NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD

The Efficacy of Ginkgo biloba on Cognitive Function

in Alzheimer Disease
Barry S. Oken, MD; Daniel M. Storzbach, PhD; Jeffrey A. Kaye, MD

Objective: To determine the effect of treatment with

Ginkgo biloba extract on objective measures of cognitive

function in patients with Alzheimer disease (AD) based
on formal review of the current literature.
Methods: An attempt was made to identify all English and

nonEnglish-language articles in which G biloba extract was

given to subjects with dementia or cognitive impairment.
Inclusion criteria for the meta-analysis were (1) sufficiently characterized patients such that it was clearly stated
there was a diagnosis of AD by either Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition,
or National Institute of Neurological Disorders and Stroke
Alzheimers Disease and Related Disorders Association criteria, or there was enough clinical detail to determine this
by our review; (2) clearly stated study exclusion criteria,
ie, those studies that did not have stated exclusions for depression, other neurologic disease, and central nervous systemactive medications were excluded; (3) use of standardized ginkgo extract in any stated dose; (4) randomized,
placebo-controlled and double-blind study design; (5) at
least 1 outcome measure was an objective assessment of
cognitive function; and (6) sufficient statistical information to allow for meta-analysis.
Results: Of more than 50 articles identified, the over-

whelming majority did not meet inclusion criteria, primarily because of lack of clear diagnoses of dementia and
AD. Only 4 studies met all inclusion criteria. In total there
were 212 subjects in each of the placebo and ginkgo treatment groups. Overall there was a significant effect size
of 0.40 (P,.0001). This modest effect size translated into
a 3% difference in the Alzheimer Disease Assessment
Scalecognitive subtest.
Conclusions: Based on a quantitative analysis of the lit-

erature there is a small but significant effect of 3- to 6month treatment with 120 to 240 mg of G biloba extract
on objective measures of cognitive function in AD. The
drug has not had significant adverse effects in formal clinical trials but there are 2 case reports of bleeding complications. In AD, there are limited and inconsistent data
that preclude determining if there are effects on noncognitive behavioral and functional measures as well as on
clinicians global rating scales. Further research in the area
will need to determine if there are functional improvements and to determine the best dosage. Additional
research will be needed to define which ingredients in
the ginkgo extract are producing its effect in individuals
with AD.
Arch Neurol. 1998;55:1409-1415

From the Department of

Neurology (Drs Oken and
Kaye) and Center for Research
on Occupational and
Environmental Toxicology
(Dr Storzbach), Oregon Health
Sciences University, and
Portland Veteran Affairs
Medical Center (Dr Kaye),
Portland.

INKGO BILOBA is a living

fossil tree having undergone little evolutionary
change over almost 200
million years. While currently it is essentially extinct in the wild,
it is widely cultivated for its nut as well
as for its leaves. The tree has a high tolerance to urban and industrial pollution
and is extremely resistant to insects, bacteria, viruses, and fungi. Extracts of the
leaves have been used for 5000 years in traditional Chinese medicine for various purposes. Medicinal extracts are made from
dried leaves. Studies on the biological activity of different components of the ginkgo
leaf began with modern scientific methods about 20 years ago.

Currently, ginkgo extracts used for

medicinal purposes are usually standardized to contain 24% ginkgo-flavone
glycosides and 6% terpenoids. The
terpenoids include bilobalide and the
ginkgolides A, B, C, M, and J that are
20-carbon cage molecules with six 5membered rings. The ginkgolides are antagonists of platelet-activating factor (PAF)
that has numerous biological effects.1 Besides causing platelet activation and aggregation, PAF produces proinflammatory effects (eg, increasing vascular
permeability), is an extremely potent ulcerogen in the stomach, and contracts
smooth muscle, including bronchial
muscle. Platelet-activating factor has a direct effect on neuronal function and long-

