Cannabinoids
The stimulatory effect of Marijuana (Cannabis) on appetite and food intake has been known for long Behav Biol. 1975 Nov;15(3):255-81 with voracious appetite being observed in Cannabis users, described as the "munchies". Tetrahydrocannabinol , the active component of marijuana was identified as early as 1964. J Am Chem Soc 1964; 86: 1646. An endogenous Cannabinoid system consisting of endocannabinoids and cannabinoid receptors has now been described. Endocannabinoids have similarity with Tetrahydrocannabinol and are produced post synaptically with actions on the presynaptic release of neurotransmitters.Trends Neurosci. 1998 Dec;21(12):521-8. An evolutionary conservation of the cannabinoid system with a high degree of homology for CB1 receptors across species, even the primitive coelenterate hydra, has been demonstrated suggesting a physiological role for this system. Neuroscience. 1999;92(1):377-87.
Cannabinoid Receptors and Endocannabinoids
Cannabinoids and endocannabinoids act via G protein coupled receptors. CB1 Nature. 1990 Aug 9;346(6284):561-4. and CB2 Nature. 1993 Sep 2;365(6441):61-5 which belong to the G protein- coupled receptor superfamily were identified as cannabinoid receptors with later discovery of their endogenous ligands which were called endocannabinoids. Science. 1992 Dec 18;258(5090):1946-9. CB1 receptors are predominantly expressed in the brain, gastrointestinal organs and adipose tissue, while CB-2 receptors are expressed on peripheral immune cells. Pharmacol Rev. 2002 Jun;54(2):161-202 Thus a central and peripheral endocannabinoid system exists. Anandamide (arachidonoyl ethanolamide) was the first endogenous cannabinoid to be identified in 1992 from porcine brain. Science. 1992 Dec 18;258(5090):1946-9. The name anandamide was inspired by the Sanskrit word "ananda", meaning internal bliss. Anandamide is present at highest concentrations in the hippocampus, cortex, thalamus, and cerebellum. FEBS Lett. 1996 Sep 16;393(2-3):231-5 Anandamide binds to both CB1 and CB2 receptors with higher affinity for CB1 receptors. Mol Pharmacol. 1995 Sep;48(3):443-50. Other PUFA (polyunsaturated fatty acid) derivatives that act as functional agonists at cannabinoid receptors were identified as endogenous Cannabinoids including Noladin ether ( 2-arachidonyl glyceryl ether) Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3662-5 , virodhamine J Pharmacol Exp Ther. 2002 Jun;301(3):1020-4 and and 2-arachidonoylglycerol (2-AG), Nature.1997 Aug 21;388(6644):773-8. the latter being the most abundant endocannabinoid in the brain with a concentration 170 times higher than anandamide. 2-AG has selectivity for CB2, with minimal affinity for CB1. Anandamide has been reported to be present in intestinal tissues as well J Neurosci. 2002 Nov 1;22(21):9612-7 with increased levels after 24 hours of fasting. A role for anandamide in peripheral signalling in the appetite pathway remains to be clarified.
The effects of endocannabinoids are mediated via cannabinoid receptor type 1 (CB-1) which is the predominant receptor type in the central nervous system. CB1 is expressed in key hypothalamic peptidergic systems of appetite regulation including the CRH- (corticotrophin releasing hormone)- system in the paraventricular nucleus, CART in the arcuate nucleus and MCH and Orexin system in the lateral hypothalamus-perifornical region. Neurobiol Dis. 1998 Dec;5(6 Pt B):417-31. Cannabinoids may thus influence hypothalamic neurotransmitters through these systems resulting in induction of a state of positive energy balance. In the CNS, CB1 is predominantly expressed presynaptically, modulating the release of neurotransmitters as GABA, dopamine, noradrenaline, glutamate and serotonin.Trends Pharmacol Sci. 2001 Nov;22(11):565-72. CB1 knock gene deficient mice are lean and resistant to diet-induced obesity. CB2 is mainly expressed in immune cells and hence mediating peripheral actions, although CB2 has been localised in brain-derived immune cells as well. Pharmacol Ther. 2001 Apr;90(1):45-60.
Endocannabinoids act on the lateral hypothalamus, the arcuate and the paraventricular nuclei to promote positive energy balance. The Hypothalamus has high levels of endocannabinoids and CB1 receptors. Diet restriction decreases the hypothalamic and hippocampal levels of dopamine, nor-adrenaline and 5 hydroxytryptamine. Anandamide restores the decrease in dopamine and 5-HT, with no effect on the nor adrenaline decrease. Eur J Pharmacol. 2000 Mar 31;392(3):147-56. The effect of Cannabinoids on Nucleus Accumbens has been discussed above under the opioid system.
Endocannabinoid release and metabolism
Unlike other neurotransmitters, endocannabinoids are not stored in synaptic vesicles, but instead are stored in phospholipid molecules within the cellular membrane. Nature. 1994 Dec 15;372(6507):686-91. Endocannabinoids are released from neurons following membrane depolarisation and calcium influx into cells. Acute food deprivation results in significant increases in brain anandamide and 2-AG levels especially in the limbic forebrain. Br J Pharmacol. 2002 Jun;136(4):550-7; with changes in2-AG levels probably being dependent on the severity and chronicity of dietary deprivation. Brain Res. 2003 Sep 5;983(1-2):144-51. Chronic food deprivation in mice resulted in a paradoxical reduction in hippocampal and hypothalamic 2-AG levels. "Normal" eating to satiety results in a physiological decrease in 2-AG levels in the hypothalamus as opposed to the severe reduction/suppression of 2-AG levels in rodents that over-fed on highly palatable feeds. Br J Pharmacol. 2002 Jun;136(4):550-7; The pre feeding rise followed by reduction in levels with feeds of endocannabinoids may be interpreted as suggesting a role for endocannabinoids in meal initiation but not in maintenance of feeding. Over-consumption with accelerated weight gain in rats using a palatable food supplement resulted in a 50% reduction in CB1 receptor density in the nucleus accumbens and other appetite regulating areas. Brain Res. 2002 Oct 18;952(2):232-8 The regulators of this meal related alteration of endocannabinoid levels and cannabinoid receptors remains to be elucidated. Obese Zucker rats have elevated hypothalamic levels of 2-AG. Nature. 2001 Apr 12;410(6830):822-5. Endocannabinoids are inactivated by a reuptake mechanism followed by hydrolysis by the fatty acid amide hydrolase (FAAH) enzyme in neurons. Trends Neurosci. 1998 Dec;21(12):521-8. Monoglyceride lipase may mediate inactivation of 2-AG by hydrolysis in neurons. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10819-24
Cannabinoids and Appetite
The appetite stimulating effects of Cannabinoids has been known for a long time. Behav Biol. 1975 Nov;15(3):255-81 Cannabinoids have been recognised as appetite stimulating drugs even in the absence of feelings of hunger Nature. 1970 May 23;226(5247):701-4 with a preference for sweet foods Appetite. 1988 Aug;11(1):1-14 while the route of drug administration ( smoking vs. oral vs. suppository) influenced food selection. Pharmacol Biochem Behav. 1994 Sep;49(1):187-95. Cannabis cigarette inhalation can produce voracious appetite preferentially for sweet food, with the observation that subjects inhaling cannabis eat 50 marshmallows as opposed to 4 marshmallows by control subjects. Nature. 1971 Mar 28;231(5300):260-1 Cannabis has been shown to produce appetite stimulation with weaker preparations (bhang), while appetite suppression occurs with potent preparations (charas/ganja). Ind Med Res Mem 1939; 31: 1-119 Anandamide administered peripherally Psychopharmacology (Berl). 1999 Apr;143(3):315-7 as well as centrally into the VMN of hypothalamus Br J Pharmacol. 2001 Nov;134(6):1151-4. stimulated feeding, although to a lesser extent than with Cannabis (tetrahydrocannabinol), although the effect was sustained for longer. Rimonabant, a selective CB1 receptor antagonist blocks this appetite stimulating effect of Anandamide. Peripheral or central administration (into nucleus accumbens) of 2-AG also induces eating in rats. Br J Pharmacol. 2002 Jun;136(4):550-7. , an effect blocked by the CB1 receptor antagonist Rimonabant.
