (Gertsch et al. 2008). 49 50 51 177 Nonetheless, binding to CB receptors is not the only characteristic to define a 52 53 178 phytocannabinoid. For instance, Nacylethanolamines present no affinity for such 54 55 179 receptors, although they are able to inhibit AEA degradation enzymes, thus promoting 56 57 58 59 8 60 Page 9 of 55 Chemical Senses

180 eCB signaling (McPartland et al. 2014)⁠ . In addition, pristimerin and euphol, two 1 2 181 triterpenoids naturally occurring in several plants, have shown to inhibit MAGL and 3 4 182 consequently the enzymatic degradation of 2AG (Sawai and Saito 2011)⁠ . This 5 6 183 evidence indicates that exogenous CBs may not only act through direct binding to CB 7 8 9 184 receptors, but also throughout different mechanisms that can modulate the ECS. 10 11 12 185 13 14 15 186 2.3.2. 16 17 187 Synthetic CBs are a class of chemicals with the property of binding to CB receptors. 18 19 For Review Only 20 188 Given the diverse actions and functions of the ECS within the organism, the 21 22 189 development of synthetic CBs was an attempt to mimic the various physiological effects 23 24 190 of eCBs avoiding their psychotropic consequences. 25 26 27 191 Based in their chemical structures, CB agonists can be classified into at least four 28 29 192 groups; classic CBs of C. sativa and its analogues, bicyclic and tricyclic analogues of 30 31 193 9THC, and nonclassical CBs with structure of fatty amides or esters and 32 33 194 aminoalkylindoles. Since the review of the hundreds of synthetic CBs is beyond the 34 35 36 195 purpose of this work, we will name only a few of the most representative families (Fig. 37 38 196 2). 39 40 9 8 41 197 An example of synthetic THC is 11hydroxy THC dimethylheptyl (HU210), a 42 43 198 particularly potent CB that has efficacy at activating both CB1 and CB2 receptors 44 45 199 (Mechoulam et al. 1988)⁠ . Specifically, HU210 resembles the affinity for CB1 and 46 47 200 CB2 receptors of other synthetic compounds like CP55,940 and WIN 55,2122. The 48 49 201 replacement of the pentyl side chain of 8THC with a dimethylheptyl enhanced its 50 51 202 affinity and efficacy at CB receptors (Pertwee 2006)⁠ . Nonclassical CBs consisting of 52 53 9 54 203 bicyclic and tricyclic analogues of THC typically lack a pyran ring. The most 55 56 204 commonly used ligand of this class is CP55,940, which has demonstrated relatively 57 58 59 9 60 Chemical Senses Page 10 of 55

205 high efficacy through both CB1 and CB2 receptors in the low nanomolar range (Pertwee, 1 2 206 2005). The first cannabinergic indoles to be developed were aminoalkylindoles, among 3 4 207 which WIN 55,2122 showed a potent agonism to CB1 and CB2 receptors, binding 5 6 208 differently to the CB receptor than classical and nonclassical CBs (Compton et al. 7 1 8 9 209 1992)⁠ . 10 11 12 210 13 14 15 211 3. Effect of cannabinoids on food intake control 16 17 212 The mechanism behind the orexigenic effects of eCBs is still today a matter of active 18 19 For Review Only 20 213 research. Although the observations that marijuana stimulates appetite and food 21 22 214 consumption are known for many years (Abel 1971; Foltin et al. 1986)⁠ , the 23 24 215 experimental evidence for CBinduced hyperphagia has beenwas not demonstrated until 25 26 216 more recently. In the late 1990s and early 2000s, Williams and coworkers 27 28 217 demonstrated showed that 9THC exerts hyperphagic action in prefed rats (Williams 29 30 218 et al. 1998)⁠ as well as freefeeding rats (Koch 2001)⁠ , a similar effect to that reported 31 32 ⁠ 33 219 using 8THC (Avraham et al. 2004) . Additionally, numerous studies demonstrated 34 35 220 Kirkham et al (2002) reported that AEA and 2AG levels are elevated by after food 36 37 221 deprivation in the limbic forebrain, while 2AG is reduced in the hypothalamus during 38 39 222 the feeding state but increased during the deprived state, which suggests a role of eCBs 40 41 223 in motivation towards food. Further, the reduction of 2AG in the hypothalamus during 42 43 224 feeding indicates that 2AG can facilitate satiation (Kirkham et al. 2002)⁠ , suggesting a 44 45 46 225 role of eCBs in motivation towards food. 47 48 226 Consistent with this idea, Di Patrizio and Simansky (2008) demonstrated that direct 49 50 51 227 administration of 2AG into the pontine parabrachial nucleus promoted highfat, high 52 53 228 sucrose, and highfat and highsucrose food intake while intake of standard pellets 54 55 229 remained unaffected. Additionally, many studies show that acute infusion of CB1 56 57 58 59 10 60 Page 11 of 55 Chemical Senses

230 agonists into distinct hypothalamic nuclei induce feeding, which provides evidence that 1 2 231 the hypothalamic neurons are directly affected by CBs (Jamshidi and Taylor 2001; 3 4 232 Koch et al. 2015). Concretely, it has been shown that CB1 agonism in the PVN 5 6 233 increased hyperphagia in hungry mice and enhanced the hyperphagic effects of ghrelin 7 8 ⁠ 9 234 in fed animals (SoriaGómez et al. 2014a) . In the lateral hypothalamus, CB1 is 10 11 235 involved in physiological control of melaninconcentrating hormones and orexinA 12 13 236 neurons (Silvestri and Di Marzo 2013)⁠ . In the ARC, Agoutirelated 14 15 237 protein/neuropeptide Y (AgRP/NPY) neurons acutely promote food intake, and POMC 16 17 238 neurons drive gradual onset of satiety (Varela and Horvath 2012)⁠ . It was also 18 19 239 demonstrated that CB1For blockade Review in the hypothalamus Only reduced NPY levels, indicating 20 21 ⁠ 22 240 local eCB control over AgRP/NPY neurons (Verty et al. 2009) . AgRP/NPY neurons 23 24 241 do not express CB1 (Cota et al. 2003)⁠ , but CB1 is expressed at GABAergic terminals 25 26 242 innervating AgRP/NPY neurons (Morozov et al. 2017)⁠ . This finding led to suggest 27 28 243 that eCBs might also promote feeding by retrograde inhibition of AgRP/NPY neurons. 29 30 31 244 Coherent with the above mentioned, it has been shown that both AEA and 2AG 32 33 245 decrease the latency of feeding onset, increase the duration of intake and the number of 34 35 246 meals, but only AEA increased total intake (Farrimond et al. 2011). These effects were 36 37 247 reverted by SR 141716A, a CB1 inverse agonist (Landsman et al. 1997)⁠ , but not by 38 39 40 248 SR 144528, a CB2 antagonist (Williams and Kirkham 2002b)⁠ . Furthermore, WIN 41 42 249 55,212 similarly increased food intake, whereas SR 141716A reverted this effect 43 44 250 (Gomez et al. 2002)⁠ . It was also demonstrated that daily administration of SR 45 46 251 141716A reduced food intake and body weight in Wistar rats (Colombo et al. 1998)⁠ . 47 48 252 More recently, Vickers et al. (2003)⁠ demonstrated that oral, chronic SR 141716A 49 50 253 administration decreased food intake and body weight gain in both lean and obese 51 52 53 254 Zucker rats and in dietinduced obese mice (Ravinet Trillou et al. 2003)⁠ . Similarly, to 54 55 255 SR 141716A, AM251 has shown to reduce food consumption in obese animals 56 57 58 59 11 60 Chemical Senses Page 12 of 55

256 (McLaughlin et al. 2003)⁠ and in overnightfasted animals (Shearman et al. 2003). 1 2 257 Moreover, AM251 also produces dosedependent reductions in reinforced response 3 4 258 paradigms under fixedratio schedules (McLaughlin et al. 2003)⁠ . Taken together, 5 6 259 these data indicate that pharmacological manipulation of the CB receptors not only 7 8 9 260 influences food consumption in total volume, but also appetitive response for food, and 10 11 261 appears effective in controlling body weight and preventing weightgain in experimental 12 13 262 models of obesity. A series of relevant studies on this matter are gathered on Table 1. 14 15 16 263 17 18 19 264 4. Cannabinoids andFor energy metabolism.Review Only 20 21 22 265 It is well established that ECS is physiologically involved in the regulation of appetite, 23 24 266 pain and inflammation, thermoregulation, intraocular pressure, sensation, muscle 25 26 267 control, motivation and /reward, mood, memory, and appetite (Silvestri and Di Marzo 27 28 268 2013). Furthermore, it has been suggested a link between eCBs and high prevalence 29 30 269 pathophysiological states, including obesity, metabolic syndrome, diabetes (Perkins and 31 32 ⁠ 33 270 Davis 2008; Pacher and Kunos 2013) and cardiovascular (Chanda et al. 34 35 271 2017)⁠ . Indeed, upon stimulation, the ECS through eCBs increases food intake and 36 37 272 weight gain, promotes lipogenesis and impairs glucose tolerance (Cota et al. 2003)⁠ , 38 39 273 and modulates growth (Li et al. 2013)⁠ . 40 41 42 274 Recently, Simon and Cota (2017)⁠ reviewed the effect of CBs on metabolism. They 43

44 275 reported that CB1 receptor activation increases lipogenesis and adipogenesis, impairs 45 46 276 mitochondrial biogenesis, favors the white adipocyte phenotype, and that, in the liver, 47 48 277 CB receptor exerts a critical role in the regulation of lipid metabolism and insulin 49 1 50 51 278 sensitivity. In this way, Miederer et al. (2017)⁠ reported that THC was able to affect 52 53 279 the glucose uptake in the rat brain, which may be of relevance in behavioral studies. 54 55 280 Interestingly, CB1 is involved in the regulation of food intake by digestive system and 56 57 58 59 12 60 Page 13 of 55 Chemical Senses

281 insulin release by pancreatic islets. Furthermore, we must consider that some of these 1 2 282 metabolic effects of CB ligands could be related, at least in part, with alternative 3 4 283 receptors such as GPR55 (Tudurí et al. 2017)⁠ . 5 6 7 284 Hypothalamic CB1 signaling also interfaces with signal transmission of metabolic 8 9 285 hormones. For instance, while leptinsuppressed feeding correlates with decreased 10 11 ⁠ 12 286 hypothalamic eCBs levels (Di Marzo et al. 2001) , ghrelintriggered feeding depends 13 14 287 on paraventricular nucleus (PVN) CB1 signaling and accompanies increased 15 16 288 hypothalamic eCB levels (Kola et al. 2008)⁠ . The activation of AMPactivated protein 17 18 289 kinase (AMPK) has been proposed as a molecular mechanism by which the CBs might 19 For Review Only 20 290 exert its effects on eating behavior (Kola et al. 2005)⁠ . AMPK plays a central role in 21 22 291 the control of energy homeostasis at both individual cellular level and globally in the 23 24 ⁠ . Furthermore, various studies demonstrate that eCBs activate 25 292 organism (Hardie 2008) 26 27 293 AMPK in the hypothalamus, enhancing orexigenic signals, while decreasing fat 28 29 294 oxidation in fat tissue and liver (Tedesco et al. 2010)⁠ . Interestingly, several feeding 30 31 295 related hormones such as leptin, ghrelin and adiponectin can also influence AMPK 32 33 296 activity (Kola et al. 2008)⁠ . The highly active interaction between ECS and many of 34 35 297 such endocrine and paracrine elements suggests a mediating role of eCBs on hormone 36 37 298 functioning. This idea is supported by various studies showing data for 38 39 40 299 heterodimerisation of CB receptors with the orexin (Ellis et al. 2006)⁠ , opioid (Hojo et 41 42 300 al. 2008)⁠ , type 2 dopamine (Kearn 2005)⁠ and ghrelin (Edwards and Abizaid 2016)⁠ 43 44 301 receptors. 45 46 47 302 Additionally, we must consider that, although to a lesser extent, the CB2 in the CNS has 48 49 303 also shown to be involved in glucose homeostasis and led to a lean phenotype (Romero 50 51 304 Zerbo et al. 2012)⁠ . Recent localization of CB2 receptors in metabolically active tissues 52 53 305 suggests that this receptor might also have a significant role in energy homeostasis and 54 55 ⁠ 56 306 body weight regulation. Accordingly, Verty et al. (2015) observed that JWH015, a 57 58 59 13 60 Chemical Senses Page 14 of 55

307 CB2 agonist, reduced food intake, fat mass and adipocyte cell size in lean and obese 1 2 308 mice without any adverse impact on mood. Thus, in the interest of pursuing improved 3 4 309 pharmacotherapy treatment involving the eCB, it would be negligent to exclude a role 5 6 310 of CB agonist/antagonists as putative target in the future of obesityrelated treatments. 7 2 8 9 311 Surprisingly, it was recently described that CB receptor activation in the POMC 10 1 11 12 312 neurons is also relevant for the hyperphagic properties of CBs, acting at pre and post 13 14 313 synaptic levels (Koch et al. 2015)⁠ . The stimulation of CB1 receptors in these POMC 15 16 314 neurons inhibits the synthesis of the α–melanocytestimulating hormone (αMSH) but 17 18 315 not βendorphin peptides, a process mediated via mitochondrial activation (Koch et al. 19 For Review Only 20 316 2015)⁠ . Further, CB1 receptors coexist in POMC neurons with orexinA receptors, 21 22 317 whose stimulation initiate the synthesis of 2AG thus promoting hyperphagia even in 23 24 ⁠ . Finally 25 318 sated rats (Morello et al. 2016) , it was also reported that CB1 signaling 26 27 319 modulates dopaminergic signaling in the nucleus accumbens and ventral tegmental area 28 29 320 (Di Marzo et al. 2009a)⁠ , a phenomenon that has been directly related to the attribution 30 31 321 of salience to stimuli in general and food in particular (Salamone and Correa 2012, 32 33 322 2013)⁠ . 34 35 36 323 Importantly, hypothalamic AgRP/NPY and POMC neurons are not only directly 37 38 324 affected by food intake itself, but also rapidly respond to sensory detection of available 39 40 325 food (Chen et al. 2015)⁠ . Thus, hypothalamus not only regulates hunger and satiety in 41 42 43 326 response to eating and internal signals of energy resources, but also receives external 44 45 327 information on the incentive value of food, such as sight, smell, and taste (Seeley and 46 47 328 Berridge 2015)⁠ . 48 49 50 329 51 52 53 330 5. Cannabinoidbased pharmacotherapy in obesity 54 55 56 57 58 59 14 60 Page 15 of 55 Chemical Senses

