George Nemecz, Ph.D.
Assistant Professor of Biochemistry

Wendell L. Combest, Ph.D.
Associate Professor of Pharmacology
Department of Pharmaceutical Sciences
Campbell University School of Pharmacy
Buies Creek, NC

Ginkgo biloba, often referred to by its common names Maidenhair tree or simply Ginkgo, is the only living member of the Ginkgo family (Ginkgoaceae). Surviving essentially unchanged for over 200 million years, the Gingko tree is recognized for its sturdiness, resistance to disease and remarkable longevity. Individual trees may live as long as 1,000 years. Traveling back in time to the era of dinosaurs we would see this tree in a "Jurassic Park." Ginkgo survives in its native state only in a few isolated mountain ranges in eastern China. However, it has been extensively cultivated in China, Korea, Japan and in other areas of the world. Ginkgo tree plantations in the U.S. have been established to supply the expanding market for the leaf extract. Today Ginkgo trees are popular in cities and parks throughout the eastern U.S. and Canada. The earliest record of Ginkgo’s medicinal use can be found in the ancient Chinese Materia Medica Pen Tsao Ching dating back to 2800 B.C., describing how aging members of the royal court were treated for senility.1

Active Ingredients and Plant Parts Used

In the West, the extract or tincture from the leaves are primarily used in medicinal preparations. In Chinese traditional medicine, the seed kernels are also commonly used. The typical standardized Ginkgo biloba leaf extract (GBE) contains ginkgolides, bilobalide, bioflavones and flavone glycosides.2 Flavone glycosides include quercetin, 3-methylquercetin and kempferol.3 Quercetin, myrcetin and the rest of the flavonoid fraction of the extract have antioxidant and free radical scavenger effects.3-4

Ginkgolides are a family of bioactive terpenes isolated from the root bark and leaves, and are thought to provide for the neuroprotective properties of the leaf extract.4

Medicinal Use

Throughout most of its medicinal history, the leaves and fruit of the Ginkgo tree have been used for their antimicrobial, anti-inflammatory, and vasodilatory effects. Today, concentrated and standardized Ginkgo biloba leaf extracts have largely replaced the more crude dried leaf preparations. The primary therapeutic use is now enhancement of various CNS functions such as short-term memory, concentration and alertness, particularly in the elderly. Indeed, most of the recent research concentrates on brain function and cerebral circulation. A summary of more than 40 recent clinical trials investigating the effect of GBE on cerebral insufficiency has been published.5

Standardized GBE administered for 4–6 weeks at a dose of 120 mg/day showed impressive positive results in almost all trials conducted. One interesting double-blinded, placebo-controlled study involving 48 patients between the ages of 51 and 79 tested the effect of GBE (120 mg/day) on general cognitive function.6 The results showed that the Ginkgo treatment group had a significantly shorter stimulus-recognition time compared to controls. Other studies in healthy subjects have documented improvements in short-term memory and other mental abilities, such as improved concentration after taking GBE.7 One long-term aging study utilizing 166 subjects showed a significant improvement in behavioral and clinical tests following three months of GBE treatment.8

The cognitive and behavioral effects of GBE may benefit certain forms of dementia, particularly Alzheimer’s disease. The efficacy of GBE in Alzheimer’s disease and multi-infarct dementia was assessed in a recent randomized, double-blinded, placebo-controlled, multicenter study involving 216 patients.9 Randomized groups received either 240 mg/day of GBE or a placebo and were assessed after a 24-week treatment period. Results based on a multidimensional evaluation tool indicated significant positive effects of GBE in both forms of dementia.

Pharmacologic Mechanisms

The pharmacologic basis of the effects of GBE on brain function has been addressed in a number of animal studies. Several studies have been performed in the rat, utilizing a cerebral insufficiency model in which the blood flow to the brain was reduced by a mechanical blockage of the carotid artery.10,11 Ginkgo biloba extract protected the animals against ischemic brain damage as evidenced by increased levels of glucose and ATP in brain neurons. Another study demonstrated that brain neuronal damage produced by exposure of mice to a neurotoxic agent was significantly reduced by treatment with GBE.12

The neuroprotective effects of GBE could be explained by biochemical effects of various constituents of the extract. The increased blood flow to the brain is likely due to GBE promotion of arterial vasodilation via stimulation of prostaglandin biosynthesis or indirectly by stimulation of norepinephrine release.13,14 Flavones in GBE reduce capillary fragility and protect against capillary blood loss and resultant edema.15 Ginkgolides, especially ginkgolide B, inhibit platelet-activating factor (PAF), which normally induces blood platelet aggregation, among many other effects.4 The resulting increase in blood fluidity could also be a factor in increasing the cerebral circulation and preventing thrombus formation and strokes.