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METHODS
We attempted to identify all randomized placebocontrolled clinical trials (both English and non
English language) in which G biloba was administered for at least 2 months to patients with dementia
or other cognitive impairment. The search for potentially relevant studies and reviews was performed through MEDLINE using the keywords
ginkgo and gingko [sic]. Trials referenced by articles that were found were also screened. Additionally, we had access to a listing of 60 articles with English summaries from a preliminary Cochrane
Collaboration Review (http://www.cochrane.co.uk)
on the use of ginkgo in dementia and related disorders. This search was done using several databases
including MEDLINE, EMBASE, and PsychLit as well
as references in review articles and textbooks. Additional search words included brand names for ginkgo
(eg, Tanakan, Tebonin, Rokan, or Ginkoba) and a
standardized extract, EGb 761.
Our goal was to evaluate only those studies that
met minimally acceptable scientific standards. We
therefore used the following criteria for inclusion in
the quantitative review.
Patients needed to be clearly and sufficiently
characterized such that there was a clearly stated diagnosis of AD by either Diagnostic and Statistical
Manual of Mental Disorders, Revised Third Edition or
National Institute of Neurological Disorders and
StrokeAlzheimers Disease and Related Disorders Association criteria, or there was enough clinical detail to determine this by our review.
Studies needed to clearly state their exclusion criteria, ie, those studies that did not have stated
exclusions for depression, other neurologic disease,
and central nervous systemactive medications were
excluded. We did not exclude trials solely for the lack
of neuroimaging studies on all subjects.
The use of standardized ginkgo extract in
any stated dose was required (24% or 25% ginkgoflavone glycosides and 6% terpenoids, see above). The
dose could be given by any route of administration.
The study needed to be randomized, placebocontrolled, and double-blind. Details of the randomization procedure were not required.
At least 1 outcome measure needed to be an
objective assessment of cognitive function.
The studies that met these inclusion criteria are
listed in Table 1. Studies also needed to include descriptive statistics from which effect sizes27,28 could
be computed. This only caused the exclusion of 1 article in Table 1 from the quantitative analysis.
Meta-analytic methodology was used to quantitatively assess the effects of ginkgo on objective measures of cognition for all studies that were found to
meet the above-listed criteria. This statistical methodology involves computation of individual effect
sizes27,28 for each study sample which, after weighting for sample size, becomes a single case to be used
in subsequent analyses. For each evaluated study we
computed the effect size (g statistic) according to the
methodology of Hedges and Olkin.28

term potentiation.2,3 An initial report4 suggested that lissencephaly, a disorder of neural migration and dendritic
branching, was associated with changes in the gene coding a PAF inactivating enzyme found in cerebral cortex,
PAF acetylhydrolase. This was not confirmed in a later
independent laboratory study.5
The other major components of ginkgo extract are
the flavonoids that contribute to ginkgos antioxidant and
free radical scavenger effects.6 Ginkgo has been found to
(1) reduce cell membrane lipid peroxidation in experimental spinal cord injury similarly to methylprednisolone7; (2) reduce bromethalin-induced cerebral lipid peroxidation and edema8; (3) protect brain neurons against
oxidative stress induced by peroxidation9-11; (4) decrease neuronal injury following ischemia or electroconvulsive shock12; and (5) reduce subchronic cold stress
effects on receptor desensitization.13
Other biological effects of G biloba extract have been
observed. It is an inhibitor of monoamine oxidase A and
B.14 Biological effects in various mammalian species have
been demonstrated in many organs, such as decreasing
retinal neovascularization following injury,15 altering the
immune system16 and promoting compensation from vestibular deafferentation.17
Therapeutically, ginkgo may be biologically plausible to use in Alzheimer disease (AD) for several reasons. While the cause and underlying pathophysiological features of AD are unknown, prominent hypotheses
as to the cause center around age-related oxidative injury.18,19 As described earlier, the flavonoid components
of ginkgo appear to be useful in animal models in preventing some types of oxidative and peroxidative neuronal injury. Another hypothesis of a cause of AD centers around an inflammatory process.20,21 Ginkgo being
a PAF antagonist has anti-inflammatory effects. Another reason for the plausibility of use of ginkgo in individuals with AD also relates to its activity as a PAF antagonist. The effect of PAF antagonism directly on brain
function is fairly unexplored. 2,3
Ginkgo has been widely used by naturopathic doctors and other alternative and complementary health care
providers. Alternative or complementary medicine is
widely used in North America with 34% of US adults interviewed in 1990 having used some form of alternative
medicine in the past year.22 In the United States people
spend an estimated $1.5 billion per year on herbal medicines with projected annual growth of 15%.23 Germany
is one of the largest herbal users among American or western European countries with total sales in 1993 of $1.9
billion for plant-based allopathic medicines (half of these
prescribed by physicians) and with 5 million prescriptions for ginkgo in 1988. Clinically, ginkgo extract is
widely used in Europe for treatment of memory disorders associated with aging, including AD and vascular
dementia. It is already widely used in the United States
as an alternative therapy for AD despite the presence of
only 1 American study.24 Prior to the publication of that
American trial, a conservative estimate at a university
cognitive assessment clinic found 10% of patients using
alternative medicines to improve cognitive function
and an additional 29% to improve general health.25 A
less conservative estimate comes from another study26

