Latin name: Gingko biloba L.
Pharmacopoeial name: Ginkgo folium
Other names: duck foot tree, maidenhair tree, silver apricot
About Ginkgo biloba
The ginkgo biloba tree is the world’s oldest living tree – its species can be dated back to over 250 million years. It is believed that they once occurred naturally in Asia, Europe and America but they disappeared from America about 7 million years ago and from Europe about 3 million years ago. It wasn’t until the eighteenth century that ginkgo was cultivated again in Europe and North America.
The medicinal use of the leaves was recorded in China in 2800 BC and a monograph still exists in the modern Chinese Pharmacopoeia.Ginkgo biloba leaf extract is the most widely sold phytomedicine in Europe, where it is used to treat the symptoms of early-stage Alzheimer’s disease, vascular dementia, peripheral claudication, and tinnitus of vascular origin. There are over 400 published clinical studies on ginkgo, primarily from Europe.
Standardized preparations contain 24 percent ginkgo flavonoid glyco- sides,6 percent terpene lactones,and no more than 5 parts per million ginkgolic acids (1,2). The mechanism of action of ginkgo is believed to be produced by its functions as a neuroprotective agent,an antioxidant, a free-radical scavenger, a membrane stabilizer, and an inhibitor of platelet-activating factor via the terpene ginkgolide B.(3-6). Other pharmacologic effects include the following: endothelium relaxation mediated by inhibition of 3’,5’-cyclic GMP (guanosine monophosphate) phosphodiesterase (7,8) ;inhibition of age-related loss of muscarinergic cholinoceptors and adrenoceptors; and stimulation of choline uptake in the hippocampus (1,9) Ginkgo extract also has been shown to inhibit beta-amyloid deposition (10).
Uses of Ginkgo biloba
Cerebrovascular disease, dementia, and memory enhancement
A systematic review of eight randomized, double-blind, placebo-controlled studies concluded that ginkgo had modest effects on improving the symptoms of dementia and cerebral insufficiency equivalent to pharmacologic therapy with ergoloid mesylates (Hydergine) (11). A later meta- analysis surveyed 50 articles to examine the effect of ginkgo on objective measures of cognitive function in patients with Alzheimer’s disease (12). Four of these studies met inclusion criteria for adequate clinical trial design (13-16).In the 212 subjects in the placebo and ginkgo groups, a significant overall effect size was found that was comparable with the benefits of donepezil (Aricept) (17). Efficacy was measured using the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other standardized measures of cognition.
A review of studies of at least six months in duration demonstrated that ginkgo extract and second-generation cholinesterase inhibitors were equally effective in treating mild to moderate Alzheimer’s dementia (18). A systematic review of nine studies on ginkgo use showed a safe and positive effect beyond placebo, but the investigators remained tentative in recommending it for treatment of dementia until better studies are conducted (19).
A Cochrane meta-analysis of 33 trials concluded that ginkgo appears to be safe, and showed promising evidence of improvement of cognition and function among patients who received the herb (20). However, three recent trials showed inconsistent results, suggesting that a large trial with modern methodology is needed to answer questions about treatment effects. One of the studies analysed in the Cochrane review was a Dutch study of 214 patients over 24 weeks using a medium dosage of ginkgo (160 mg per day),a high dosage of ginkgo (240 mg per day),or placebo in a crossover design (21). This study failed to show improvement in age-associated memory impairment or mild or moderate dementia in several neuropsychological and behaviour outcome measures. However, it included patients with age-associated memory impairment rather than just persons with dementia, which may have limited the statistical power of its conclusions about the role of ginkgo in dementia (22)
A randomized, placebo-controlled trial of the effects of ginkgo in healthy, non-institutionalized adults without dementia or other known mental deficits found no benefit from six weeks of ginkgo therapy (120 mg per day) on several standardized neuropsychological measures of memory and learning (23). However, a study using a similar design with a higher dosage of ginkgo (180 mg per day) showed clinically significant cognitive benefits in healthy persons (24).
