Paul E Szmitko; Subodh Verma
Nat Clin Pract Cardiovasc Med. 2006;3(3):116-117. ©2006 Nature Publishing Group
Obesity, particularly visceral adiposity, and its related metabolic and cardiovascular disorders, is a worldwide pandemic. The biological properties of one of the most widespread illicit drugs of abuse, marijuana, have been recruited for obesity management. By uncovering the cellular interactions of the cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC)—the major active component of marijuana—researchers have identified new molecular pathways for treating cardiometabolic disease. Studies have demonstrated that modulation of the endocannabinoid system holds great therapeutic promise for the treatment of obesity, dyslipidemia, insulin resistance and atherosclerosis.[1,2]
The endocannabinoid system contributes to the regulation of food intake, energy balance, inflammation, and lipid and glucose metabolism, and might therefore play a fundamental role in the development of obesity and atherosclerosis.[3] To date, two G-protein-coupled cannabinoid receptors that bind Δ9-THC with equal affinity have been identified: CB1 and CB2. The CB1 receptor, believed to mediate the psychotropic effects of cannabis and to participate in the modulation of food intake and adipogenesis, is expressed at high levels by brain cells and by several peripheral tissues including the gastrointestinal tract, the adrenal gland, the heart and adipose tissue. CB1 knockout mice exhibit a lean phenotype and appear to be resistant to diet-induced obesity and insulin resistance.[4] By contrast, CB2 receptors are located primarily on blood cells and immune tissues, and stimulation of these receptors with Δ9-THC results in an immunosuppressive phenotype via the modulation of immune-cell cytokine production.[5] This molecular system might have a role in the development of obesity, the metabolic syndrome and atherosclerosis, and its modulation might form the basis of new therapeutic strategies for these pathophysiologically linked conditions.
Using apolipoprotein E knockout mice Steffens et al. demonstrated that Δ9-THC can protect against the development of atherosclerosis.[1] CB2 receptors were expressed in both human and mouse atherosclerotic lesions, but were absent in nondiseased arteries. Apolipoprotein E knockout mice fed a high cholesterol diet developed extensive atherosclerotic lesions in the aortic root; however, when 1 mg/kg Δ9-THC daily was added to the diet—a dose not associated with CB1 activation and psychotropic effects—a significant reduction in the progression of atherosclerotic lesions was observed. Concomitant CB2 receptor antagonist treatment abolished this observed anti-atherosclerotic effect. Even though Δ9-THC-fed mice continued to have elevated serum lipid levels, fewer inflammatory cells were recruited into atherosclerotic lesions, suggesting that Δ9-THC treatment had a beneficial effect on the inflammatory milieu. Indeed, Steffens and co-workers demonstrated that the immunosuppressive properties of Δ9-THC interfered with the adhesion, migration, proliferation and function of immune cells involved in atherosclerotic plaque formation.
These promising results do not imply that smoking marijuana is the key to a healthy heart.[6] Too often there is failure to translate promising results observed in murine models to human patients. The effects of Δ9-THC on atherogenesis in man have not been studied, so whether this cannabinoid does more cardiovascular harm than good remains to be seen. The beneficial effects of Δ9-THC observed by Steffens et al. followed a U-shaped distribution with a very narrow therapeutic window, suggesting that the blood concentrations of Δ9-THC obtained from smoking marijuana would be too variable to provide sustained clinical benefit.[1] Furthermore, it is unlikely that purified Δ9-THC extract or marijuana would be legalized for use as an adjunctive treatment of cardiovascular disease, since both compounds could serve as drugs of abuse. In addition, smoking marijuana increases carboxyhemoglobin levels, and Δ9-THC activation of CB1 receptors induces a cardiovascular stress response; raising heart rate and blood pressure, decreasing the anginal threshold, and promoting acute coronary syndromes. Overall, smoking marijuana probably has a negative effect on the cardiovascular system. For these reasons, therapeutic strategies using the apparent anti-inflammatory properties of Δ9-THC will probably depend upon developing specific CB2-receptor agonists, to prevent the onset of psychotropic effects. Once thoroughly tested in animal models, translation to human trials could see the positive effects reported by Steffens et al. clinically realized.