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1998 American Medical Association. All rights reserved.

Table 1. Studies Satisfying Inclusion Criteria*

Source, y
Hofferberth,81 1994
Le Bars et al,24 1997
Kanowski et al,86
1996
Wesnes et al,87 1987

Rai et al,85 1991

No. of
Study
Daily
Subjects Duration, Dropout Dose,
Ginkgo
Analyzed
wk
Rate, % mg Formulation

Diagnoses
AD
AD (DSM-III-R)
AD (DSM-III-R)
AD (dementia with
appropriate medical
and psychiatric
exclusions)
AD (dementia with
appropriate medical
and psychiatric
exclusions)

Cognitive
Outcome Measures

Other Outcome
Measures

40
207
125

12
26
24

?5
20
30

240
120
240

EGb 761
EGb 761
EGb 761

SKT, choice reaction time

ADAS-cog
SKT

SCAGS, EEG
CGIC, GERRI
CGI, NAB, EEG

58

12

120

Tanakan

27

24

120

Tanakan

10-Item battery including

Quality-of-life scale
Benton Visual Retention Test,
Digit Symbol, word
list recall, and reaction time
MMSE, Kendrick Digit
EEG
Copying and Object
Learning tasks, digit recall,
and classification task

*AD indicates Alzheimer disease; EGb 761, a ginkgo extract (Dr Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany); SKT, Synrom-Kurztest; SCAGS,
Sandoz Clinical Assessment Geriatric Scale; EEG, electroencephalogram; DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition;
ADAS-cog, Alzheimer Disease Assessment Scalecognitive subtest; CGIC, Clinical Global Impression of Change; GERRI, Geriatric Evaluation by Relatives Rating
Instrument; CGI, Clinical Global Impressions; NAB, Nurnberger Alters-Beobachtungsskala; and MMSE, Mini-Mental State Examination. The dropout rate is for
26-week data in the study by Le Bars et al.24 The study by Rai et al 85 met criteria for inclusion other than lack of sufficient statistics for meta-analysis.

that found 55% of caregivers had used at least 1 alternative medicine to improve the patients memory. Ginkgo
was the major alternative treatment besides vitamins in
those studies.
To help define the efficacy of G biloba in AD, a review of the current literature and a meta-analysis of studies that met minimally acceptable scientific criteria was
performed.
RESULTS

STUDIES REVIEWED AND INCLUDED

Fifty-seven articles24,29-84 were identified, of which several were review articles. There were dozens of studies
mostly in the French and German literature suggesting
the efficacy of ginkgo for the treatment of memory impairment associated with aging but only a limited number were properly blinded and placebo-controlled with
well-characterized subjects. Almost all reported positive effects of ginkgo. The overwhelming majority contained the diagnosis of cerebral insufficiency. However,
the term cerebral insufficiency is vague and overinclusive with criteria that include depressed mood, fatigue,
lack of motivation, dizziness, and tinnitus. Without sufficiently detailed description all articles simply using the
diagnosis of cerebral insufficiency were excluded from
the meta-analysis. Other potentially relevant studies were
excluded for other reasons. Weitbrecht and Jansen63 studied patients with primary degenerative dementia but did
not further describe the inclusion or exclusion criteria.
The patients in the study of Chartres et al36 were receiving decreasing doses of neuroleptics and tranquilizers.
There was 1 study85 that otherwise met the inclusion criteria but could not be included in the formal metaanalysis because of a lack of sufficiently descriptive statistics. Four studies24,81,86,87 were identified that met all
criteria (Table 2). These 4 studies included patients with
mild or moderate dementia severity. Although 2 of these
studies86,24 reported additionally on patients with vascu-

