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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
whelming majority did not meet inclusion criteria, pri- Ginkgo biloba extract on objective measures of cognitive marily because of lack of clear diagnoses of dementia and function in patients with Alzheimer disease (AD) based AD. Only 4 studies met all inclusion criteria. In total there on formal review of the current literature.
were 212 subjects in each of the placebo and ginkgo treat-ment groups. Overall there was a significant effect size Methods: An attempt was made to identify all English and
of 0.40 (PϽ.0001). This modest effect size translated into non–English-language articles in which G biloba extract was a 3% difference in the Alzheimer Disease Assessment given to subjects with dementia or cognitive impairment.
Inclusion criteria for the meta-analysis were (1) suffi-ciently characterized patients such that it was clearly stated Conclusions: Based on a quantitative analysis of the lit-
there was a diagnosis of AD by either Diagnostic and Sta- erature there is a small but significant effect of 3- to 6- tistical Manual of Mental Disorders, Revised Third Edition, month treatment with 120 to 240 mg of G biloba extract or National Institute of Neurological Disorders and Stroke– on objective measures of cognitive function in AD. The Alzheimer’s Disease and Related Disorders Association cri- drug has not had significant adverse effects in formal clini- teria, or there was enough clinical detail to determine this cal trials but there are 2 case reports of bleeding compli- by our review; (2) clearly stated study exclusion criteria, cations. In AD, there are limited and inconsistent data ie, those studies that did not have stated exclusions for de- that preclude determining if there are effects on noncog- pression, other neurologic disease, and central nervous sys- nitive behavioral and functional measures as well as on tem–active medications were excluded; (3) use of stan- clinician’s global rating scales. Further research in the area dardized ginkgo extract in any stated dose; (4) randomized, will need to determine if there are functional improve- placebo-controlled and double-blind study design; (5) at ments and to determine the best dosage. Additional least 1 outcome measure was an objective assessment of research will be needed to define which ingredients in cognitive function; and (6) sufficient statistical informa- the ginkgo extract are producing its effect in individuals Results: Of more than 50 articles identified, the over-
GINKGOBILOBAisaliving Currently,ginkgoextractsusedfor
rently 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 tol- tagonists of platelet-activating factor (PAF) and is extremely resistant to insects, bac- that has numerous biological effects.1 Be- teria, viruses, and fungi. Extracts of the sides causing platelet activation and ag- leaves have been used for 5000 years in tra- ditional Chinese medicine for various pur- permeability), is an extremely potent ul- dried leaves. Studies on the biological ac- Sciences University, andPortland Veteran Affairs tivity of different components of the ginkgo muscle. Platelet-activating factor has a di- rect effect on neuronal function and long- 1998 American Medical Association. All rights reserved.
term potentiation.2,3 An initial report4 suggested that lis-sencephaly, a disorder of neural migration and dendritic METHODS
branching, was associated with changes in the gene cod-ing a PAF inactivating enzyme found in cerebral cortex,PAF acetylhydrolase. This was not confirmed in a later We attempted to identify all randomized placebo- controlled clinical trials (both English and non– The other major components of ginkgo extract are English language) in which G biloba was adminis-tered for at least 2 months to patients with dementia the flavonoids that contribute to ginkgo’s antioxidant and or other cognitive impairment. The search for po- free radical scavenger effects.6 Ginkgo has been found to tentially relevant studies and reviews was per- (1) reduce cell membrane lipid peroxidation in experi- formed through MEDLINE using the keywords mental spinal cord injury similarly to methylpredniso- “ginkgo” and “gingko [sic].” Trials referenced by ar- lone7; (2) reduce bromethalin-induced cerebral lipid per- ticles that were found were also screened. Addition- oxidation and edema8; (3) protect brain neurons against ally, we had access to a listing of 60 articles with En- oxidative stress induced by peroxidation9-11; (4) de- glish summaries from a preliminary Cochrane crease neuronal injury following ischemia or electrocon- Collaboration Review (http://www.cochrane.co.uk) vulsive shock12; and (5) reduce subchronic