The National Institutes of Health and the National Centre for Complementary and Alternative Medicine have sponsored a multicentre, six-year, randomized, two-arm, double-blind, placebo-controlled trial of 2,000 patients. The trial will evaluate the safety and efficacy of ginkgo in preventing dementia and age-related cognitive decline and is currently underway and headed by investigators at the University of Pittsburgh. Another phase III trial is under- way at the Oregon Health Sciences Centre, Portland, to study the effects of ginkgo on cognitively intact elderly patients older than 85 years, and the effect on their progression to mild cognitive impairment. This study will use volumetric quantitative magnetic resonance imaging measures of brain size and peripheral oxidative markers.
Intermittent claudication
Another indication for ginkgo is intermittent claudication from peripheral vascular disease. A meta-analysis of eight studies concluded that the effects of ginkgo, though statistically significant and positive on increasing pain-free walking, were of modest effect size and questionable clinical relevance (25). Another trial that compared dosages of 120 mg and 240 mg of ginkgo demonstrated a substantial therapeutic benefit on pain- free walking distance with the higher dosage (26).
Two placebo- controlled trials, with a total of190 patients, showed improved walking distance and decreased pain in patients with peripheral vascular disease (27,28).
Tinnitus
Another common indication for ginkgo is tinnitus. A recent study of 1,121 subjects conducted using questionnaires and telephone interviews, without the use of standard audiometric testing as an outcome measure, failed to show a benefit of ginkgo in the treatment of tinnitus (29).
However, another randomized, placebo-controlled trial of 103 patients showed 50 percent of patients with new-onset tinnitus had improvement or disappearance of symptoms in 70 days compared with 119 days to improvement in those receiving placebo (30). A review of five heterogeneous randomized controlled trials concluded that extracts of ginkgo biloba are moderately effective in treating tinnitus (31).
Other uses
Studies have shown positive results from the use of ginkgo for the following conditions: sexual dysfunction secondary to the use of selective serotonin reuptake inhibitors, mountain sickness and decreasing vaso-activity in response to cold, macular degeneration, asthma, and hypoxia (32-36).
The World Health Organization has recommended the use of ginkgo in Raynaud’s disease, acro- cyanosis,and post-phlebitic syndrome.
Safety
During the past 20 years, an estimated 2 billion daily doses (120 mg) of ginkgo have been sold. The most important potential clinical problem with ginkgo is caused by its inhibition of the platelet-activating factor; this makes the use of ginkgo in conjunction with warfarin, aspirin, or other antiplatelet agents a matter of clinical judgment.
A recent safety study of the interaction of ginkgo and warfarin showed no change in the international normalized ratio. Ginkgo should be discontinued between 36 hours and 14 days before surgery, based on either pharmacokinetics or consensus opinion (37-38). Herbal medications that may increase the risk of bleeding if used concurrently with ginkgo include the following: feverfew, garlic, ginseng, dong quai, red clover, and other natural coumarins.
Ginkgo is generally well tolerated, with side effects being rare, usually mild, and including nausea, vomiting, diarrhoea, headaches, dizziness, palpitations, restlessness, weakness, or skin rashes. Although no studies have been performed to support any restrictions on the use of ginkgo during pregnancy or lactation, it seems prudent not to administer ginkgo in the absence of any data
Keywords: Cerebrovascular disease, dementia, and memory enhancement; Intermittent claudication; Tinnitus;
Adopted monograph
Assessment report
References
References
1. Blumenthal M. The complete German Commission E monographs: therapeutic guide to herbal medicines. Austin, Tex.: American Botanical Council, 1998:11-12.
2. Blumenthal M. Commission E. Herbal medicine: expanded Commission E monographs. Newton, Mass.: Integrative Medicine Communications, 2000:160-9, 479-80.