The well-demonstrated potent antioxidant effect of GBE is also an important part of the neuroprotective effect. The ability of GBE to exhibit antioxidant properties has been actively studied in numerous models of oxidative stress. One study, using macrophages and vascular endothelial cells, involved exposure of cells to an oxidative stress that normally results in cell membrane damage and loss of cell viability.16 Ginkgo biloba extract protected biomembranes from oxidative injury and minimized cell loss by acting as an oxygen free radical scavenger. In another study, cultured rat cerebellar neuronal cells were exposed to hydroxyl radicals, creating an oxidative stress which induced a programmed cell death.17 Pretreatment of cells with GBE reduced the hydroxyl radical-induced cell damage and death. Another study in rats involved carotid artery occlusion and examination of oxidative damage in the brain following ischemia and reperfusion.18 Ginkgo was shown to prevent much of this oxidative brain damage. The antioxidant/free-radical protective effect of GBE has also been studied in various cardiac ischemic models. The GBE-treated group in one study showed a significant decrease in the intensity of ventricular fibrillation as well as in the occurrence of other arrhythmias.19 These studies in the brain and heart clearly indicate GBE’s potential value in preventing and treating disorders related to free radical-induced pathology.

Another apparent benefit of GBE is in treating certain cases of tinnitus (ringing in the ears).20 Although GBE may help some patients, it can also fail in other cases due to the diverse etiology of tinnitus. Similar results have been published for the successful treatment of hearing loss by GBE.21 GBE’s efficacy in treating these conditions is likely related to its ability to increase cerebral blood flow and prevent oxidative brain damage.

Consistent with GBE’s ability to increase blood flow to the brain, it improves peripheral circulation in patients with intermittent claudication. Ginkgo biloba treatment (120 mg/day) for up to 24 weeks significantly extended pain-free walking distance in patients with angiographically proven peripheral arterial occlusive disease of the lower extremities.22 This randomized, placebo-controlled, double-blind trial involved 60 patients aged 47 to 82.

The anti-inflammatory results seen with GBE are most likely due to its inhibition of platelet-activating factor (PAF), a potent inflammatory autocoid, as well as its inhibition of platelet aggregation. Ginkgolides—especially ginkgolide B—are responsible for this inhibitory action. Platelet-activating factor is produced and plays a significant role in an allergic response.23 It is increasingly apparent that PAF plays an important role in many pathologies, such as asthma, ischemia, renal disease and CNS disorders. Therefore, the pharmacologic basis of many of GBE’s therapeutic effects could involve PAF inhibition and reduction of the inflammatory aspect of a number of disease states.

In summary, GBE has basically three important effects on the body: 1) It improves blood flow to most tissues and organs, especially the brain and heart; 2) It protects against oxidative cell damage from free radicals; and 3) It blocks many of the effects of PAF that have been implicated in the development of a number of cardiovascular, renal, respiratory and CNS disorders.

Available Preparations

Ginkgo biloba is most commonly sold as capsules or tablets containing 40, 60, or 120 mg of a concentrated (50:1) leaf extract. The extract is standardized to contain 24% flavonoids (mostly flavone glycosides) and 6% terpenes (principally ginkgolides). This standardized product was originally manufactured in Germany and was based upon clinical studies to determine the level of the major leaf extract components necessary for the maximum therapeutic benefit. Ginkgo biloba extract has for many years been one of the best-selling drugs in Germany, both as a prescription and an over-the-counter drug. Because of the need to concentrate the leaf extract to achieve a proven clinical effect, it is doubtful that whole leaf preparations are effective, although several such preparations are available. Usual dosage recommendations are a total of 120 mg of standardized extract per day for treatment periods up to six weeks. Other formulations include sublingual sprays, which deliver 40 mg per spray, or concentrated liquid extracts.

Dosage Recommendations and Side Effects

Few, if any, significant side effects have been documented. Rarely, gastrointestinal disturbances, headaches and allergic skin reactions have been reported. However, these side effects usually arise following prolonged administration. A small number of cases of bilateral subdural hematomas have been reported and putatively linked to prolonged use of GBE (up to two years).24,25 Ginkgo biloba’s ability to inhibit PAF-induced platelet aggregation could prolong bleeding time and should be considered, especially when other anticoagulant drugs, including aspirin, are given.

Although Ginko biloba has been shown to inhibit platelet-activating factor, there seems to be little evidence in the literature that indicates problems with prolonged bleeding when it is taken in the usual therapeutic doses for short periods of time. Because there has been at least one report demonstrating a prolonged bleeding time associated with chronic Ginkgo biloba treatment (daily intake for a two-year period), it seems prudent to exercise caution, especially when taking Ginkgo biloba along with other herbs or drugs known to have anticoagulant effects. When used judiciously in appropriate patients, however, Ginkgo biloba appears to offer a number of promising benefits.

References

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