331 Interestingly, in addition to its orexigenic effects, THC has been reported to be 1 2 332 anorexigenic as well. While low, oral doses of THC increase acute food intake, higher 3 4 333 doses decrease feeding when administered systemically (Sofia and Knobloch 1976)⁠ . 5 6 334 Other studies also indicate that the hyperphagic effect produced by is not longlasting 7 8 9 335 (Järbe and Di Patrizio, 2005). Hence, CBs and eCBs seem to have a biphasic effect on 10 11 336 feeding, which is to say that different levels of stimulation lead to opposite outcome. 12 13 337 Further, many studies report elevated levels of circulating eCB in obese individuals 14 15 338 (Engeli et al. 2005;⁠ Di Marzo et al. 2009b; Matias et al. 2012. Little et al. 2018). Since 16 17 339 eCBs levels are increased in both the food deprived and in obesity, the theory that eCB 18 19 340 dysfunction plays anFor important Review role in this condition Only seems especially relevant. 20 21 22 341 A recent examination of two US national surveys identified a lower prevalence of 23 24 ⁠ . These observations are paradoxical 25 342 obesity in cannabis users (Le Foll et al. 2013) 26 27 343 considering previous reports of acute cannabis stimulating appetite and food intake. 28 29 344 However, preclinical studies also support this observation, showing that both lean and 30 31 345 obese animals decreased body weight after chronic combined administration of CBD 32 33 346 and THC (Klein et al. 2011)⁠ . Interestingly, this reduction in energy intake was also 34 35 347 observed after the chronic administration of THC alone, an effect which has been 36 37 348 attributed to interactions with the gut microbiota (Cluny et al. 2015)⁠ . Thus, chronic 38 39 40 349 agonism of the ECS may be an underexplored therapeutic strategy in treating obesity. 41 42 350 The mechanism underlying the relationship between chronic cannabis use and absence 43 44 351 of obesity is unclear. However, provided that THC is a partial agonist and may 45 46 352 functionally act as an antagonist under conditions of high eCB tone such as in obesity 47 48 353 (Le Foll et al. 2013), chronic cannabis use may share a similar mechanism of action to 49 50 354 (Acomplia®) and other CB antagonist in preventing weight gain. In this 51 1 52 53 355 regard, Rimonabant was approved as an antiobesity by European Union, UK and 54 55 356 USA after clinical trials conducted by Aventis successfully showed weight loss, 56 57 58 59 15 60 Chemical Senses Page 16 of 55

357 a decrease in plasma triglycerides, a reduction of waist circumference, and an increase 1 2 358 in high density lipoprotein cholesterol (HDL) (Van Gaal et al. 2005; Despreś et al. 3 4 359 2006; PiSunyer et al. 2006). 5 6 7 360 Unfortunately, Rimonobant was discontinued due to an increased risk of depression and 8 9 361 suicide after continuous use. Since this withdrawal, other CB antagonist have 10 1 11 12 362 been halted in the process of development. (Merch & Co.) also induced 13 14 363 weight loss (Addy et al. 2008)⁠ , although phase III trials were stopped in October 2008 15 16 364 due to a high level of central side effects, including and depression. 17 18 365 Interestingly, Willimas and Kirkham (2002a) observed that 9THCinduced 19 For Review Only 20 366 hyperphagia could be attenuated by the opioid antagonist , which provides 21 22 367 further evidence of the aforementioned link between opioid food reward processing and 23 24 25 368 the ECS (Koch et al. 2015). Promisingly, (Marinol®), an oral preparation of

26 9 9 27 369 THC, and (Cesamet®), a synthetic analogue of THC are already 28 29 370 licensed for clinical use in some countries as appetite and attenuating weight 30 31 371 loss associated to anorexia (Verty et al. 2011)⁠ or AIDS (Badowski and Perez 2016) . 32 33 34 372 A key aspect of the history of pharmacological strategies targeting the ECS in managing 35 36 373 obesity and metabolic disorders is the severe affective symptomatology and/or the focus 37 38 374 on neurobiological systems involved in the affective response. This is interesting in the 39 40 375 context of this review, since depression and anxiety disorders often coexist with 41 42 43 376 alterations in chemosensory perception (Parker et al. 2014; Takahashi et al. 2015; 44 45 377 Taalman et al. 2017; Hur et al. 2018)⁠ . Traditionally, it is assumed that the alterations 46 47 378 in chemosensory response are consequence of the neurobiochemical changes induced by 48 49 379 depressionlike states. However, the opposite direction of this relationship has never 50 51 380 been tested. How is it to know that disturbances in perception do not act as a trigger for 52 53 381 altered, negative mood? Indeed, there is evidence showing that changes in taste can 54 55 ⁠ 56 382 affect mood (Karita et al. 2012; Platte et al. 2013; Sugawara et al. 2013) 57 58 59 16 60 Page 17 of 55 Chemical Senses

3 83 1 2 3 384 6. Effect of cannabinoid on chemo perception 4 5 6 385 Taste and flavor are sensory experiences involving the oral perception of foodderived 7 8 386 chemicals and drive a primal sense of acceptable or unacceptable for what is sampled. 9 10 387 Therefore, deciphering the effect of CB on the perception of chemical senses and 11 12 388 consequently in the pattern of feeding has been a focus of interest within the CB 13 14 389 research in the last decades. There is considerable amount of evidence describing the 15 16 17 390 participation of the ECS on the chemosensory response to food (Ward and Dykstra 18 19 391 2005; Yoshida etFor al. 2010). Review Specifically, circulating Only eCBs influence olfactory 20 21 392 perception, with differences between lean and obese individuals (Pastor et al. 2016). 22

23 393 Additionally, the activation of CB1 has been shown to enhance gustatory properties of 24 25 394 food in both animals and humans (Limebeer et al. 2012; Niki et al. 2015)⁠ . Other 26 27 395 studies show that the processing of olfactory or gustatory sensations involves CB 28 1 29 30 396 signaling (Table 2). For instance, fasted mice displayed CB1 dependent increased odor 31 32 397 detection in the olfactory bulb (SoriaGómez et al. 2014b)⁠ . As described above, CB 33 34 398 receptors and other CBbinding receptors (i.e. TPRV1) are not only modulated by eCBs 35 36 399 and 9THC, but also by other phytocannabinoids like cannabidiol (Campos et al. 37 38 400 2013)⁠ and other synthetic CBs (Castaneto et al. 2014)⁠ . In this section, we 39 40 401 summarize relevant research covering the effect of the ECS and CBs on smell and taste, 41 42 43 402 as primary chemosensory processes relevant to food choice and food intake. 44 45 46 403 47 48 404 6.1. Cannabinoids and smell 49 50 51 405 Smell is one of the primary senses among mammals. In humans, contributes drastically 52 53 54 406 to experience flavor not only as a chemosensory response, but also as an important 55 56 407 component of the affective response to food (Stevenson 2009)⁠ . The olfactory 57 58 59 17 60 Chemical Senses Page 18 of 55

408 information is processed within brain regions also associated with the processing of 1 2 409 cognitive and affective information (i.e. amygdala, hippocampus, PFC). Many studies 3 4 410 show that olfactory perception is affected in metabolic disturbed states, including 5 6 411 obesity but also anorexia and bulimia nervosa (Richardson et al. 2004; Palouzier 7 8 9 412 Paulignan et al. 2012; Karine et al. 2014; SoriaGómez et al. 2014c). Furthermore, it 10 11 413 was recently demonstrated that smell is associated with central and peripheral systems 12 13 414 that regulate food intake. Interestingly, people with obesity show significant differences 14 15 415 regarding olfactory capacity in comparison with healthy subjects (Richardson et al. 16 17 416 2004; Pastor et al. 2016)⁠ . And this has been shown even in children (Jansen et al. 18 19 417 2003)⁠ . Thus, the Forolfactory systemReview can influence Onlyeating behavior by acting on hunger 20 21 22 418 and satiety signals as a sort of metabolic regulator, hence affecting energy homeostasis 23 24 419 (Yeomans 2006; PalouzierPaulignan et al. 2012)⁠ . 25 26 27 420 One of the systems with which olfaction interacts closely is the ECS (Palouzier 28 29 421 Paulignan et al. 2012). From basic organisms to humans, experimental evidence 30 31 422 demonstrates the close participation of the ECS on olfactory function. For instance, 32 33 423 Breuning and colleagues showed that hungerinduced 2AG synthesis in the olfactory 34 35 424 epithelium increases neuron activity and controls odor sensory threshold via CB1 36 37 425 activity in larvae X. laevis (Breunig et al. 2010)⁠ . Interestingly, despite these 38 39 40 426 properties, it seems that eCBs do not modulate olfaction per se (Hutch et al. 2015). 41 42 43 427 Further evidence shows that one of the mechanisms through which the ECS stimulates 44 45 428 eating behavior is smell. This is coherent with findings of numerous CB1 receptors in 46 47 429 terminal axons project towards the olfactory bulb (BusquetsGarcia et al. 2015)⁠ . In a 48 49 430 series of experiments, SoriaGomez and colleagues demonstrated that AEA, 2AG and 50 51 431 THC increased odor detection and food intake in fasted mice by decreasing signal input 52 53 432 from the olfactory cortex to the olfactory bulb (SoriaGómez et al. 2014b)⁠ . Also, it is 54 55 56 433 known that ECSinteracting endocrine and paracrine hormones involved in the hunger 57 58 59 18 60 Page 19 of 55 Chemical Senses

434 satiety processes can influence smell thresholds (Ketterer et al. 2011; Thanos et al. 1 2 435 2013)⁠ . And evidence from clinical studies indicates that the activation of the CB 3 4 436 receptors enhances smell, taste, and has an orexigenic effect (Støving et al. 2009; 5 6 437 Brisbois et al. 2011). 7 8 9 438 Recently, some research investigated the participation of phytocannabinoids and 10 11 12 439 synthetic CBs on smell. It was recently demonstrated that WIN552122 and WIN 13 14 440 552123, are capable of binding to CB1 and CB2 receptors in neurons of the olfactory 15 16 441 bulb, not affecting olfactory function (Hutch et al. 2015). Considering the resurgence of 17 18 442 THC in medical use, including neuropathic pain or analgesia treatment in cancer, it is 19 For Review Only 20 443 important to assess the olfactory effects of phytocannabinoids and synthetic CBs. 21 22 444 Walter et al. (2014)⁠ reported that 9THC impaired the performance of healthy 23 24 25 445 volunteers in olfactory tests. Furthermore, these authors demonstrated that THC 26 27 446 induced reduction in the pleasantness of a pleasurable odor was accompanied by 28 29 447 reduced activation in the limbic system. These findings suggest that THCbased 30 31 448 medications will be among the drugs displaying side effects on chemoperception. 32 33 449 Interestingly, when THC was administered to cancer patients with chemosensory 34 35 450 alterations, THC was effective in palliating chemosensory alterations and improving 36 37 451 food enjoyment (Brisbois et al. 2011). 38 39 40 452 41 42 43 453 6.2. Cannabinoids and taste 44 45 46 454 Smell is not the only chemosensory system interacting with the ECS to modulate 47 48 455 feeding. Gustatory perception is also closely related to the ECS, and genetic variations 49 50 51 456 of various elements within the ECS has shown to also influence taste and food 52 53 457 preference (De Luis et al. 2010, 2013b, 2013a, 2016a, 2016b), together with other 54 55 458 processes related to eating behavior, such as reward sensitivity (Hariri et al. 2009), 56 57 58 59 19 60 Chemical Senses Page 20 of 55

