The Use of Ginkgo biloba for Alzheimer Dementia

By Susan T. Marcolina, MD, FACP. Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Part 1 of a series on alzheimer's disease

The geriatric (persons older than 65 years of age) segment of the U.S. population, which numbered 36.3 million or 12.4% of the total population in 2004, is projected to increase to 71.5 million or 20% of the population by 2030.1 As this demographic increases, Alzheimer's disease (AD) and other dementing illnesses will become greater sources of morbidity, mortality, and increasing health care costs.

Although some risk factors for Alzheimer's disease (see table 1) cannot be altered,2 certain strategies (such as regular physical exercise and increased dietary consumption of plant-based flavonoids) can improve quality of life and prolong independent life expectancy, thereby reducing economic costs and social burdens. Additionally, phytomedicines like Ginkgo biloba that target specific degenerative processes, such as free radical formation and lipid membrane peroxidation, that impair brain and other bodily functions may provide additional benefits when used judiciously.

Botanical History of Ginkgo biloba

The ginkgo tree is the last surviving species on earth of the Ginkgoaceae family of trees whose origins date back 200 million years. Although the ginkgo became extinct in Europe and North America during the Ice Age, one species, Ginkgo biloba survived in China. The leaves, fruit, and seed of this tree have been part of Chinese herbal medicine since 2800 BC, employed for the treatment of asthma and as a wound dressing and memory enhancer. It has been reintroduced to other countries worldwide. Darwin called this tree a "living fossil" and its resilience has sparked the interest of Western medicine in the last half of the 20th century with regard to the biologic and pharmacologic utility of extracts of the ginkgo leaf.3,4

Standardization of Ginkgo biloba Products

The standardization of ginkgo leaf extract is important in reducing variability in results of clinical research studies. EGb 761 is a patented extract developed from the leaves of the Ginkgo biloba tree in 1964 by Dr. Willmar Schwabe GmbH & Co., a phytopharmaceutical company in Karlsruhe, Germany. The bulk of scientific research, including most of the European and U.S. clinical trials, has used this extract.

This product contains 24% flavonoids (including quercetin, isorhamnetins, and kaempferol) and 6% terpenes (including the diterpenes ginkgolide A, B, and C, and the sesquiterpene bilobalide) with less than 5 ppm of ginkgolic acids. The standardization process systematically verifies 70% of the total constituents of EGb 761, regardless of the origin of the raw material and in particular aims to maintain the low concentration of ginkgolic acids because they are allergenic.5

EGb 761 has been marketed in Europe under various brand names such as Tebonin forte, Kaveri, Rokan, and Tanakan. In the United States, ginkgo is classified as a dietary supplement; the American brand that is comparable to EGb 761 is Ginkgold.6

Mechanism of Action

The rationale behind testing EGb 761 in Alzheimer dementia derives from its polyvalent mode of action as a free radical scavenger, an antioxidant, and a platelet-activating factor antagonist (PAF), an effect mediated primarily by the constituent ginkgolide B. EGb 761 also has pharmacologic effects as a vasomodulator and an energy enhancer.

Animal studies have shown that EGb 761 decreases lipid peroxidation,7 protects hippocampal neurons against cell death by amyloid beta peptide,8 and restores the age-related loss of neurotransmitter receptor density, especially increasing the number of hippocampal muscarinic acetylcholine and alpha adrenoceptors and cortical 5-hydroxytryptamine 1A receptors. Restoration of these receptors is important because they exist in areas of the brain that regulate cognitive functioning.6,9 EGb 761 also protects energy metabolism of neurons under conditions of oxygen and glucose deficiency and maintains Na/K ATPase activity, which ensures normal membrane functioning.10

In vitro studies by Ramassamy et al examined the effect of EGb 761 on stimulated oxidation of phospholipids in hippocampal and frontal cortical samples from AD patients with different apolipoprotein E genotypes (ApoE is a glycoprotein involved in cholesterol homeostasis and lipid turnover).11 Inheritance of the e4 allele of apolipoprotein E is considered a major risk factor for late-onset familial and sporadic forms of AD.2

