When two science-based therapies meet …

Ginkgo Enhances Galantamine
Additional cognitive and functional benefits emerge

By Will Block

This leaf from a tree in the East,
Has been given to my garden.
It reveals a certain secret,
Which pleases me and thoughtful people.

— Goethe, Gingo biloba (a poem)

Moly [galantamine] the gods call it, difficult for mortals
to uproot, though the gods of course can do anything.

— Homer, The Odyssey, Book Ten

T he world’s most ancient extant tree, Ginkgo biloba, is a living fossil, recognizably similar to plant relics dating back 270 million years. Its natural medicinal offerings are among the most researched of all plants. And according to the German Commission E (the equivalent of the FDA), Ginkgo is currently the most investigated and adopted herbal remedy for cognitive disorders and Alzheimer’s disease (AD), helping to prevent the onset of dementia or delay its progression. Possible mechanisms of Ginkgo’s action against AD include antioxidant and antiapoptotic properties along with the potential inhibiting effects against caspase-3 (a key enzyme in the apoptosis cell-signaling cascade) activation and amyloid-beta aggregation. Nevertheless, Ginkgo’s efficacy in the prevention and treatment of dementia still remains contentious.

Better Together than Galantamine Alone

Now comes new European research showing that Ginkgo’s promises unfold when consumed together with acetylcholinesterase inhibitors (AChEIs), including galantamine.1 Until now, the added effects of Ginkgo in subjects already receiving “conventional” anti-dementia treatments have barely been investigated. With this in mind, the new study’s researchers evaluated whether the use of Ginkgo is associated with additional cognitive and functional benefit in AD patients already in treatment with AChEIs. They found additional cognitive and/or functional benefits for AD.


Possible mechanisms of Ginkgo’s
action against AD include antioxidant
and antiapoptotic properties along
with the potential inhibiting effects
against caspase-3 activation and
amyloid-beta aggregation.


The data came from the Impact of Cholinergic Treatment USe (ICTUS) study, a prospective multicenter cohort study aimed at evaluating the clinical course, treatment outcomes, and socioeconomic impact of AD in Europe. It involved 29 participating centers from 12 European countries, all members of the European Alzheimer Disease Consortium (EADC), a network of clinical and research institutions specializing in the diagnosis and treatment of AD.

The subjects recruited for this study suffered from mild to moderate AD and were under AChEI treatment. Tests used for analysis were the Mini Mental State Examination (MMSE), the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score, and the Activities of Daily Living (ADL) scale over a follow-up of 1 year.


All the patients on combined therapy
received a Ginkgo extract at a daily
dosage of 120 mg in most cases.


AChEIs and AChEIs Plus Ginkgo

Participants (828 subjects) were divided into two groups: (1) AD patients receiving only AChEIs (i.e. donepezil, rivastigmine, and galantamine) at the baseline and 12-month follow-up visits; and (2) AD patients receiving ChEIs and an additional Ginkgo supplement at the baseline and 12-month follow-up visits. All the patients on combined therapy received a Ginkgo extract at a daily dosage of 120 mg in most cases. All AChEIs were given in the usual therapeutic range.

Changes of the MMSE and ADAS-Cog scores after 12 months of follow-up were considered the most important cognitive outcome variables. The MMSE includes 30 items focused at measuring different cognitive aspects (orientation, registration, attention, recall, and language). The total score ranges from 0 to 30 with higher scores indicating better cognitive performance.

The ADAS-Cog test represents the most widely adopted cognitive outcome measure in AD trials. It examines eleven items assessing different cognitive domains (memory, language, and praxis). The total ADAS-Cog score ranges from 0 to 70, with higher scores indicating greater cognitive impairment.

The analyses were restricted to the first 12 months to avoid a potential selection bias. Selection bias refers to the selection of individuals, groups or data for analysis such that proper randomization is not achieved. However, this cannot guarantee that the sample obtained is representative of the population to be analyzed. In the study it is likely that subjects taking Ginkgo for a longer time are those who have benefited more from the therapy. Thus, extending the period of observation may have led to the selection of participants principally showing a positive response to treatment.