The appetite inducing action of Cannabinoids may find application in stimulating appetite and weight gain in patients suffering from cancer Forsch Komplementarmed. 1999 Oct;6 Suppl 3:21-2 and HIV cachexia. J Pain Symptom Manage. 1997 Jul;14(1):7-14. Weight gain has been consistently demonstrated in HIV patients treated with twice daily pre-prandial 5 mg Dronabinol, with no fatal events and minimal side effects as psychotropic symptoms which resolved within hours of discontinuation. Ann Pharmacother. 1993 Jul-Aug;27(7-8):827-31; J Pain Symptom Manage. 1995 Feb;10(2):89-97 The anti-emetic properties of Tetrahydrocannabinol has been demonstrated to be effective in combating nausea and vomiting in patients undergoing cancer chemotherapy.N Engl J Med. 1975 Oct 16;293(16):795-7 with FDA approval of Dronabinol use for chemotherapy induced vomiting in 1985 and for the treatment of HIV wasting syndrome in 1992. In fact, smoked marijuana is better tolerated than the oral preparation, an effect attributed to the presence of other cannabinoids including cannabidiol in marijuana which might attenuate the psychotropic effect of tetrahydrocannabinol. Forsch Komplementarmed. 1999 Oct;6 Suppl 3:21-2
Cannabinoids and the Opioid system
Endocannabinoids act on the lateral hypothalamus, the arcuate and the paraventricular nuclei to promote positive energy balance. The Nucleus Accumbens contains a high density of CB1 (Cannabinoid receptor-1) receptors, Proc Natl Acad Sci U S A. 1990 Mar;87(5):1932-6. through which endogenous cannabinoids may influence feeding related activity. 2-AG administration into the nucleus accumbens results in more potent feeding Br J Pharmacol. 2002 Jun;136(4):550-7. than the peripheral J Neurosci. 2002 Nov 1;22(21):9612-7. or central Br J Pharmacol. 2001 Nov;134(6):1151-4 administrations of anandamide. Interactions with the opioid system may contribute to an addictive nature to feeding behaviour. The ingestive responses (lick-rate in rats) can be assessed to analyse the effect of palatability on food ingestion. The lick-rate in rats produced by CB1 receptor ligands were shown to be similar to those produced by varying sucrose drink concentrations Psychopharmacology (Berl). 2003 Feb;165(4):370-7. suggesting an endocannabinoid involvement in the mediation of food palatability. Rimonabant was shown to decrease the reward value of the sucrose solution further ratifying this hypothesis. In the nucleus accumbens the dopamine neurons synapse with enkephalinergic neurons (endogenous opioid system) which are critical to the processing of reward. Naloxone, a general opioidreceptor antagonist decreases tetrahydrocannabinol induced c-FOS immunoreactivity in the appetite related brain regions including ventromedial and dorsomedial hypothalamus. Neuropharmacology. 2003 Feb;44(2):264-74. Naloxone also reverses the CB1 receptor agonist induced response to palatable solutions. Psychopharmacology (Berl). 1999 Mar;142(3):302-8 Cannabinoids may thus interact with the endogenous opioid system to modulate the motivation for food ingestion. Further proof for this hypothesis has been made available using the combined administration of Rimonabant and Naloxone to demonstrate a synergistic interaction between Cannabinoid receptor antagonists and opioid antagonists. Low doses of both drugs, which were enough to reverse the actions of the selective agonists at their respective binding sites but without any effect on food intake, were used. These studies Psychopharmacology (Berl). 2001 Jan 1;153(2):267-70.; Psychopharmacology (Berl). 2001 Dec;159(1):111-6 demonstrated that at these low doses, Rimonabant or Naloxone in isolation did not produce any effect on food intake, but in combination they potentiated the effect of each other with significant suppression of food intake.
Other Actions of Cannabinoids
Endocannabinoids demonstrate a peripheral lipogenesis effect on adipose tissue. CB1 receptors are expressed by adipocytes and stimulation of these receptors by agonists dose stimulates lipogenesis. J Clin Invest. 2003 Aug;112(3):423-31. CB1 activation in isolated mouse adipocytes increase the activity of lipogenic enzyme lipoprotein lipase. J Clin Invest. 2003 Aug;112(3):423-31. CB1 receptor activation in the liver increases denovo synthesis of fatty acids in mice by activating the transcription factor-SREBP1c, J Clin Invest. 2005 May;115(5):1298-305. Thus high-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB(1) density, and basal rates of fatty acid synthesis, contributing to obesity development. CB1 blockade on the other hand, increases adiponectin gene expression in adipose tissue with increased circulating adiponectin levels in the obese Zucker rat. Mol Pharmacol. 2003 Apr;63(4):908-14. In keeping with these findings, CB1 gene deficient mice are lean and resistant to diet-induced obesity. Int J Obes Relat Metab Disord. 2004 Apr;28(4):640-8.
