Page 1

Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 156e162


Rimonabant: A cannabinoid receptor blocker for the treatment of metabolic and cardiovascular risk factors Serena Tonstad* Department of Preventive Cardiology, Ulleva˚l University Hospital, N-0407 Oslo, Norway Received 20 April 2005; accepted 26 October 2005

KEYWORDS Rimonabant; Endocannabinoid system; Cardiovascular; Obesity; Smoking cessation; Cardiometabolic

Abstract Aims: The endocannabinoid system modulates synaptic neurotransmission centrally and peripherally and is involved in the brain pathways concerned with addiction, central regulation of body weight and adipose tissue function. The system is overactivated in animal models of obesity and nicotine use. This review discusses the role of rimonabant, a cannabinoid receptor 1 blocker, which has undergone Phase III clinical testing, in the treatment of obesity and tobacco dependence. Data synthesis: Results of Phase III clinical trials have shown that rimonabant has promising efficacy in the treatment of obesity, dyslipidaemia and diabetes associated with obesity, in preventing weight gain following smoking cessation, and possibly in smoking cessation. No critical problems with the tolerance and safety of the compound have appeared in studies to date. Conclusion: Rimonabant may prove to be a useful aid in the treatment of the most widespread cardiometabolic risk factors. ª 2005 Elsevier B.V. All rights reserved.

Introduction The discovery of the first cannabinoid receptor [1] and one of its endogenous ligands in the early 1990s [2] has provided the molecular basis for understanding a novel neuromodulatory system. This system has been named the endogenous cannabinoid system, or the endocannabinoid system, and * Tel.: þ47 22 11 79 39; fax: þ47 22 11 99 75. E-mail address:

is a physiological system that regulates synaptic neurotransmission [3,4]. Its ligands have been named endocannabinoids [4]. The two most widely studied endocannabinoids are anandamide and 2-arachidonoylglycerol, both of which are lipid compounds synthesised from arachidonic acid. In the nervous system endocannabinoids are produced postsynaptically but act on the presynaptic release of neurotransmitters, usually causing inhibition of their release [4]. Endocannabinoids are only produced on demand and are rapidly taken

0939-4753/$ - see front matter ª 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2005.10.011

The endocannabinoid system and cardiovascular risk factors up by neurons and inactivated by hydrolytic enzymes [4]. A comprehensive review of the system has recently been published [5]. The picture that emerges from research carried out during the past decade and a half is that the endocannabinoid system responds to stressful stimuli. Activation of the endocannabinoid system re-establishes the steady-state condition of other neurotransmitters, mediators and hormones, and, as a result, promotes food ingestion, relaxation, pain reduction and the extinction of aversive memories [4,6,7]. Notably, the endocannabinoid system is present in all brain and peripheral sites (adipose tissue, liver, and muscle) involved in the control of energy balance and body weight [8]. Tonic endocannabinoid activity seems to be a key component in the neurochemical regulation of appetite and in modulating food intake [8]. In addition, the system is active in the limbic areas of the brain that are involved in reward pathways [9]. Blocking the endocannabinoid system may, therefore, be a potentially useful treatment for obesity, substance addiction and other cardiovascular risk factors.

Pharmacology In 1994 the first cannabinoid receptor antagonist (also defined as an inverse agonist), SR141716, was characterised [10]. This substance (Fig. 1), later named rimonabant, was developed by Sanofi-Synthelabo (now sanofi-aventis). Rimonabant binds selectively to the first of the two subtypes of the cannabinoid receptor cloned to date, cannabinoid receptor 1 (CB1). Both CB1 and cannabinoid receptor 2 (CB2) belong to the family of G-proteincoupled receptors [11]. Rimonabant has a 1000-fold higher affinity for the CB1 receptor than for the



Cl Figure 1

The structure of rimonabant.


