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Research Analysis of Ginkgo Biloba for Cognitive Decline



The use of Ginkgo Biloba as a medicinal substance stem from Traditional Chinese Medicine, where it has a long history of application. An extract of the leaves was first introduced to western medicine in 1965 (1). Since then, multiple studies on its pharmacological effects primarily on peripheral circulation and cerebral insufficiency has been observed (1). And more recently, there is an increased interest on its potential use for the prevention of cognitive decline and improvement of memory in an increasingly elderly population. Because there is no current drug that could prevent cognitive decline, and dementia has progressively become a significant health and economic concern in developed countries, scientists are interested in finding potential treatment drugs. Ginkgo Biloba has demonstrated promising results in past trials, attributed to its vasodilator, antiplatelet, and antioxidant properties (1). These actions are believed to exert a protective effect on the brain (1). In addition, Ginkgo Biloba has shown close to no side effects or drug interactions, making it a safe alternative for the elderly population (1)


In this blog, I will analyze 5 publicly available studies with varied views and conclusions about the efficacy of Ginkgo Biloba for cognitive decline in the at-risk population. All these studies use the herb’s proprietary extract EGb 761. From oldest to newest, below are some of the most recent experiments done in this subject:


Ginkgo biloba for Prevention of Dementia A Randomized Controlled Trial (GEM study).

This controlled study was performed in humans between 2000 and 2008 in 5 different medical centers in the United States with volunteers over 75 years of age. The experiment was set to measure: How does Ginkgo Biloba affects the incidence of all-cause dementia? And to test the main hypothesis: 240 mg of Ginkgo Biloba daily would decrease the incidence of all-cause dementia. A total of 3,069 participants were recruited. They had to meet specific criteria to be included in the study. For example, those who scored less than 0.5 on the Clinical Dementia Rating scale were excluded, and also those who were currently taking anticoagulants, cholinesterase inhibitors, over the counter Ginkgo Biloba, antidepressants, antipsychotics, more than 400-IU vitamin E, and those with history of bleeding disorders, hospitalizations for depression, Parkinson’s disease, abnormal thyroid tests and other abnormal tests were excluded. However, participants with mild cognitive impairment (MCI) were included (2).


The subjects were randomized to either a double-blind placebo or Ginkgo Biloba. There were 1,545 replications in the Ginkgo Biloba group and 1,524 replications in the placebo group. The group that got Ginkgo, received a dose of 120 mg, 2 times a day and the controlled group received a placebo pill with similar appearance. Participants underwent a thorough cognitive evaluation at the start of the experiment and at the end; they used the same method for all participants. In addition, the study kept track of new dementia diagnoses. The time to dementia was measured at the midpoint between the last follow up visit when the participant was not demented and the diagnosis date (2). The results showed that the total rate of dementia did not significantly differ between participants in the Ginkgo Biloba group 3.3 per 100 person-years vs the placebo group 2.9 per 100 person-years (P=0.21) (2). Clinicians concluded that treatment with Ginkgo Biloba did not decrease the incidence of all-cause dementia in participants compared to the placebo (2). This claim matches the experiment.


This was a well put together large-sized long-term controlled, randomized double-blind study setup correctly to investigate the effectiveness of Gingko Biloba in reducing cognitive decline in the elderly population. However, the sample population was older than 75 years of age, excluding a younger population who could also be afflicted by dementia. These results wouldn’t be applicable to the elderly population from 65-74 years of age, only to those 75 years of age and up. Other than that, I believe this is sound study that deserves consideration.


A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline.