cold stress on the use of ginkgo in dementia and related disor-ders. This search was done using several databases including MEDLINE, EMBASE, and PsychLit as well Other biological effects of G biloba extract have been as references in review articles and textbooks. Addi- observed. It is an inhibitor of monoamine oxidase A and tional search words included brand names for ginkgo B.14 Biological effects in various mammalian species have (eg, Tanakan, Tebonin, Rokan, or Ginkoba) and a been demonstrated in many organs, such as decreasing retinal neovascularization following injury,15 altering the Our goal was to evaluate only those studies that immune system16 and promoting compensation from ves- met minimally acceptable scientific standards. We therefore used the following criteria for inclusion in Therapeutically, ginkgo may be biologically plau- sible to use in Alzheimer disease (AD) for several rea- • Patients needed to be clearly and sufficiently characterized such that there was a clearly stated di- sons. While the cause and underlying pathophysiologi- agnosis of AD by either Diagnostic and Statistical cal features of AD are unknown, prominent hypotheses Manual of Mental Disorders, Revised Third Edition or as to the cause center around age-related oxidative in- National Institute of Neurological Disorders and jury.18,19 As described earlier, the flavonoid components Stroke–Alzheimer’s Disease and Related Disorders As- of ginkgo appear to be useful in animal models in pre- sociation criteria, or there was enough clinical de- venting some types of oxidative and peroxidative neu- tail to determine this by our review.
ronal injury. Another hypothesis of a cause of AD cen- • Studies needed to clearly state their exclu- ters around an inflammatory process.20,21 Ginkgo being sion criteria, ie, those studies that did not have stated a PAF antagonist has anti-inflammatory effects. An- exclusions for depression, other neurologic disease, other reason for the plausibility of use of ginkgo in in- and central nervous system–active medications wereexcluded. We did not exclude trials solely for the lack dividuals with AD also relates to its activity as a PAF an- of neuroimaging studies on all subjects.
tagonist. The effect of PAF antagonism directly on brain • The use of standardized ginkgo extract in any stated dose was required (24% or 25% ginkgo- Ginkgo has been widely used by naturopathic doc- flavone glycosides and 6% terpenoids, see above). The tors and other alternative and complementary health care dose could be given by any route of administration.
providers. Alternative or complementary medicine is • The study needed to be randomized, placebo- widely used in North America with 34% of US adults in- controlled, and double-blind. Details of the random- terviewed in 1990 having used some form of alternative ization procedure were not required.
medicine in the past year.22 In the United States people • At least 1 outcome measure needed to be an spend an estimated $1.5 billion per year on herbal medi- objective assessment of cognitive function.
The studies that met these inclusion criteria are cines with projected annual growth of 15%.23 Germany listed in Table 1. Studies also needed to include de-
is one of the largest herbal users among American or west- scriptive statistics from which effect sizes27,28 could ern European countries with total sales in 1993 of $1.9 be computed. This only caused the exclusion of 1 ar- billion for plant-based allopathic medicines (half of these ticle in Table 1 from the quantitative analysis.
prescribed by physicians) and with 5 million prescrip- Meta-analytic methodology was used to quan- tions for ginkgo in 1988. Clinically, ginkgo extract is titatively assess the effects of ginkgo on objective mea- widely used in Europe for treatment of memory disor- sures of cognition for all studies that were found to ders associated with aging, including AD and vascular meet the above-listed criteria. This statistical meth- dementia. It is already widely used in the United States odology involves computation of individual effect as an alternative therapy for AD despite the presence of sizes27,28 for each study sample which, after weight-ing for sample size, becomes a single case to be used only 1 American study.24 Prior to the publication of that in subsequent analyses. For each evaluated study we American trial, a conservative estimate at a university computed the effect size (g statistic) according to the cognitive assessment clinic found 10% of patients using alternative medicines to improve cognitive functionand an additional 29% to improve general health.25 Aless conservative estimate comes from another study26 1998 American Medical Association. All rights reserved.
