Abstract
Ginkgo Biloba extract is widely used by older adults as a cognitive enhancer although efficacy studies show inconsistent results. A review was done of three quantitative studies with the hypothesis that once-daily use of Ginkgo Biloba does not help improve the memory of adults aged 50 years or older. One article was a clinical trial on the differences in electrical activity in the brain when Ginkgo Biloba or placebo is used during a working memory test. The second article is also a clinical trial that determined the efficacy of Ginkgo Biloba in reducing cognitive and therefore memory decline in patients with early-stage dementia. The third study is a retrospective review comparing the rate of cognitive decline among users of Ginkgo Biloba, piracetam, or no treatment. There was marked heterogeneity among the three studies. There were differences in design, sample, measurement, and treatments used. Thus, a definitive conclusion from comparing these studies is not possible. Taking each study separately, however, the hypothesis must be rejected because of the positive effects on memory associated with long or short-term daily use of varying doses of Ginkgo Biloba among older adults.
Alternative or complementary medications are used by a significant portion of the population. Ginkgo Biloba is a tree whose leaves have been used in traditional Chinese medicine as an unregulated memory enhancer for older adults (Diamond & Bailey, 2013). However, claims of safety and effectiveness must be established to reduce harm and provide appropriate advice to patients. Users of Ginkgo Biloba provide inconsistent reports of a positive outcome. Thus, it is reasonable to hypothesize that if Ginkgo Biloba is taken on a regular basis by patients over the age of 50 years, then it will not improve memory. This review is done to validate if this hypothesis holds true or not.
Brain Cognition Effects of Ginkgo Biloba Extract
The study was motivated by the dearth in electrophysiological studies on the effects of Ginkgo Biloba extract (GBE) on working memory. In literature, only electrophysiological studies in at-rest subjects have been studied thus far. The value of this type of research is that it provides a physiological basis for the global effects of the extract on cognition that is widely studied but with conflicting results (Silberstein et al., 2011). For example, the extract arrests age-related cognitive decline in some trials and a recent large-scale study in Europe but was not noted in a similarly large-scale study in the U.S. In some studies, GBE was also associated with improvements in working memory.
It is thought that GBE exerts its effects on memory by influencing several types of transmitters, primarily the cholinergic system, besides antioxidant properties that may protect against tissue injury (Silberstein et al., 2011). Increased cholinergic neurotransmission is linked with greater cerebral blood flow and enhanced working memory. On the contrary, reduced cholinergic neurotransmission is associated with reduced blood flow in the brain and poorer working memory. The researchers hypothesized that “there would be a significant improvement in both the speed and accuracy of performance in an object working memory task following chronic GBE treatment” (Silberstein et al., 2011, p. 3).
The study is a randomized, double-blind, and cross-over trial. Participants were randomly assigned to two groups. One group received 14 days of placebo tablets followed by 14 days of Blackmore’s Ginkgoforte at two tablets or 80 mg daily (Silberstein et al., 2011). The procedure was reversed for the other group. The brand of GBE used contained standardized doses of GBE components. After the treatment period, participants were asked to hold an irregular polygon and then view images on a screen. An irregular polygon was then presented and the participants asked if this was the same object they held. Pushing a button with the right hand meant a match while a non-match was indicated by the left hand.
The sample consisted of 19 adults aged 50 to 61 years. Ten were male and nine were female. The criteria for inclusion was right-handedness validated by an instrument and uncorrected normal vision. Persons with histories of head and neurological conditions such as psychiatric illness, developmental disability, head trauma, and epilepsy were excluded. Informed consent was a precondition for participation (Silberstein et al., 2011). However, there was no discussion on sampling procedures.
Data on brain electrical activity, specifically the steady-state visually evoked potential (SSVEP), was obtained using scalp electrodes applied to 64 sites (Silberstein et al., 2011). The signals were subsequently translated into amplitudes and used in the statistical analyses. GBE intake was significantly associated with SSVEP amplitude increase and SSVEP latency decrease. Amplitude increase reflects a reduction in cortical activity that is indicative of decreased cognitive effort and better performance (Silberstein et al., 2011). Latency decrease denotes faster brain processing. These physiological measures were noted in conjunction with greater accuracy in the working memory task, thus suggesting the positive effect of GBE on cognition. No limitations or recommendations were discussed.
Ginkgo Biloba Extract and Dementia
The aim of this study was to investigate the safety, effectiveness, and tolerability of EGb 761, a type of Ginkgo Biloba extract, as a once-daily treatment for dementia. Among other symptoms, the disease is associated with memory impairment. The authors recognized the inconsistent findings in literature with regard to Ginkgo Biloba outcomes among dementia patients. In filling this gap in research, the study generated further evidence of the potential of EGb 761 as an alternative treatment in the early stages of dementia, thus preventing disease progression. The study employed null hypotheses in that were no expected significant differences in the two primary efficacy outcomes between the experimental and placebo groups (Ihl et al., 2010).
The clinical trial was conducted in Ukraine and designed to be double-blind with two parallel arms. Participants stopped all other cognitive treatments during the investigation except for Ginkgo Biloba. They were randomly assigned to a 24-week EGb 761 treatment or placebo for the same duration (Ihl et al., 2010). Controls included the placebo and EGb being of similar appearance, labeling, and packaging. These were dispensed by pharmacists unaware of the study. EGb 761 was also standardized in terms of content. The daily dose was set at 240 mg as a prior systematic review established greater benefits of this dose compared to lower doses. Patients had no knowledge of their group allocation.