lar dementia, only groups composed solely of patients

diagnosed as having AD were included in the analysis.
ANALYSIS TECHNIQUES
Of the 4 studies that met criteria, 2 reported means and
SDs.86,87 For these studies we computed the g statistic based
on pooled SDs.28 Wesnes et al87 reported statistical analyses that aggregated their multiple cognitive measures
across multiple assessments. However, we deemed it more
appropriate to calculate the effect size for Wesnes et al87
by averaging the effect sizes of their multiple cognitive
measures reported for their final assessment (12 weeks).
To provide more comparable treatment duration and increase total sample size, the intention-to-treat sample of
Le Bars et al24 at 26 weeks was used to calculate the studys
effect size. As this study reported means and 95% confidence intervals (instead of SDs or SEs), the 95% confidence interval was used to calculate the SE, which in
turn was used to calculate the SD for use in effect size
calculation. Hofferberth81 reported P values for the MannWhitney U statistic, but did not report means or SDs. The
effect size for the final assessment (12 weeks) was calculated from the reported P value and sample sizes using the formula reported by Hedges and Olkin.28
The 4 studies24,81,86,87 reported analyzable data for 212
patients treated with ginkgo and 212 with placebo. Individual group sample sizes, as shown in Table 2, ranged
from 19 to 104. After appropriate weighting for sample
size,28 the mean effect size of the 4 samples was 0.41 (95%
confidence interval, 0.22-0.61). This indicates that the
weighted mean effect size was equivalent to a little less
than half of an SD. There was significant variability in
effect sizes (range, 0.1-1.1).
ADVERSE EFFECTS
In a previous review,31 no serious adverse effects were
noted in any of the older studies and the incidence of significant adverse effects was similar in all placebo-treated

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cebo group. Rai et al 85 reported a decrease in slow

frequency activity in the treatment group.

Table 2. Studies Satisfying Inclusion Criteria

and With Sufficiently Descriptive Statistics

Source, y
Kanowski et al,86
1996
Le Bars et al,24
1997
Wesnes et al,87
1987
Hofferberth,81
1994
Overall