This controlled study was published in 2009. It took place during a 42-month period with 118 human participants over the age of 85 who were cognitively intact and met other specific criteria, such as medical exclusions. The subjects were randomized into either a Ginkgo Biloba group or a placebo-controlled group. The study was looking to measure: How does Ginkgo Biloba affects the incidence of dementia in the 85+ oldest old population? This age group was chosen because at the time, 50% of those who had dementia in developed countries were octogenarians or older, so clinicians felt that this population was the most relevant for the study. A Ginkgo Biloba dose of 240 mg daily (separated in 3 doses of 80 mg, 3 times a day) or placebo were employed in this double-blind study. Furthermore, all participants were given a multivitamin containing vitamin E 40 IU to prevent them from supplementing during the experiment. There were 60 replications in the Ginkgo Biloba group and 58 replications in the placebo group. Follow ups were done every 6 months, in which time clinicians measured the subjects’ Clinical Dementia Rating (CDR), tracked when and if participants transition from CDR = 0 no dementia to CDR = 0.5 or above diagnosis of dementia. During the study, out of the 118 subjects, 21 progressed to dementia, 14 from the placebo group and 7 from the Ginkgo Biloba group (3). The results showed that the conversion rate from CRD = 0 to CDR =0.5 was 80.4 per 1,000 person-years in the placebo group vs. 35.4 per 1,000 person-years in the Ginkgo Biloba group. (3) A significant result was determined by P being less than 0.05. The clinicians concluded that there was no significant difference in risk of progression to dementia (P= 0.06) or less decline in memory (P= 0.05) between the Ginkgo Biloba group and the placebo group (3). However, in a secondary analysis, accounting for medication adherence, the Ginkgo Biloba group showed a significant difference in a reduced risk of progression to dementia (P= 0.02) and less memory decline (P= 0.04) compared to the placebo group (3). These claims match the experiment.


The pros of this study are that it was controlled, randomized double-blind and setup correctly to investigate the effectiveness of Gingko Biloba in reducing cognitive. The main drawback of this study is the very small samples size and secondly clinicians were not able to control medication adherence. This happened because most participants were non-institutionalized so they were in charge of taking their own medication. Clinicians believed that compliance inconsistencies could be associated with subclinical dementia (3). If the participant did not take the medication, it would in turn lower the efficacy of the medication, and clinicians wouldn’t be able to correctly evaluate it. Another drawback of this study is that it required subjects to take a low dose of Ginkgo Biloba 3 times a day instead of a higher dose 2 or 1 time a day. The 3 times a day dosage could have made it hard for participants to adhere to the medication’s schedule, long-term


Ginkgo Biloba Extract and Long-Term Cognitive Decline: A 20-Year Follow-Up Population-Based Study.

This is comparative experiment that took place in the Paquid community in France over a 20-year period, which culminated in 2013 and consisted of 10 follow ups spaced in 2-3 years intervals. A total of 3612 human subjects aged 65 and older met the criteria for the study, which included no prior dementia diagnosis and not taking both Ginkgo Biloba and Piracetam. Piracetam is a nootropic commonly prescribed for memory impairment not related to dementia. This study was looking to measure: How does Ginkgo Biloba affects long-term cognitive decline? Clinicians used self-reporting questioners and the following three tests: MMSE to evaluate their mental status (main test used in statistical comparisons), Benton Visual Retention Test (BVRT) to measure visual memory, and the Isaacs Set Test (IST) to assess verbal fluency. They combined these results with dementia screenings (4).


Subjects were divided into three groups: 1) those reporting use of Ginkgo Biloba at any one of the 10 follow up visits, 2) those reporting use of piracetam at any one of the 10 follow up visits, and 3) those not reporting use of either piracetam or Ginkgo Biloba. Out of all the 3612 participants, 589 (replications) reported use of Ginkgo Biloba at any time, 149 (replications) reported use of piracetam at any time, and the rest 2,874 (replications) reported use of neither (4). Over the 20 years study period, significant differences in MMSE scores were reported for all three groups. The Ginkgo Biloba group had MMSE scores that declined significantly less rapidly compared to the piracetam and neither groups (4). Clinicians concluded that there may be a correlation between taking Ginkgo Biloba and the reduced incidence of cognitive decline (4). This correlation statement matches what is being measured in the experiment.