459 binging (Monteleone et al. 2009)⁠ and cravings (Haughey et al. 2008). Thus, the 1 2 460 perception of taste is also essential for the assessment of edibility of food and for the 3 4 461 evaluation of its nutritional values. For instance, a polymorphism in the CB1 receptor 5 6 462 gene (CNR1), the (AAT)n, is associated with changes in the sensitivity to sweetness. 7 8 9 463 Concretely, the sweetness threshold in women with obesity that carried was 10 11 464 significantly lower compared to those without the (AAT)n repeat (Umabiki et al. 12 13 465 2011)⁠ . 14 15 16 466 Yoshida and colleagues (2010) observed that the administration of AEA and 2AG 17 18 467 increased taste responses to sweet rather than salty, sour, bitter or umami flavors in 19 For Review Only 20 468 wildtype but not in CB1 knockout animals. This effect has been further explored as an 21 22 469 opposite action of the anorexigenic hormone leptin (Yoshida et al. 2010; Niki et al. 23 24 25 470 2015). These opposite effects of eCBs and leptin on sweet taste were also confirmed by 26 27 471 Jyotaki et al. (2010)⁠ . However, Wierucka et al. (2014)⁠ reported that CB1 antagonist, 28 29 472 AM251, attenuated body weight gain in rats maintained on highcalorie rich in fat and 30 31 473 carbohydrates but did not affect preferences for sweet food. Thus, the effects of ECS 32 33 474 and CBs on sweet taste seem to be still controversial. 34 35 36 475 Interestingly, some evidence indicates that circulating levels of eCB can also modulate 37 38 476 bitterness sensitivity in nonoverweight individuals (Tomassini Barbarossa et al. 2013; 39 40 477 Tepper et al. 2014)⁠ . Furthermore, the ECS seems to participate in the gustatory 41 42 ⁠ 43 478 perception of fats (Di Patrizio 2014) . According to various studies, the ECS is 44 45 479 specifically related to the perception of one kind of unsaturated fatty acids (FA), as the 46 47 480 presence of saturated FA failed to stimulate the synthesis of eCB in the small intestine 48 49 481 (Mindell et al. 1990; Di Patrizio et al. 2011, 2013)⁠ . However, these findings should be 50 51 482 considered carefully, since physiological differences between humans and rodents may 52 53 483 affect FA taste sensitivity thresholds (Kawai and Fushiki 2003; Stewart et al. 2010). All 54 55 56 57 58 59 20 60 Page 21 of 55 Chemical Senses

484 together suggest that eCBs and CBs seem to constitute a selective reinforcement signal 1 2 485 for palatable food. 3 4 5 486 Finally, given the relevance on taste in regards hedonic salience to food, there is an 6 7 487 increasing interest in elucidating the mechanisms behind the affective response to 8 9 488 different foods. It seems clear that the ECS plays an important part on this process. 10 11 12 489 Pharmacological studies provide strong evidence to support this. For instance, 13 14 490 CP55,940 increases beer and sucrose consumption whereas both SR 141716A, a CB1 15 16 491 antagonist, and naloxone block these effects on spontaneous sucrose drinking (Higgs et 17 18 492 al. 2003)⁠ and operant responding for sucrose (McLaughlin et al. 2003), suggesting a 19 For Review Only 20 493 role of CB1 and opioid receptors (Gallate et al. 1999)⁠ in these behaviors. In this way, 21 22 494 Simiand et al. (1998)⁠ reported that SR 141716A reduced consumption of a highly 23 24 25 495 palatable sweetened food and suggested that eCBs may modulate “the appetitive value 26 27 496 of food”. However, other authors have challenged this idea. Particularly, the results 28 29 497 obtained by Freedland et al. (2000)⁠ suggested that appetitive value or enhanced 30 31 498 palatability was not necessary to the effects of this CB1 antagonist. Recently, 32 33 499 Wakeford et al. (2016)⁠ observed that THC exposure had no effect on taste 34 35 500 conditioning in adolescent animals. However, de Brujin and colleagues investigated 36 37 501 whether low doses of inhaled 9THC and cannabidiol affected sweet taste sensitivity, 38 39 40 502 reported no change in sweet sensitivity either perception or subjective response (i.e. 41 42 503 liking) after inhalation of the various cannabis preparations (de Bruijn et al. 2017)⁠ . It 43 44 504 is also worth mentioning that Jarret et al. (2005)⁠ observed that THC increases intake 45 46 505 of palatable (sweet) food 2 hours, but not earlier, following a low dose of THC, an 47 48 506 effect that involved CB1 receptor and can partially explain the above apparent 49 50 507 incongruities. On the other hand, SR 141716A is sufficient to attenuate the reinforcing 51 52 53 508 effect of fat, while activation of the central CB1 system is enough to enhance its 54 55 509 reinforcement properties (Ward and Dykstra 2005)⁠ . 56 57 58 59 21 60 Chemical Senses Page 22 of 55

510 Apparently, the debate on the role of the ECS and CBs on foodrelated affective 1 2 511 response is not over, and it will be necessary more studies on this topic. Unfortunately, 3 4 512 the research on the role of the ECS and CBs on chemosensory response is not as 5 6 513 abundant as in other fields. With the increasing rate of dysfunctional dietary habits, we 7 8 9 514 believe this should be neglected no longer. 10 11 12 515 CB2 is a recent guest to this history. βcaryophyllene, a CB2 agonist, was used to 13 14 516 investigate the role of this receptor in mediating alcohol intake and ethanolinduced 15 16 517 conditioned place preference and sensitivity in rodents. Specifically, βcaryophyllene 17 18 518 decreased alcohol consumption and ethanolinduced place preference in a dose 19 For Review Only 20 519 dependent manner but did not alter taste function. Interestingly, this effect was 21 22 520 abrogated by a selective CB (AM630) (Al Mansouri et al. 2014)⁠ , 23 2 24 25 521 thus suggesting a connection between the CB2 receptor and ethanol consumption and 26 27 522 representing a potential novel pharmacological target for the treatment of alcoholism. In 28 29 523 this way, Marcus et al. (2017)⁠ reported that mutant mice expressing a “hyper 30 31 524 sensitive” form of CB1 show similar taste preference for sucrose, quinine and alcohol 32 33 525 and did not change ethanol consumption. 34 35 36 526 37 38 39 527 7. Effects of cannabinoids on food flavor and on peripheral mechanisms to the control 40 41 528 of feeding pattern 42 43 44 529 Flavor corresponds to the combination of sensations that includes taste, odor and 45 46 530 trigeminal inputs. Innate and learned flavor preferences influence food and drink 47 48 531 choices (see Tarragon and Moreno 2017 for a more indepth description of the role of 49 50 51 532 the ECS on food preference). It has a major role in the final (gestalt) perception and 52 53 533 enjoyment of food, thus being considered the main endogenous factor for food 54 55 534 preferences and intake (Bodnar 2016)⁠ . 56 57 58 59 22 60 Page 23 of 55 Chemical Senses

535 The two primary forms of learned preferences involve flavorflavor and flavornutrient 1 2 536 associations. In these, a specific flavor element (e.g., odor) is paired with an innately 3 4 537 preferred flavor element (e.g., sweet taste) and/or with a positive postoral nutrient 5 6 538 consequence (i.e. higher energy available) (Touzani et al. 2010)⁠ . It has been proposed 7 8 9 539 that these two dimensions of learned preferences are driven by related albeit different 10 11 540 neural mechanisms, among which the dopaminergic, the opioid and the eCBs are of 12 13 541 remarked relevance. Given the scope of this review, we will focus primarily on the 14 15 542 latter. 16 17 9 18 543 Pharmacological manipulations of CB1 receptors with eCBs, synthetic CBs, THC 19 For Review Only 20 544 and other phytocannabinoids are widely reported among the literature on eating 21 22 545 behavior (Gamage and Lichtman 2012)⁠ . For instance, the exogenous administration of 23 24 25 546 AEA has proved to affect eating pattern by reducing the latency to food consumption, 26 27 547 and by increasing the size of the meal and consumption duration (Hao et al. 2000; 28 29 548 Jamshidi and Taylor 2001; Williams and Kirkham 2002a). Also, the administration of 30 31 549 dronabiol (a synthetic CB), 9THC, THCderived phytocanabinnoids, and nonTHC 32 33 550 derived phytocannabinoids are capable of stimulating feeding behavior in rats (Williams 34 35 551 and Kirkham 2002b; Farrimond et al. 2010, 2012a, 2012b)⁠ . According to these 36 37 552 studies, the enhanced feeding response is mediated by the activation of the CB 38 1 39 40 553 receptor. Further, CB1 agonist did not only increased total volume of food, but also 41 42 554 affected other parameters of feeding pattern including the aforementioned delay to food 43 44 555 and meal size, two features that mostly fall within the flavorflavor category mentioned 45 46 556 above. 47 48 49 557 In the 1970s some of the first experimental studies investigating the effects of THC on 50 51 558 food intake in humans reported significant increases in consumption of chocolate milk 52 53 559 shakes and marshmallows (Abel 1971)⁠ , a finding which now underlines the two main 54 55 56 560 aspects of the ECS in modulating both appetite and the hedonic of highly palatable 57 58 59 23 60 Chemical Senses Page 24 of 55

561 foods such as sweets and fats (Harrold and Williams 2003)⁠ . The implication of CB1 1 2 562 receptor in human weight homeostasis has also been confirmed measuring CB1 3 4 563 availability by positron emission tomography in volunteers and patients with food 5 6 564 eating disorders (FED) such as anorexia nervosa, bulimia nervosa, and also in obesity 7 8 ⁠ 9 565 (Ceccarini et al. 2016) . More specifically, data shows an inverse association between 10 11 566 CB1 receptor availability and body mass index (BMI) in the hypothalamus and the 12 13 567 brainsteam in healthy subjects and patients with food eating disorders both. However, 14 15 568 other brain regions involved in the processing of reward and hedonic value of food (i.e. 16 17 569 striatum, insula, amygdala, and OFC) only correlated with BMI in FED patients. 18 19 570 Coherent with this, Fora recent study Review showed that , Only a CB antagonist, increased 20 1 21 22 571 responses to chocolate stimuli and to aversive stimuli in the amygdala, the insula and 23 24 572 the OFC (Tudge et al. 2015)⁠ . 25 26 27 573 A recent study shows that the hyperphagia observed in obese mice that followed a 28 29 574 typical western style diet for 60 days is dependent on CB1 receptors. Specifically, the 30 31 575 inhibition of peripheral CB1 receptors reduced food consumption in the western diet but 32 33 576 not in the standard diet group (Argueta and Di Patrizio 2017)⁠ . This information is 34 35 577 coherent with other studies showing that smell can enhance response to food via CB1 36 37 578 receptors in terminal axons project towards the olfactory bulb (SoriaGómez et al. 38 39 40 579 2014b; BusquetsGarcia et al. 2015)⁠ . In addition, Mathes and colleagues demonstrated 41 42 580 that the blockade of CB1 receptors is able to prevent body weight by selectively 43 44 581 decreasing the selection of fattening foods in an obesityinduced protocol in rats 45 46 582 (Mathes et al. 2008)⁠ . 47 48 49 583 Interestingly, another recent study showed that there is no difference when comparing 50 51 584 the administration of phytocannabinoids, synthetic CBs, and eCBs with respect body 52 53 585 weight regulation, food intake, and glucose homeostasis (Marcus et al. 2016)⁠ . Also, it 54 55 56 586 has been shown that cannabidiol does not affect negatively the affective response to 57 58 59 24 60 Page 25 of 55 Chemical Senses

587 emotional stimuli in humans (Arndt and de Wit 2017)⁠ . Despite that this study was 1 2 588 carried out with facial stimuli, the results from Arndt and de Wit could provide a 3 4 589 starting point to explore the effect of phytocannabinoids and synthetic CBs on other 5 6 590 levels of the emotional continuum, like the affective response to food. 7 8 9 591 It has also been observed that the presence of fat in the oral cavity induces a cephalic 10 11 12 592 phase response resulting in jejunal production of eCBs, further linked with increased fat 13 14 593 intake (Di Patrizio et al. 2011)⁠ . It was hypothesized that this effect might be triggered 15 16 594 by ghrelin, since gastric CB1 activation leads to ghrelin secretion, which increases fat 17 18 595 taste perception and promotes fat intake (Perello et al. 2010). Interestingly, salivary 19 For Review Only 20 596 eCBs are found in higher concentration in obese patients in comparison with healthy 21 22 597 subjects (Matias et al. 2012)⁠ and might be associated with ω6/ω3 ratio intake 23 24 25 598 (Zimmer et al. 2018, unpublished data). Further, eCBs can increase neural response 26 27 599 specifically to sweet taste through a CB1dependent mechanism (Yoshida et al. 2010). 28 29 30 600 Considering that ECS can also modulate olfactory responses, it is worth noting the role 31 32 601 of this system in the regulation of sensory information (flavor) associated with food 33 34 602 intake and feeding pattern. Both exogenous and endogenous CBs strongly stimulate 35 36 603 intake of sugars and fats in particular (Koch 2001; Kirkham 2005)⁠ . Moreover, it has 37 38 604 been observed that CB1 antagonism reduced the expression of fructoseconditioned 39 40 605 flavor preference while failing to affect the acquisition of such preference (Miner et al. 41 42 ⁠ 43 606 2008) . 44 45 46 607 The evidence presented indicates that modifications in the strength of learned flavor 47 48 608 associations could influence behavior towards food. Moreover, given the motivational 49 50 609 properties of palatability, manipulating these flavorflavor and flavornutrient 51 52 610 associations could serve as a therapeutic tool in illnesses where taste perception is 53 54 611 altered, thus potentiating adherence to the treatment. Unfortunately, despite all the 55 56 57 58 59 25 60 Chemical Senses Page 26 of 55

612 information collected around the CB system and the flavorflavor dimension, the role of 1

