Ginkgo biloba for Prevention of Dementia

Background: Ginkgo biloba (GB) is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of GB on dementia incidence are lacking.

Objective: Determine effectiveness of GB vs placebo in reducing the incidence of dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI).

Methods: The study was a randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008.  Volunteers aged 75 years or older were recruited from September 2000 to June 2002 using voter registration and other purchased mailing lists from 4 US communities with academic medical centers. All participants were required to identify a proxy willing to be interviewed every 6 months at the time of each study visit. Individuals with prevalent dementia or a score >0.5 on the Clinical Dementia Rating scale were excluded from participation. Also excluded were individuals meeting any of the following criteria (1) currently taking the anticoagulant warfarin; (2) taking cholinesterase inhibitors for cognitive problems or dementia (3) unwilling to discontinue taking over-the-counter GB for the duration of the study; (4) currently being treated with tricyclic antidepressants, antipsychotics, or other medications with significant psychotropic or central cholinergic effects (excluding SSRIs); (5) daily use of more than 400-IU vitamin E or unwillingness to reduce intake to this level; (6) history of bleeding disorders; (7) hospitalization for depression within the last year or electroconvulsive therapy within last 10 years; (8) history of Parkinson disease or taking anti-Parkinson medications; (9) abnormal thyroid tests, serum creatinine level greater than 2.0 mg/dL, or liver function tests more than 2 times the upper limit of normal at baseline; (10) baseline vitamin B12 levels 210 pg/mL or lower; (11) hematocrit level less than 30%; (12) platelet count lower than 100; (13) disease-related life expectancy of less than 5 years; or (14) known allergy to GB.  A total of 3072 subjects were enrolled (1545 randomized to receive GB and 1527 randomized to placebo). Participants were randomized to either 120mg GB or an identical placebo twice daily. The study lasted from 2000-2008 with an average follow-up of 6.1 years.  Every 6 months subjects were assessed for incident dementia.  When calculating the sample size necessary, it was assumed that in the placebo group, the rate of dementia would be 4% per year and that the combined mortality and dropout rate would be 6% per year.  With these estimates, the planned sample size of 3000 with an average follow-up of 5.0 years results in 96% power to detect a 30% reduction in the rate of dementia at a 2-sided significance level of .05. Under these assumptions, the expected total number of dementia cases at the conclusion of the trial would be 439.  Sample size provided 86% power. Intent-treat-analysis was utilized.

Results:  The primary outcome of the study was the incidence of dementia and AD.  The study participant drop out rate was 6.2% and 6.4% in the GB and placebo groups, respectively. A total of 246 in the placebo group and 277 in the GB group were diagnosed with dementia (p value of .21, 0.94-1.33, 95% CI).  The adverse event profiles for GB and placebo were similar and there were no statistically significant differences in the rate of serious adverse events.  During the subgroup analysis, there was statistically significant differences in those who went on to develop vascular dementia with 17 placebo subjects developing dementia and 7 GB developing dementia (P value 0.05, 0.17-0.98, 95% CI) and HR of 0.41. 

Strengths: This study utilized a randomized, placebo-controlled, double-blind study, which is the gold standard for clinical trials.  In addition, the compositions of the herbal products were confirmed by independent laboratory analysis. The extract tested is among the best characterized and is the one for which the most efficacy data are available.  Bias did not play a role in the study.  Dementia was diagnosed using many recognizable standardized tests, and MRIs.  Panels of experts carefully reviewed all date before diagnosing a patient with AD or dementia.

Weaknesses: Study duration may not have been accurate, since it’s not known how long it takes for dementia and AD to develop.  In addition we don’t know how long, if ever, GB takes to affect mental status either positively or negatively. Therefore, the 8 year course of the study may not have been adequate to accurately study dementia and AD.  There are many commercially available formulations of GB available to the public, so these study results may not be applicable to all GB products.  In addition, patients on SSRIs were allowed to continue taking the medication, which may have altered the results of the study.

Conclusions: The authors concluded that GB is not effective in preventing or delaying the onset of dementia in people older than 75 years old.  GB also had no effect on the risk for developing AD in this age group. Additionally, the very small number of purely vascular dementia cases identified in the study (n = 24) was statistically significant, but not clinically significant. Although no firm conclusion can be drawn from the higher number of hemorrhagic strokes in the GB group, this finding should be explored in future studies.  Based on the results of this trial, GB cannot be recommended for the purpose of preventing dementia or AD.

DeKosky St, Williamson JD, et al. Ginkgo biloba for Prevention of Dementia. JAMA. 2008;300(19):2253-2262.

Sean Lamont, Doctor of Pharmacy Candidate