Cannabinoids are involved in anti-nociception, control of movement, and inhibition of short-term memory. Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):123-42 Cannabinoids also inhibit Prolactin and Growth hormone secretion while increasing adrenocorticotrophin (ACTH) secretion. J Clin Endocrinol Metab. 2001 Jun;86(6):2687-96. Cannabinoid agonists also demonstrate anxiolytic effects in a dose dependent manner. Neuroreport. 1997 Jan 20;8(2):491-6. Other physiological functions modulated by cannabinoid system include immune and inflammatory responses, Chem Phys Lipids. 2000 Nov;108(1-2):191-209 alteration of heart rate and cardiac output with vasodilatation, Eur J Pharmacol. 2001 Jul 6;423(2-3):203-10 bronchodilatation, Nature. 2000 Nov 2;408(6808):96-101. inhibition of testosterone secretion, Biochem Biophys Res Commun. 2001 Jun 8;284(2):363-8. and reduction in intraocular pressure. J Ocul Pharmacol Ther. 2000 Jun;16(3):217-30. Endocannabinoids are also thought to offer neuroprotection from hypoxic and traumatic injury. Nature. 2001 Oct 4;413(6855):527-31. and CB1 receptor agonists are being tried as treatment for demyelination Mini Rev Med Chem. 2005 Jul;5(7):671-5. and the dyskinesia of Parkinson's disease. Nat Rev Drug Discov. 2004 Sep;3(9):771-84.
Smoking up regulates the endogenous cannabinoid system with increased expression of CB1 receptors and increased hypothalamic endocannabinoid levels. Chronic nicotine exposure thus increases endocannabinoid levels in the mesolimbic system, Brain Res. 2002 Nov 1;954(1):73-81. thus blocking the GABAergic inhibition of dopamine. Behav Pharmacol. 2002 Sep;13(5-6):451-63. The increased dopamine levels contribute to development of nicotine dependence. Rimonabant can be highly effective in this state of up-regulated endogenous endocannabinoid activity, with improvement in nicotine dependence. (Stratus-us study)
[Oleoyl ethanolamide (OEA) is a natural analog of anandamide synthesised in the intestines J Neurosci. 2002 Nov 1;22(21):9612-7 in response to feeding. The synthesis of OEA is inhibited by starvation. Neuropsychopharmacology. 2003 Jul;28(7):1311-6 OEA administration reduces food intake and body weight in feeding animals and starved animals. Nature. 2001 Nov 8;414(6860):209-12. OEA can enhance Rimonabant induced anorexia, but interestingly OEA does not activate cannabinoid receptors. OEA may mediate its effects through adiponectin-related mechanisms as well as by acting as an agonist at the PPAR-α receptors.Nature. 2003 Sep 4;425(6953):90-3]
Cannabinoid System Effectors and Regulators
Systemic endocannabinoid levels of circulating Anandamide and 2-AG have been found to be higher in obese postmenopausal women. Diabetes. 2005 Oct;54(10):2838-43 These subjects also show a reduction in CB1 receptor density and decreased FAAH gene expression in the adipose tissue, possibly suggesting that the increased circulating endocannabinoid levels may be secondary to lower degradation by FAAH enzyme. In fact, polymorphisms of the FAAH enzyme has been shown to be associated with obesity. The homozygous FAAH 385 A/A genotype was significantly associated with overweight and obesity in white and black subjects. Int J Obes (Lond). 2005 Jul;29(7):755-9.
High fat feeding increases intrahepatic endocannabinoid levels even before development of obesity, accompanied by a decrease in FAAH levels. J Clin Invest.2005 May;115(5):1298-305. Leptin could possibly have a role in mediating this FAAH levels, as shown by high endocannabinoid levels in leptin deficient ob/ob mice. Nature. 2001 Apr 12;410(6830):822-5. Weight loss of up to 5% did not change the circulating endocannabinoid levels, CB1 expression or FAAH mRNA levels in adipose tissue. Diabetes. 2005 Oct;54(10):2838-43 Factors regulating CB1 receptor expression remains to be elicited.
It has been noted that tetrahydrocannabinol decreases the threshold level of stimulation required at the Lateral Hypothalamus to induce feeding. Unsurprisingly, Rimonabant increases the threshold for Lateral hypothalamus stimulation required to elicit feeding. Psychopharmacology (Berl). 2001 Sep;157(3):254-9. Leptinwhich is high in the fed state, also raises this stimulation threshold, thus decreasing feeding stimulation. Science. 2000 Jan 7;287(5450):125-8. Hypothalamic Cannabinoids are suppressed by leptin. Leptin negatively regulates the synthesis of hypothalamic Anandamide and 2-AG. in normal rats. In the genetically obese hyperphagic rats with deficient leptin signalling, (ob/ob and fa/fa rats) hypothalamic Anandamide and 2-AG levels are high, but are decreased in response to leptin. Nature. 2001 Apr 12;410(6830):822-5. This reciprocal relationship between Leptin and hypothalamic endocannabinoid levels may suggest that Leptin may act partly through the down-regulation of endocannabinoids producing a reduction in the general incentive value of food. At the same time, there seems to be no correlation between plasma leptin levels and brain CB1 receptor expression in normal animals that become obese and hyperleptinaemic through over-consumption of a palatable diet, Brain Res. 2002 Oct 18;952(2):232-8. casting doubt on the hypothesis of a cannabinoid-mediated action of leptin.
CB1 receptors have been found to be co-expressed with prepro-Orexin in mouse hypothalamus. J Clin Invest. 2003 Aug;112(3):423-31. Activation of CB1 receptors increases Orexin signalling, J Biol Chem. 2003 Jun 27;278(26):23731-7 suggesting the possibility of a cross talk between the Cannabinoid receptors and the Orexin (OX1r) receptors. Rimonabant has been shown to block the Orexin-A induced feeding.
The MCH system, another orexigenic system directly connects to the endogenous Cannabinoid system. Targeted deletion of the MCH system also results in a lean phenotype. Nature. 1998 Dec 17;396(6712):670-4.
The importance of the Cannabinoid system in body weight regulation and feeding is emphasised by the fact that CB1 receptor knock out mice are hypophagic. Importantly, knock out of potent orexigenic peptides as NPY and AgRP do not produce significant alterations in feeding behaviour and body weight Mol Cell Biol.2002 Jul;22(14):5027-35. stressing the greater role of cannabinoid system in energy homeostasis. CB1 receptor knock out mice which are hypophagic show higher levels of mRNA for CRH, an anorexigen. J Clin Invest. 2003 Aug;112(3):423-31.
Effects of Cannabinoid receptor blockade
Rimonabant (SR 141716), a synthetic CB1 receptor antagonist, was developed in 1994 by Rinaldi-Carmona and colleagues . FEBS Lett. 1994 Aug 22;350(2-3):240-4. It has been withdrawn from the market as of 2008 due to concerns about its mental health side effects in the form of depression. I have left the previous data on this drug at this site for anyone interested in the history of cannabinoid receptor blockers in general.