2 613 CB1 in flavornutrient learning has yet to be investigated. 3 4 5 614 There is no literature, to the best of our knowledge, covering the affective response to 6 7 615 food after the administration of CB derivatives nor synthetic CBs. It is reasonable to 8 9 616 hypothesize that the same operating mechanisms for eCBs and 9THC are operating in 10 11 12 617 the brain, thus exerting similar effects regarding energy homeostasis and the regulation 13 14 618 of eating behavior (Fig. 3). However, as mentioned, the experimental evidence to claim 15 16 619 this is circumstantial. 17 18 19 620 The evidence on humanFor subjects Review with respect the effectOnly of ECS on feeding pattern is not 20 21 621 as numerous as in rodent models. Ethical concerns with respect the use of THC 22 23 622 derivatives with potential psychotropic effects on the volunteers maybe a reason for the 24 25 623 limited number of studies. Hence, synthetic and nonpsychotropic THC derivatives may 26 27 624 represent a promising alternative to study how the ECS participates in eating behavior 28 29 30 625 in general, and in chemosensory response to food, particularly. Thus, THC and ghrelin 31 32 626 have been proposed in the palliation of chemosensory alterations (dysgeusia) to improve 33 34 627 food enjoyment (Vancleef et al. 2015; Sun et al. 2016)⁠ . A growing number of studies 35 36 628 currently focus on this promising area, although more research is needed to fully grasp 37 38 629 the potential implication of these CBrelated compounds on smell, taste, and other 39 40 630 properties of the eating experience. 41 42 43 631 44 45 46 632 8. Conclusion 47 48 49 633 Since the isolation of the psychoactive component of the C. sativa in the early 1960s, 50 51 634 hundreds of CB derivatives have been discovered in plants and developed in 52 53 54 635 laboratories. All these compounds bind to a certain degree to specific CB receptors 55 56 636 located both in the brain and peripherally, from where regulate and modulate a great 57 58 59 26 60 Page 27 of 55 Chemical Senses

637 deal of physiological and psychological processes. Some of these compounds present 1 2 638 promising properties as therapeutic drugs for several conditions, particularly in those 3 4 639 related to obesity. Unfortunately, the amount of research covering the putative effects of 5 6 640 phytocannabinoids and synthetic CBs on metabolicrelated disorders is remarkably 7 8 9 641 scarce, particularly in regard to relevant aspects of eating behavior, such as smell, and 10 11 642 sweet and fat taste sensitivity. In this review, we summarized the role of the ECS in 12 13 643 chemosensory perception, given it is pivotal function in eating behavior. Understanding 14 15 644 that the ECS also affects energy homeostasis through its influence on how taste and 16 17 645 smell are perceived is relevant for developing better strategies targeting body weight 18 19 646 homeostasis disruptionrelatedFor Review conditions. Further,Only we believe that both 20 21 22 647 phytocannabinoids and synthetic CB compounds would be promising pharmacological 23 24 648 alternatives in the treatment of high prevalence such as obesity, type 2 diabetes 25 26 649 and metabolic syndrome. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 27 60 Chemical Senses Page 28 of 55

6 9.50 References 1 2 3 651 1. Abel EL. 1971. Effects of marihuana on the solution of anagrams, memory and 4 652 appetite. Nature. 231:260261. 5 6 653 2. Adams R, Cain CK, McPhee WD, Wearn RB. 1941. Structure of Cannabidiol. XII. 7 654 Isomerization to . J. Am. Chem. Soc. 63:2209–2213. 8 9 655 3. Addy C, Wright H, Van Laere K, Gantz I, Erondu N, Musser BJ, Lu K, Yuan J, 10 656 SanabriaBohórquez SM, Stoch A, et al. 2008. The Acyclic CB1R Inverse Agonist 11 12 657 Taranabant Mediates Weight Loss by Increasing Energy Expenditure and 13 658 Decreasing Caloric Intake. Cell Metab. 7:6878. 14 15 659 4. Al Mansouri S, Ojha S, Al Maamari E, Al Ameri M, Nurulain SM, Bahi A. 2014. 16 660 The 2 agonist, βcaryophyllene, reduced voluntary alcohol 17 18 661 intake and attenuated ethanolinduced place preference and sensitivity in mice. 19 662 Pharmacol BiochemFor Behav. Review 124:260268. Only 20 21 663 5. Argueta DA, Di Patrizio NV. 2017. Peripheral endocannabinoid signaling controls 22 664 hyperphagia in western dietinduced obesity. Physiol Behav. 171:32–39. 23 24 665 6. Arndt DL, de Wit H. 2017. Cannabidiol Does Not Dampen Responses to Emotional 25 666 Stimuli in Healthy Adults. Cannabis Cannabinoid Res. 2:105113. 26 27 667 7. Avraham Y, BenShushan D, Breuer A, Zolotarev O, Okon A, Fink N, Katz V, 28 668 Berry EM. 2004. Very low doses of 8THC increase food consumption and alter 29 30 669 neurotransmitter levels following weight loss. Pharmacol Biochem Behav. 77:675 31 670 684. 32 33 671 8. Badowski ME, Perez SE. 2016. Clinical utility of dronabinol in the treatment of 34 672 weight loss associated with HIV and AIDS. HIV AIDS (Auckl). 8:3745. 35 36 673 9. Ben Amar M. 2006. Cannabinoids in medicine: A review of their therapeutic 37 674 potential. J Ethnopharmacol. 105:125. 38 39 675 10. Bisogno T, Melck D, Bobrov MY, Gretskaya NM, Bezuglov VV, de Petrocellis L, 40 676 Di Marzo V. 2000. Nacyldopamines: novel synthetic CB1 cannabinoidreceptor 41 42 677 ligands and inhibitors of anandamide inactivation with cannabimimetic activity in 43 678 vitro and in vivo. Biochem J. 351:817. 44 45 679 11. Bisogno T, Ligresti A, Di Marzo V. 2005. The endocannabinoid signalling system: 46 680 Biochemical aspects. Pharmacol Biochem Behav. 81:224–238. 47 48 681 12. Bluher M, Engeli S, Kloting N, Berndt J, Fasshauer M, Batkai S, Pacher P, Schon 49 682 MR, Jordan J, Stumvoll M. 2006. Dysregulation of the Peripheral and Adipose 50 683 Tissue Endocannabinoid System in Human Abdominal Obesity. Diabetes. 55:3053– 51 52 684 3060. 53 54 685 13. Bodnar RJ. 2016. Conditioned flavor preferences in animals: Merging 55 686 pharmacology, brain sites and genetic variance. Appetite. 122:1725. 56 57 58 59 28 60 Page 29 of 55 Chemical Senses

687 14. Breivogel CS, Sim LJ, Childers SR. 1997. Regional differences in cannabinoid 1 688 receptor/Gprotein coupling in rat brain. J Pharmacol Exp Ther. 282:1632–1642. 2 3 689 15. Breunig E, Manzini I, Piscitelli F, Gutermann B, Di Marzo V, Schild D, Czesnik D. 4 690 2010. The Endocannabinoid 2ArachidonoylGlycerol Controls Odor Sensitivity in 5 6 691 Larvae of Xenopus laevis. J Neurosci. 30:8965–8973. 7 8 692 16. Brisbois TD, de Kock IH, Watanabe SM, Mirhosseini M, Lamoureux DC, Chasen 9 693 M, MacDonald N, Baracos VE, Wismer WV. 2011. Delta9tetrahydrocannabinol 10 694 may palliate altered chemosensory perception in cancer patients: results of a 11 695 randomized, doubleblind, placebocontrolled pilot trial. Ann Oncol. 22:2086–2093. 12 13 696 17. BusquetsGarcia A, Desprez T, MetnaLaurent M, Bellocchio L, Marsicano G, 14 15 697 SoriaGómez E. 2015. Dissecting the cannabinergic control of behavior: The where 16 698 matters. BioEssays. 37:1215–1225. 17 18 699 18. Campos AC, Ortega Z, Palazuelos J, Fogaça MV., Aguiar DC, DíazAlonso J, 19 700 OrtegaGutiérrezFor S, VázquezVilla Review H, Moreira OnlyFA, Guzmán M, et al. 2013. The 20 701 anxiolytic effect of cannabidiol on chronically stressed mice depends on 21 22 702 hippocampal neurogenesis: involvement of the endocannabinoid system. Int J 23 703 Neuropsychopharmacol. 16:1407–1419. 24 25 704 19. Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S, Huestis MA. 26 705 2014. Synthetic cannabinoids: Epidemiology, pharmacodynamics, and clinical 27 706 implications. Drug Alcohol Depend. 144:12–41. 28 29 707 20. Ceccarini J, Weltens N, Ly HG, Tack J, Van Oudenhove L, Van Laere K. 2016. 30 708 Association between cerebral cannabinoid 1 receptor availability and body mass 31 32 709 index in patients with food intake disorders and healthy subjects: a [(18)F]MK9470 33 710 PET study. Transl . 6:e853. 34 35 711 21. Chanda D, Oligschlaeger Y, Geraets I, Liu Y, Zhu X, Li J, Nabben M, Coumans W, 36 712 Luiken JJFP, Glatz JFC, et al. 2017. 2Arachidonoylglycerol ameliorates 37 38 713 inflammatory stressinduced insulin resistance in cardiomyocytes. J Biol Chem. 39 714 292:71057114. 40 41 715 22. Chen J, Papies EK, Barsalou LW. 2015. A core eating network and its modulations 42 716 underlie diverse eating phenomena. Brain Cogn. 110:20–42. 43 44 717 23. Cluny NL, Keenan CM, Reimer RA, Le Foll B, Sharkey KA. 2015. Prevention of 45 718 DietInduced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated 46 719 Chronically with 9Tetrahydrocannabinol. PLoS One. 10(12):e0144270. 47 48 720 24. Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. 1998. Appetite 49 50 721 supression and weight loss after the cannabinoid antagonist SR 141716. Life Sci. 51 722 63:PL113PL117. 52 53 723 25. Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR. 1992. Aminoalkylindole 54 724 analogs: cannabimimetic activity of a class of compounds structurally distinct from 55 725 delta 9tetrahydrocannabinol. J Pharmacol Exp Ther. 263:11181126. 56 57 58 59 29 60 Chemical Senses Page 30 of 55

726 26. Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, Auer D, 1 727 Yassouridis A, ThöneReineke C, Ortmann S, et al. 2003. The endogenous 2 3 728 cennabinoid system affects energy balance via central orexigenic drive and 4 729 peripheral lipogenesis. J Clin Invest. 112:423431. 5 6 730 27. D’Addario C, Micioni Di Bonaventura MV, Pucci M, Romano A, Gaetani S, 7 731 Ciccocioppo R, Cifani C, Maccarrone M. 2014. Endocannabinoid signaling and 8 732 food addiction. Neurosci Biobehav Rev. 47C:203–224. 9 10 733 28. de Bruijn SEM, de Graaf C, Witkamp RF, Jager G. 2017. Explorative Placebo 11 734 Controlled DoubleBlind Intervention Study with Low Doses of Inhaled 9 12 13 735 Tetrahydrocannabinol and Cannabidiol Reveals No Effect on Sweet Taste Intensity 14 736 Perception and Liking in Humans. Cannabis Cannabinoid Res. 2:114122. 15 16 737 29. de Luis DA, González Sagrado M, Aller R, Izaola O, Conde R, Romero E. 2010. 17 738 G1359A polymorphism of the cannabinoid receptor gene (CNR1) and insulin 18 739 resistance in patients with diabetes mellitus type 2. Nutr Hosp. 25:34–8. 19 For Review Only 20 740 30. de Luis DA, Aller R, Izaola O, Conde R, de de la Fuente B, Sagrado MG. 2013a. 21 22 741 Genetic variation in the endocannabinoid degrading fatty acid amide 23 742 hydrolase (FAAH) and their influence on weight loss and insulin resistance under a 24 743 high monounsaturated fat hypocaloric diet. J Diabetes Complications. 27:235–239. 25 26 744 31. de Luis DA, Aller R, Sagrado MG, Conde R, Izaola O, de la Fuente B. 2013b. 27 745 Genetic variation in the cannabinoid receptor gene (CNR1) (G1359A 28 29 746 polymorphism) and their influence on anthropometric parameters and metabolic 30 747 parameters under a high monounsaturated vs. high polyunsaturated fat hypocaloric 31 748 diets. J Nutr Biochem. 24:1431–1435. 32 33 749 32. de Luis DA, Ballesteros M, Lopez Guzman A, Ruiz E, Muñoz C, Penacho MA, 34 750 Iglesias P, Maldonado A, San Martin L, Izaola O, et al. 2016a. Polymorphism 35 36 751 G1359A of the cannabinoid receptor gene (CNR1): Allelic frequencies and 37 752 influence on cardiovascular risk factors in a multicentre study of CastillaLeon. J 38 753 Hum Nutr Diet. 29:112–117. 39 40 754 33. de Luis DA, Izaola O, Aller R, Lopez JJ, Torres B, Diaz G, Gomez E, Romero E. 41 755 2016b. Association of G1359A polymorphism of the cannabinoid receptor gene 42 43 756 (CNR1) with macronutrient intakes in obese females. J Hum Nutr Diet. 29:118– 44 757 123. 45 46 758 34. Despreś JP, Lemieux I, Alméras N. 2006. Contribution of CB1 blockade to the 47 759 management of highrisk abdominal obesity. Int J Obes (Lond). 30 Suppl 1:S44– 48 760 S52. 49 50 761 35. Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC. 1988. 51 52 762 Determination and characterization of a cannabinoid receptor in rat brain. Mol 53 763 Pharmacol. 34:60513. 54 55 56 57 58 59 30 60 Page 31 of 55 Chemical Senses