3. Oberpichler H, Sauer D, Rossberg C, Mennel HD, Krieglstein J. J Cereb Blood Flow Metab 1990;10:133-5.
4. Sastre J, Millan A, Garcia de la Asuncion J, Pla R, Juan G, Pallardo, et al. Free Radic Biol Med 1998;24:298-304.
5. Van Beek T, Bombardelli E, Peterlongo G. Ginkgo biloba L. Fitoterapia 1998;69:195-244.
6. Ahlemeyer B, Kriegelstein J. In: Lawson LD, Bauer R. Phytomedicines of Europe: Washington, D.C.: American
Chemical Society, 1998:210-20.
7. World Health Organization. WHO monographs on selected medicinal plants. Vol. 1, Ch. 16. Folium Gingko. Geneva: World Health Organization, 1999:154-67.
8. DeFeudis FV. Ginkgo biloba extract (EGb 761): pharmacological activities and clinical applications. Amsterdam: Elsevier, 1991:1187.
9. DeFeudis FV. Ginkgo biloba extract (EGb 761): from chemistry to the clinic. Wesbaden: Ullstein Medical, 1998.
10. Watanabe CM, Wolffram S, Ader P, Rimbach G, Packer L, Maquire JJ, et al. Proc Natl Acad Sci U S A 2001;98:6577-80.
11. Kleijnen J, Knipschild P. Br J Clin Pharmacol 1992;34:352-8.
12. Oken BS, Storzbach DM, Kaye JA. Arch Neurol 1998; 55:1409-15.
13. Hofferberth B. Hum Psychopharmacol 1994;9:215-22.
14. Kanowski S, Herrmann WM, Stephan K, Wierich W, Horr R. Pharmacopsychiatry 1996;29:47-56.
15. Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. JAMA 1997;278:1327-32.
16. Wesnes K, Simmons D, Rook M, Simpson P. Hum Psychopharmacol. 1987; 2:159-69.
17. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. Neurology 1998;50:136-45.
18. Wettstein A. Phytomedicine 2000;6:393-401.
19. Ernst E, Pittler MH. Clin Drug Invest 1999;17:301-8.
20. Birks J, Grimley E, Van Dongen M. Cochrane Database Syst Rev 2002; 4:CD003120.
21. van Dongen MC, van Rossum E, Kessels AG, Sielhorst HJ, Knipschild PG. J Am Geriatr Soc 2000;48:1183-94.
22. Weber W. Lancet 2000;356:1333.
23. Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. JAMA 2002;288:835-40.
24. Mix JA, Crews WD Jr. Hum Psychopharmacol 2002;17:267-77.
25. Pittler MH, Ernst E. Am J Med 2000;108:276-81.
26. Schweizer J, Hautmann C. Arzneimittelforschung 1999;49:900-4.
27. Peters H, Kieser M, Holscher U. Vasa 1998;27:106-10.
28. Bauer U. Arzneimittelforschung 1984;34:716-20.
29. Drew S, Davies E. BMJ 2001;332:73.
30. Meyer B. Presse Med 1986;15:1562-4.
31. Ernst E, Stevinson C. Clin Otolaryngol 1999;24:164-7.
32. Cohen AJ, Bartlik B. J Sex Marital Ther 1998;24:139-43.
33. Roncin JP, Schwartz F, D’Arbigny P. Aviat Space Environ Med 1996;67:445-52.
34. Evans JR. Cochrane Database Syst Rev 2003;(2):CD001775.
35. Li M, Yange B, Yu H, Zhang H. Chinese Journal of Integrative Medicine 1997;3:264-7.
36. Schaffler K, Reeh PW. Arzneimittelforschung 1985;35:1283-6.
37. Engelsen J, Dalsgaard N, Winther K. Thromb Haemost 2001;(Supp)(Abstract No. P796).
38. Ang-Lee MK, Moss J, Yuan CS. JAMA 2001;286:208-16.