Effect
Size

95%
Confidence
Interval

0.5156 +0.16 to +0.87

No. of
No. of
Subjects Subjects
Taking Taking
Ginkgo Placebo

COMMENT
P

61

64

.005

0.311

+0.04 to +0.59

104

103

.03

0.108

20.44 to +0.65

26

26

.69

1.117
0.413

+0.45 to +1.78
+0.22 to +0.61

21
212

19
212

.001
,.0001

and ginkgo-treated groups. In the studies we reviewed and

the studies in our meta-analysis there were also no significant adverse effects. In all these studies doses have
ranged up to 240 mg/d. Ginkgo may prolong the bleeding time and there are 2 case reports of hemorrhage in subjects who were taking ginkgo. A 33-year-old woman had
been taking 120 mg of ginkgo for 2 years prior to developing bilateral subacute subdural hematomas without a
known history of trauma.88 Two simultaneously drawn
bleeding times were 15 and 9.5 minutes with the upper
limit for the laboratory being 9 minutes. One month after
stopping ginkgo, 2 simultaneously drawn bleeding times
were both 6.5 minutes. A second case report concerned a
70-year-old man who was taking aspirin daily for 3 years
following coronary artery bypass surgery.89 He developed spontaneous bleeding from the iris into the anterior
chamber 1 week after beginning 80 mg/d of Ginkoba, a
ginkgo extract. Another case report90 concerned a 72-yearold who developed a small subdural hematoma several
months after beginning ginkgo therapy. A final case report91 was that of a 78-year-old who had been stable receiving warfarin for atrial fibrillation for 5 years with a prothrombin time of 16.9 seconds who presented with a left
parietal intracerebral hemorrhage 2 months after beginning ginkgo therapy. These case reports are clearly of concern. However, given the large but unknown number of
people taking ginkgo and the lack of such serious adverse effects reported in any of the published articles to
date totaling several thousand subjects, the incidence of
bleeding complications with administration of ginkgo is
of unknown magnitude and significance.
NEUROPHYSIOLOGY
Several studies on AD have included neurophysiological outcome measures. The trial by Kanowski et al86 performed electroencephalographic frequency analysis in 36
of the subjects (17 ginkgo-treated and 19 placebotreated subjects) enrolled at one site and found significant improvement in several electroencephalographic variables in the ginkgo group, including greater dominant
posterior frequency and less theta activity. Hofferberth81 also found a significant decrease in the theta/
alpha ratio in the active group compared with the pla-

Despite the widespread use of G biloba and more than

50 publications on its use in age-related functional and
cognitive changes, there are only a handful of randomized, well-controlled studies of its use in patients with a
diagnosis of AD. We identified only 1 article before 1991
that met inclusion criteria. This is consistent with the study
by Kleijnen and Knipschild30 who reviewed 40 studies
through 1991 concerning the use of G biloba for dementia and cerebral insufficiency. Among the 40 studies, 8
were chosen to meet certain criteria for a good study (a
subset of our criteria) and were discussed in more detail
in a later article.31 None of these 8 articles specifically
stated that the diagnosis was AD. A single article among
8 had sufficient description such that the diagnoses were
determined to be probable AD and it is included in our
meta-analysis.87 The other 7 articles and most of the clinical articles published since, especially the nonEnglishlanguage articles, do not have sufficiently stringent inclusion criteria with cerebral insufficiency the most
common diagnosis.
While all studies can be criticized for some aspects
of design and analysis, we believe that 4 studies meet reasonable criteria for an adequate clinical trial in AD. There
are some concerns regarding the performance of the studies as well as the quantitative analysis. The studies varied in length of treatment and daily dose of ginkgo (120
or 240 mg). The correct dose of ginkgo has never been
formally established. While 120- and 240-mg/d doses are
typical among clinical trials, animal studies have used
doses of 100 mg/kg. The dose issue will need to be addressed in future studies. The dropout rate in the study
of Le Bars et al24 at 1 year was fairly high. However, to
maintain comparability with the trial durations in the other
studies we used the 6-month intention-to-treat data from
the study of Le Bars et al.24 The 6-month data did not have
a particularly high dropout rate. The outcome measures
are of variable quality with only 1 using the Alzheimer Disease Assessment Scalecognitive subtest (ADAS-cog).24
However, the Syndom Kurztest is a short neuropsychological battery with high reliability that is similar to the
ADAS-cog.92
While the small number of trials is a limitation of
this meta-analysis, the aggregate sample is fairly large.
Despite the heterogeneity among study results, the similarity of effect sizes of the 2 largest studies accounting
for more than 75% of the sample supports a real effect.
Additionally, the fairly low effect size in the study by
Wesnes et al87 appears to be, at least in part, related to
having to average the effect over their 10 outcome measures, some of which would be predicted to be insensitive to intervention. Some of the heterogeneity of effect
may be related to dose with the 2 studies using a 240mg/d dose producing greater effect sizes. Despite all
the concerns, the administration of standardized G biloba extract appears to have a modest effect on cognitive
function in AD with an effect size of about 0.4. The effect size is comparable with the donepezil trial by Rog-