In this study, EGb 761 prevented oxidation of phospholipids in control tissues and tissues in AD patients with the e3/e3 or e3/e4 genotype of the apolipoprotein E, whereas this protective effect was less potent in tissues of the AD patients with the e4/e4 genotype. Such results indicate that patients who possess the e4 allele show more aberrant lipid homeostasis and that, although treatment with EGb 761 can mitigate these disturbances, it may be less effective for people with AD who are homozygous for e4.11

Domains for Evaluating Efficacy of Antidementia Drugs

Because dementia is a multifaceted chronic medical problem with numerous interrelated symptoms, standardization of outcome measures is necessary to evaluate whether a specific treatment intervention beneficially alters the natural history of the disease. To achieve this effect, the Committee for Proprietary Medicinal Products has published guidelines for the assessment of pharmacotherapy in dementia. Significant improvement must be demonstrated in at least two of three primary variables covering the domains of cognition, activities of daily living, and overall clinical response.12

Although many psychometric tests have been developed and used for each of the domains, the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) has been generally accepted as the primary outcome measure. The scores range from 1 to 70, with lower scores consistent with better cognitive functioning. Psychologists, physicians, and study staff perform this assessment, which evaluates memory, concentration, and speech and motor ability. The annual increase in untreated Alzheimer patients is from 2 to 10 points. In several studies, "responders" were classified as patients whose scores decreased by 4 points or greater during the course of a minimum of 24 weeks of therapy.13

For the second domain of overall assessment of social functioning, one validated test used as an outcome measure is the Geriatric Evaluation by Relatives Rating Instrument (GERRI). The instrument assesses the ability of the patient to perform daily activities associated with personal care and social behavior such as washing, dressing, eating, mobility, etc. The observers are relatives, nursing staff, and caregivers. The score ranges from 1 to 5; higher scores indicate increasing functional impairment.

An example of an assessment of the third domain is the Clinical Global Impression of Change (CGI-C).13 This instrument evaluates the patient's overall treatment response compared to baseline status in terms of cognitive functioning, behavior, and daily activities. It is scored by the physician after consultation with the patient and caregivers. The measurement is given as a number on a 7-point scale with a range of very much improved to very much worse.

Clinical Studies

A Cochrane systematic analysis of 33 trials conducted by Birks et al overall showed no significant adverse effects of treatment with EGb 761 compared to placebo.14 Although the authors concluded that the studies showed evidence of improvement in cognition and social functioning measures in patients with dementia after ginkgo treatment of 12-24 weeks duration with dosages of up to 240 mg daily, they recommended larger studies to confirm these findings because some recent trials showed conflicting results despite similar, good quality study designs.

One such trial analyzed in the Cochrane review was that of LeBars et al in the North American EGb 761 Study Group.5 This was a placebo-controlled, double-blind, randomized trial of EGb 761 for dementia that enrolled 327 outpatients with AD or Multi-Infarct Dementia. The treatment group received a daily dose of 120 mg of EGb 761 over 52 weeks. The authors reported less impairment for the ginkgo-treated group compared to the placebo group on the ADAS-Cog score (-0.1 vs. +1.5, respectively, P = 0.04) and a small beneficial effect on the GERRI score (-0.06 vs. +0.08, respectively), which resulted in a statistically significant mean treatment effect (P = 0.004). There was no difference on the CGI-C (4.2 vs. 4.2).