CB2 receptor [11]. CB1 is the more widespread of the two receptors in mammalian tissue. CB1 is highly concentrated on presynaptic nerve terminals in the central nervous system [12], but is also present in many other peripheral organs, including nerve terminals innervating the gastrointestinal tract [13]. CB2 is primarily associated with cells of the immune system [12]. The putative effect of blockade of centrally and peripherally located CB1 receptors may result in decreased motivation to eat palatable food (nucleus accumbens), anorexigenic effect (hypothalamus), stimulation of satiating signals engaging CB1 in sensory terminals (gastrointestinal tract), increased adiponectin production, inhibition of lipogenesis (adipose tissue and liver), and increased glucose uptake (muscles) [14]. Animal studies have shown that rimonabant reduced food intake and body weight in treated animals, as well as altering adipose tissue metabolic activity [15], whilst inducing the expression of the adiponectin gene [16]. Recently, interesting new evidence with respect to the mode of action of rimonabant demonstrating a direct weight loss independent effect on adiponectin levels was shown for the first time in a Phase III study (Rimonabant in Obesity (RIO)-Lipids) in overweight/obese dyslipidaemic patients [17]. Changes in adiponectin observed in the RIO-Lipids trial were correlated with changes in HDL-cholesterol and apolipoprotein AI [17]. Maximum plasma concentrations of rimonabant are reached 1e3 h after its administration. Systemic exposure generally increases with increasing doses, although the increment is less than doseproportional. The plasma terminal half-life of rimonabant ranges from 6 to 10 days in young adult subjects, but is longer in elderly or obese subjects, averaging up to 15 days in these individuals. Rimonabant is rapidly absorbed upon oral administration, with median Tmax (first time to reach maximum plasma concentration observed; Cmax) values in the range of 1e3.75 h that were generally independent of dose and dosing day. Exposure, as assessed by Cmax, AUC0-24 (area under plasma concentration curve from time zero to 24 h) and/or AUC (area under plasma concentration curve extrapolated to infinity) increased with dose after single doses of 1 mg to 300 mg and repeated once-daily doses of 3 mg to 60 mg in healthy patients. Rimonabant was well tolerated in up to 300 mg single doses, and up to 60 mg given for 28 days. The primary pathway of metabolism is de-esterification. Oxidative metabolism is primarily mediated by CYP3A4 (data on file at SanofiAventis).

158 Rimonabant demonstrated no clinically significant interaction with other drugs when studied with commonly prescribed therapies including anti-hypertensive drugs, agents for dyslipidaemia (statins), anti-diabetic drugs (biguanides, sulfonylurea), oral contraceptives and other therapies including warfarin and digoxin when studied in healthy subjects [18e21].

Pre-clinical studies in obesity Studies conducted on the effects of the primary active component of marijuana, D9-tetrahydrocannabinol, and on synthetic cannabinoid agonists and endogenous ligands have shown that these substances increase food intake and the body weight of experimental animals [8]. Genetically obese rodents have elevated hypothalamic levels of endocannabinoids, suggesting that their endocannabinoid system is over-stimulated [22]. Furthermore, animal models show that activation of cannabinoid receptors modulates the release or expression of a number of hypothalamic orexigenic mediators of appetite [8] and specifically potentiates the orexin 1 receptor [23]. In turn, hypothalamic endocannabinoid levels are depressed by leptin [22]. In addition to central actions, the endocannabinoid system modulates body weight through receptors in the gastrointestinal tract [24] and in adipocytes [8], the liver [25] and muscle [26]. CB1 receptors in adipocytes are upregulated in obese mice [24], and their activation stimulates lipoprotein lipase activity and fat accumulation [8]. Activation of CB1 receptors in the liver plays a key role in increased serum lipid production, fatty liver and diet-induced obesity [25].  CB 1 /CB1 knockout mice demonstrate the effects of central and peripheral endocannabinoid blockade. These mice are lean compared to their agematched, wild-type littermates, have a reduced hyperphagic response to fasting, are resistant to diet-induced obesity and have enhanced insulin and leptin sensitivity [8,22,27]. Their metabolic and hormonal profiles remain unchanged and they do not develop fatty liver, even when their caloric intake is similar to that of wild-type mice on a high-fat diet [28]. Thus, the endocannabinoid system is one of the few orexigenic components of body weight regulation that when ablated causes animals to be lean [8]. Early studies showed that rimonabant reduced motivation for highly palatable foods, for example sucrose and alcohol in animals [29]. Subsequently, animal models that are more similar to human obesity have been studied. In mice with diet-induced