Intracerebroventricular administration of Rimonabant or its analogue (AM281) reduced appetite in satiated as well as food deprived rats. Brain Res. 2003 Mar 28;967(1-2):290-2 Peripheral administration of Rimonabant reduced food intake Behav Pharmacol. 1998 Mar;9(2):179-81 and decreased lipogenesis significantly, resulting in reduction in adipose stores while preserving lean mass Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R345-53 with increased energy expenditure. Life Sci. 1998;63(8):PL113-7. The predominant effect of Rimonabant was to preferentially attenuate the intake of palatable foods, Behav Pharmacol. 1998 Mar;9(2):179-81 although less palatable food intake are also decreased. Life Sci. 1998;63(8):PL113-7. Rimonabant also blocks theNeuropeptide Y induced stimulation of sucrose drinking in rats. Psychopharmacology (Berl). 1997 Jul;132(1):104-6. Tetrahydrocannabinol-induced, as well as Anandamide-induced hyperphagia, is attenuated by selective blockade of CB1 receptors using the receptor antagonist Rimonabant but not by the blockade of peripheral CB2 receptors. Pharmacol Biochem Behav. 2002 Jan-Feb;71(1-2):333-40.
CB1 receptor knockout mice eat less than their wild-type litter mates Nature. 2001 Apr 12;410(6830):822-5. CB1 receptor knock out animals, not surprisingly, tend to be leaner. CB1 receptor knockout mice as well as Rimonabant-treated mice Eur J Pharmacol. 2001 May 11;419(2-3):207-14. fail to initiate suckling during the first 24 hours of birth with fatal consequences. This anti-suckling effect can be reversed by administration of cannabinoid receptor agonists. Anandamide and 2-AG are present in animal and human milk and may have a facilitatory role in suckling. Nature. 1998 Dec 17;396(6712):636-7. These may suggest a role for the endocannabinoid system in feeding behaviour. CB1 knock out mice show a reduced hyperdipsic response to a palatable sucrose solution Neurosci Lett. 2003 Jun 12;343(3):216-8 implying the role of the cannabinoid system in modulating food intake in the context of palatability.
Rimonabant therapy in rats has shown that tolerance to appetite effects developed in 5 days although weight loss persisted. Life Sci. 1998;63(8):PL113-7;Psychopharmacology (Berl). 2003 Apr;167(1):103-11 ; Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R345-53 AM-251, a close structural analogue of Rimonabant J Med Chem. 1999 Feb 25;42(4):769-76 also produces a dose dependent reduction in food intake and weight loss in diet-induced obese rats. Eur J Pharmacol. 2003 Feb 21;462(1-3):125-32 Zucker rats which have higher levels of hypothalamic 2-AG Nature. 2001 Apr 12;410(6830):822-5. showed a greater inhibition of food intake and reduction in weight as well as a later development of tolerance to Rimonabant compared to lean rats (13 days vs. 4 days). Psychopharmacology (Berl). 2003 Apr;167(1):103-11 Discontinuation of Rimonabant has consistently shown a rebound hyperphagia starting after 4-5 days of drug discontinuation. It has been noted that despite the recurrence of hyperphagia in the drug-free period, weight loss was sustained in many studies. Pair fed studies also show that Rimonabant-treated animals lose more weight than untreated animals ingesting similar amounts of food. Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R345-53 These might suggest other mechanisms of action for Rimonabant-stimulated weight loss than merely a modulation of dietary calorie intake. Increased fatty acid oxidation with lower plasma free-fatty acids in Rimonabant treated dietary obese mice has been demonstrated. Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R345-53 which might be mediated by an increase in sympathetic activity in the hypothalamus. Rimonabant has been shown to produce a 37% increase in basal oxygen consumption in the muscle, Int J Obes (Lond). 2005 Feb;29(2):183-7. and this activation of thermogenesis could account for its diet-independent effects on weight loss. Rimonabant in humans wasshown to be effective in reducing hunger ratings and weight with improvement of insulin sensitivity and HDL levels in a 2-year Phase III study in 3040 subjects. RIO-North America trial The improved insulin sensitivity noted with Rimonabant therapy might be mediated through increases inAdiponectin mRNA expression in adipose tissue as has been shown in Zucker obese rats, Mol Pharmacol. 2003 Apr;63(4):908-14. and is mediated by CB-1 receptors, as this effect of Rimonabant is absent in CB-1 knock out mice. 1-year treatment of obese subjects with BMI>30 with Rimonabant 5 mg, 20 mg or placebo resulted in weight loss of 3.4 kg, 6.6 kg and 1.8 kg respectively. Weight loss was more likely in the Rimonabant group as shown in the RIO-Europe study at 1 year.Lancet. 2005 Apr;365(9468):1389-97. Improvement of cardiovascular risk factors as hypertension and LDL levels was not observed in the RIO trial despite expectations from rat studies. Int J Obes Relat Metab Disord. 2004 Apr;28(4):640-8. The one year results of the RIO Lipids study of 1036 obese or overweight patients with untreated dyslipidaemia showed a significant mean weight loss of 6.7 kgs in the group treated with 20 mgs of Rimonabant. N Engl J Med. 2005 Nov 17;353(20):2121-34. Improvements in lipid profile was also demonstrable, with an increase in adiponectin levels. [ Rio-North America study - Sanofi data]. Many other studies were ongoing to evaluate various aspects of Rimonabant. While none of these are relevant anymore, they are provided here for historical reasons. The STRADIVARIUS (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant-The Intravascular Ultrasound Study) and the AUDITOR (Atherosclerosis Underlying Development Assessed By Intima-Media Thickness In Patients On Rimonabant) studies will be evaluating the potential of Rimonabant to retard atherosclerosis, while the CRESCENDO (Comprehensive Rimonabant Evaluation Study of Cardiovascular ENDpoints andOutcomes) study will be assessing the cardiovascular risk reduction with Rimonabant. The STRATUS study ( Studies with Rimonabant And Tobacco Use ) has been set up world wide and in the US and Europe to evaluate the potential of Rimonabant to facilitate smoking cessation, while another study is currently recruiting to study the effects on reducing alcohol consumption. The ADAGIO-Lipids (An International Study of Rimonabant in Dyslipidemia With AtheroGenic Risk In Abdominally Obese Patients) hopes to assess Rimonabant's effects on HDL and triglycerides in centrally obese patients with abnormal lipid profile.Ageing in rodents seems to diminish the central actions of Cannabinoids J Clin Invest. 2003 Aug;112(3):423-31 with a potential explanation of the anorexia of ageing if similar chronologically related reduction can be demonstrated in humans. It makes sense to assume that any antagonist is likely to more effective if the peptide or receptor being antagonised is up-regulated or over-expressed. Starved or food deprived mice are more likely to have increased release of endogenous cannabinoids Br J Pharmacol. 2002 Jun;136(4):550-7. as well as increased expression of CB1 receptors, resulting in greater efficiency with CB1 blockade. Cannabinoid receptor antagonists thus have the potential to evolve into anti-obesity treatments which might improve the addictive aspect of food intake seen in many obese individuals. The rebound weight-gain with drug discontinuation in humans, ideal duration of therapy to sustain effectiveness, and the need for interrupted therapy await clarification. Better neurophysiological studies along with application of evolving molecular biology will hopefully further clarify the exact contribution of this system to the pathogenesis of obesity.