The sample consisted of 410 patients from 20 outpatient settings (Ihl et al., 2010). The study was limited to adults 50 years or older. Inclusion criteria included a diagnosis of mild to moderate dementia for at least six months and supported by scores on a cognitive test, neuropsychiatric inventory, mini-mental state examination, neuroimaging, and other clinically accepted criteria. Dementia must be secondary to Alzheimer’s disease, of vascular origin, or mixed in etiology (Ihl et al., 2010). Participants had to have caregivers knowledgeable with the patients’ functional levels and behaviors. Those with serious and acute illnesses and other psychiatric disorders were excluded. The characteristics of the sample accurately represented the population of patients being treated for dementia in the outpatient setting and who will directly benefit from the results of the study.
Results showed that in the treatment arm, there were statistically significant improvements in both the SKT and NPI results which are the primary measures. This implies that symptom severity improved as did cognitive performance while there was a small change or no change at all in the control group. Hence, EGb 761 at the current treatment dose is effective in alleviating dementia and the attendant negative effects on memory and cognition (Ihl et al., 2010). Outcomes for the secondary measures were also significantly better in the treatment group. Although adverse events occurred during treatment that included tinnitus and stroke, these conditions were ruled out to be unassociated with the intake of either Ginkgo Biloba or placebo (Ihl et al., 2010). This suggests a high safety and tolerability profile of the former. There was no discussion on limitations and recommendations.
Ginkgo Biloba Extract and Long-term Cognitive Decline
This study was a retrospective analysis exploring longitudinal data from the PAQUID, a prospective study with follow-ups conducted nine times during the past 20 years (Amiela et al., 2013). The PAQUID used a cohort of older adults in two communities in France. The initial size was 3,777 persons who were 65 years old or older. However, only 3,612 participants were included as the others were already diagnosed with dementia at the onset of the PAQUID or were taking combinations of piracetam and EGb 761. The final participants were categorized into three groups: EGb 761 users, piracetam users, and non-EGb 761 or piracetam users (Amiela et al., 2013).
Trained psychologists collected patient data using a home-administered questionnaire. The initial tool included questions on physical health, functional status, medications, psychosocial health, and mental status. Over time, visual retention memory and verbal fluency were measured as well (Amiela et al., 2013). The interview was also supplemented by a DSM-III-R based assessment for dementia, and those who fulfilled the criteria were referred to specialists for further examination, diagnostics, and treatment.
Analyses showed that the rate in measures for mental status was statistically significant over time in the group using Ginkgo Biloba and the piracetam group compared with participants taking neither of the two drugs. EGb 761 users had a less rapid cognitive decline compared to the “neither” group while the piracetam group had a more accelerated decline (Amiela et al., 2013). The positive outcome in EGb 761 users, however, were noted after several follow-ups suggesting that the benefits from using this medication develop over a long period of continued use. In addition, the retrospective study showed that EGb 761 was associated with a reduction in the use of antipsychotics and other psychotropic drugs. (Amiela et al., 2013) This may have increased the positive outcomes as one side-effect of these drugs is cognitive decline. With regard to verbal fluency and visual retention memory, which are also measures of cognitive decline, the three groups showed no significant differences even after an added analysis controlled for the use of psychotropic medications.
Conclusion
The studies used different research methods, e.g. controlled trial and retrospective review, and measured different variables, e.g. behavioral, physiological, and clinical outcomes, using different tools although these were all associated with different aspects of memory such as working memory and visual retention memory. The studies also used different samples and sample sizes. Although all were older adults and aged 50 years or older, healthy subjects or participants with mild to moderate dementia were employed. The three studies used Ginkgo Biloba extract of varying doses and the large retrospective study did not specify the dose. Duration of use was either short term or long term. Only one study compared the drug with another. The wide heterogeneity makes an apples-to-apples comparison difficult.
The only conclusion common to the three studies is that Gingko Biloba has positive effects on memory as concluded by studies with methods corresponding to level III and IV evidence on the evidence hierarchy. Short-term use is associated with electrical activity in the brain that is consistent with enhanced memory in a small study. Long-term use also prevents a decline in memory among otherwise healthy older adults with no signs of dementia, and short-term use at higher doses induces the same effect in patients with early dementia. In the long-term, Ginkgo Biloba seems more effective than piracetam. It is therefore with great caution that these results are used to reject the hypothesis of this literature review. Further reviews with a higher level of homogeneity and larger samples are necessary to further establish this conclusion.
References
Amieva, H., Meillon, C., Helmer, C., Bargerger-Gateua, P., & Dartigues, J.F. (2013). Ginkgo Biloba extract and long-term cognitive decline: A 20-year follow-up population-based study. PLoS ONE, 8(1), 1-8. doi:10.1371/journal.pone.0052755.
Diamond, B.J., & Bailey, M.R. (2013). Ginkgo biloba indications, mechanisms, and safety. Psychiatric Clinics of North America, 36(1), 73-83. doi: 10.1016/j.psc.2012.12.006.
Ihl, R., Bachinskaya, N., Korczyn, A.D., Vakhapova, V., Tribanek, M., Hoerr, R., & Napryeyenko, O. (2010). Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: A randomized controlled trial. International Journal of Geriatric Psychology, 26(11), 1186- 1194. doi: 10.1002/gps.2662.
Silberstein, R.B., Pipingas, A., Song, J., Camfield, D.A., Nathan, P.J., & Stough, C. (2011). Examining brain-cognition effects of ginkgo biloba extract: Brain activation in the left temporal and left prefrontal cortex in an object working memory task. Evidence- based Complementary and Alternative Medicine, 2011(164139), 1-15. doi: 10.1155/2011/164139.