Problems with this study include the fact that only 137 patients completed it (50% for ginkgo and 38% for placebo), which clearly could have affected the study outcome. There was a wide range of impairment as assessed by Mini-Mental Status Examination (MMSE), with scores ranging from 9 to 26. Subsequently, the data were reanalyzed using MMSE cutoffs of 23 and 14 for an additional six months. This intention-to-treat analysis showed a favorable treatment effect of EGb 761 with respect to cognitive performance (P = 0.02) and social functioning (P = 0.001) regardless of the stage of dementia. However, the relative changes from baseline measured at endpoint depended upon the baseline dementia severity. The MMSE cutoff scores segregated out two different patterns of response. While patients with mild cognitive impairment showed improvement on the EGb 761, the group of more severely demented patients stabilized in their cognitive decline compared to the deterioration noted in the placebo-treated group.5,15

Another trial reviewed in the Cochrane meta-analysis was conducted by van Dongen et al.16 This trial evaluated 214 retirement home residents over a 24-week period using three arms: two treatment groups of EGb 761, 160 mg daily (medium dose) and 240 mg daily (high dose), and placebo in a randomized, controlled, double-blind, crossover study design. This study also included patients with a broad range of baseline MMSE scores (range, 7-29) and failed to show statistically significant improvement in age-associated memory impairment and mild and moderate dementia between treatment and placebo patients in several neuropsychological and behavior outcome measures. The study's statistical power may have been limited, however, by the inclusion of patients with age-associated memory impairment.

Currently, a multicenter, randomized, double-blind, placebo-controlled trial, the Ginkgo Evaluation of Memory (GEM) Study, is ongoing.17 This trial is sponsored by the National Institutes of Health and includes 3,000 non-demented participants older than age 75. One of the endpoints is an evaluation of the efficacy and safety of EGb 761 (240 mg/d) for the prevention of dementia and age-related cognitive decline. The study is scheduled to continue through 2009.

Dosage

For patients with memory problems and dementia, the dosage used safely and effectively in many clinical studies is 120-240 mg/d taken in 2-3 divided doses. An initial period of 6-12 weeks is generally recommended to assess effectiveness, although results in individual patients may be observed within four weeks.

Name brands using the same extract (EGb 761) as used in clinical research studies are to be recommended as the most reliable in the current herbal market in the United States.18

Effects of Discontinuing Medication

An interesting comparative outpatient study of persons with AD by Rainer et al showed that average increases in ADAS-Cog scores within six weeks of ending the acetylcholinesterase inhibitors (ChE) donepezil, rivastigmine, and galantamine was 3.41 points compared with only a 1.17 point increase after stopping common nootropics (agents that enhance cognitive ability), particularly EGb.19 This effect was not modified by gender, apolipoprotein E genotype, or extent of ventricular enlargement on computer tomography scans. Such findings have practical clinical relevance because even for initial drug responders, antidementia drugs, in many cases, cannot be continued for the duration of a patient's life due to side effects, cost, increasing debility, or a combination of these effects.13,19

Adverse Effects and Drug Interactions

Although clinical studies with EGb 761 have not revealed significant side effects, it does have a potent antiplatelet effect. Therefore, it should not be used in patients on antiplatelet or anticoagulant therapy and should be used cautiously in patients on nonsteroidal anti-inflammatory therapy due to potential synergistic effects that could result in bleeding complications.20 Certain herbal medications (see Table 2) may also increase the risk of bleeding if used in conjunction with ginkgo.21 Although there is no clear consensus,22 ginkgo should be discontinued at least 36 hours prior to surgery and ideally two weeks prior to surgery. Case reports of bleeding complications associated with Ginkgo biloba use include subdural hematoma,23 hyphema,24 intracerebral hemorrhage,25 and subarachnoid hemorrhage.26

The side effects reported in studies using EGb 761 are rare and usually mild and may include nausea, vomiting, diarrhea, headaches, dizziness, palpitations, restlessness, and weakness. Hypersensitivity to ginkgo is a contraindication to its use and persons allergic to urushiols such as mango rind, poison ivy, poison oak, sumac, and cashews may be cross-reactive to ginkgo products.

Uncooked ginkgo seeds, and to a lesser extent unprocessed ginkgo leaves, contain ginkgotoxin, a chemical that can cause seizures and ultimately death if large quantities are ingested over time.21

Because ginkgo may affect insulin and blood sugar levels, patients with diabetes who choose to take ginkgo leaf extract preparations should monitor sugar levels carefully as adjustments to diabetic medications may be necessary.