The stimulatory effect of Marijuana (Cannabis) on appetite and food intake has been known for long Behav Biol. 1975 Nov;15(3):255-81 with voracious appetite being observed in Cannabis users, described as the "munchies". Tetrahydrocannabinol , the active component of marijuana was identified as early as 1964. J Am Chem Soc 1964; 86: 1646. An endogenous Cannabinoid system consisting of endocannabinoids and cannabinoid receptors has now been described. Endocannabinoids have similarity with Tetrahydrocannabinol and are produced post synaptically with actions on the presynaptic release of neurotransmitters.Trends Neurosci. 1998 Dec;21(12):521-8. An evolutionary conservation of the cannabinoid system with a high degree of homology for CB1 receptors across species, even the primitive coelenterate hydra, has been demonstrated suggesting a physiological role for this system. Neuroscience. 1999;92(1):377-87.
Cannabinoid Receptors and Endocannabinoids
Cannabinoids and endocannabinoids act via G protein coupled receptors. CB1 Nature. 1990 Aug 9;346(6284):561-4. and CB2 Nature. 1993 Sep 2;365(6441):61-5 which belong to the G protein- coupled receptor superfamily were identified as cannabinoid receptors with later discovery of their endogenous ligands which were called endocannabinoids. Science. 1992 Dec 18;258(5090):1946-9. CB1 receptors are predominantly expressed in the brain, gastrointestinal organs and adipose tissue, while CB-2 receptors are expressed on peripheral immune cells. Pharmacol Rev. 2002 Jun;54(2):161-202 Thus a central and peripheral endocannabinoid system exists. Anandamide (arachidonoyl ethanolamide) was the first endogenous cannabinoid to be identified in 1992 from porcine brain. Science. 1992 Dec 18;258(5090):1946-9. The name anandamide was inspired by the Sanskrit word "ananda", meaning internal bliss. Anandamide is present at highest concentrations in the hippocampus, cortex, thalamus, and cerebellum. FEBS Lett. 1996 Sep 16;393(2-3):231-5 Anandamide binds to both CB1 and CB2 receptors with higher affinity for CB1 receptors. Mol Pharmacol. 1995 Sep;48(3):443-50. Other PUFA (polyunsaturated fatty acid) derivatives that act as functional agonists at cannabinoid receptors were identified as endogenous Cannabinoids including Noladin ether ( 2-arachidonyl glyceryl ether) Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3662-5 , virodhamine J Pharmacol Exp Ther. 2002 Jun;301(3):1020-4 and and 2-arachidonoylglycerol (2-AG), Nature.1997 Aug 21;388(6644):773-8. the latter being the most abundant endocannabinoid in the brain with a concentration 170 times higher than anandamide. 2-AG has selectivity for CB2, with minimal affinity for CB1. Anandamide has been reported to be present in intestinal tissues as well J Neurosci. 2002 Nov 1;22(21):9612-7 with increased levels after 24 hours of fasting. A role for anandamide in peripheral signalling in the appetite pathway remains to be clarified.
The effects of endocannabinoids are mediated via cannabinoid receptor type 1 (CB-1) which is the predominant receptor type in the central nervous system. CB1 is expressed in key hypothalamic peptidergic systems of appetite regulation including the CRH- (corticotrophin releasing hormone)- system in the paraventricular nucleus, CART in the arcuate nucleus and MCH and Orexin system in the lateral hypothalamus-perifornical region. Neurobiol Dis. 1998 Dec;5(6 Pt B):417-31. Cannabinoids may thus influence hypothalamic neurotransmitters through these systems resulting in induction of a state of positive energy balance. In the CNS, CB1 is predominantly expressed presynaptically, modulating the release of neurotransmitters as GABA, dopamine, noradrenaline, glutamate and serotonin.Trends Pharmacol Sci. 2001 Nov;22(11):565-72. CB1 knock gene deficient mice are lean and resistant to diet-induced obesity. CB2 is mainly expressed in immune cells and hence mediating peripheral actions, although CB2 has been localised in brain-derived immune cells as well. Pharmacol Ther. 2001 Apr;90(1):45-60.
Endocannabinoids act on the lateral hypothalamus, the arcuate and the paraventricular nuclei to promote positive energy balance. The Hypothalamus has high levels of endocannabinoids and CB1 receptors. Diet restriction decreases the hypothalamic and hippocampal levels of dopamine, nor-adrenaline and 5 hydroxytryptamine. Anandamide restores the decrease in dopamine and 5-HT, with no effect on the nor adrenaline decrease. Eur J Pharmacol. 2000 Mar 31;392(3):147-56. The effect of Cannabinoids on Nucleus Accumbens has been discussed above under the opioid system.
Endocannabinoid release and metabolism
Unlike other neurotransmitters, endocannabinoids are not stored in synaptic vesicles, but instead are stored in phospholipid molecules within the cellular membrane. Nature. 1994 Dec 15;372(6507):686-91. Endocannabinoids are released from neurons following membrane depolarisation and calcium influx into cells. Acute food deprivation results in significant increases in brain anandamide and 2-AG levels especially in the limbic forebrain. Br J Pharmacol. 2002 Jun;136(4):550-7; with changes in2-AG levels probably being dependent on the severity and chronicity of dietary deprivation. Brain Res. 2003 Sep 5;983(1-2):144-51. Chronic food deprivation in mice resulted in a paradoxical reduction in hippocampal and hypothalamic 2-AG levels. "Normal" eating to satiety results in a physiological decrease in 2-AG levels in the hypothalamus as opposed to the severe reduction/suppression of 2-AG levels in rodents that over-fed on highly palatable feeds. Br J Pharmacol. 2002 Jun;136(4):550-7; The pre feeding rise followed by reduction in levels with feeds of endocannabinoids may be interpreted as suggesting a role for endocannabinoids in meal initiation but not in maintenance of feeding. Over-consumption with accelerated weight gain in rats using a palatable food supplement resulted in a 50% reduction in CB1 receptor density in the nucleus accumbens and other appetite regulating areas. Brain Res. 2002 Oct 18;952(2):232-8 The regulators of this meal related alteration of endocannabinoid levels and cannabinoid receptors remains to be elucidated. Obese Zucker rats have elevated hypothalamic levels of 2-AG. Nature. 2001 Apr 12;410(6830):822-5. Endocannabinoids are inactivated by a reuptake mechanism followed by hydrolysis by the fatty acid amide hydrolase (FAAH) enzyme in neurons. Trends Neurosci. 1998 Dec;21(12):521-8. Monoglyceride lipase may mediate inactivation of 2-AG by hydrolysis in neurons. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10819-24
Cannabinoids and Appetite
The appetite stimulating effects of Cannabinoids has been known for a long time. Behav Biol. 1975 Nov;15(3):255-81 Cannabinoids have been recognised as appetite stimulating drugs even in the absence of feelings of hunger Nature. 1970 May 23;226(5247):701-4 with a preference for sweet foods Appetite. 1988 Aug;11(1):1-14 while the route of drug administration ( smoking vs. oral vs. suppository) influenced food selection. Pharmacol Biochem Behav. 1994 Sep;49(1):187-95. Cannabis cigarette inhalation can produce voracious appetite preferentially for sweet food, with the observation that subjects inhaling cannabis eat 50 marshmallows as opposed to 4 marshmallows by control subjects. Nature. 1971 Mar 28;231(5300):260-1 Cannabis has been shown to produce appetite stimulation with weaker preparations (bhang), while appetite suppression occurs with potent preparations (charas/ganja). Ind Med Res Mem 1939; 31: 1-119 Anandamide administered peripherally Psychopharmacology (Berl). 1999 Apr;143(3):315-7 as well as centrally into the VMN of hypothalamus Br J Pharmacol. 2001 Nov;134(6):1151-4. stimulated feeding, although to a lesser extent than with Cannabis (tetrahydrocannabinol), although the effect was sustained for longer. Rimonabant, a selective CB1 receptor antagonist blocks this appetite stimulating effect of Anandamide. Peripheral or central administration (into nucleus accumbens) of 2-AG also induces eating in rats. Br J Pharmacol. 2002 Jun;136(4):550-7. , an effect blocked by the CB1 receptor antagonist Rimonabant.