764 36. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, 1 765 Mandelbaum A, Etinger A, Mechoulam R. 1992. Isolation and structure of a brain 2 3 766 constituent that binds to the cannabinoid receptor. Science. 258:1946–9. 4 767 37. Di Marzo V. 1998. “Endocannabinoids” and other fatty acid derivatives with 5 6 768 cannabimimetic properties: Biochemistry and possible physiopathological 7 769 relevance. Biochim Biophys Acta Lipids Lipid Metab. 1392:153175. 8 9 770 38. Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, 10 771 Palmiter RD, Sugiura T, et al. 2001. Leptinregulated endocannabinoids are 11 772 involved in maintaining food intake. Nature. 410:822–825. 12 13 773 39. Di Marzo V, Ligresti A, Cristino L. 2009a. The endocannabinoid system as a link 14 15 774 between homoeostatic and hedonic pathways involved in energy balance regulation. 16 775 Int J Obes. 33:S18–S24. 17 18 776 40. Di Marzo V, Côte M, Matias I, Lemmieux I, Arsenault BJ, Cartier A, Piscitelli F, 19 777 Petrosino S, AlmerasFor N, DespresReview JP. 2009b. Changes Only in plasma endocannabinoid 20 778 levels in viscerally obese men following a 1 year lifestyle modification programme 21 22 779 and waist circumference reduction: associations with changes in metabolic risk 23 780 factors. Diabetologia 52:213. 24 25 781 41. Di Patrizio NV, Simansky K J. 2008. Activating Parabrachial Cannabinoid CB1 26 782 Receptors Selectively Stimulates Feeding of Palatable Foods in Rats. J Neurosci. 27 783 28:97029709. 28 29 784 42. Di Patrizio NV, Astarita G, Schwartz G, Li X, Piomelli D. 2011. Endocannabinoid 30 785 signal in the gut controls dietary fat intake. Proc Natl Acad Sci U S A. 108:12904– 31 32 786 8. 33 34 787 43. Di Patrizio NV, Joslin A, Jung KM, Piomelli D. 2013. Endocannabinoid signaling 35 788 in the gut mediates preference for dietary unsaturated fats. FASEB J. 27:2513– 36 789 2520. 37 38 790 44. Di Patrizio NV. 2014. Is fat taste ready for primetime? Physiol Behav. 136:145– 39 791 154. 40 41 792 45. Edwards A, Abizaid A. 2016. Driving the need to feed: Insight into the 42 43 793 collaborative interaction between ghrelin and endocannabinoid systems in 44 794 modulating brain reward systems. Neurosci Biobehav Rev. 66: 3353. 45 46 795 46. Ellis J, Pediani JD, Canals M, Milasta S, Milligan G. 2006. Orexin1 receptor 47 796 cannabinoid CB1 receptor heterodimerization results in both liganddependent and 48 797 independent coordinated alterations of receptor localization and function. J Biol 49 50 798 Chem. 281:3881224. 51 799 47. Elmquist JK, Elias CF, Saper CB. 1999. From lesions to leptin: Hypothalamic 52 53 800 control of food intake and body weight. Neuron. 22:221232. 54 55 56 57 58 59 31 60 Chemical Senses Page 32 of 55

801 48. Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Janke J, Bátkai S, Pacher P, 1 802 HarveyWhite J, Luft FC, Sharma AM, et al. 2005. Activation of the peripheral 2 3 803 endocannabinoid system in human obesity. Diabetes. 54:2838–2843. 4 804 49. Farrimond JA, Whalley BJ, Williams CM. 2010. A low9tetrahydrocannabinol 5 6 805 cannabis extract induces hyperphagia in rats. Behav Pharmacol. 21:769772. 7 8 806 50. Farrimond JA, Mercier MS, Whalley BJ, Williams CM. 2011. Cannabis sativa and 9 807 the endogenous cannabinoid system: Therapeutic Potential for Appetite Regulation. 10 808 Phytother Res. 25:170188. 11 12 809 51. Farrimond JA, Whalley BJ, Williams CM. 2012a. and cannabidiol exert 13 810 opposing effects on rat feeding patterns. Psychopharmacology (Berl). 223:117–129. 14 15 811 52. Farrimond JA, Whalley BJ, Williams CM. 2012b. Non9tetrahydrocannabinol 16 812 phytocannabinoids stimulate feeding in rats. Behav Pharmacol. 23:113–117. 17 18 813 53. Foltin RW, Brady JV, Fischman MW. 1986. Behavioral analysis of marijuana 19 For Review Only 20 814 effects on food intake in humans. Pharmacol Biochem Behav. 25:577582. 21 815 54. Freedland CS, Poston JS, Porrino LJ. 2000. Effects of SR141716A, a central 22 23 816 cannabinoid receptor antagonist, on foodmaintained responding. Pharmacol 24 817 Biochem Behav. 67:265270. 25 26 818 55. Freund TF, Katona I, Piomelli D. 2003. Role of Endogenous Cannabinoids in 27 819 Synaptic Signaling. Physiol Rev. 83:10171066. 28 29 820 56. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula 30 821 M, Shire D, Le Fur G, Casellas P. 1995. Expression of central and peripheral 31 32 822 cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur 33 823 J Biochem. 232:5461. 34 35 824 57. Gallate JE, Saharov T, Mallet PE, McGregor IS. 1999. Increased motivation for 36 825 beer in rats following administration of a cannabinoid CB1receptor agonist. Eur J 37 826 Pharmacol. 370:233240. 38 39 827 58. Gamage TF, Lichtman AH. 2012. The endocannabinoid system: role in energy 40 828 regulation. Pediatr Blood Cancer. 58:144148. 41 42 829 59. Gao XB, Horvath TL. 2016. Feeding Behavior: Hypocretin/Orexin Neurons Act 43 44 830 between Food Seeking and Eating. Curr Biol. 26:R845–R847. 45 831 60. Gaoni Y, Mechoulam R. 1964. Isolation, Structure, and Partial Synthesis of an 46 47 832 Active Constituent of Hashish. J Am Chem Soc 86:16461647. 48 49 833 61. GattaCherifi B, Cota D. 2016. New insights on the role of the endocannabinoid 50 834 system in the regulation of energy balance. Int J Obes. 26:114124. 51 52 835 62. Gerard CM, Mollereau IIC, Parmentier M. 1991. Molecular cloning of a human 53 836 cannabinoid receptor which is also expressed in testis. Biochem J. 279:129–134. 54 55 56 57 58 59 32 60 Page 33 of 55 Chemical Senses

837 63. Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak 1 838 M, Zimmer A. 2008. Betacaryophyllene is a dietary cannabinoid. Proc Natl Acad 2 3 839 Sci. 105:9099–9104. 4 840 64. Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, del Arco I, Cippitelli A, Nava 5 6 841 F, Piomelli D, Rodriguez de Fonseca F. 2002. A peripheral mechanism for CB1 7 842 cannabinoid receptordependent modulation of feeding. J Neurosci. 22:96127. 8 9 843 65. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR. 2006. 10 844 Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain 11 845 Res. 1071:1023. 12 13 846 66. Hanus L, AbuLafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, 14 15 847 Mechoulam R. 2001. 2Arachidonyl glyceryl ether, an endogenous agonist of the 16 848 cannabinoid CB1 receptor. Proc Natl Acad Sci. 98:36623665. 17 18 849 67. Hao S, Avraham Y, Mechoulam R, Berry EM. 2000. Low dose anandamide affects 19 850 food intake, cognitiveFor function, Review neurotransmitter Only and corticosterone levels in diet 20 851 restricted mice. Eur J Pharmacol. 392: 147156. 21 22 852 68. Hardie DG. 2008. AMPK: a key regulator of energy balance in the single cell and 23 853 the whole organism. Int J Obes. 32:S7–S12. 24 25 854 69. Hariri AR, Gorka A, Hyde LW, Kimak M, Halder I, Ducci F, Ferrell RE, Goldman 26 27 855 D, Manuck SB. 2009. Divergent Effects of Genetic Variation in Endocannabinoid 28 856 Signaling on Human Threat and RewardRelated Brain Function. Biol Psychiatry. 29 857 66:9–16. 30 31 858 70. Harrold JA, Williams G. 2003. The cannabinoid system: a role in both the 32 859 homeostatic and hedonic control of eating? Br J Nutr. 90:729. 33 34 860 71. Haughey HM, Marshall E, Schacht JP, Louis A, Hutchison KE. 2008. Marijuana 35 861 withdrawal and craving: influence of the cannabinoid receptor 1 (CNR1) and fatty 36 37 862 acid amide hydrolase (FAAH) genes. Addiction. 103:1678–1686. 38 39 863 72. Herkenham M, Lynn AB, Litrle MD, Johnsont MR, Melvin LS, De Costa BR, 40 864 Riceo KC. 1990. Cannabinoid receptor localization in brain. Neurobiology. 41 865 87:19321936. 42 43 866 73. Higgs S, Williams CM, Kirkham TC. 2003. Cannabinoid influences on palatability: 44 867 microstructural analysis of sucrose drinking after 9tetrahydrocannabinol, 45 46 868 anandamide, 2arachidonoyl glycerol and SR141716. Psychopharmacology (Berl). 47 869 165:370–377. 48 49 870 74. Hill AJ, Williams CM, Whalley BJ, Stephens GJ. 2012. Phytocannabinoids as novel 50 871 therapeutic agents in CNS disorders. Pharmacol Ther. 133:7997. 51 52 872 75. Hillard CJ. 2018. Circulating Endocannabinoids: From Whence Do They Come and 53 873 Where are They Going? Neuropsychopharmacology. 43:155172. 54 55 874 76. Hojo M, Sudo Y, Ando Y, Minami K, Takada M, Matsubara T, Kanaide M, 56 875 Taniyama K, Sumikawa K, Uezono Y. 2008. MuOpioid Receptor Forms a 57 58 59 33 60 Chemical Senses Page 34 of 55

876 Functional Heterodimer With Cannabinoid CB Receptor: Electrophysiological and 1 877 FRET Assay Analysis. J Pharmacol Sci. 108:308319. 2 3 878 77. Howlett AC, BidautRussell M, Devane WA, Melvin LS, Johnson MR, Herkenham 4 879 M. 1990. The cannabinoid receptor: biochemical, anatomical and behavioral 5 6 880 characterization. Trends Neurosci. 13:420–423. 7 8 881 78. Hur K, Choi JS, Zheng M, Shen J, Wrobel B. 2018. Association of alterations in 9 882 smell and taste with depression in older adults. Laryngoscope Investig Otolaryngol. 10 883 3:94–99. 11 12 884 79. Hutch CR, Hillard CJ, Jia C, Hegg CC. 2015. An endocannabinoid system is 13 885 present in the mouse olfactory epithelium but does not modulate olfaction. 14 15 886 Neuroscience. 300:539–553. 16 887 80. Ishiguro H, Carpio O, Horiuchi Y, Shu A, Higuchi S, Schanz N, Benno R, Arinami 17 18 888 T, Onaivi ES. 2010. A nonsynonymous polymorphism in cannabinoid CB2 receptor 19 889 gene is associatedFor with eating Review disorders in humans Only and food intake is modified in 20 890 mice by its ligands. Synapse. 64:92–96. 21 22 891 81. Jamshidi N, Taylor DA. 2001. Anandamide administration into the ventromedial 23 892 hypothalamus stimulates appetite in rats. Br J Pharmacol. 134:11511154. 24 25 893 82. Jansen A, Theunissen N, Slechten K, Nederkoorn C, Boon B, Mulkens S, Roefs A. 26 27 894 2003. Overweight children overeat after exposure to food cues. Eat Behav. 4:197– 28 895 209. 29 30 896 83. Järbe TU, Di Patrizio NV. 2005. Delta9THC induced hyperphagia and tolerance 31 897 assessment: interactions between the CB1 receptor agonist delta9THC and the 32 898 CB1 receptor antagonist SR141716 (rimonabant) in rats. Behav Pharmacol. 33 34 899 16:373380. 35 900 84. Jarrett MM, Limebeer CL, Parker LA. 2005. Effect of 9tetrahydrocannabinol on 36 37 901 sucrose palatability as measured by the taste reactivity test. Physiol Behav. 86:475– 38 902 479. 39 40 903 85. JuanPico P, Fuentes E, BermudezSilva FJ, DiazMolina FJ, Ripoll C, Rodriguez 41 904 de Fonseca F, Nadal A. 2006. Cannabinoid receptors regulate Ca(2+) signals and 42 43 905 insulin secretion in pancreatic betacell. Cell Calcium. 39: 155–162. 44 906 86. Jyotaki M, Shigemura N, Ninomiya Y. 2010. Modulation of sweet taste sensitivity 45 46 907 by orexigenic and anorexigenic factors. Endocr J. 57:467–475. 47 908 87. Kapur A, Zhao P, Sharir H, Bai Y, Caron MG, Barak LS, Abood ME. 2009. 48 49 909 Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J 50 910 Biol Chem. 284:2981729827. 51 52 911 88. Karine B, MarieChristine L, Didier D, Régine M, Monique C, Christine B. 2014. 53 912 Rat strains with different metabolic statuses differ in food olfactorydriven 54 55 913 behavior. Behav Brain Res. 270:228–239. 56 57 58 59 34 60 Page 35 of 55 Chemical Senses