The use of ginkgo is not recommended during pregnancy and breastfeeding due to a lack of scientific study. Ginkgo use may result in significant bleeding complications during labor and delivery.18,21

Conclusion

There have been several well designed clinical trials showing that the Ginkgo biloba extract EGb 761 has efficacy in the treatment of Alzheimer's disease. Only products with this formulation should be used as it has been shown to be safe and reliable in two to three divided daily doses of 120-240 mg and has efficacy that is nearly equivalent to that of acetylcholinerase inhibitors with less adverse side effects and cost.

Current ongoing multicenter trials such as the GEM study endeavor to demonstrate whether EGb 761 is effective as a preventive measure for dementia.

Patients on anticoagulant medications should not be treated with ginkgo products due to the possibility of serious bleeding sequelae. Patients undergoing dental or surgical procedures should stop taking ginkgo preoperatively according to the advice of their physicians. Patients with known hypersensitivities to ginkgo or urushiols should avoid its use. Ginkgo products should not be given to pregnant or breastfeeding women.

Recommendation

Ginkgo biloba in the form of EGb 761 is a safe, effective treatment for dementia, which although statistically less effective than ChE inhibitors, has a lower cost, better side effect profile, and less rebound effect, as measured in one study. The choice of ginkgo product should be restricted to brands such as Ginkgold, which contain the standardized extract EGb 761 that has been used in all of the clinical trials.

References

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2. Strittmatter WJ, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993;90:1977-1981.

3. Wincor MZ. Ginkgo biloba for dementia: A reasonable alternative? J Am Pharm Assoc (Wash) 1999;39:415-416.

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9. Taylor JE. The effects of chronic oral Ginkgo biloba extract administration on neuroreceptor binding in young and aged Fisher 344 rats. In: Agnoli A, et al, eds. Effects of Ginkgo biloba extract on organic cerebral Impairment. London: Libbey; 1985.

10. Pierre S, et al. Ginkgo biloba extract (EGb 761) protects Na,K-ATPase activity during cerebral ischemia in mice. Neuroreport 1999;10:47-51.

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12. Committee for Proprietary Medical Products. Note for Guidance on Medicinal Products in the Treatment of Alzheimer's Disease. London: 1997: CPMP/EWP/554/95.

13. Schulz V. Ginkgo extract or cholinesterase inhibitors in patients with dementia: What clinical trials and guidelines fail to consider. Phytomedicine 2003;10(Suppl 4):74-79.

14. Birks J, et al. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2002;(4):CD003120.

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16. van Dongen M, et al. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: New results of a randomized clinical trial. J Am Geriatr Soc 2000;48:1183-1194.

17. The Ginkgo Evaluation of Memory (GEM) Study. Available at: www.nccam-ginkgo.org/. Accessed March 8, 2006.

18. Mayo Clinic. Drugs and Supplements: Ginkgo biloba L. Available at www.mayoclinic.com/health/ginkgo-biloba/NS_patient-ginkgo. Accessed March 9, 2006.

19. Rainer M, et al. Cognitive relapse after discontinuation of drug therapy in Alzheimer's disease: Cholinesterase inhibitors versus nootropics. J Neural Transm 2001;108:1327-1333.

20. Frank B, Gupta S. A review of antioxidants and Alzheimer's disease. Ann Clin Psychiatry 2005;17:269-286.

21. Sierpina VS, et al. Ginkgo biloba. Am Fam Physician 2003;68:923-926.

22. Ang-Lee MK, et al. Herbal medications and perioperative care. JAMA 2001;286:208-216.

23. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology 1996;46:1775-1776.

24. Rosenblatt M, Mendel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med 1997;336:1108.

25. Matthews MK Jr. Association of Ginkgo biloba with intracerebral haemorrhage. Neurology 1998;50:1933-1934.

26. Vale S. Subarachnoid hemorrhage associated with Ginkgo biloba. Lancet 1998;352:36.