Drug Profile

Background

Ginkgo biloba is a dietary supplement thought to be helpful in treating dementia. It is thought that an extract from the leaf of the ginkgo biloba (or maidenhair) tree was used in “traditional” Chinese herbal medicines. The tree is indigenous to China, Korea and Japan, although to satisfy the demand for its use as a “natural therapy,” it is now cultivated on an industrial scale in South Carolina, France, Korea, Japan and China.

In Germany, the extract was introduced in 1965 and has been approved in that country for the treatment of dementia. The active ingredients in ginkgo biloba extract are thought to be the flavonoids, terpenoids and terpene lactones. The most common extract is called EGb 761, but there are several others.[1],[2]

Claimed uses

Although a multitude of conditions said to be improved by ginkgo biloba have been set forth, the primary focus has been on the treatment of memory loss and dementia. (We do not review in detail studies of normal people investigating the supplement’s effect on memory enhancement, but two randomized, placebo-controlled trials show no such effectiveness.)[3],[4]

Memory loss and dementia

There are many problems that prevent a proper evaluation of the very large amount of literature on this use of ginkgo biloba. Many studies are in foreign languages, do not appear in the National Library of Medicine’s database and are small or unblinded (meaning results can be unrepresentative because the people in the study do not adequately represent the population as a whole). Others involved healthy volunteers or a variety of patients carrying different or unclear diagnoses. Many studies use nonstandardized measures of mental function and these vary from study to study.

Despite these inconsistencies, there is a meta-analysis of the effect of ginkgo biloba on “cognitive impairment and dementia.”[5] The meta-analysis combined studies with different outcomes, different doses and formulations of ginkgo biloba, and different patient populations and included many short-term studies, all factors which weaken the strength of the meta-analysis results. It concluded that “there is promising evidence of improvement in cognition and function associated with Ginkgo.”[5]

This conclusion does not seem supportable. The studies should probably not have been combined in the first place because the individual studies were not sufficiently similar to be compared. The studies usually conducted “completers” analyses only; this means that only patients who completed the trial (and were probably more likely to be benefiting) were included in the analyses, and most researchers agree that this is not the best basis for analysis. The Food and Drug Administration (FDA) would doubtless not accept a “completers” analysis. Further, even the authors of the meta-analysis concede that “the three more modern trials show inconsistent results” and call for a large trial “using modern technology” with an intention-to-treat analysis.[1]

Even these three so-called modern trials provide little support for the use of ginkgo biloba for dementia or related conditions. The first study had a 35 percent dropout rate and allowed patients with unsatisfactory responses in the ginkgo biloba or placebo groups to take ginkgo biloba.[5] The second study mentioned in the meta-analysis is not in the National Library of Medicine database. The most recent study made a particular effort to ensure that the placebo had a similar harsh taste to the ginkgo biloba pills and showed no statistically significant benefits.[6]

A 2009 JAMA article featured another study, also looking at the effectiveness of ginkgo biloba compared to a placebo for the prevention of dementia. The results of this study found that ginkgo biloba showed no benefit over placebo in preventing dementia. [7]

Ringing in the ears (tinnitus)

We were able to identify only two studies evaluating ginkgo biloba for the treatment of tinnitus.

In the first, all patients were treated with intravenous ginkgo biloba before being randomized to ginkgo biloba or placebo.[8] The small effect claimed cannot be interpreted because only 37 percent of patients completed the study.

A much larger, randomized, placebo-controlled trial did not involve any intravenous infusions and simply randomized patients to ginkgo biloba or placebo for 12 weeks.[9] The study was dependent on self-reported data from the patients. There was no evidence of ginkgo biloba effectiveness for tinnitus.

Other claimed uses

The Ginkgo Evaluation of Memory Study trial was conducted to determine the effects of ginkgo biloba and the incidence of dementia. A secondary outcome of the trial was to evaluate the effects of ginkgo biloba and cardiovascular disease. The conclusion of this secondary analysis, according to the authors of the article, stated that the data did not show evidence that ginkgo biloba reduced cardiovascular disease mortality or events.[10]

We identified numerous other potential uses for which only a single randomized, controlled trial had been conducted. In general, any positive finding needs to be replicated by at least one more study of adequate quality before it should gain acceptance. A single study each claimed effectiveness for ginkgo biloba against peripheral arterial disease,[11] vitiligo (patches of light-colored skin),[12] glaucoma[13] and schizophrenia,[14] but these studies were small, not properly randomized, and/or lacking in objective measurements of outcomes.

Single studies of ginkgo biloba for cocaine dependence,[15] sexual dysfunction[16] and winter depression[17] all showed no impact of the supplement.

Interactions with other drugs

The FDA has warned that ginkgo biloba can increase the effectiveness of warfarin (COUMADIN), which could lead to bleeding.[18] While the warfarin label must warn of this interaction with ginkgo biloba, ginkgo biloba may be sold without warning of the interaction with warfarin. Interactions with ginkgo biloba have also been suggested for aspirin, ticlodipine (TICLID), clopidogrel (PLAVIX) and dipyridamole (PERSANTINE).[19],[20],[21]

Side effects

Like all dietary supplements, there is no assurance that the supplement actually contains the advertised ingredient. Thirteen of 14 ginkgo biloba products sampled in Hong Kong turned out to have amounts of ginkgolic acid (a known cause of allergies) higher than those recommended by the World Health Organization.[22] Another study demonstrated that the amount of ginkgo biloba released into the bloodstream by different formulations of the supplement varied widely.[23]

Although ginkgo biloba is generally well tolerated, there are multiple reports of seizures[24],[25] and bleeding into the brain,[26],[27],[28],[29] eye[30],[31] and abdomen[32] associated with use of the supplement.

Conclusion

There are a variety of reasons that have been suggested as an explanation for the apparent benefits of ginkgo biloba:

1. dilation of blood vessels and consequent improved blood flow, particularly to the brain;
2. interference with platelet aggregation and prevention of clots;
3. modifying neurotransmitter systems;
4. an antioxidant action that may curb the creation of free radicals that may injure nerve and other cells.[1]

In the end, however, these reasons are only based in theory; for both drugs and dietary supplements, there is a need to demonstrate clinical effectiveness in properly designed studies. In this case, the reality of the studies gives lie to the theories.

The available data are insufficient to support the use of ginkgo biloba for improving mental function, dementia, tinnitus or anything else. The U.S. National Institute on Aging is now sponsoring a clinical trial on the effectiveness of ginkgo biloba in the treatment of Alzheimer’s disease.

In 2009 an article was published by the Cochrane database looking at the efficacy and safety of ginkgo biloba when used for dementia and cognitive decline. Data were reviewed from published reports and the author concluded that there is “no convincing evidence that Ginkgo biloba is efficacious for dementia and cognitive impairment.” The author went on to say:

Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. The evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.[33]

A recent Journal of Parenteral and Enteral Nutrition (JPEN) systematic review revealed that, with a few possible exceptions, dietary supplements offer no benefits to well-nourished adults eating a Western diet and, in many cases, may be harmful. The results of this study reinforce Worst Pills, Best Pills News’ longstanding view that there is little evidence that dietary supplements are either safe or effective.

The study authors concluded that with the possible exception of vitamin D in elderly patients and omega-3 fatty acids in patients with a history of cardiovascular disease, no data support the widespread use of dietary supplements in the U.S. and other Western countries. Indeed, the data suggest that certain commonly used dietary supplements, including beta-carotene, vitamin A and vitamin E, may be harmful. We agree.[34]