914 89. Karita K, Harada M, Yoshida M, Kokaze A. 2012. Factors Associated with Dietary 1 915 Habits and Mood States Affecting Taste Sensitivity in Japanese College Women. J 2 3 916 Nutr Sci Vitaminol (Tokyo). 58:360–365. 4 917 90. Katona I, Sperlágh B, Maglóczky Z, Sántha E, Köfalvi A, Czirják S, Mackie K, 5 6 918 Vizi ES, Freund TF. 2000. GABAergic interneurons are the targets of cannabinoid 7 919 actions in the human hippocampus. Neuroscience. 100:797804. 8 9 920 91. Kawai T, Fushiki T. 2003. Importance of lipolysis in oral cavity for orosensory 10 921 detection of fat. Am J Physiol Regul Integr Comp Physiol. 285:R447–R454. 11 12 922 92. Kearn CS. 2005. Concurrent Stimulation of Cannabinoid CB1 and Dopamine D2 13 923 Receptors Enhances Heterodimer Formation: A Mechanism for Receptor Cross 14 15 924 Talk? Mol Pharmacol. 67:16971704. 16 925 93. Ketterer C, Heni M, Thamer C, HerzbergSchäfer SA, Häring HU, Fritsche A. 17 18 926 2011. Acute, shortterm hyperinsulinemia increases olfactory threshold in healthy 19 927 subjects. Int J Obes.For 35:1135–1138. Review Only 20 21 928 94. Kirkham TC, Williams CM, Fezza F, Di Marzo V. 2002. Endocannabinoid levels in 22 929 rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: 23 930 Stimulation of eating by 2arachidonoyl glycerol. Br J Pharmacol. 136:550557. 24 25 931 95. Kirkham TC. 2005. Endocannabinoids in the regulation of appetite and body 26 27 932 weight. Behav Pharmacol. 16:297313. 28 933 96. Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, Gunasekaran N, Karl 29 30 934 T, Long LE, Huang XF, et al. 2011. Cannabidiol potentiates 9 31 935 tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics 32 936 during acute and chronic treatment in adolescent rats. Psychopharmacology (Berl). 33 34 937 218:443457. 35 938 97. Koch JE. 2001. Delta9THC stimulates food intake in Lewis rats: Effects on chow, 36 37 939 highfat and sweet highfat diets. Pharmacol Biochem Behav. 68: 539–543. 38 39 940 98. Koch M, Varela L, Kim JG, Kim JD, HernándezNuño F, Simonds SE, Castorena 40 941 CM, Vianna CR, Elmquist JK, Morozov YM, et al. 2015. Hypothalamic POMC 41 942 neurons promote cannabinoidinduced feeding. Nature. 519:4550. 42 43 943 99. Kola B, Farkas I, ChristCrain M, Wittmann G, Lolli F, Amin F, HarveyWhite J, 44 944 Liposits Z, Kunos G, Grossman AB, et al. 2008. The orexigenic effect of ghrelin is 45 46 945 mediated through central activation of the endogenous cannabinoid system. PLoS 47 946 One. 3(3):e1797. 48 49 947 100. Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, 50 948 Hawley SA, Hardie DG, Grossman AB, et al. 2005. Cannabinoids and ghrelin have 51 949 both central and peripheral metabolic and cardiac effects via AMPactivated protein 52 53 950 kinase. J Biol Chem. 280:2519625201. 54 55 56 57 58 59 35 60 Chemical Senses Page 36 of 55

951 101. Landsman RS, Burkey TH, Consroe P, Roeske WR, Yamamura HI. 1997. 1 952 SR141716A is an inverse agonist at the human cannabinoid CB1 receptor. Eur J 2 3 953 Pharmacol. 334:R1R2. 4 954 102. Lauckner JE, Hille B, Mackie K. 2005. The cannabinoid agonist WIN55,2122 5 6 955 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc 7 956 Natl Acad Sci. 102:1914419149. 8 9 957 103. Le Foll B, Trigo JM, Sharkey KA, Strat Y Le. 2013. Cannabis and 9 10 958 tetrahydrocannabinol (THC) for weight loss? Med Hypotheses. 80:564567. 11 12 959 104. Lee H, Yang B, Lee E. 2011. Modulation by the GABAB receptor siRNA of 13 960 ethanolmediated PKAα, CaMKII, and pCREB intracellular signaling in prenatal 14 15 961 rat hippocampal neurons. Anat Cell Biol. 44:210. 16 962 105. Leggett JD, Aspley S, Beckett SRG, D’Antona AM, Kendall DA, Kendall DA. 17 18 963 2004. Oleamide is a selective endogenous agonist of rat and human 19 964 CB1cannabinoidFor receptors. Review Br J Pharmacol. 141:253262. Only 20 21 965 106. Li L, Li X, Zhou W, Messina JL. 2013. Acute psychological stress results in the 22 966 rapid development of insulin resistance. J Endocrinol. 217:175–84. 23 24 967 107. Limebeer CL, Rock EM, Mechoulam R, Parker LA. 2012. The antinausea effects 25 968 of CB1 agonists are mediated by an action at the visceral insular còrtex. Brit J 26 27 969 Pharmacol. 167:11261136. 28 970 108. Little TJ, Cvijanovic N, Di Patrizio NV, Argueta DA, Rayner CK, FeinteBisset C, 29 30 971 Young RL. 2018. Plasma endocannabinoid levels in lean, overweight and obese 31 972 humans: relationships with intestinal permeability markers, inflammation and 32 973 incretin secretion. Am J Physiol Endocrinol Metabol. [Epub ahead of print]. 33 34 974 109. Marcus DJ, Zee ML, Davis BJ, Haskins CP, Andrews MJ, Amin R, Henderson 35 975 Redmond AN, Mackie K, Czyzyk TA, Morgan DJ. 2016. Mice Expressing a 36 37 976 "HyperSensitive" Form of the Cannabinoid Receptor 1 (CB1) Are 38 977 Neither Obese Nor Diabetic. PLoS One. 11(8):e016046. 39 40 978 110. Marcus DJ, HendersonRedmond AN, Gonek M, Zee ML, Farnsworth JC, Amin 41 979 RA, Andrews MJ, Davis BJ, Mackie K, Morgan DJ. 2017. Mice expressing a 42 43 980 “hypersensitive” form of the CB1cannabinoid receptor (CB1) show modestly 44 981 enhanced alcohol preference and consumption. PLoS One. 12(4):e017482. 45 46 982 111. Mathes CM, Ferrara M, Rowland NE. 2008. Cannabinoid1 receptor antagonists 47 983 reduce caloric intake by decreasing palatable diet selection in a novel dessert 48 984 protocol in female rats. Am J Physiol Regul Integr Comp Physiol. 295:R67–R75. 49 50 985 112. Matias I, GattaCherifi B, Tabarin A, Clark S, LesteLasserre T, Marsicano G, 51 986 Piazza PV, Cota D. 2012. Endocannabinoids measurement in human saliva as 52 53 987 potential biomarker of obesity. PLoS One. 7:e42399. 54 55 56 57 58 59 36 60 Page 37 of 55 Chemical Senses

988 113. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. 1990. Structure of 1 989 a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 2 3 990 346:561564. 4 991 114. Matsuda LA, Bonner TI, Lolait SJ. 1993. Localization of cannabinoid receptor 5 6 992 mRNA in rat brain. J Comp Neurol. 327:535550. 7 8 993 115. McLaughlin PJ, Winston K, Swezey L, Wisniecki A, Aberman J, Tardif DJ, Betz 9 994 AJ, Ishiwari K, Makriyannis A, Salamone JD. 2003. The cannabinoid CB1 10 995 antagonists SR 141716A and AM 251 suppress food intake and foodreinforced 11 996 behavior in a variety of tasks in rats. Behav Pharmacol. 14:583588. 12 13 997 116. McPartland JM, Guy GW, Di Marzo V. 2014. Care and feeding of the 14 15 998 endocannabinoid system: A systematic review of potential clinical interventions 16 999 that upregulate the endocannabinoid system. PLoS One. 9(3):e89566. 17 18 1000 117. Mechoulam R, Gaoni Y. 1967. Recent Advances in the Chemistry of Hashish. In: 19 1001 Fortschritte DerFor Chemie OrganischerReview Naturstoffe Only / Progress in the Chemistry of 20 1002 Organic Natural Products / Progrès Dans La Chimie Des Substances Organiques 21 22 1003 Naturelles. p.175213. 23 1004 118. Mechoulam R, Feigenbaum JJ, Lander N, Segal M, Järbe TUC, Hiltunen AJ, 24 25 1005 Consroe P. 1988. Enantiomeric cannabinoids: stereospecificity of psychotropic 26 1006 activity. Experientia. 44:762764. 27 28 1007 119. Mechoulam R, BenShabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, 29 1008 Gopher A, Almog S, Martin BR, Compton DR, et al. 1995. Identification of an 30 1009 endogenous 2monoglyceride, present in canine gut, that binds to cannabinoid 31 32 1010 receptors. Biochem Pharmacol. 50:83–90. 33 34 1011 120. Mechoulam R. 2007. Conversation with Raphael Mechoulam. Addiction. 102:887– 35 1012 893. 36 37 1013 121. Miederer I, Uebbing K, Röhrich J, Maus S, Bausbacher N, Krauter K, Weyer 38 1014 Elberich V, Lutz B, Schreckenberger M, Urban R. 2017. Effects of 39 1015 tetrahydrocannabinol on glucose uptake in the rat brain. Neuropharmacology. 40 41 1016 117:273281. 42 43 1017 122. Mindell S, Smith GP, Greenberg D. 1990. Corn oil and mineral oil stimulate sham 44 1018 feeding in rats. Physiol Behav. 48:283–287. 45 46 1019 123. Miner P, Abayev Y, Kandova E, Gerges M, Styler E, Wapniak R, Touzani K, 47 1020 Sclafani A, Bodnar RJ. 2008. Role of systemic endocannabinoid CB1 receptor 48 1021 antagonism in the acquisition and expression of fructoseconditioned flavorflavor 49 50 1022 preferences in rats. Pharmacol Biochem Behav. 90:318324. 51 1023 124. Moldrich G, Wenger T. 2000. Localization of the CB1 cannabinoid receptor in the 52 53 1024 rat brain. An immunohistochemical study. Peptides. 21:173542. 54 55 1025 125. Monteleone P, Bifulco M, Di Filippo C, Gazzerro P, Canestrelli B, Monteleone F, 56 1026 Proto MC, Di Genio M, Grimaldi C, Maj M. 2009. Association of CNR1 and 57 58 59 37 60 Chemical Senses Page 38 of 55

1027 FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia 1 1028 nervosa: Evidence for synergistic effects. Genes Brain Behav. 8:728–732. 2 3 1029 126. Morello G, Imperatore R, Palomba L, Finelli C, Labruna G, Pasanisi F, Sacchetti L, 4 1030 Buono L, Piscitelli F, Orlando P, et al. 2016. OrexinA represses satietyinducing 5 6 1031 POMC neurons and contributes to obesity via stimulation of endocannabinoid 7 1032 signaling. Proc Natl Acad Sci. 113:4759–4764. 8 9 1033 127. Morley JE, Levine AS. 1982. The role of the endogenous opiates as regulators of 10 1034 appetite. Am J Clin Nutr. 35:75761. 11 12 1035 128. Morozov YM, Koch M, Rakic P, Horvath TL. 2017. Cannabinoid type 1 receptor 13 1036 containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus. Mol 14 15 1037 Metab. 6:374–381. 16 1038 129. Munro S, Thomas KL, AbuShaar M. 1993. Molecular characterization of a 17 18 1039 peripheral receptor for cannabinoids. Nature. 365:61–65. 19 For Review Only 20 1040 130. Niki M, Jyotaki M, Yoshida R, Yasumatsu K, Shigemura N, Di Patrizio NV, 21 1041 Piomelli D, Ninomiya Y. 2015. Modulation of sweet taste sensitivities by 22 1042 endogenous leptin and endocannabinoids in mice. J Physiol. 593:2527–2545. 23 24 1043 131. Nogueiras R, López M, Diéguez C. 2010. Regulation of lipid metabolism by 25 1044 energy availability: a role for the central nervous system. Obes Rev. 11:185–201. 26 27 1045 132. O’Keefe L, Simcocks AC, Hryciw DH, Mathai ML, Mcainch AJ. 2014. The 28 1046 cannabinoid receptor 1 and its role in influencing peripheral metabolism. Diabetes 29 30 1047 Obes Metab. 16:294–304. 31 32 1048 133. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N. 2004. Molecular 33 1049 Characterization of a Phospholipase D Generating Anandamide and Its Congeners. 34 1050 J Biol Chem. 279:5298–5305. 35 36 1051 134. Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA, Myers L, Mora 37 1052 Z, Tagliaferro P, Gardner E, et al. 2006. Discovery of the presence and functional 38 39 1053 expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci. 1074:514 40 1054 536. 41 42 1055 135. Onaivi ES, Carpio O, Ishiguro H, Schanz N, Uhl GR, Benno R. 2008. Behavioral 43 1056 effects of CB2 cannabinoid receptor activation and its influence on food and alcohol 44 1057 consumption. Ann N Y Acad Sci. 1139:4263. 45 46 1058 136. Overton HA, Babbs AJ, Doel SM, Fyfe MCT, Gardner LS, Griffin G, Jackson HC, 47 1059 Procter MJ, Rasamison CM, TangChristensen M, et al. 2006. Deorphanization of a 48 49 1060 G proteincoupled receptor for oleoylethanolamide and its use in the discovery of 50 1061 smallmolecule hypophagic agents. Cell Metab. 3:167175. 51 52 1062 137. Overton HA, Fyfe MCT, Reynet C. 2008. GPR119, a novel G proteincoupled 53 1063 receptor target for the treatment of type 2 diabetes and obesity. Brit J Pharmacol. 54 55 1064 153:S76S81. 56 57 58 59 38 60 Page 39 of 55 Chemical Senses