S. Tonstad obesity, blockade of CB1 receptors with rimonabant induces a transient central anorectic effect, followed by a significant and sustained reduction in body weight [30]. The reduction in body weight cannot be attributed to a decrease in energy intake [30] and may be partly due to the peripheral effects of rimonabant. Rimonabant increases adiponectin expression in adipocytes and inhibits the activity of enzymes involved in fat accumulation, thus inducing a number of favourable metabolic changes [16]. In a recent study of both white (WAT) and brown (BAT) adipose tissues from a diet-induced obesity mouse model, it was shown that rimonabant reversed the phenotype of obese adipocytes [15]. A functional analysis of these modulations indicated that the reduction of adipose mass by rimonabant resulted from an enhanced lipolysis through the induction of enzymes of the beta-oxidation and tricarboxylic (citric) acid cycle, as well as increased energy expenditure, mainly through the futile cycling of calcium and substrate, and regulation of glucose homeostasis [15]. In a genetically obese female Lep(ob)/Lep(ob) mouse model of energy expenditure and glucose uptake, it was seen that there was an increase in basal oxygen consumption and a significant increase in glucose uptake in isolated soleus muscle preparations [26]. The authors concluded that the direct effect of rimonabant on energy expenditure suggests that its antiobesity effect is due to activation of thermogenesis in addition to the initial hypophagia. Glucose uptake by the soleus muscle may contribute to the improved glycaemia seen in previous studies with rimonabant [26].

Pre-clinical studies in nicotine addiction Dopaminergic transmission in the nucleus accumbens is a critical substrate to the process of acquiring and maintaining drug addiction, including nicotine addiction [31,32]. Like non-cannabinoid addictive drugs, D9-tetrahydrocannabinol and cannabinoid agonists act on the neurons of the mesolimbic system that participate in reinforcing reward and in translating motivation into action [33]. This involvement in brain reward systems modulates the action of drugs of abuse other than cannabinoids, including nicotine [34]  and opiates [35,36]. CB 1 /CB1 knockout mice have no opioid-induced dopamine release in the nucleus accumbens shell and demonstrate reduced susceptibility to the addictive effects of opiates, indicating that their reward pathways are impaired [35,36].

The endocannabinoid system and cardiovascular risk factors Similar to over-stimulation of the endocannabinoid system in obese animals, the endocannabinoid system seems to be overactivated following the chronic use of nicotine [37]. Nicotine enhances anandamide levels in the nucleus accumbens [37]. Blocking the system with a cannabinoid receptor antagonist could potentially inhibit nicotine’s stimulation of limbic dopaminergic transmission and the reward associated with its use. This is supported by findings in rats trained for 2 weeks to self-administer nicotine, where rimonabant decreased nicotine-seeking behaviour and did not substitute for nicotine in a nicotine discrimination procedure [33]. A putative mechanism for this action was also described, as the drug blocked nicotine-induced dopamine release in the shell of the nucleus accumbens in these rodents [33]. A recent study showed that rimonabant reduced the response to nicotine in rats that is maintained by nicotine-conditioned cues, even after several months of nicotine abstinence [38]. The authors suggested that the compound may be effective in the maintenance of abstinence from nicotine.

Obesity treatment In a short-term trial, treatment with 20 mg/day of rimonabant for 7 days decreased hunger, and energy and fat intake [39]. In a randomised, controlled 16-week Phase IIb study, the effect of rimonabant on body weight and waist circumference was tested in 287 subjects whose BMI values were between 29 and 41 kg/m2 and who followed a mildly hypocaloric diet [40]. Rimonabant in doses of 5, 10 or 20 mg/day lowered body weight and waist circumference measurements compared with placebo [40]. Notably, the decreases in body weight and waist circumference were maintained at a follow-up visit 4 weeks after the end of treatment. Phase III clinical trials of rimonabant were initiated in August 2001. In the RIO-North America trial, 3043 patients with a BMI 30 kg/m2 or a BMI 27 kg/m2 with treated or untreated hypertension and/or treated or untreated dyslipidaemia were enrolled. The study compared weight loss and maintenance with rimonabant (5 or 20 mg/day) or placebo during year 1 and the prevention of weight regain during year 2 following re-randomisation. Another placebo-controlled study is a 2-year European and US trial (RIO-Europe) that has enrolled 1507 patients with the same inclusion criteria as the North American trial. This study aimed to assess weight loss and maintenance after


