Ginkgo biloba: a living fossil

In 1998, Americans spent about 4 billion dollars on botanical medicines (1, 2) and Ginkgo biloba ranked first among herbal medications sold in health food stores (3). Ginkgo biloba, whose medicinal uses were described in the Chinese Materia Medica more than 2,000 years ago, is used most frequently to treat memory and cognitive impairment, for which it has moderate efficacy with minimal side effects (4 –9). Some patients also use ginkgo to treat symptoms of claudication, a condition for which the German Federal Health Agency considers it to be effective (10). Ginkgo biloba comes from the leaves of the ginkgo tree, one of the oldest living plant species. Dating back more than 200 million years, it is often referred to as “a living fossil.” Because its leaves resemble the maidenhair fern, it is also known as the maidenhair tree. Unrelated to any other living plant species, it grows throughout China, Korea, Japan, Europe, and the United States. Ginkgo trees can be up to 100 feet tall, 50 feet in circumference, and can live for as long as 1000 years. After the nuclear bomb was detonated in Hiroshima, they were the first plants to re-grow and were free of signs of genetic mutation. Partly because of their hardiness, the trees are frequently planted in large cities such as New York and Tokyo. The ginkgo leaf contains many active ingredients, including flavonol and flavone glycosides, diterpene lactones, ginkgolides, sesquiterpenes, iron-based superoxide dismutase, p-hydroxybenzoic acid, ascorbic acid, and catechin. The crude drug formulation of ginkgo is obtained from the dried green leaves. An acetone-water mixture is used to extract and concentrate the active constituents and remove toxic compounds such as ginkgolic acids. The German government has approved a standardized form of ginkgo leaf extract (Egb761) which contains 22% to 27% flavonoid glycosides, 5% to 7% terpene lactones, and , 5 parts per million of ginkgolic acids. The flavonoid glycosides are considered to be a major active ingredient in the extract, and manufacturers commonly standardize their product to a flavonoid glycosides content of 24%. Ginkgolic acids are potentially allergenic and toxic; they share similar properties to the urushiols that are found in mango rind, cashew nut shells, and the sumac-poison ivy family. How might this living fossil help patients with dementia or peripheral arterial disease? A common pathway for both diseases may be improved tissue perfusion and increased tolerance of hypoxia. The flavonoid glycosides seem to have antioxidant activity, and they may reduce endothelial cell injury due to free radical oxidation, thereby reducing the progression of atherosclerosis (11, 12). Flavonoids may also protect hypoxic tissue. In the early phases of brain ischemia, massive release of free fatty acids and the accumulation of platelet activating factor result in the production of free radicals that are extremely neurotoxic. Ginkgolide B, a terpene, is a platelet-activating factor antagonist and may provide some of the neuroprotective and antithrombotic properties attributed to ginkgo (13–15). Additional suggested mechanisms include reduced capillary fragility and decreased erythrocyte aggregation activity (13,16). Finally, the flavonoid glycosides and ginkgolide B may inhibit other events, which include platelet aggregation, platelet adherence, and oxidized lipoprotein formation, that lead to atherosclerosis and vascular injury. In this issue of The Green Journal, Pittler and Ernst report the results of their meta-analysis of the use of Ginkgo biloba extract for patients with intermittent claudication (17). Peripheral arterial disease affects about 1 in 8 elderly patients (18), although not all have intermittent claudication (19). While the majority of nondiabetic patients with this condition remain stable, approximately 10% to 15% have progressive disease, and some require amputation. Therapeutic interventions are targeted at reducing cardiovascular risk factors, especially tobacco smoking, and promoting regular exercise with the goal of increasing exercise tolerance. Pharmacologic treatment has been less successful; in particular, vasodilators have not proven effective. Current options approved by the Food and Drug Administration (FDA) include pentoxifylline and cilostazol. It can be difficult to determine the efficacy of therapies for intermittent claudication. Proper evaluation requires using objective measures such as exercise performance and hemodynamic measurements, as well as subjective measures that include questions about walking impairment, physical activity, and general health status (20). In the meta-analysis reported in this issue of The Green Journal, Pittler and Ernst used pain-free and maximal walking distance as their primary outcomes. There is controversy about which of these two measurements provides a better assessment of clinical status. Recently, Muller-Beuhl and colleagues evaluated a cohort of 150 patients to determine which of these two parameters was more closely associated with angiographic findings and Am J Med 2000;108:341–342. From the Osher Center for Integrative Medicine (BPJ) and Department of Medicine (BPJ, WSB), University of California at San Francisco, San Francisco, California. Correspondence should be addressed to Bradly P. Jacobs, MD, Senior Clinical Research Fellow, Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, California 94121.