1065 138. Pacher P, Kunos G. 2013. Modulating the endocannabinoid system in human health 1 1066 and disease Successes and failures. FEBS J. 280:19181943. 2 3 1067 139. PalouzierPaulignan B, Lacroix MC, Aime P, Baly C, Caillol M, Congar P, 4 1068 Julliard AK, Tucker K, Fadool DA. 2012. Olfaction Under Metabolic Influences. 5 6 1069 Chem Senses. 37:769–797. 7 8 1070 140. Parker MR, Feng D, Chamuris B, Margolskee RF. 2014. Expression and nuclear 9 1071 translocation of glucocorticoid receptors in type 2 taste receptor cells. Neurosci 10 1072 Lett. 571:72–77. 11 12 1073 141. Pastor A, FernándezAranda F, Fitó M, JiménezMurcia S, Botella C, Fernández 13 1074 Real JM, Frühbeck G, Tinahones FJ, Fagundo AB, Rodriguez J, et al. 2016. A 14 15 1075 Lower Olfactory Capacity Is Related to Higher Circulating Concentrations of 16 1076 Endocannabinoid 2Arachidonoylglycerol and Higher Body Mass Index in Women. 17 1077 PLoS One. 11:e0148734. 18 19 1078 142. Perello M, SakataFor I, Birnbaum Review S, Chuang JC, OsborneLawrenceOnly S, Rovinsky SA, 20 1079 Woloszyn J, Yanagisawa M, Lutter M, Zigman JM. 2010. Ghrelin Increases the 21 22 1080 Rewarding Value of HighFat Diet in an OrexinDependent Manner. Biol 23 1081 Psychiatry. 67:880886. 24 25 1082 143. Perkins JM, Davis SN. 2008. Endocannabinoid system overactivity and the 26 1083 metabolic syndrome: Prospects for treatment. Curr Diab Rep. 8:1219. 27 28 1084 144. Pertwee RG, Ross RA. 2002. Cannabinoid receptors and their ligands. 29 1085 Prostaglandins Leukot Essent Fat Acids. 66:10121. 30 31 1086 145. Pertwee RG. 2006. The pharmacology of cannabinoid receptors and their ligands: 32 1087 An overview. Int J Obes. 30:S13S18. 33 34 1088 146. PiSunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. 2006. Effect of 35 1089 rimonabant, a cannabinoid1 receptor blocker, on weight and cardiometabolic risk 36 37 1090 factors in overweight or obese patients: RIONorth America: a randomized 38 1091 controlled trial. JAMA. 295:761–775. 39 40 1092 147. Platte P, Herbert C, Pauli P, Breslin PAS. 2013. Oral Perceptions of Fat and Taste 41 1093 Stimuli Are Modulated by Affect and Mood Induction. PLoS One. 8(6):e65006. 42 43 1094 148. Porter AC. 2002. Characterization of a Novel Endocannabinoid, , with 44 1095 Antagonist Activity at the CB1 Receptor. J Pharmacol Exp Ther. 301:10201024. 45 46 1096 149. Radhakrishnan R, Wilkinson ST, D’Souza DC. 2014. Gone to Pot A Review of 47 48 1097 the Association between Cannabis and Psychosis. Front Psychiatry. 5:54. 49 1098 150. Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, 50 51 1099 Soubrié P. 2003. Antiobesity effect of SR141716, a CB1 receptor antagonist, in 52 1100 dietinduced obese mice. Am J Physiol Regul Integr Comp Physiol. 284:R345– 53 1101 R353. 54 55 1102 151. Richardson BE, Woude EA Vander, Sudan R, Thompson JS, Leopold DA. 2004. 56 1103 Altered olfactory acuity in the morbidly obese. Obes Surg. 14:967–969. 57 58 59 39 60 Chemical Senses Page 40 of 55

1104 152. Rodríguez De Fonseca F, Navarro M, Gómez R, Escuredo L, Nava F, Fu J, 1 1105 MurilloRodríguez E, Giuffrida A, Loverme J, Gaetani S, et al. 2001. An anorexic 2 3 1106 lipid mediator regulated by feeding. Nature. 414:209212. 4 1107 153. RomeroZerbo SY, GarciaGutierrez MS, Suárez J, Rivera P, RuzMaldonado I, 5 6 1108 Vida M, Rodriguez de Fonseca F, Manzanares J, BermúdezSilva FJ. 2012. 7 1109 Overexpression of Cannabinoid CB2 Receptor in the Brain Induces 8 1110 Hyperglycaemia and a Lean Phenotype in Adult Mice. J Neuroendocrinol. 24:1106 9 10 1111 1119. 11 1112 154. Russo EB. 2013. Cannabis and Cannabinoids: Pharmacology, Toxicology, 12 13 1113 Therapeutic Potential. p.478. 14 15 1114 155. Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring 16 1115 T, Nilsson K, Drmota T, Greasley PJ. 2007. The orphan receptor GPR55 is a novel 17 1116 cannabinoid receptor. Br J Pharmacol. 152:10921101. 18 19 1117 156. Salamone JD, CorreaFor M. Review2012. The mysterious Only motivational functions of 20 1118 mesolimbic dopamine. Neuron. 76:470–85. 21 22 1119 157. Salamone JD, Correa M. 2013. Dopamine and food addiction: lexicon badly 23 1120 needed. Biol Psychiatry. 73:e1524. 24 25 1121 158. Sartim AG, Moreira FA, Joca SRL. 2017. Involvement of CB1and TRPV1 26 27 1122 receptors located in the ventral medial prefrontal cortex in the modulation of stress 28 1123 coping behavior. Neuroscience. 340:126134. 29 30 1124 159. Sawai S, Saito K. 2011. Triterpenoid Biosynthesis and Engineering in Plants. Front 31 1125 Plant Sci. 2:25. 32 33 1126 160. Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, George SR, 34 1127 O’Dowd BF. 1999. Identification and cloning of three novel human G protein 35 1128 coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively 36 37 1129 expressed in human brain. Brain Res Mol Brain Res. 64:1938. 38 39 1130 161. Seeley RJ, Berridge KC. 2015. The hunger Games. Cell. 160:805806. 40 1131 162. Shearman LP, Rosko KM, Fleischer R, Wang J, Xu S, Tong XS, Rocha BA. 2003. 41 42 1132 Antidepressantlike and anorectic effects of the cannabinoid CB1 receptor inverse 43 1133 agonist AM251 in mice. Behav Pharmacol. 14:573582. 44 45 1134 163. Silvestri C, Di Marzo V. 2013. The endocannabinoid system in energy homeostasis 46 1135 and the etiopathology of metabolic disorders. Cell Metab. 17:475–490. 47 48 1136 164. Simiand J, Keane M, Keane PE, Soubrie P. 1998. SR 141716, a CB1 cannabinoid 49 1137 receptor antagonist, selectively reduces sweet food intake in marmoset. Behav 50 51 1138 Pharmacol. 9:17981. 52 1139 165. Simon V, Cota D. 2017. Mechanisms in endocrinology: Endocannabinoids and 53 54 1140 metabolism: Past, present and future. Eur J Endocrinol. 176:R309R324. 55 56 57 58 59 40 60 Page 41 of 55 Chemical Senses

1141 166. Sofia RD, Knobloch LC. 1976. Comparative effects of various naturally occurring 1 1142 cannabinoids on food, sucrose and water consumption by rats. Pharmacol Biochem 2 3 1143 Behav. 4:591599. 4 1144 167. Solinas M, Goldberg SR. 2005. Motivational effects of cannabinoids and opioids 5 6 1145 on food reinforcement depend on simultaneous activation of cannabinoid and opioid 7 1146 systems. Neuropsychopharmacology. 30:20352045. 8 9 1147 168. SoriaGómez E, Bellocchio L, Marsicano G. 2014a. New insights on food intake 10 1148 control by olfactory processes: The emerging role of the endocannabinoid system. 11 1149 Mol Cell Endocrinol. 397:59–66. 12 13 1150 169. SoriaGómez E, Bellocchio L, Reguero L, Lepousez G, Martin C, Bendahmane M, 14 15 1151 Ruehle S, Remmers F, Desprez T, Matias I, et al. 2014b. The endocannabinoid 16 1152 system controls food intake via olfactory processes. Nat Neurosci. 17:407–15. 17 18 1153 170. SoriaGómez E, Massa F, Bellocchio L, RuedaOrozco PE, Ciofi P, Cota D, Oliet 19 1154 SHR, ProspéroGarcíaFor O, ReviewMarsicano G. 2014c. Only Cannabinoid type1 receptors in the 20 1155 paraventricular nucleus of the hypothalamus inhibit stimulated food intake. 21 22 1156 Neuroscience. 263:46–53. 23 1157 171. Stella N, Schweitzer P, Piomelli D. 1997. A second endogenous cannabinoid that 24 25 1158 modulates longterm potentiation. Nature. 388:773778. 26 27 1159 172. Stella N. 2010. Cannabinoid and cannabinoidlike receptors in microglia, 28 1160 astrocytes, and astrocytomas. Glia. 58:10171030. 29 30 1161 173. Stevenson RJ. 2009. An initial evaluation of the functions of human olfaction. 31 1162 Chem Senses. 35:3–20. 32 33 1163 174. Stewart JE, FeinleBisset C, Golding M, Delahunty C, Clifton PM, Keast RSJ. 34 1164 2010. Oral sensitivity to fatty acids, food consumption and BMI in human subjects. 35 1165 Br J Nutr. 104:145–152. 36 37 1166 175. Støving RK, Andries A, Brixen K, Flyvbjerg A, Hørder K, Frystyk J. 2009. Leptin, 38 39 1167 ghrelin, and endocannabinoids: Potential therapeutic targets in anorexia nervosa. J 40 1168 Psychiatr Res. 43:671–679. 41 42 1169 176. Sugawara Y, Shigetho A, Yoneda M, Tuchiya T, Matumura T, Hirano M. 2013. 43 1170 Relationship between Mood Change, Odour and Its Physiological Effects in 44 1171 Humans While Inhaling the Fragrances of Essential Oils as well as Linalool and Its 45 46 1172 Enantiomers. Molecules. 18:3312–3338. 47 1173 177. Sugiura T, Waku K. 2000. 2Arachidonoylglycerol and the cannabinoid receptors. 48 49 1174 Chem Phys Lipids. 108:89106. 50 51 1175 178. Sun X, Veldhuizen MG, Babbs AE, Sinha R, Small DM. 2016. Perceptual and 52 1176 brain response to odors is associated with body mass index and postprandial total 53 1177 ghrelin reactivity to a meal. Chem Senses. 41:233–248. 54 55 1178 179. Taalman H, Wallace C, Milev R. 2017. Olfactory functioning and depression: A 56 1179 systematic review. Front Psychiatry. 8:1–11. 57 58 59 41 60 Chemical Senses Page 42 of 55

1180 180. Takahashi T, Itoh H, Nishikawa Y, Higuchi Y, Nakamura M, Sasabayashi D, 1 1181 Nishiyama S, Mizukami Y, Masaoka Y, Suzuki M. 2015. Possible relation between 2 3 1182 olfaction and anxiety in healthy subjects. Psychiatry Clin Neurosci. 69:431–438. 4 1183 181. Tarragon E, Moreno JJ. 2018. Role of Endocannabinoids on Sweet Taste 5 6 1184 Perception, Food Preference, and Obesityrelated Disorders. Chem Senses. 43:3–16. 7 8 1185 182. Tedesco L, Valerio A, Dossena M, Cardile A, Ragni M, Pagano C, Pagotto U, 9 1186 Carruba MO, Vettor R, Nisoli E. 2010. The Role of eNOS, p38 MAPK, and AMPK 10 1187 Pathways. Diabetes. 59:2826–2836. 11 12 1188 183. Tepper BJ, Banni S, Melis M, Crnjar R, Barbarossa IT. 2014. Genetic sensitivity to 13 1189 the bitter taste of 6npropylthiouracil (PROP) and its association with physiological 14 15 1190 mechanisms controlling Body Mass Index (BMI). Nutrients. 6:3363–3381. 16 1191 184. Thanos PK, Robison LS, Robinson JK, Michaelides M, Wang GJ, Volkow ND. 17 18 1192 2013. Obese rats with deficient leptin signaling exhibit heightened sensitivity to 19 1193 olfactory food cues.For Synapse. Review 67:171–178. Only 20 21 1194 185. Tomassini Barbarossa I, Carta G, Murru E, Melis M, Zonza A, Vacca C, Muroni P, 22 1195 Di Marzo V, Banni S. 2013. Taste sensitivity to 6npropylthiouracil is associated 23 1196 with endocannabinoid plasma levels in normalweight individuals. Nutrition. 24 25 1197 29:531–536. 26 27 1198 186. Touzani K, Bodnar RJ, Sclafani A. 2010. Neuropharmacology of learned flavor 28 1199 preferences. Pharmacol Biochem Behav. 97:55–62. 29 30 1200 187. Tsou K, Brown S, SanudoPena MC, Mackie K, Walker JM. 1998. 31 1201 Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central 32 1202 nervous system. Neuroscience. 83:393411. 33 34 1203 188. Tudge L, Williams C, Cowen PJ, McCabe C. 2015. Neural effects of cannabinoid 35 1204 CB1 neutral antagonist on food reward and aversion in 36 37 1205 healthy volunteers. Int J Neuropsychopharmacol. 18:1–9. 38 39 1206 189. Tudurí E, López M, Diéguez C, Nadal A, Nogueiras R. 2017. GPR55 and the 40 1207 regulation of glucose homeostasis. Int J Biochem Cell Biol. 88:204207. 41 42 1208 190. Umabiki M, Kotani K, Tsuzaki K, Higashi A, Sakane N. 2011. Letter To The 43 1209 Editor: Sweet taste and (AAT)12 repeat in the cannabinoid receptor gene in obese 44 1210 females. Endocr J. 58:323–324. 45 46 1211 191. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S. 2005. Effects of the 47 1212 cannabinoid1 receptor blocker rimonabant on weight reduction and cardiovascular 48 49 1213 risk factors in overweight patients: 1Year experience from the RIOEurope study. 50 1214 Lancet. 365:13891397. 51 52 1215 192. Vancleef L, Van Den Broeck T, Thijs T, Steensels S, Briand L, Tack J, Depoortere 53 1216 I. 2015. Chemosensory signalling pathways involved in sensing of amino acids by 54 55 1217 the ghrelin cell. Sci Rep. 5:1–14. 56 57 58 59 42 60 Page 43 of 55 Chemical Senses