1 and 2 years with the same dosages of rimonabant as the previous trial, but without re-randomisation. Recently the 1-year results were published [41]. In the intent-to-treat (ITT) last observation carried forward (LOCF) population, patients treated with 20 mg/day of rimonabant experienced significant changes in body weight with a mean reduction of 6.6 kg (SD 7.2 kg) versus a reduction of 1.8 (SD 6.4 kg) in the placebo group (p < 0.001), while the effects of the 5 mg dose were of lesser clinical significance. Patients also experienced significant changes in waist circumference with a mean reduction of 6.5 cm (SD 7.4) versus a reduction of 2.4 cm (SD 6.9) for placebo (p < 0.001). Improvements in HDL cholesterol (p < 0.001), triglycerides (p < 0.001), insulin resistance (p Âź 0.002) and the prevalence of metabolic syndrome (p < 0.001) were also greater in the rimonabant 20 mg group than placebo. A complementary trial, RIO-Diabetes [42], has assessed the 1-year effect of rimonabant or placebo on weight loss and maintenance in 1047 patients with overweight or obesity and type 2 diabetes treated with biguanides or sulfonylureas. All these trials include assessment of metabolic syndrome and its individual components in addition to weight loss as endpoints.

Treatment of obesity associated with dyslipidaemia In a multicentre, placebo-controlled trial (RIOLipids), two doses of rimonabant, 5 and 20 mg/ day, were compared with placebo in 1036 non-diabetic patients with a BMI between 27 and 40 kg/m2 and untreated dyslipidaemia [17]. Dyslipidaemia was defined as triglyceride concentrations of 1.7e7.9 mmol/l and/or a total/high density lipoprotein (HDL) cholesterol ratio >4.5 (women) or >5 (men). The percentage of patients who lost more than 10% of their body weight was 32.6% (p < 0.001 vs placebo), 10.6% and 7.2% in the rimonabant 20 mg/day, 5 mg/day and placebo groups, respectively. Rimonabant 20 mg/day significantly reduced waist circumference by 7.1 cm (SD 6.8) compared with 2.4 cm (SD 5.7) for placebo (p < 0.001). Treatment with rimonabant 20 mg/ day was significantly associated with reductions in triglyceride (p < 0.001) and C-reactive protein levels (p Âź 0.02) and an increase in HDL cholesterol (p < 0.001) compared with placebo. As in the RIO-Europe study, the prevalence of metabolic syndrome was decreased by approximately 50% in the rimonabant 20 mg group when compared to placebo [17].


Treatment of tobacco dependence Phase II clinical trials found that rimonabant prolonged abstinence from cigarette smoking [39]. Clinically troublesome diarrhoea and nausea were noted with the 40 mg/day dose of rimonabant. These effects were expected based on previous data showing that colon motility and emesis are regulated tonically by the endocannabinoid system in animals [5]. Subsequently the doses of 5 mg/day and 20 mg/day of rimonabant were chosen for further investigation. In a randomised, controlled, Phase III clinical trial (STudies with Rimonabant And Tobacco Use (STRATUS-US)) conducted in centres across the US [43], 787 subjects smoking at least 10 cigarettes a day and wishing to quit were randomised to receive placebo, or rimonabant 5 mg/day or 20 mg/ day. There were equal numbers of men and women who smoked an average of 23 cigarettes/day. The study included a 2-week screening period, 10-week treatment period and 42-week follow-up. The subjectsâ&#x20AC;&#x2122; self-report of having quitted smoking was verified with measurements of carbon monoxide in expired air (10 ppm indicating cessation) and plasma cotinine concentrations (8 mg/L indicating cessation). Abstinence from smoking during the final 4 weeks of the treatment period was boosted from approximately 16% in the placebo and rimonabant 5 mg/day groups to approximately 28% in the rimonabant 20 mg/day group. A further study has enrolled 789 European smokers in a study with the same design as the STRATUS-US trial (STRATUS-Europe). Finally, 5055 smokers in Australia, Canada and the US (STRATUS-WORLDWIDE) have been included in a study first testing the effects of 5 mg/day or 20 mg/day of rimonabant compared with placebo for 10 weeks followed by re-randomisation to a further 42 weeks of active or placebo treatment with follow-up for another 50 weeks. This study will clarify the role of rimonabant in long-term maintenance of cessation and prevention of post-cessation weight gain. In addition to smoking cessation, the STRATUSUS study aimed to assess the effect of rimonabant in the prevention of post-cessation weight gain. Preliminary results have indicated that weight gain was minimized in subjects treated with rimonabant [43]. This effect has also been shown in Phase II studies [39].

