Get Involved
About Us
Our Members
Ginkgo Extract Does Not Prevent Dementia or Alzheimer’s Disease in Large 6-year Clinical Trial—The GEM Study

Reviewed: DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia. A randomized controlled trial. JAMA. 2008; 300(19):2253-2262.

Standardized extracts made from the leaves of the ginkgo (Ginkgo biloba, Ginkgoaceae) tree are used worldwide to enhance numerous cognitive and circulatory functions and to treat symptoms associated with cognitive decline and impaired circulation. Currently no medications—conventional or alternative—have been shown to be effective and thus approved by regulatory bodies for the primary prevention of dementia. And no studies have been published with an adequate design or power to sufficiently evaluate the efficacy and safety of ginkgo extracts for preventing dementia. During the past decade 2 well-powered long-term clinical trials have been initiated to assess the efficacy of ginkgo in preventing dementia. The results of one of these studies—the Ginkgo Evaluation of Memory (GEM) Study—is presented here. The Guidage trial is still underway and its results will not be known for another year or two.1

The GEM study is a randomized, double-blind, placebo-controlled study sponsored by the National Center for Complementary and Alternative Medicine and the National Institute on Aging of the National Institutes of Health (NIH). Volunteers (N = 3069) aged 75 years or older were recruited using voter registration and other purchased mailing lists from 4 US communities with academic medical centers: Hagerstown, Maryland (Johns Hopkins); Pittsburgh, Pennsylvania (University of Pittsburgh); Sacramento, California (University of California–Davis); and Winston-Salem and Greensboro, North Carolina (Wake Forest University). All participants had a proxy (representative) willing to be interviewed every 6 months.

Individuals with prevalent dementia (meeting Diagnostic and Statistical Manual of Mental Disorders Fourth Edition [DSM-IV] criteria for dementia or a score > 0.5 on the Clinical Dementia Rating scale) were excluded from the study. However, participants with mild cognitive impairment were not excluded. Participants were randomized to twice-daily doses of either 120 mg ginkgo (EGb 761®, W. Schwabe Pharmaceuticals, Karlsruhe, Germany; n = 1545) or an identically appearing placebo (n = 1524). The 240 mg per day dose of EGb 761 was chosen based on information from prior clinical studies. It is also the upward dose approved by the German Commission E and is a standard dosage used in more cognitively impaired adults.2 The primary hypothesis was that 240 mg/day of ginkgo extract would decrease the incidence of all-cause dementia and specifically reduce the incidence of Alzheimer’s disease (AD). The secondary objectives were to evaluate the effect of ginkgo extract on the following end points: overall cognitive decline, functional disability, total mortality, and incidence of cardiovascular disease. The primary efficacy endpoint was the diagnosis of dementia by DSM-IV criteria. When a participant’s dementia scores declined by a pre-specified number of points from his or her study entry scores, or there was onset of new memory or other cognitive problems, the participant underwent the full GEM study neuropsychological battery, which included 12 tests.

The ginkgo and placebo groups were similar in their baseline characteristics. The mean age at entry was 79.1 years and 46% of the participants were women. The median follow-up time was 6.1 years (maximum 7.3 years). The dementia rate was extremely low (< 1%) during the first year in both groups. Approximately 61% of those taking placebo and 40% of those taking ginkgo guessed their actual drug assignment correctly. During the intervention period, 246 (16.1%) of the participants in the placebo group and 277 (17.9%) in the ginkgo group were diagnosed with dementia. The rate of total dementia did not differ between participants assigned to ginkgo or placebo (P = 0.21, 3.3/100 person-years and 2.9/100 person-years, respectively). The rate of Alzheimer-type dementia also did not differ between the 2 treatment groups (P = 0.11, 3.0/100 person-years and 2.6/100 person-years, respectively). The results were similar when the endpoint was AD only versus AD with evidence of vascular disease of the brain. The number of participants with cardiovascular disease, pure vascular dementia, myocardial infarction, or stroke was too small to draw any firm conclusions.

The adverse event (AE) profiles for ginkgo and placebo were similar. There were no statistically significant differences in the rate of serious AEs. The mortality rate was similar in the 2 treatment groups. There were no differences between treatment groups in the incidence of coronary heart disease or stroke. The rates of major bleeding did not differ between the treatment groups. Also, for participants taking aspirin, the bleeding incidence did not differ between treatment groups.

The authors conclude that in this study gingko was not effective in preventing or delaying the onset of all-cause dementia in participants older than 75 years. Also, ginkgo had no effect on the risk for developing AD in this population.

It should be noted that at study end, only 60.3% of the active participants were taking their assigned study medications. There is the possibility that this poor adherence to the assigned treatment might have had a negative effect on the trial’s results. An NIH-sponsored study in the United States in 2008 demonstrated a beneficial effect of a standardized ginkgo extract on the risk of developing dementia in only the trial subjects taking the ginkgo on a regular basis.3 In the present study it does not appear that any statistics were done on the population having good compliance (i.e., excluding the participants who were not in compliance). It would be interesting to see the results of the compliant population. Also, there is no conventional pharmaceutical drug that has the ability to prevent the onset of dementia or diminish its progression, so there is no drug to act as a positive control. Hence, it is unknown to what extent the particular population being tested would respond to any treatment.

