LONDON - Researchers in the UK are designing a clinical trial to evaluate the use of a constituent of cannabis in rheumatoid arthritis, following promising results in a mouse model of the disease.

A recently published study by the group has shown that cannabidiol, a non-psychoactive part of cannabis, is as effective in treating rheumatoid arthritis in mice as antibody therapies that block the cytokine, tumor necrosis factor (TNF).

Marc Feldmann, head of the Cytokine and Cellular Immunology Department at the Kennedy Institute of Rheumatology Division of Imperial College School of Medicine in London, told BioWorld International: "We showed that cannabidiol worked well when given orally, in both short-term and long-term arthritis models in mice."

The study, by Feldmann in collaboration with researchers Rafi Mechoulam and Ruth Gallily at Hadassah Medical School in Jerusalem, was reported in the Aug. 15, 2000, Proceedings of the National Academy of Sciences in a paper titled, "The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis."

Feldmann and clinical colleague Ravinder Maini at the Kennedy Institute of Rheumatology will receive the Crafoord Prize from the Royal Swedish Academy on Sept. 18 for their discovery of the principle that TNF is a good therapeutic target in rheumatoid arthritis.

The group is looking for partners to help develop the work reported in PNAS. "There are obstacles to using cannabis constituents clinically but these can be negotiated if there is good reason, as provided by these encouraging results," Feldmann said.

Earlier this year, the UK Medical Research Council said it was spending #950,000 (US$1.4 million) on a trial to evaluate the therapeutic effects of cannabis extract on leg spasms in patients with multiple sclerosis. Some patients in this trial will receive a constituent of cannabis called tetrahydrocannabinol.

Many studies, said Feldmann, have shown that tetrahydrocannabinol has anti-inflammatory properties, but his Israeli collaborators had shown that other cannabinoids also had similar effects. "Cannabidiol is not psychoactive and would therefore be the least difficult agent to move forward with clinically," he said. "We therefore set out to see if it was anti-inflammatory enough to have an important effect on a condition like rheumatoid arthritis."

The group also was motivated in part by the need to identify new oral anti-inflammatory agents for rheumatoid arthritis (RA). Previous research initiated by Feldmann and Maini had shown that blocking TNF could be therapeutically helpful in RA, but such treatments must be injected. This work provided the rationale for the use of TNF inhibitors and now two such therapies - Remicade and Enbrel - are approved for use in the U.S. and Europe for RA.

For the studies reported in PNAS, the group used a mouse model of rheumatoid arthritis that involves immunizing the animals with collagen type II. Depending on whether the collagen used is bovine or murine, acute or chronic arthritis develops in the animals.

Cannabidiol was given either intraperitoneally or orally, starting with the first signs of arthritis. The researchers found that very low and high doses of cannabidiol intraperitoneally had little effect, but that an intermediate dose of 5 milligrams per kilogram of body weight was optimal, and suppressed the animals' symptoms.

When the team scored mice with chronic disease according to disease severity over a period of 28 days, the score for mice in the group treated with 5 mg per day was 28.9, while that for controls was 38.4.

Cannabidiol also was effective when given orally. The dose most effective in suppressing symptoms in mice with acute arthritis was 25 milligrams per kilogram of body weight. This dose in the mouse model of chronic arthritis produced severity scores over a period of four weeks of 49.7, compared with 72.3 for controls.

One of the most important findings, said Feldmann, was that in acute collagen-induced arthritis, animals treated with 5 mg/kg of cannabidiol, given intraperitoneally, were protected to some degree from joint damage. In these experiments, none of the control animals had normal feet, while 34 percent of feet of treated mice were completely normal.

Histological and immunological tests further demonstrated some of the mechanisms by which the cannabidiol had its effect. For example, cells from the synovium - the lining of the joints - in mice with arthritis produce large amounts of TNF when cultured in vitro. But synovial cells taken from mice that had been treated with cannabidiol released significantly less TNF when cultured in vitro, than synovial cells taken from control mice. Feldmann said, "We also carried out tests on lymph node cells which showed that these produced markedly less interferon-gamma, which is an important proinflammatory T-cell mediator."

In PNAS, Feldmann and his colleagues concluded: "The anti-arthritic potency of cannabidiol seems to be the result of a combination of immunosuppression . . . and an anti-inflammatory action by way of reducing TNF in the synovium, a combination that has proven successful in the past."

The efficacy of cannabidiol when given orally, they added, "renders it an attractive candidate for the treatment of rheumatoid arthritis." Trials of cannabidiol for the treatment of Huntington's disease already have found that giving this substance orally for six weeks at up to 10 mg/kg a day had no side effects, the group observed.

Further studies planned will attempt to answer the question of whether cannabidiol itself is responsible for the therapeutic effects observed, or whether a metabolite is involved. Secondly, the team wants to know which receptor cannabidiol binds to. Studies already have shown that cannabidiol has only weak affinity for the two cannabinoid receptors, CB1 and CB2, which have been identified so far.

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