This comparative study, even though set-up correctly to investigate Ginkgo Biloba in the prevention of cognitive decline, had no structure in tracking consistent use of Ginkgo Biloba among the subjects. Participants were categorized as users as long as they reported taking Ginkgo Biloba once during the 20-year period. It is not clear whether they were long-term users of Ginkgo Biloba or they took it for a very short period of time during the study. This is an important variable because the study is set to test the premise that taking Ginkgo Biloba could decrease the incidence of long-term cognitive decline. If Ginkgo Biloba is to be associated with reduced cognitive decline, I believe the study should also consider long-term use of Ginkgo Biloba and a more even number of replications among each group. Furthermore, this study did not consider other health factors that could contribute to dementia, and certain medications that could alter results. However, the clinicians made adjustments to their statistics for psychotropic medications.


Although this study presents an interesting view and sheds some light and considerations regarding the pre-dementia phase, and includes all the elderly population of 65 years old and up, I don’t believe this study is overall applicable and should be used in determining the efficacy of Ginkgo Biloba for cognitive decline.


Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia.

This meta-analysis-controlled study was performed in 2015 with 9 similar randomized controlled trials dating from 1966 to 2014, that studied Ginkgo Biloba for the treatment of dementia in human subjects. These 9 trials are considered the replications. Studies were from 12 to 52 weeks in duration and participants received a minimum daily dosage ranging from 120 mg to 240 mg. This meta-analysis was interested in answering the question: How does Ginkgo Biloba affects cognitive decline in subjects with dementia? This analysis would be applicable to the population diagnosed with dementia.


The statistics used the standard mean difference (SMD) of the average value of cognitive tests KST (in 7 studies) and ADAS-Cog (in 2 studies). A higher score would indicate a higher level of dementia. The change in score in all the studies that used SKT was from -3.3 to -0.90 in the Ginkgo Biloba groups and from -1.2 to 1.3 in the placebo groups (5). The result of the compounded SMD was significantly higher for Ginkgo Biloba compared to the placebo (-0.90) in the SKT studies (5). On the other hand, the change in score in the two studies that used ADAS-Cog was from -0.3 to 1.6 in the Ginkgo Biloba groups and from 0.9 to 1.0 in the placebo groups (5). However, the compounded SMD results did not yield a significant difference between the two groups in the ADAS-Cog studies (0.06). (5).


The authors concluded that Gingko Biloba appears to be more effective than placebo in the treatment of dementia when using the SKT cognitive test (5). This claim matches the experiment.


The pros of this meta-analysis are that it used similar controlled, randomized double-blind studies. The main drawback is that it used few studies to build the aggregate data and conclusions. More studies would have been more beneficial to include and compare with multiple cognitive tests. Another drawback is that the studies were short in length. Longer studies would have been more beneficial to include; but, I understand the limitations of the current research available. Nonetheless, I believe this was a well put together meta-analysis that deserves consideration.


Efficacy and safety of Ginkgo biloba standardized extract in the treatment of vascular cognitive impairment: a randomized, double-blind, placebo-controlled clinical trial.

This controlled study occurred in 2017, and had a length of 6 months. The main objective was to answer the question: how does Ginkgo Biloba affects patients diagnosed with vascular cognitive impairment (VCI)? They recruited 90 patients (humans) between the ages of 59 and 75. However, they had a high dropout rate and only 58 participants completed the 6-month study period. Subjects were divided into 3 groups: Ginkgo Biloba at 120 mg daily, Ginkgo Biloba at 60 mg daily, and placebo. The distribution was randomized and double blinded. The 120 mg Ginkgo Biloba group had 20 replications, the 60 mg Ginkgo Biloba group had 19 replications, and the placebo group had 19 replications. Subjects attended a total of 7 follow ups in 30-day intervals during the 180 days study period. Laboratory testing, TCD, and neuropsychological tests (MDRS, CFI, SCAG, and MMSE) were provided in 90-day intervals, and ECG and CAVA were provided at the beginning and end of the study. The results showed no significant difference between the Ginkgo Biloba groups and placebo in the MDRS, SCAG, and MMSE scores (P= 0.749, 0.676, 0.766 respectively) (6). However, there was a significant difference between the Ginkgo Biloba groups and placebo in the CFI score (P=0.038) (6). Clinicians concluded “G. Biloba seemed to slow down the cognitive deterioration in patients with VCI”. (6) This claim matches the experiment.