The appetite inducing action of Cannabinoids may find application in stimulating appetite and weight gain in patients suffering from cancer Forsch Komplementarmed. 1999 Oct;6 Suppl 3:21-2 and HIV cachexia. J Pain Symptom Manage. 1997 Jul;14(1):7-14. Weight gain has been consistently demonstrated in HIV patients treated with twice daily pre-prandial 5 mg Dronabinol, with no fatal events and minimal side effects as psychotropic symptoms which resolved within hours of discontinuation. Ann Pharmacother. 1993 Jul-Aug;27(7-8):827-31; J Pain Symptom Manage. 1995 Feb;10(2):89-97 The anti-emetic properties of Tetrahydrocannabinol has been demonstrated to be effective in combating nausea and vomiting in patients undergoing cancer chemotherapy.N Engl J Med. 1975 Oct 16;293(16):795-7 with FDA approval of Dronabinol use for chemotherapy induced vomiting in 1985 and for the treatment of HIV wasting syndrome in 1992. In fact, smoked marijuana is better tolerated than the oral preparation, an effect attributed to the presence of other cannabinoids including cannabidiol in marijuana which might attenuate the psychotropic effect of tetrahydrocannabinol. Forsch Komplementarmed. 1999 Oct;6 Suppl 3:21-2
Cannabinoids and the Opioid system
Endocannabinoids act on the lateral hypothalamus, the arcuate and the paraventricular nuclei to promote positive energy balance. The Nucleus Accumbens contains a high density of CB1 (Cannabinoid receptor-1) receptors, Proc Natl Acad Sci U S A. 1990 Mar;87(5):1932-6. through which endogenous cannabinoids may influence feeding related activity. 2-AG administration into the nucleus accumbens results in more potent feeding Br J Pharmacol. 2002 Jun;136(4):550-7. than the peripheral J Neurosci. 2002 Nov 1;22(21):9612-7. or central Br J Pharmacol. 2001 Nov;134(6):1151-4 administrations of anandamide. Interactions with the opioid system may contribute to an addictive nature to feeding behaviour. The ingestive responses (lick-rate in rats) can be assessed to analyse the effect of palatability on food ingestion. The lick-rate in rats produced by CB1 receptor ligands were shown to be similar to those produced by varying sucrose drink concentrations Psychopharmacology (Berl). 2003 Feb;165(4):370-7. suggesting an endocannabinoid involvement in the mediation of food palatability. Rimonabant was shown to decrease the reward value of the sucrose solution further ratifying this hypothesis. In the nucleus accumbens the dopamine neurons synapse with enkephalinergic neurons (endogenous opioid system) which are critical to the processing of reward. Naloxone, a general opioidreceptor antagonist decreases tetrahydrocannabinol induced c-FOS immunoreactivity in the appetite related brain regions including ventromedial and dorsomedial hypothalamus. Neuropharmacology. 2003 Feb;44(2):264-74. Naloxone also reverses the CB1 receptor agonist induced response to palatable solutions. Psychopharmacology (Berl). 1999 Mar;142(3):302-8 Cannabinoids may thus interact with the endogenous opioid system to modulate the motivation for food ingestion. Further proof for this hypothesis has been made available using the combined administration of Rimonabant and Naloxone to demonstrate a synergistic interaction between Cannabinoid receptor antagonists and opioid antagonists. Low doses of both drugs, which were enough to reverse the actions of the selective agonists at their respective binding sites but without any effect on food intake, were used. These studies Psychopharmacology (Berl). 2001 Jan 1;153(2):267-70.; Psychopharmacology (Berl). 2001 Dec;159(1):111-6 demonstrated that at these low doses, Rimonabant or Naloxone in isolation did not produce any effect on food intake, but in combination they potentiated the effect of each other with significant suppression of food intake.
Other Actions of Cannabinoids
Endocannabinoids demonstrate a peripheral lipogenesis effect on adipose tissue. CB1 receptors are expressed by adipocytes and stimulation of these receptors by agonists dose stimulates lipogenesis. J Clin Invest. 2003 Aug;112(3):423-31. CB1 activation in isolated mouse adipocytes increase the activity of lipogenic enzyme lipoprotein lipase. J Clin Invest. 2003 Aug;112(3):423-31. CB1 receptor activation in the liver increases denovo synthesis of fatty acids in mice by activating the transcription factor-SREBP1c, J Clin Invest. 2005 May;115(5):1298-305. Thus high-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB(1) density, and basal rates of fatty acid synthesis, contributing to obesity development. CB1 blockade on the other hand, increases adiponectin gene expression in adipose tissue with increased circulating adiponectin levels in the obese Zucker rat. Mol Pharmacol. 2003 Apr;63(4):908-14. In keeping with these findings, CB1 gene deficient mice are lean and resistant to diet-induced obesity. Int J Obes Relat Metab Disord. 2004 Apr;28(4):640-8.