Significantly different modifications at the MMSE score over the 12-month follow-up were reported between patients on combined therapy compared to those only taking AChEIs. However, no significant changes of the two outcome measures were observed at the mid-term 6-month evaluation. But over time (1 year) there were significant changes in the MMSE analyses. The researchers’ findings indicate that Ginkgo may provide added cognitive benefits in AD patients already under AChEI treatment.

Baseline Analysis Data

The mean age of the patients was 75.8 (SD 7.8) years. MMSE and ADAS-Cog scores at baseline were 20.5 (SD 3.9) and 20.4 (SD 8.9), respectively, indicating a moderate cognitive decline at the beginning of the study. ADL score was 5.5 (SD 0.8), indicating a minimal impairment of functional abilities.

At the baseline and 12-month visits, 799 participants (96.5%) were on AChEIs alone treatment, and 29 (3.5%) were on a combined therapy of AChEIs and Ginkgo. At the baseline visit, donepezil was the most consumed AChEI (55%) followed by galantamine (27%) and rivastigmine (18%). The two groups (AChEIs alone and AChEIs plus Ginkgo) were comparable for age, gender, and co-morbidities. Of interest, the participants on combined treatment were found to be more educated and less cognitively impaired.


Significantly different increases of
the MMSE score over the 12-month
follow-up were reported between
patients on combined therapy
compared to those
only taking AChEIs.


MMSE Scores Confirm Cognitive Uplift

Significant different changes of the MMSE score over the 12-month follow-up were reported between patients on combined therapy compared to those only taking AChEIs.

Contrarily, the changes of the ADAS-Cog score between the two groups did not show statistically significant differences, although similar trends were noticed. Similarly, no significant modifications of the two adopted outcome measures were observed in secondary analyses exploring cognitive function modifications at the mid-term 6-month assessment. The changes over time of the ADL score did not show statistically significant differences between the two groups of interest.

Findings Positive for Ginkgo in the Longer Term

The researchers explored changes of cognitive and functional performance over one year of follow-up in a large cohort of mild to moderate AD patients treated with AChEIs alone or with added Ginkgo. To repeat, a significant increase in MMSE scores were reported between participants using the combined therapy compared to those only taking AChEI after one year of follow-up.

The cognitive benefit observed among patients on combined therapy (as measured by an increase of the MMSE score) was found to be statistically significant only at the 12-month, but not at the 6-month assessment. The cognitive and functional modifications occurred in the second year of follow-up of the ICTUS group. In fact, it is likely that patients experiencing the greatest benefit from the added Ginkgo therapy would have more probably completed the observation period compared to participants reporting minor efficacy.


Ginkgo might offer some added
cognitive benefits in AD patients
already under AChEI treatment in the
longer term.


Another Study Not Long Enough

To the researchers’ knowledge, only one other study had previously investigated the cognitive efficacy of a combined AChEI + Ginkgo treatment in AD.2 In this study, 96 AD outpatients were randomly assigned to Ginkgo at 240 mg/day, donepezil initially 5 mg/day, then 10 mg/day after 4 weeks, or to the combined treatment (same doses). After 22 weeks, no significant differences concerning cognitive, behavioral, and functional outcomes were measured in the three treatment groups. This is consistent with the ICTUS Ginkgo study, which did not show results at 6 months. Interestingly, compared to donepezil alone, the adverse event rate was lower under Ginkgo treatment and even under the combined treatment.

Nevertheless, the small sample size did not allow any definitive conclusion. Unfortunately, cognitive tests used (i.e. Syndrom Kurz Test, Clock-Drawing Test, and Verbal Fluency Test) were different from those employed in the ICTUS study, thus preventing a direct comparison with the findings.

Strengths of the ICTUS Study

The ICTUS Ginkgo study had several advantages. The analyses involved a large sample of AD patients, recruited at numerous dementia clinics across several European countries. The changes in cognitive performance were assessed through two widely used outcome measures (i.e. the MMSE, and ADAS-Cog) aimed at reducing observation bias. Moreover, the study design with semi-annual clinical assessments provided a detailed monitoring of cognitive changes.