Adverse effects No increase in mechanism-based adverse events or unexpected serious adverse events has been

S. Tonstad reported in studies to date [39,40,43]. In RIOEurope, the most frequent adverse events occurring more with rimonabant 5 and 20 mg than placebo were nausea (5.1%, 12.9%, and 4.3%, respectively), diarrhoea (6.0%, 7.2% and 3.0%, respectively), dizziness (7.0%, 8.7% and 4.9%, respectively) and mood disorders (2.3%, 3.7% and 3.0%, respectively). These findings were similar for the RIO-Lipids study. There were no deleterious changes in blood pressure or pulse observed during treatment with rimonabant. The adverse events reported were generally mild or moderate, transient and seen early in the treatment period [17,41].

Potential clinical applications The incidence of metabolic syndrome, characterised by a clustering of abdominal obesity, dyslipidaemia, hyperglycaemia and hypertension, is reaching epidemic proportions in many parts of the world. Evidence is accumulating that people with metabolic syndrome are at increased risk of cardiovascular disease relative to people without the syndrome [44], making its components appropriate targets for therapeutic interventions. Enormous progress has been made in treating dyslipidaemia and hypertension with statins and antihypertensive drugs. However, the treatment of obesity, which is the common denominator underlying the variable symptoms of metabolic syndrome remains a challenge for physicians. Preliminary results of clinical trials suggest that rimonabant aids weight loss and reduces metabolic syndrome manifestations, and may thus prove to be a useful support to lifestyle changes. The recently demonstrated weight loss independent effect of rimonabant may also be clinically important as a high adiponectin concentration has been reported to be predictive of a reduced risk of diabetes and cardiovascular events [17]. Tobacco use is still one of the major causes of cardiovascular disease, chronic obstructive pulmonary disease and cancer, despite widespread prevention and education efforts. Smoking cessation is difficult for many individuals because of nicotine dependence. Nicotine replacement therapy and bupropion are currently the two medical therapies that have an established role in aiding smoking cessation. A third approach, blocking the endocannabinoid system involved in brain pathways of addiction with rimonabant, has shown promise in initial studies. Because the endocannabinoid system also plays a pivotal role in body weight regulation, rimonabant may help prevent weight gain after smoking cessation. This effect could be

The endocannabinoid system and cardiovascular risk factors therapeutically useful in order to stop the risk of replacing tobacco dependence with overweight or obesity [45].

References [1] Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346(6284):561e4. [2] Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258(5090):1946e9. [3] Salzet M, Breton C, Bisogno T, Di Marzo V. Comparative biology of the endocannabinoid system possible role in the immune response. Eur J Biochem 2000;267(16):4917e27. [4] Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci 1998;21(12): 521e8. [5] Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004;3(9):771e84. [6] Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 2002; 418(6897):530e4. [7] Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990;87(5):1932e6. [8] Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003;112(3):423e31. [9] Kirkham TC, Williams CM. Endogenous cannabinoids and appetite. Nutr Res Rev 2001;14(1):65e86. [10] Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B, Congy C, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 1994;350(2e3):240e4. [11] Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997;74(2):129e80. doi:10.1016/ S0163-7258(97)82001-3. [12] Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002;54(2):161e202. [13] Massa F, Storr M, Lutz B. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. J Mol Med 2005 (e-pub ahead of print). [14] Pagotto U, Pasquali R. Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors. Lancet 2005;365(9468):1363e4. doi:10.1016/S0140-6736(05) 66348-9. [15] Jbilo O, Ravinet-Trillou C, Arnone M, Buisson I, Bribes E, Peleraux A, et al. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J 2005; 19(11):1567e9. [16] Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 2003;63(4):908e14.