Table 1. Studies Satisfying Inclusion Criteria*
Subjects Duration, Dropout Dose,
Cognitive
Other Outcome
Source, y
Diagnoses
Analyzed
Formulation
Outcome Measures
Measures
*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 Scale–cognitive subtest; CGIC, Clinical Global Impression of Change; GERRI, Geriatric Evaluation by Relative’s RatingInstrument; CGI, Clinical Global Impressions; NAB, Nurnberger Alters-Beobachtungsskala; and MMSE, Mini-Mental State Examination. The dropout rate is for26-week data in the study by Le Bars et al.24 The study by Rai et al85 met criteria for inclusion other than lack of sufficient statistics for meta-analysis.
that found 55% of caregivers had used at least 1 alterna- lar dementia, only groups composed solely of patients tive medicine to improve the patient’s memory. Ginkgo diagnosed as having AD were included in the analysis.
was the major alternative treatment besides vitamins inthose studies.
ANALYSIS TECHNIQUES
To help define the efficacy of G biloba in AD, a re- view of the current literature and a meta-analysis of stud- Of the 4 studies that met criteria, 2 reported means and ies that met minimally acceptable scientific criteria was SDs.86,87 For these studies we computed the g statistic based on pooled SDs.28 Wesnes et al87 reported statistical analy-ses that aggregated their multiple cognitive measures across multiple assessments. However, we deemed it moreappropriate to calculate the effect size for Wesnes et al87 STUDIES REVIEWED AND INCLUDED
by averaging the effect sizes of their multiple cognitivemeasures reported for their final assessment (12 weeks).
Fifty-seven articles24,29-84 were identified, of which sev- To provide more comparable treatment duration and in- eral were review articles. There were dozens of studies crease total sample size, the intention-to-treat sample of mostly in the French and German literature suggesting Le Bars et al24 at 26 weeks was used to calculate the study’s the efficacy of ginkgo for the treatment of memory im- effect size. As this study reported means and 95% con- pairment associated with aging but only a limited num- fidence intervals (instead of SDs or SEs), the 95% con- ber were properly blinded and placebo-controlled with fidence interval was used to calculate the SE, which in well-characterized subjects. Almost all reported posi- turn was used to calculate the SD for use in effect size tive effects of ginkgo. The overwhelming majority con- calculation. Hofferberth81 reported P values for the Mann- tained the diagnosis of cerebral insufficiency. However, Whitney U statistic, but did not report means or SDs. The the term cerebral insufficiency is vague and overinclu- effect size for the final assessment (12 weeks) was cal- sive with criteria that include depressed mood, fatigue, culated from the reported P value and sample sizes us- lack of motivation, dizziness, and tinnitus. Without suf- ing the formula reported by Hedges and Olkin.28 ficiently detailed description all articles simply using the The 4 studies24,81,86,87 reported analyzable data for 212 diagnosis of cerebral insufficiency were excluded from patients treated with ginkgo and 212 with placebo. In- the meta-analysis. Other potentially relevant studies were dividual group sample sizes, as shown in Table 2, ranged excluded for other reasons. Weitbrecht and Jansen63 stud- from 19 to 104. After appropriate weighting for sample ied patients with primary degenerative dementia but did size,28 the mean effect size of the 4 samples was 0.41 (95% not further describe the inclusion or exclusion criteria.
confidence interval, 0.22-0.61). This indicates that the The patients in the study of Chartres et al36 were receiv- weighted mean effect size was equivalent to a little less ing decreasing doses of neuroleptics and tranquilizers.
than half of an SD. There was significant variability in There was 1 study85 that otherwise met the inclusion cri- teria but could not be included in the formal meta-analysis because of a lack of sufficiently descriptive sta- ADVERSE EFFECTS
tistics. Four studies24,81,86,87 were identified that met all
criteria (Table 2). These 4 studies included patients with
In a previous review,31 no serious adverse effects were mild or moderate dementia severity. Although 2 of these noted in any of the older studies and the incidence of sig- studies86,24 reported additionally on patients with vascu- nificant adverse effects was similar in all placebo-treated 1998 American Medical Association. All rights reserved.
cebo group. Rai et al85 reported a decrease in slow Table 2. Studies Satisfying Inclusion Criteria
frequency activity in the treatment group.