According to Mark Blumenthal, the founder and executive director of the American Botanical Council, “Ginkgo’s benefits must be viewed in the context of the entirety of the published clinical data. There is a significant body of scientific and clinical evidence supporting the safety and efficacy of ginkgo extract for both cognitive function and improved circulation.”4 In fact, a randomized controlled clinical trial (RCT) published in JAMA in 1997 demonstrated efficacy of EGb 761 versus placebo, producing positive results in treating symptoms associated with early stages of Alzheimer’s dementia.5 Numerous subsequent RCTs have also shown beneficial effects. In addition, an RCT comparing EGb 761 versus the pharmaceutical drug donepezil (Aricept®, Pfizer) showed the ginkgo extract to have similar efficacy in treating dementia symptoms with less AEs,6 while a review article in 2000 showed that EGb 761 had a similar effect of 4 pharmaceutical cholinesterase-inhibiting drugs, with fewer adverse effects for ginkgo.7

A large (n=400) multicenter RCT in Russia using 240 mg/day of EGb 761 on patients with clinically evaluated mild to moderate dementia and moderate neuropsychiatric symptoms for 22 weeks resulted in improvement in the ginkgo patients with respect to the neuropsychiatric symptoms and activities of daily living.8 In contrast, those who received placebo deteriorated slightly or remained unchanged. EGb 761 was significantly superior to placebo with respect to all efficacy variables (P < 0.001). And in a yet-to-be published RCT, one daily dose of 240mg EGb used in the treatment of dementia was significantly superior to placebo.9 This trial was presented at the International Congress on Alzheimer’s Disease in Chicago in July 2008.

In addition to being tested for cognitive impairment, at least 16 RCTs have evaluated various ginkgo extracts for healthy, non-cognitively impaired adults. A comprehensive review has shown that in 11 of these trials, the ginkgo extract increased short-term memory, concentration, and time to process mental tasks.10 Finally, as noted by ABC in its press release, numerous RCTs demonstrate the efficacy of ginkgo extract in treating symptoms associated with peripheral arterial occlusive disease (a.k.a. intermittent claudication, a condition experienced by many elderly adults, characterized by pain and difficulty in walking, due to poor circulation).11

—Heather S. Oliff, PhD


  1. Andrieu S, Ousset PJ, Coley N, Ouzid M, Mathiex-Fortunet H, Vellas B, GuidAge Study Group. GuidAge study: a 5-year double-blind, randomized trial of EGb 761 for the prevention of Alzheimer’s disease in elderly subjects with memory complaints. I Rationale, Design and baseline data. Curr Alz Res. 2008;5:406-415.

  2. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW, Rister RS, eds, Klein S, Rister RS, trans. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines.

    Austin, TX: American Botanical Council; Boston, MA: Integrative Medicine Communications; 1998.
  3. Dodge HH, Zitzelberger T, Oken BS, Howieson D, Kaye J. A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline. Neurology. 2008;70:1809-1817.

  4. Ginkgo’s benefits for treatment of symptoms of cognitive decline and other uses are supported by scientific research [press release]. Austin, TX: American Botanical Council. Nov. 18, 2008.

  5. Crews W, Harrison DW, Griggin ML, Falwell KD, Crist T, Longest L, Hehemann L, Rey ST. The neuropsychological efficacy of ginkgo preparations in healthy and cognitively intact adults; A comprehensive review. HerbalGram. 2005;67:42-62.

  6. Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA. October 22-29, 1997;278(16):1327-1332.

  7. Mazza M. Gingko biloba and donepezil: a comparison in the treatment of Alzheimer’s dementia in a randomized placebo-controlled double blind study. Eur J Neurol. 2006;13(9):981-985.

  8. Napryeyenko O, Borzenko I [GINDEM-NP Study Group]. Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trial. Arzneimittelforschung. 2007;57(1):4-11.

  9. Ihl R, Tribanek M, Napryeyenko O, 240-mg once-daily formulation of Ginkgo biloba extract EGb 761 is effective in both Alzheimer’s disease and vascular dementia: Results from a randomized controlled trial [conference abstract]. Chicago: International Congress on Alzheimer’s Disease; July 2008.

  10. Wettstein, A. Cholinesterase inhibitors and ginkgo extracts: Are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months’ duration. Phytomed. 2000;6(6):393-401.

  11. Horsch S, Walther C. Ginkgo biloba special extract EGb 761 in the treatment of peripheral arterial occlusive disease (PAOD): a review based on randomized, controlled studies. Int J Clin Pharmacol Ther. 2004 Feb;42(2):63-72.