Cannabinoids are involved in anti-nociception, control of movement, and inhibition of short-term memory. Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):123-42 Cannabinoids also inhibit Prolactin and Growth hormone secretion while increasing adrenocorticotrophin (ACTH) secretion. J Clin Endocrinol Metab. 2001 Jun;86(6):2687-96. Cannabinoid agonists also demonstrate anxiolytic effects in a dose dependent manner. Neuroreport. 1997 Jan 20;8(2):491-6. Other physiological functions modulated by cannabinoid system include immune and inflammatory responses, Chem Phys Lipids. 2000 Nov;108(1-2):191-209 alteration of heart rate and cardiac output with vasodilatation, Eur J Pharmacol. 2001 Jul 6;423(2-3):203-10 bronchodilatation, Nature. 2000 Nov 2;408(6808):96-101. inhibition of testosterone secretion, Biochem Biophys Res Commun. 2001 Jun 8;284(2):363-8. and reduction in intraocular pressure. J Ocul Pharmacol Ther. 2000 Jun;16(3):217-30. Endocannabinoids are also thought to offer neuroprotection from hypoxic and traumatic injury. Nature. 2001 Oct 4;413(6855):527-31. and CB1 receptor agonists are being tried as treatment for demyelination Mini Rev Med Chem. 2005 Jul;5(7):671-5. and the dyskinesia of Parkinson's disease. Nat Rev Drug Discov. 2004 Sep;3(9):771-84.
Smoking up regulates the endogenous cannabinoid system with increased expression of CB1 receptors and increased hypothalamic endocannabinoid levels. Chronic nicotine exposure thus increases endocannabinoid levels in the mesolimbic system, Brain Res. 2002 Nov 1;954(1):73-81. thus blocking the GABAergic inhibition of dopamine. Behav Pharmacol. 2002 Sep;13(5-6):451-63. The increased dopamine levels contribute to development of nicotine dependence. Rimonabant can be highly effective in this state of up-regulated endogenous endocannabinoid activity, with improvement in nicotine dependence. (Stratus-us study)
[Oleoyl ethanolamide (OEA) is a natural analog of anandamide synthesised in the intestines J Neurosci. 2002 Nov 1;22(21):9612-7 in response to feeding. The synthesis of OEA is inhibited by starvation. Neuropsychopharmacology. 2003 Jul;28(7):1311-6 OEA administration reduces food intake and body weight in feeding animals and starved animals. Nature. 2001 Nov 8;414(6860):209-12. OEA can enhance Rimonabant induced anorexia, but interestingly OEA does not activate cannabinoid receptors. OEA may mediate its effects through adiponectin-related mechanisms as well as by acting as an agonist at the PPAR-α receptors.Nature. 2003 Sep 4;425(6953):90-3]
Cannabinoid System Effectors and Regulators
Systemic endocannabinoid levels of circulating Anandamide and 2-AG have been found to be higher in obese postmenopausal women. Diabetes. 2005 Oct;54(10):2838-43 These subjects also show a reduction in CB1 receptor density and decreased FAAH gene expression in the adipose tissue, possibly suggesting that the increased circulating endocannabinoid levels may be secondary to lower degradation by FAAH enzyme. In fact, polymorphisms of the FAAH enzyme has been shown to be associated with obesity. The homozygous FAAH 385 A/A genotype was significantly associated with overweight and obesity in white and black subjects. Int J Obes (Lond). 2005 Jul;29(7):755-9.
High fat feeding increases intrahepatic endocannabinoid levels even before development of obesity, accompanied by a decrease in FAAH levels. J Clin Invest.2005 May;115(5):1298-305. Leptin could possibly have a role in mediating this FAAH levels, as shown by high endocannabinoid levels in leptin deficient ob/ob mice. Nature. 2001 Apr 12;410(6830):822-5. Weight loss of up to 5% did not change the circulating endocannabinoid levels, CB1 expression or FAAH mRNA levels in adipose tissue. Diabetes. 2005 Oct;54(10):2838-43 Factors regulating CB1 receptor expression remains to be elicited.
It has been noted that tetrahydrocannabinol decreases the threshold level of stimulation required at the Lateral Hypothalamus to induce feeding. Unsurprisingly, Rimonabant increases the threshold for Lateral hypothalamus stimulation required to elicit feeding. Psychopharmacology (Berl). 2001 Sep;157(3):254-9. Leptinwhich is high in the fed state, also raises this stimulation threshold, thus decreasing feeding stimulation. Science. 2000 Jan 7;287(5450):125-8. Hypothalamic Cannabinoids are suppressed by leptin. Leptin negatively regulates the synthesis of hypothalamic Anandamide and 2-AG. in normal rats. In the genetically obese hyperphagic rats with deficient leptin signalling, (ob/ob and fa/fa rats) hypothalamic Anandamide and 2-AG levels are high, but are decreased in response to leptin. Nature. 2001 Apr 12;410(6830):822-5. This reciprocal relationship between Leptin and hypothalamic endocannabinoid levels may suggest that Leptin may act partly through the down-regulation of endocannabinoids producing a reduction in the general incentive value of food. At the same time, there seems to be no correlation between plasma leptin levels and brain CB1 receptor expression in normal animals that become obese and hyperleptinaemic through over-consumption of a palatable diet, Brain Res. 2002 Oct 18;952(2):232-8. casting doubt on the hypothesis of a cannabinoid-mediated action of leptin.
CB1 receptors have been found to be co-expressed with prepro-Orexin in mouse hypothalamus. J Clin Invest. 2003 Aug;112(3):423-31. Activation of CB1 receptors increases Orexin signalling, J Biol Chem. 2003 Jun 27;278(26):23731-7 suggesting the possibility of a cross talk between the Cannabinoid receptors and the Orexin (OX1r) receptors. Rimonabant has been shown to block the Orexin-A induced feeding.
The MCH system, another orexigenic system directly connects to the endogenous Cannabinoid system. Targeted deletion of the MCH system also results in a lean phenotype. Nature. 1998 Dec 17;396(6712):670-4.
The importance of the Cannabinoid system in body weight regulation and feeding is emphasised by the fact that CB1 receptor knock out mice are hypophagic. Importantly, knock out of potent orexigenic peptides as NPY and AgRP do not produce significant alterations in feeding behaviour and body weight Mol Cell Biol.2002 Jul;22(14):5027-35. stressing the greater role of cannabinoid system in energy homeostasis. CB1 receptor knock out mice which are hypophagic show higher levels of mRNA for CRH, an anorexigen. J Clin Invest. 2003 Aug;112(3):423-31.
Effects of Cannabinoid receptor blockade
Rimonabant (SR 141716), a synthetic CB1 receptor antagonist, was developed in 1994 by Rinaldi-Carmona and colleagues . FEBS Lett. 1994 Aug 22;350(2-3):240-4. It has been withdrawn from the market as of 2008 due to concerns about its mental health side effects in the form of depression. I have left the previous data on this drug at this site for anyone interested in the history of cannabinoid receptor blockers in general.