[17] Despre ´s JP, Golay A, Sjo ¨stro ¨m L, for the RIO-Lipids study group. Effect of rimonabant on body weight and the metabolic syndrome in overweight patients. N Engl J Med 2005; 353:2121e34. [18] Kanamaluru V, Lockwood G, Bonnet D, Newton J. Lack of effect of rimonabant on the pharmacokinetics of digoxin. J Clin Pharmacol 2005;49(9):1081. [19] Kanamaluru V, Lockwood G, Bonnet D, Newton J. Lack of effect of rimonabant on the pharmacokinetics of oral contraceptives. J Clin Pharmacol 2005;45(9):1081. [20] Grandison M, Kanamaluru V, Lockwood G, Bonnet D, Newton J. Lack of rimonabant on the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 2005;45(9):1082. [21] Grandison M, Kanamaluru V, Lockwood G, Bonnet D, Newton J. Lack of effect of rimonabant on the pharmacokinetics of midazolam. J Clin Pharmacol 2005;45(9): 1082. [22] Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001;410(6830):822e5. [23] Hilairet S, Bouaboula M, Carriere D, Le Fur G, Casellas P. Hypersensitization of the Orexin 1 receptor by the CB1 receptor: evidence for cross-talk blocked by the specific CB1 antagonist, SR141716. J Biol Chem 2003;278(26):23731e7. [24] Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I, et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 2002;22(21):9612e7. [25] Lichtman AH, Cravatt BF. Food for thought: endocannabinoid modulation of lipogenesis. J Clin Invest 2005;115(5): 1130e3. [26] Liu Y, Connoley I, Wilson C, Stock M. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lepob/ Lepob mice. Int J Obes Relat Metab Disord 2005;29(2): 183e7. [27] Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord 2004;28(4):640e8. [28] Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005;115(5):1298e305. [29] Harrold JA, Williams G. The cannabinoid system: a role in both the homeostatic and hedonic control of eating? Br J Nutr 2003;90(4):729e34. [30] Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 2003;284(2):R345e53. [31] Corrigall WA, Franklin KB, Coen KM, Clarke PB. The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 1992; 107(2e3):285e9. [32] Pontieri FE, Tanda G, Orzi F, Di Chiara G. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 1996;382(6588):255e7. [33] Cohen C, Perrault G, Voltz C, Steinberg R, Soubrie P. SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav Pharmacol 2002;13(5e6):451e63. [34] Mascia MS, Obinu MC, Ledent C, Parmentier M, Bohme GA, Imperato A, et al. Lack of morphine-induced dopamine






[39] [40]

S. Tonstad release in the nucleus accumbens of cannabinoid CB(1) receptor knockout mice. Eur J Pharmacol 1999;383(3): R1e2. doi:10.1016/S0014-2999(99)00656-1. Castane A, Valjent E, Ledent C, Parmentier M, Maldonado R, Valverde O. Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 2002;43(5):857e67. doi:10.1016/S0028-3908(02)00118-1. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 1999;283(5400):401e4. Gonzalez S, Cascio MG, Fernandez-Ruiz J, Fezza F, Di Marzo V, Ramos JA. Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine. Brain Res 2002;954(1):73e81. doi: 10.1016/ S0006-8993(02)03344-9). Cohen C, Perrault G, Griebel G, Soubrie P. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology 2005;30(1):145e55. Fernandez JR, Allison DB. Rimonabant Sanofi-Synthelabo. Curr Opin Investig Drugs 2004;5(4):430e5. Pi-Sunyer F.X., Marbury T.C., Garland W.T., et al., The selective CB1-receptor antagonist rimonabant reduces body weight and waist circumference in obese subjects. In:






86th Annual Meeting of the Endocrine Society 2004. New Orleans, USA; 2004. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Ro ¨ssner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIOEurope study. Lancet 2005;365(9468):1389e97. doi: 10.1016/S0140-6736(05)66374-X. Scheen A. Rimonabant in patients with type 2 diabetes: results from the RIO-Diabetes Trial. In: In: 65th Scientific Sessions of the American Diabetes Association. San Diego, CA, USA.: American Diabetes Congress (ADA); June 2005. p. 10e4. Anthenelli R, Dale L. Rimonabant helps cigarette smokers stop smoking and prevents post cessation weight gain: results from the STRATUS-US trial. In: Final Program and Abstracts of 6th Annual Conference of the SRNT Europe; Tu ¨bingen, Germany; 2004. p. 35. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middleaged men. JAMA 2002;288(21):2709e16. Koh-Banerjee P, Chu NF, Spiegelman D, Rosner B, Colditz G, Willett W, et al. Prospective study of the association of changes in dietary intake, physical activity, alcohol consumption, and smoking with 9-y gain in waist circumference among 16 587 US men. Am J Clin Nutr 2003;78(4):719e27.


KEYWORDS The discovery of the first cannabinoid receptor [1] and one of its endogenous ligands in the early 1990s [2] has provided the molecu...