The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis

Abstract

The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA͞1 mice with type II collagen (CII) in complete Freund's adjuvant. The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg͞kg per day i.p. or 25 mg͞kg per day orally. Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-␥ production, as well as a decreased release of tumor necrosis factor by knee synovial cells. In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes. It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57͞BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.

Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

“…Although stimulation of VR1 receptors leads to vasodilation and in¯ammation, capsaicin and its long chain analogues exert anti-in¯ammatory e ects by rapidly desensitizing VR1 receptors to the action of nociceptive stimuli and causing depletion of sensory vasoactive neuropeptides (Szallasi & Blumberg, 1999). CBD also induces anti-in¯ammatory e ects, a possible explanation for this property being its capability of modulating the release of anti-in¯ammatory or pro-in¯ammatory mediators (Srivastava et al, 1998, Malfait et al, 2000. CBD and capsaicin also have in common anti-convulsive and anti-rheumatoidarthritis e ects (Consroe et al, 1981;Dib & Falchi, 1996;Malfait et al, 2000;Lorton et al, 2000).…”

“…CBD also induces anti-in¯ammatory e ects, a possible explanation for this property being its capability of modulating the release of anti-in¯ammatory or pro-in¯ammatory mediators (Srivastava et al, 1998, Malfait et al, 2000. CBD and capsaicin also have in common anti-convulsive and anti-rheumatoidarthritis e ects (Consroe et al, 1981;Dib & Falchi, 1996;Malfait et al, 2000;Lorton et al, 2000). Here we found that CBD, compared to capsaicin, is a full, although weak, agonist of human VR1 at concentrations that might be (4) Cannabidiol, VR1 receptors and anandamide inactivation T. Bisogno et alattained after administration of this compound at the doses often used in vivo (10 ± 50 mg kg 71 in men), and lower than those required for CBD to bind to cannabinoid receptors.…”

“…together with the earlier ®nding of the anti anxiety (Guimaraes et al, 1994), neuro-protective and anti-convulsive activity of CBD and some of its analogues (Consroe et al, 1981;Martin et al, 1987), indicate that CBD may also exert cyto-protective e ects by inhibiting the release of in¯ammatory cytokines from blood cells (Srivastava et al, 1998;Malfait et al, 2000), thus producing an antiin¯ammatory action, for example against rheumatoid arthritis (Malfait et al, 2000). These e ects of CBD may be due to its anti-oxidant properties (Hampson et al, 1998), to its direct interaction with cytochrome p450-enzymes (Bornheim & Correia, 1989) and other enzymes of the`arachidonate cascade' (Burstein et al, 1985), or to an action at a speci®c receptor.…”

Cannabinoids and neuroinflammation

“…THC induces apoptosis in macrophages (Zhu et al, 1998). Cannabidiol causes a dose-dependent suppression of lymphocyte proliferation (Malfait et al, 2000). D 8 -THC, CP55940, and anandamide also suppress T-and B-cell proliferation (Schwarz et al, 1994).…”

“…2-AG increases NO in human monocytes, and this is blocked by SR141716A, but not SR144528 (Stefano et al, 2000). 2-AG does not alter NO from mouse macrophages (Gallily et al, 2000). Why plant and synthetic cannabinoid agonists induce the opposite response to endocannabinoids is an open question.…”