and With Sufficiently Descriptive Statistics
Subjects Subjects
Confidence
Despite the widespread use of G biloba and more than Source, y
Interval
50 publications on its use in age-related functional and cognitive changes, there are only a handful of random- ized, 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 demen- tia and cerebral insufficiency. Among the 40 studies, 8 were chosen to meet certain criteria for a good study (asubset of our criteria) and were discussed in more detailin a later article.31 None of these 8 articles specificallystated that the diagnosis was AD. A single article among and ginkgo-treated groups. In the studies we reviewed and 8 had sufficient description such that the diagnoses were the studies in our meta-analysis there were also no sig- determined to be probable AD and it is included in our nificant adverse effects. In all these studies doses have meta-analysis.87 The other 7 articles and most of the clini- ranged up to 240 mg/d. Ginkgo may prolong the bleed- cal articles published since, especially the non–English- ing time and there are 2 case reports of hemorrhage in sub- language articles, do not have sufficiently stringent in- jects who were taking ginkgo. A 33-year-old woman had clusion criteria with cerebral insufficiency the most been taking 120 mg of ginkgo for 2 years prior to devel- oping bilateral subacute subdural hematomas without a While all studies can be criticized for some aspects known history of trauma.88 Two simultaneously drawn of design and analysis, we believe that 4 studies meet rea- bleeding times were 15 and 9.5 minutes with the upper sonable criteria for an adequate clinical trial in AD. There limit for the laboratory being 9 minutes. One month after are some concerns regarding the performance of the stud- stopping ginkgo, 2 simultaneously drawn bleeding times ies as well as the quantitative analysis. The studies var- were both 6.5 minutes. A second case report concerned a ied in length of treatment and daily dose of ginkgo (120 70-year-old man who was taking aspirin daily for 3 years or 240 mg). The correct dose of ginkgo has never been following coronary artery bypass surgery.89 He devel- formally established. While 120- and 240-mg/d doses are oped spontaneous bleeding from the iris into the anterior typical among clinical trials, animal studies have used chamber 1 week after beginning 80 mg/d of Ginkoba, a doses of 100 mg/kg. The dose issue will need to be ad- ginkgo extract. Another case report90 concerned a 72-year- dressed in future studies. The dropout rate in the study old who developed a small subdural hematoma several of Le Bars et al24 at 1 year was fairly high. However, to months after beginning ginkgo therapy. A final case re- maintain comparability with the trial durations in the other port91 was that of a 78-year-old who had been stable re- studies we used the 6-month intention-to-treat data from ceiving warfarin for atrial fibrillation for 5 years with a pro- the study of Le Bars et al.24 The 6-month data did not have thrombin time of 16.9 seconds who presented with a left a particularly high dropout rate. The outcome measures parietal intracerebral hemorrhage 2 months after begin- are of variable quality with only 1 using the Alzheimer Dis- ning ginkgo therapy. These case reports are clearly of con- ease Assessment Scale–cognitive subtest (ADAS-cog).24 cern. However, given the large but unknown number of However, the Syndom Kurztest is a short neuropsycho- people taking ginkgo and the lack of such serious ad- logical battery with high reliability that is similar to the verse effects reported in any of the published articles to date totaling several thousand subjects, the incidence of While the small number of trials is a limitation of bleeding complications with administration of ginkgo is this meta-analysis, the aggregate sample is fairly large.
of unknown magnitude and significance.
Despite the heterogeneity among study results, the simi-larity of effect sizes of the 2 largest studies accounting NEUROPHYSIOLOGY
for more than 75% of the sample supports a real effect.