1218 193. Varela L, Horvath TL. 2012. Leptin and insulin pathways in POMC and AgRP 1 1219 neurons that modulate energy balance and glucose homeostasis. EMBO Rep. 2 3 1220 13:10791086. 4 1221 194. Verty ANA, Boon WM, Mallet PE, McGregor IS, Oldfield BJ. 2009. Involvement 5 6 1222 of hypothalamic peptides in the anorectic action of the CB 1 receptor antagonist 7 1223 rimonabant (SR 141716). Eur J Neurosci. 29:22072216. 8 9 1224 195. Verty ANA, Evetts MJ, Crouch GJ, McGregor IS, Stefanidis A, Oldfield BJ. 2011. 10 1225 The cannabinoid receptor agonist THC attenuates weight loss in a rodent model of 11 1226 activitybased anorexia. Neuropsychopharmacology. 36:13491358. 12 13 1227 196. Verty ANA, Stefanidis A, McAinch AJ, Hryciw DH, Oldfield B. 2015. Anti 14 15 1228 obesity effect of the CB2 receptor agonist JWH015 in dietinduced obese mice. 16 1229 PLoS One. 10:1–19. 17 18 1230 197. Vettor R, Pagano C. 2009. The role of the endocannabinoid system in lipogenesis 19 1231 and fatty acid metabolism.For Review Best Pract Res Clin OnlyEndocrinol Metab. 23:51–63. 20 21 1232 198. Vickers SP, Webster LJ, Wyatt A, Dourish CT, Kennett GA. 2003. Preferential 22 1233 effects of the cannabinoid CB1receptor antagonist, SR 141716, on food intake and 23 1234 body weight gain of obese (fa/fa) compared to lean Zucker rats. 24 25 1235 Psychopharmacology (Berl). 167:10311. 26 27 1236 199. Wakeford AGP, Flax SM, Pomfrey RL, Riley AL. 2016. Adolescent delta9 28 1237 tetrahydrocannabinol (THC) exposure fails to affect THCinduced place and taste 29 1238 conditioning in adult male rats. Pharmacol Biochem Behav. 140:7581. 30 31 1239 200. Walter C, Oertel BG, Ludyga D, Ultsch A, Hummel T, Lötsch J. 2014. Effects of 32 1240 20 mg oral 9tetrahydrocannabinol on the olfactory function of healthy volunteers. 33 34 1241 Br J Clin Pharmacology. 78:961–969. 35 1242 201. Ward SJ, Dykstra LA. 2005. The role of CB1 receptors in sweet versus fat 36 37 1243 reinforcement: effect of CB1 receptor deletion, CB1 receptor antagonism 38 1244 (SR141716A) and CB1 receptor agonism (CP55940). Behav Pharmacol. 16:381–8. 39 40 1245 202. Whalley B, Williams CM, Stephens GJ, Futamura T. 2015. Use of the 41 1246 phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy. United States. 42 43 1247 203. WieruckaRybak M, Wolak M, Bojanowska E. 2014. The effects of leptin in 44 1248 combination with a cannabinoid receptor 1 antagonist, AM 251, or cannabidiol on 45 46 1249 food intake and body weight in rats fed a highfat or a freechoice high sugar diet. J 47 1250 Physiol Pharmacol. 65:487–96. 48 49 1251 204. Williams CM, Rogers PJ, Kirkham TC. 1998. Hyperphagia in prefed rats 50 1252 following oral delta9THC. Physiol Behav. 65:343346. 51 52 1253 205. Williams CM, Kirkham TC. 2002a. Observational analysis of feeding induced by 53 1254 Delta9THC and anandamide. Physiol Behav. 76:241250. 54 55 56 57 58 59 43 60 Chemical Senses Page 44 of 55

1255 206. Williams CM, Kirkham TC. 2002b. Reversal of 9THC hyperphagia by 1 1256 SR141716 and naloxone but not . Pharmacol Biochem Behav. 2 3 1257 71:341344. 4 1258 207. Yeomans MR. 2006. Olfactory influences on appetite and satiety in humans. 5 6 1259 Physiol Behav. 89:10–14. 7 8 1260 208. Yoshida R, Ohkuri T, Jyotaki M, Yasuo T, Horio N, Yasumatsu K, Sanematsu K, 9 1261 Shigemura N, Yamamoto T, Margolskee RF, et al. 2010. Endocannabinoids 10 1262 selectively enhance sweet taste. Proc Natl Acad Sci U S A. 107:935–9. 11 12 13 14 15 16 17 18 19 For Review Only 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 44 60 ↑(Kirkham 2005) 2005) ↑(Kirkham Effect on body weight weight body Effect on 2005) ↑(Kirkham Patrizio, and Di ↑(Jarbe 2005) 2009) al. et ↓(Riedel 2011) al. et ↓(Ignatowska 2000) al. et ↓(Giuliani 2010) al. et ↓(Hadcock

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Company Company Univ. Hebrew Pfizer Pzifer Original report report Original 1995 al., et Mechoulam 1992 al., et Devane 1970 al., et BenZvi 1970 al., Gill et Baker, and Adams 1940 1988 Mechoulam, al., 1988 et Little 2008 al., Kim et

THC THC THCV 9 9 Ligand Ligand 2AG AEA CBD HU210 CP 55,940 CP945,598 Table 1. Brief overview of the main CB receptor liga receptor main CB of the Brief overview Table 1.

1263 1263 Page 45 of 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 46 of 55 ↓(Riedel et al. 2009) 2009) al. et ↓(Riedel 2011) et al. ↓(Cluny 2010) et al., ↓(Tam 2007) et al. ↓(Fong 2007) et al. ↓(Horswill ↓(Riedel et al. 2009) 2009) al. et ↓(Riedel 2011) et al. ↓(Cluny 2011) et al. ↓(Cluny 2007) et al. ↓(Fong 2007) et (Horswill al. ↓ 2006) Mallet and ↓(Gardner 2005) and Patrizio, Di ↓(Jarbe JWH133 JWH018, ZCZ Org27,569, GAT100, 011 O2545 O2113, O2372, () SR147778 JWH203, UR12, UR144, MDA19, WIN55,225, Antag Antag Antag Ag 46 46 Chemical Senses Antag Antag Antag Antag Antag Ag Antag Ag Antag Antag Antag Negative allosteric allosteric Negative Drinabant Taranabant Rimonabant (Acomplia, Zimulti) For Review Only Sanofi Aventis Aventis Sanofi Aventis Sanofi Aventis Sanofi of University Connecticut Huffman John W Merck Commm Virginia Univ. Aventis Sanofi Aventis Sanofi Gatley et al., 1996 1996 et al., Gatley 1995 al., et Pertween 2007 al., Sink et al., et Makriyannis 2010 1994 et al., Huffman 2007 al., et Arstrong 2007 al., et Horswill 2002 al., et Martin 1994 al., et Rinaldi 1998 al., et Rinaldi AM251 AM251 AM630 AM4113 AM6545 JWH015 MK0364 PSNCBAM1 O2050 SR141716A SR144528

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47 47 Chemical Senses Antag Antag Ag Antag

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1264 1264 Page 47 of 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 48 of 55 48 48 Chemical Senses of the ECS on chemosensory perception chemosensory ECS the on of Effect on chemosensory perception perception chemosensory Effect on pellets. food standard to intake compared food sweet reduced Selectively protocol. learning ratio a progressive following solutions fatty and sweetened for acquisition response Facilitates protocol. learning ratio a progressive following solutions fatty and sweetened for response enhanced Impairs responses. odor food anddelay Diminish food. of properties gustatory the with associated nucleus response, parabrachial pontine Impaired intake. fat and sucrose, sucrose, and fat of increase Strong odorants. of presence in the prolonged were neurons response olfactory individual andof amplitude The delay threshold. sensitivity the olfactory and lowered sensitivity olfactory Restored compounds. umami bitter, and sour, salty, to not but sweeteners to response gustatory Increases sweeteners. to response gustatory Diminishes sweeteners. to response gustatory affect not Does patients. in chemotherapy response and gustatory perception chemosensory and enhanced improved Improved

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For Review Only antag ag antag antag antag CB and ag CB and antag antag ag 1 1 1 1 1 1 1 1 1 2 1 Effect on ECS Effect on ECS CB CB CB CB CB CB blockers DAG lipase CB CB CB CB CB Ligand Ligand SR141716A CP55940 SR141716A and AM251, AM281, LY320135 AM251 2AG OMDM RHC80267, and OMDM188 187, HU210 2AG AEA, AM251 AM630 THC Reference Reference 1998 al., et Simiand and Dykstra, Ward 2005 2007 al., et Czesnik and Di Patrizio 2008 Simansky, 2010 al., et Breuning 2010 al., et Yoshida 2011 al., et Brisbois Table 2. Summary of studies exploring the influence the influence exploring of studies Summary Table 2.

1265 1265 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

receptor. receptor. 1 49 49 Chemical Senses Higher sweet sensitivity threshold in non carriers of the (AAT)12 repeat gene, coding for theCB for coding gene, repeat the (AAT)12 of carriers non in threshold sensitivity sweet Higher bulb. olfactory the main of glomeruli in the patterns firing neuron regulates agonism/antagonism Cannabinoid rats. nontreated in observed acids, fatty dienoic and in monoenoic rich solutions for preference Diminishes with to individuals compared and2AG plasmatic AEA of levels greater showed to 6npropylthiouracil individuals sensitive Highly sensitivity. lower AEA. of levels elevated with mice in fasted intake bulb reduced olfactory the main of layer the granular into Administration intake. food fastinginduced bulb enhanced olfactory the main of layer the granular into Administration Genetically mice. obese dietinduce obese or genetically not but mice, lean in impaired solution sweetened for response Enhanced AM251. of the administration after cells intaste and DAGL 2AG levels of increased showed mice obese women in obese percentage fat body higher and 2AG lower with associated was capacity Thresholddiscriminationidentification women. nonobese to compared drink. the preferred of consumption ad libitum or liking, threshold, sensitivity sweetness affected CBD nor THC neither inhaled, When neither. affected not was preference Food

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For Review Only receptor gene receptor ag antag antag CB and antag CB and antag CB and CB and 1 1 1 1 1 1 1 1 1 1 CB CB CB CB CB CB CB CB CB CB (AAT)12 repeat repeat (AAT)12 WIN55,2122 AEA, AM251 URB447 AM6546, 2AG AEA, AM251 THC AM251 2AG AEA, CBD THC, Umabiki et al., 2011 2011 al., et Umabiki 2012 et al., Wang 2013 al., et DiPatrizio 2013 al., et Barbarossa al., et SoriaGomez 2014 2016 al., et Pastor 2017 al., et Brujin de Niki et al., 2015 2015 al., Niki et

Page 49 of 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Chemical Senses Page 50 of 55

1 2 3 1266 Figure 1. Synthesis of synthetic, phyto, and endocannabinoids. Schematic 4 5 1267 representation of the synthesis process from which synthetic cannabinoids, 6 7 1268 phytocannabinoids and endocannabinoids are obtained. 8 9 10 11 12 13 14 15 16 17 18 19 For Review Only 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 50 60 Page 51 of 55 Chemical Senses

1 2 3 1269 Figure 2. Synthetic, phyto, and endocannabinoids. Here there are some of the most 4 5 1270 popular among the hundreds of cannabinoid molecules discovered since the 1970s. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 For Review Only 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 51 60 Chemical Senses Page 52 of 55

1 2 3 1271 Figure 3. Chemosensory response and the ECS. The molecular reaction initiated by the 4 5 1272 perception of aromas is entangled with the ECS functioning. As well as by endogenous 6 7 1273 and exogenous cannabinoids, CB receptors are activated by the chemosensory response 8 9 1274 in the olfactory bulb and along the brain circuitry involved in the emotional and 10 11 1275 cognitive effect triggered by taste and smell. This activity is afterwards involved in 12 13 14 1276 several physiological and psychological aspects of eating behavior, such as developing 15 16 1277 preferences for certain tastes and foods, and even modulating food intake. 17 18 19 For Review Only 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 52 60 Page 53 of 55 Chemical Senses

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 For Review Only 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 Synthesis of synthetic, phyto-, and endocannabinoids. Schematic representation of the synthesis process 38 from which synthetic cannabinoids, phytocannabinoids and endocannabinoids are obtained. 39 116x108mm (150 x 150 DPI) 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Chemical Senses Page 54 of 55

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 For Review Only 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 Synthetic, phyto-, and endocannabinoids. Here there are some of the most popular among the hundreds of 39 cannabinoid molecules discovered since the 1970s. 40 41 153x149mm (150 x 150 DPI) 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 55 of 55 Chemical Senses

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 For Review Only 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Chemosensory response and the ECS. The molecular reaction initiated by the perception of aromas is 46 entangled with the ECS functioning. As well as by endogenous and exogenous cannabinoids, CB receptors 47 are activated by the chemosensory response in the olfactory bulb and along the brain circuitry involved in 48 the emotional and cognitive effect triggered by taste and smell. This activity is afterwards involved in 49 several physiological and psychological aspects of eating behavior, such as developing preferences for 50 certain tastes and foods, and even modulating food intake.

51 224x286mm (150 x 150 DPI) 52 53 54 55 56 57 58 59 60