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ers et al.93 Using their ADAS-cog placebo-treatment difference of 2.5 and 2.9 (5 and 10 mg of donepezil) and
an SD of 6, estimated from their figure 1, the effect size
is 0.42 and 0.48 for the doses.93 The actual ADAS-cog difference in the donepezil trial of 2.5 and 2.9 for the 2 doses
is slightly greater than that presented in the study by Le
Bars et al, 2 4 which also used the ADAS-cog and
observed a difference from placebo of 1.7 in their 26week intention-to-treat data. The effect size estimate of
0.4 will be useful for design of future studies. For
example, an independent samples t test would require
about 110 subjects per group to attain a power of 90%
at an effect size of 0.427. Our article does not address
the issue of efficacy of ginkgo in other dementia syndromes, eg, vascular dementia, for which there is some
preliminary positive results in 2 of the studies24,88
included in our meta-analysis.
The clinical significance of this effect size of about
0.4 is less clear. Not all 4 studies24,81,86,87 had functional,
behavioral, or global change outcome measures. Since
there was an insufficient number for quantitative analysis on these measures, they are briefly summarized
herein. The study by Kanowski et al86 reported a significant difference in a clinicians global rating scale but not
in an activities of daily living scale. The study by Le
Bars et al24 reported no significant difference in the clinicians global rating scale, but did on the Geriatric
Evaluation by Relatives Rating Instrument, their functional scale. Hofferberth81 reported improvement in a
daily function measure (the Sandoz Clinical Assessment
Geriatric Scale). We need further research to determine
whether there is improvement in noncognitive behavior
or daily function since this is critical in evaluating the
use of treatment in AD.
The component of ginkgo extract that produces its
clinical effect is not known. If it turns out that the flavonoid components are producing the clinical effect, then
other antioxidants may prove as effective and safer. For
example, is the effect of ginkgo additive with vitamin E?
Alternatively, if the terpenoid components are producing the clinical effect, then it needs to be determined which
of the terpenoids is most effective (eg, ginkgolide B). This
aspect of ginkgo is potentially of most interest since the
unique chemical structure of the terpenoids makes it one
of a limited number of good PAF antagonists. The currently available standardized extracts are only standardized to percentage of flavonoids and terpenoids. The implication of this is that the relative amounts of the
ginkgolide and bilobalide components of the terpenoids
or the various flavonoids may vary across preparations
and even seasons.94 The individual component chemicals in ginkgo extract, eg, ginkgolide B, are available from
some manufacturers.
The enriched or special extract EGb 761 developed
by Dr Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany, has been used in most of the trials in Table 1. The
patent for extract EGb 761 has expired so other manufacturers can use the same extraction process from the
ginkgo leaf. There are no data comparing the efficacy of
different formulations of ginkgo in AD, the so-called phytogenerics, even though most are standardized to 24%
flavonoids and 6% terpenoids.

This article is not intended to produce specific

clinical recommendations on the use of ginkgo in individuals with AD. Only additional high-quality research
can address this issue. In general, physicians should
inquire about alternative therapy use by patients to be
aware of potential drug interactions and to ensure that
the patient feels comfortable discussing alternative
therapies with their nonalternative health care provider.
In general, when considering alternative therapies, clinicians should ensure that patients are actually taking
what is recommended. Some of the products are not
pharmacy grade, do not contain known amounts of the
intended drug, and may contain unknown amounts of
other compounds. If considering the use of ginkgo,
ensure that a standardized extract (24% flavonoids or
ginkgo-flavone-glycosides and 6% terpenoids) is used.
Given its mode of action on PAF and the case reports
of possible hemorrhagic complications, it certainly
seems prudent to be cautious in its use in patients taking anticoagulants or antiplatelet agents, or with a
bleeding diathesis.
Accepted for publication May 28, 1998.
This study was supported in part by grants AG15171
(Dr Oken) and AG08017 (Dr Kaye), National Institutes of
Health, Bethesda, Md.
The Cochrane Collaboration was invaluable and provided many of the reference titles along with a structured
English-language summary. Dan Zajdel assisted in the preparation of the manuscript.
Reprints: Barry S. Oken, MD, Department of Neurology, CR120, Oregon Health Sciences University, 3181 SW
Sam Jackson Park Rd, Portland, OR 97201 (e-mail:
oken@ohsu.edu).
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