Intracerebroventricular administration of Rimonabant or its analogue (AM281) reduced appetite in satiated as well as food deprived rats. Brain Res. 2003 Mar 28;967(1-2):290-2 Peripheral administration of Rimonabant reduced food intake Behav Pharmacol. 1998 Mar;9(2):179-81 and decreased lipogenesis significantly, resulting in reduction in adipose stores while preserving lean mass Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R345-53 with increased energy expenditure. Life Sci. 1998;63(8):PL113-7. The predominant effect of Rimonabant was to preferentially attenuate the intake of palatable foods, Behav Pharmacol. 1998 Mar;9(2):179-81 although less palatable food intake are also decreased. Life Sci. 1998;63(8):PL113-7. Rimonabant also blocks theNeuropeptide Y induced stimulation of sucrose drinking in rats. Psychopharmacology (Berl). 1997 Jul;132(1):104-6. Tetrahydrocannabinol-induced, as well as Anandamide-induced hyperphagia, is attenuated by selective blockade of CB1 receptors using the receptor antagonist Rimonabant but not by the blockade of peripheral CB2 receptors. Pharmacol Biochem Behav. 2002 Jan-Feb;71(1-2):333-40.
CB1 receptor knockout mice eat less than their wild-type litter mates Nature. 2001 Apr 12;410(6830):822-5. CB1 receptor knock out animals, not surprisingly, tend to be leaner. CB1 receptor knockout mice as well as Rimonabant-treated mice Eur J Pharmacol. 2001 May 11;419(2-3):207-14. fail to initiate suckling during the first 24 hours of birth with fatal consequences. This anti-suckling effect can be reversed by administration of cannabinoid receptor agonists. Anandamide and 2-AG are present in animal and human milk and may have a facilitatory role in suckling. Nature. 1998 Dec 17;396(6712):636-7. These may suggest a role for the endocannabinoid system in feeding behaviour. CB1 knock out mice show a reduced hyperdipsic response to a palatable sucrose solution Neurosci Lett. 2003 Jun 12;343(3):216-8 implying the role of the cannabinoid system in modulating food intake in the context of palatability.
Rimonabant therapy in rats has shown that tolerance to appetite effects developed in 5 days although weight loss persisted. Life Sci. 1998;63(8):PL113-7;Psychopharmacology (Berl). 2003 Apr;167(1):103-11 ; Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R345-53 AM-251, a close structural analogue of Rimonabant J Med Chem. 1999 Feb 25;42(4):769-76 also produces a dose dependent reduction in food intake and weight loss in diet-induced obese rats. Eur J Pharmacol. 2003 Feb 21;462(1-3):125-32 Zucker rats which have higher levels of hypothalamic 2-AG Nature. 2001 Apr 12;410(6830):822-5. showed a greater inhibition of food intake and reduction in weight as well as a later development of tolerance to Rimonabant compared to lean rats (13 days vs. 4 days). Psychopharmacology (Berl). 2003 Apr;167(1):103-11 Discontinuation of Rimonabant has consistently shown a rebound hyperphagia starting after 4-5 days of drug discontinuation. It has been noted that despite the recurrence of hyperphagia in the drug-free period, weight loss was sustained in many studies. Pair fed studies also show that Rimonabant-treated animals lose more weight than untreated animals ingesting similar amounts of food. Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R345-53 These might suggest other mechanisms of action for Rimonabant-stimulated weight loss than merely a modulation of dietary calorie intake. Increased fatty acid oxidation with lower plasma free-fatty acids in Rimonabant treated dietary obese mice has been demonstrated. Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R345-53 which might be mediated by an increase in sympathetic activity in the hypothalamus. Rimonabant has been shown to produce a 37% increase in basal oxygen consumption in the muscle, Int J Obes (Lond). 2005 Feb;29(2):183-7. and this activation of thermogenesis could account for its diet-independent effects on weight loss. Rimonabant in humans wasshown to be effective in reducing hunger ratings and weight with improvement of insulin sensitivity and HDL levels in a 2-year Phase III study in 3040 subjects. RIO-North America trial The improved insulin sensitivity noted with Rimonabant therapy might be mediated through increases inAdiponectin mRNA expression in adipose tissue as has been shown in Zucker obese rats, Mol Pharmacol. 2003 Apr;63(4):908-14. and is mediated by CB-1 receptors, as this effect of Rimonabant is absent in CB-1 knock out mice. 1-year treatment of obese subjects with BMI>30 with Rimonabant 5 mg, 20 mg or placebo resulted in weight loss of 3.4 kg, 6.6 kg and 1.8 kg respectively. Weight loss was more likely in the Rimonabant group as shown in the RIO-Europe study at 1 year.Lancet. 2005 Apr;365(9468):1389-97. Improvement of cardiovascular risk factors as hypertension and LDL levels was not observed in the RIO trial despite expectations from rat studies. Int J Obes Relat Metab Disord. 2004 Apr;28(4):640-8. The one year results of the RIO Lipids study of 1036 obese or overweight patients with untreated dyslipidaemia showed a significant mean weight loss of 6.7 kgs in the group treated with 20 mgs of Rimonabant. N Engl J Med. 2005 Nov 17;353(20):2121-34. Improvements in lipid profile was also demonstrable, with an increase in adiponectin levels. [ Rio-North America study - Sanofi data]. Many other studies were ongoing to evaluate various aspects of Rimonabant. While none of these are relevant anymore, they are provided here for historical reasons. The STRADIVARIUS (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant-The Intravascular Ultrasound Study) and the AUDITOR (Atherosclerosis Underlying Development Assessed By Intima-Media Thickness In Patients On Rimonabant) studies will be evaluating the potential of Rimonabant to retard atherosclerosis, while the CRESCENDO (Comprehensive Rimonabant Evaluation Study of Cardiovascular ENDpoints andOutcomes) study will be assessing the cardiovascular risk reduction with Rimonabant. The STRATUS study ( Studies with Rimonabant And Tobacco Use ) has been set up world wide and in the US and Europe to evaluate the potential of Rimonabant to facilitate smoking cessation, while another study is currently recruiting to study the effects on reducing alcohol consumption. The ADAGIO-Lipids (An International Study of Rimonabant in Dyslipidemia With AtheroGenic Risk In Abdominally Obese Patients) hopes to assess Rimonabant's effects on HDL and triglycerides in centrally obese patients with abnormal lipid profile.Ageing in rodents seems to diminish the central actions of Cannabinoids J Clin Invest. 2003 Aug;112(3):423-31 with a potential explanation of the anorexia of ageing if similar chronologically related reduction can be demonstrated in humans. It makes sense to assume that any antagonist is likely to more effective if the peptide or receptor being antagonised is up-regulated or over-expressed. Starved or food deprived mice are more likely to have increased release of endogenous cannabinoids Br J Pharmacol. 2002 Jun;136(4):550-7. as well as increased expression of CB1 receptors, resulting in greater efficiency with CB1 blockade. Cannabinoid receptor antagonists thus have the potential to evolve into anti-obesity treatments which might improve the addictive aspect of food intake seen in many obese individuals. The rebound weight-gain with drug discontinuation in humans, ideal duration of therapy to sustain effectiveness, and the need for interrupted therapy await clarification. Better neurophysiological studies along with application of evolving molecular biology will hopefully further clarify the exact contribution of this system to the pathogenesis of obesity.