In a recent paper in Public Library of
Science One,
over a much longer-
term period (20 years), cognitive
decline in a non-demented elderly
population was lower in subjects who
reported using Ginkgo than in those
who did not.


Possible Biases and Probable Promises

One possible bias in the ICTUS study may be that the observational design did not allow the researchers to determine causality. Particularly, the two groups were significantly different with regard to education and ADAS-Cog scores at baseline, two well-established factors associated with the course of the disease, the performance at cognitive testing, and the response to treatments.

Thus, it could be that patients on combined ChEIs + Ginkgo therapy may have presented a more relevant cognitive benefit because they were more educated and less cognitively impaired. Even so, if the factors of education and less cognitive impairment were properly taken into account in the adjusted models, the consequent bias might have not been completely erased.

Moreover, despite considering potential confounders, third factors may have affected or may differently explain our findings. For example, the treatment doses were not stable and uniform during the study. Healthier patients may have had easier access to the Ginkgo treatment, and the concomitant use of other psychoactive drugs may have interacted with the tested pharmacological interventions.

Also, the study design and available data do not allow appreciating and sufficiently taking into account the possible exposure to the Ginkgo before the ICTUS baseline visit. But then it may have increased the benefit of long-term use. It is possible there was a residual effect of previously stopped Ginkgo treatment in the AChEI group, as well as an overestimation of benefits in participants who had been taking the combined therapy for several years before.


If you want to stay around cognitively
for an extended period, Ginkgo (plus
Galantamine) may be for you.


Long-Term Benefits of Ginkgo and Galantamine

In conclusion, the paper’s findings suggest that the Ginkgo might offer some added cognitive benefits in AD patients already under AChEI treatment in the longer term. This is consistent with the findings of other Ginkgo studies. For example, long-term treatment with Ginkgo—remember: a clinically available and well-tolerated herbal medication—ameliorates AD pathology by antiinflammatory and Aβ-directed mechanisms.3

Noteworthy, in a recent paper published in Public Library of Science One, over a much longer-term period (20 years), cognitive decline in a non-demented elderly population was lower in subjects who reported using Ginkgo than in those who did not.4 There is additional evidence from long-term observational controlled studies that early initiation and persistent exposure to AChEI therapy leads to delays in nursing home admission and significantly slower rates of cognitive and functional impairment.5 Long-term use of galantamine appears to parallel the long-term benefits of Ginkgo. If you want to stay around cognitively for an extended period, Ginkgo (plus Galantamine) may be for you.

References

  1. Canevelli M, Adali N, Kelaiditi E, Cantet C, Ousset PJ, Cesari M. ICTUS/DSA Group: Effects of Ginkgo biloba supplementation in Alzheimer’s disease patients receiving cholinesterase inhibitors: data from the ICTUS study. Phytomedicine. 2014;21:888–92.
  2. Yancheva S, Ihl R, Nikolova G, Panayotov P, Schlaefke S, Hoerr R; GINDON Study Group. Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer’s disease with neuropsychiatric features: a randomised, double-blind, exploratory trial. Aging Ment Health. 2009 Mar;13(2):183-90.
  3. Liu X, Hao W, Qin Y, Decker Y, Wang X, Burkart M, Schötz K, Menger MD, Fassbender K, Liu Y. Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer’s disease. Brain Behav Immun. 2015 May;46:121-31.
  4. Amieva H, Meillon C, Helmer C, Barberger-Gateau P, Dartigues JF. Ginkgo biloba extract and long-term cognitive decline: a 20-year follow-up population-based study. PLoS One. 2013;8(1):e52755. doi: 10.1371/journal.pone.0052755. Epub 2013 Jan 11. PubMed PMID: 23326356; PubMed Central PMCID: PMC3543404.
  5. Deardorff WJ, Feen E, Grossberg GT. The Use of Cholinesterase Inhibitors Across All Stages of Alzheimer’s Disease. Drugs Aging. 2015 Jun 2. [Epub ahead of print] PubMed PMID: 26033268.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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