Activation of the endocannabinoid system through the CB1 receptor plays an important role in central and peripheral regulation of energy balance, body weight and food intake. Blockade of the CB1 receptor appears to offer great promise in cardiometabolic risk reduction, and 1-year results from the RIO program are very encouraging.[2] In this trial, 1,507 patients with a BMI of at least 30 kg/m2, or at least 27 kg/m2 or more with treated or untreated dyslipidemia, hypertension or both, received double-blind treatment with 5 mg rimonabant—a selective CB1 receptor blocker—daily, 20 mg rimonabant daily, or placebo, in addition to a hypocaloric diet. Treatment with 20 mg rimonabant for 1 year significantly decreased total body weight and waist circumference, and produced a significant weight-independent effect on lipid parameters and several other cardiovascular risk factors. The beneficial changes to the lipid profile remained significant after adjusting for weight loss. Furthermore, treatment resulted in a significant reduction in fasting plasma glucose, fasting plasma insulin, insulin resistance and the proportion of patients who fulfilled the criteria for the metabolic syndrome compared with placebo. To explain the observed weight-independent effect on both lipid and glycemic variables, Van Gaal et al. hypothesized that enhanced rimonabant-induced expression of adiponectin—a cytokine that has a role in the regulation of hyperglycemia, hyperinsulinemia and fatty acid oxidation and is reduced in obese individuals—could be responsible.[2] Thus, by improving adipocyte function, rimonabant might contribute to beneficial changes in other adipokines, such as C-reactive protein, reinforcing the link between obesity and atherosclerosis.[7] Further investigation of in vivo effects of rimonabant are required to fully elucidate this mechanism, especially given the concern that CB1 antagonists might raise blood pressure.[8] Furthermore, rimonabant appears to be a useful agent for smoking cessation, yet another cardiac risk factor.[9] Thus, pharmacologic manipulation of cannabinoid-receptor signaling might combat the development of atherosclerosis through the treatment of obesity, the metabolic syndrome, vascular inflammation and smoking. The beneficial effects with rimonobant appear to be consistent in over 6,600 patients enrolled in the RIO program. Patients administered this drug enjoy sustained reductions in weight, BMI and visceral adiposity, and improvements in insulin sensitivity and dyslipidemia. More importantly, the beneficial effects to counter insulin resistance, improve dyslipidemia and increase adiponectin, are only partly explained by the reduction in weight, indicating a potential direct role for CB1 in adipogenesis and lipid derangement.
The results of the RIO program and the study by Steffens et al. indicate that modulating the activity of the endocannabinoid system holds promise as an approach to treating obesity, dyslipidemia and atherogenesis.[1,2] The CB1 and CB2 receptors might have opposing effects on atherogenesis: whereas central CB1-receptor blockade offers hope for atherogenic risk reduction, peripheral CB2-receptor stimulation in animals has powerful anti-atherosclerotic effects. It is possible that a strategy of CB1-receptor antagonism and CB2-receptor agonism might emerge as the most effective treatment across the spectrum of insulin resistance and vascular disease. It is paradoxical that studying the effects of cannabis, an illicit drug that provides society with numerous social problems, could serve as the basis for novel therapeutic strategies to reduce cardiometabolic risk.
References
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Van Gaal LF et al. (2005) Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365: 1389-1397
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Osei-Hyiaman D et al. (2005) Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 115: 1298-1305
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Le Foll B et al. (2004) Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place preferences. Neuroreport 15: 2139-2143
Correspondence: Subodh Verma, Division of Cardiac Surgery, St Michael’s Hospital—8th floor Bond Wing, 30 Bond Street, Toronto, ON M5B 1W8, Canada. Email: subodh.verma@sympatico.ca
PE Szmitko is a Resident in the Division of General Internal Medicine, and S Verma is a Scientist and Assistant Professor in the Division of Cardiac Surgery, St Michael’s Hospital, at the University of Toronto, Toronto, ON, Canada.
Competing interests: The authors declared no competing interests.