Additionally, the fairly low effect size in the study by Several studies on AD have included neurophysiologi- Wesnes et al87 appears to be, at least in part, related to cal outcome measures. The trial by Kanowski et al86 per- having to average the effect over their 10 outcome mea- formed electroencephalographic frequency analysis in 36 sures, some of which would be predicted to be insensi- of the subjects (17 ginkgo-treated and 19 placebo- tive to intervention. Some of the heterogeneity of effect treated subjects) enrolled at one site and found signifi- may be related to dose with the 2 studies using a 240- cant improvement in several electroencephalographic vari- mg/d dose producing greater effect sizes. Despite all ables in the ginkgo group, including greater dominant the concerns, the administration of standardized G bi- posterior frequency and less theta activity. Hoffer- loba extract appears to have a modest effect on cognitive berth81 also found a significant decrease in the theta/ function in AD with an effect size of about 0.4. The ef- alpha ratio in the active group compared with the pla- fect size is comparable with the donepezil trial by Rog- 1998 American Medical Association. All rights reserved.
ers et al.93 Using their ADAS-cog placebo-treatment dif- This article is not intended to produce specific ference of 2.5 and 2.9 (5 and 10 mg of donepezil) and clinical recommendations on the use of ginkgo in indi- an SD of 6, estimated from their figure 1, the effect size viduals with AD. Only additional high-quality research is 0.42 and 0.48 for the doses.93 The actual ADAS-cog dif- can address this issue. In general, physicians should ference in the donepezil trial of 2.5 and 2.9 for the 2 doses inquire about alternative therapy use by patients to be is slightly greater than that presented in the study by Le aware of potential drug interactions and to ensure that Bars et al,24 which also used the ADAS-cog and the patient feels comfortable discussing alternative observed a difference from placebo of 1.7 in their 26- therapies with their nonalternative health care provider.
week intention-to-treat data. The effect size estimate of In general, when considering alternative therapies, cli- 0.4 will be useful for design of future studies. For nicians should ensure that patients are actually taking example, an independent samples t test would require what is recommended. Some of the products are not about 110 subjects per group to attain a power of 90% pharmacy grade, do not contain known amounts of the at an effect size of 0.427. Our article does not address intended drug, and may contain unknown amounts of the issue of efficacy of ginkgo in other dementia syn- other compounds. If considering the use of ginkgo, dromes, eg, vascular dementia, for which there is some ensure that a standardized extract (24% flavonoids or preliminary positive results in 2 of the studies24,88 ginkgo-flavone-glycosides and 6% terpenoids) is used.
Given its mode of action on PAF and the case reports The clinical significance of this effect size of about of possible hemorrhagic complications, it certainly 0.4 is less clear. Not all 4 studies24,81,86,87 had functional, seems prudent to be cautious in its use in patients tak- behavioral, or global change outcome measures. Since ing anticoagulants or antiplatelet agents, or with a there was an insufficient number for quantitative analy- sis on these measures, they are briefly summarizedherein. The study by Kanowski et al86 reported a signifi- Accepted for publication May 28, 1998. cant difference in a clinician’s global rating scale but not This study was supported in part by grants AG15171 in an activities of daily living scale. The study by Le (Dr Oken) and AG08017 (Dr Kaye), National Institutes of Bars et al24 reported no significant difference in the cli- nician’s global rating scale, but did on the Geriatric The Cochrane Collaboration was invaluable and pro- Evaluation by Relative’s Rating Instrument, their func- vided many of the reference titles along with a structured tional scale. Hofferberth81 reported improvement in a English-language summary. Dan Zajdel assisted in the prepa- daily function measure (the Sandoz Clinical Assessment Geriatric Scale). We need further research to determine Reprints: Barry S. Oken, MD, Department of Neurol- whether there is improvement in noncognitive behavior ogy, CR120, Oregon Health Sciences University, 3181 SW or daily function since this is critical in evaluating the Sam Jackson Park Rd, Portland, OR 97201 (e-mail: The component of ginkgo extract that produces its clinical effect is not known. If it turns out that the fla-vonoid components are producing the clinical effect, then other antioxidants may prove as effective and safer. Forexample, is the effect of ginkgo additive with vitamin E? 1. Koltai M, Hosford D, Guinot P, Esanu A, Braquet P. Platelet-activating factor (PAF): Alternatively, if the terpenoid components are produc- a review of its effects, antagonists and future clinical implications. Drugs. 1991; ing the clinical effect, then it needs to be determined which 2. del Cerro S, Arai A, Lynch G. Inhibition of long-term potentiation by an antago- of the terpenoids is most effective (eg, ginkgolide B). This nist of platelet-activating factor receptors. Behav Neural Biol. 1990;54:213-217.
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