Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice

Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries(1). Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions(2) and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1 mg kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor ( the main cannabinoid receptor expressed on immune cells(2,3)) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis(1), was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist(4). Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.