Taking a closer look at the statistics in table 2, the CFI test scores showed no difference of cognition in the Ginkgo Biloba groups compared to reduced cognition in the placebo group. The conclusion favoring Ginkgo Biloba is therefore based on no change in cognition in the subjects. The clinicians also mentioned that the CFI test is somewhat subjective (6). Giving this, I believe it shouldn’t be used to draw the main conclusion of the study.


The main pros of the study are that it was controlled, randomized and double-blinded. Nevertheless, this experiment had various drawbacks. First, I agree with the clinicians that the study period was too short and the sample size was very limited to provide adequate conclusions. Second, this study would only apply to those diagnosed with VCI, excluding other types of dementia. Lastly, this study was funded by Milsing d.o.o., a vitamin and supplement company. This could have posed a potential biased in favor of Ginkgo Biloba, a popular herbal supplement.


Overall, all the studies were correctly set to measure cognitive decline/dementia with the use of Ginkgo Biloba. However, some were better than others as described within each study section. I have chosen to consider the following two studies because they are both controlled studies, have quality data and relatively large sample size. With quality data I refer to multiple components including medication adherence, no significant participant dropout, no significant heterogeneity differences, etc.

  • Ginkgo biloba for Prevention of Dementia A Randomized Controlled Trial (GEM study).

  • Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia.

The GEM study and meta-analysis, each presented opposing views regarding the efficacy of Ginkgo Biloba for cognitive decline. I believe more studies are needed. Especially long-term experiments with a minimum of 15-20 years that include a younger population of 50 years of age and older. Including a younger population in a long-term study will account for the pre-dementia phase that is known to occur a decade or so before symptoms present, typically when the patient has reached elderly years. The cognitive tests used in these studies only measure cognitive decline when it occurs or deteriorates, and they don’t account for a possible prevention window in which Ginkgo Biloba could exert the most potential benefit.


Conclusion

I believe, out of the 5 reviewed experiments, the GEM study and the meta-analysis deserve consideration because they are both controlled studies with quality data and relatively large sample size. However, they both present contradicting evidence to be able to reach a conclusion on whether Ginkgo Biloba is or is not beneficial to prevent cognitive decline in the at-risk population.


Citations:

1. Hoffmann, David. Medical Herbalism, The Science and Practice of Herbal Medicine, 2003. p. 553-554.

2. DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, et al. (2008) Ginkgo biloba for Prevention of Dementia A Randomized Controlled Trial. Retrieved from: www.ncbi.nlm.nih.gov/pmc/articles/PMC2823569/

3. Dodge HH, Zitzelberger T, MPH, Oken BS, Howieson D, Kaye J (2009) A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline. Retrieved from: www.ncbi.nlm.nih.gov/pmc/articles/PMC2639649/

4. Amieva H, Meillon C, Helmer C, Barberger-Gateau P, Dartigues JF (2013) Ginkgo Biloba Extract and Long-Term Cognitive Decline: A 20-Year Follow-Up Population-Based Study. Retrieved from: www.ncbi.nlm.nih.gov/pmc/articles/PMC3543404/

5. Hashiguchi M, Ohta Y, Shimizu M, Maruyama J, Mochizuki M. (2015) Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia. Retrieved from: www.ncbi.nlm.nih.gov/pmc/articles/PMC4729005/

6. Demarin V, Kes VB, Trkanjec Z, Budisic M, Pasic MB, Crnac P, Budincevic H. (2017) Efficacy and safety of Ginkgo biloba standardized extract in the treatment of vascular cognitive impairment: a randomized, double-blind, placebo-controlled clinical trial. Retrieved from: www.ncbi.nlm.nih.gov/pmc/articles/PMC5317341/

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