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Ginkgo Biloba increases cognitive function by dilating the blood vessels, thereby allowing blood to flow to the brain more freely, and by acting as an antioxidant, protecting nerves and the eyes from the damage of free radicals.

Ginkgo supplements can improve concentration, short-term memory, and overall brain function.  In patients with Alzheimer’s disease and other dementias, ginkgo may help reduce
the symptoms of these disorders.
           
The two important chemicals in ginkgo are flavonoids and terpenoids.  Flavon-oids attack free radicals, harmful particles which exist naturally in the body but which can destroy cells and important nutrients.  The presence of free radicals may increase with exposure to certain other environmental conditions such as ultraviolet light, radiation, cigarette smoke, and pollution.  Flavonoids protect the heart muscles, nerves, and retina from damage from these harmful substances.

 

(See Mayo Clinic's Comments on Ginkgo Biloba)

 

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Terpenoids are compounds which dilate the blood vessels and keep platelets in the blood from clotting together.  Studies performed by the National Institutes of Health have confirmed the health benefits of ginkgo, and in Europe it remains one of the most popular herbal supplements on the market. 


OTHER USES:

Other uses for ginkgo include treatments for pre-menstrual syndrome, altitude sickness, claudication (pain in the legs caused by blood clots), and depression.  Ginkgo is at least as effective, and possibly even more so, as some prescription drugs in treating claudication and dementia.  For example, for people with early stage dementia, one study showed that ginkgo was more effective at treating symptoms than the prescription drug donepezil (Aricept®), according to the Mayo Clinic. 

The Mayo Clinic also cites ginkgo biloba extract as a possible treatment for cerebral insufficiency, acute hemorrhoidal attacks, age-associated memory impairment, chemotherapy side effects, deafness, seasonal affective disorder, gastric cancer, glaucoma, macular degeneration, multiple sclerosis, pulmonary interstitial fibrosis, retinopathy, tinnitus, sexual dysfunction, stroke, vertigo, and vitiligo.

For healthy adults, ginkgo is a safe and effective way to increase daily cognitive function.  In elderly people suffering from age-related mental disorders, ginkgo may be a healthy means of preventing or mitigating the symptoms of some common conditions. 

Grading of Ginkgo Biloba by the Mayo Clinic:

EVIDENCE
These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Uses based on scientific evidence          Grade*

CLAUDICATION (PAINFUL LEGS FROM CLOGGED ARTERIES)
Numerous studies suggest that Ginkgo biloba taken by mouth causes small improvements in claudication symptoms (leg pain with exercise or at rest due to clogged arteries). However, ginkgo may not be as helpful for this condition as exercise therapy or prescription drugs. Preliminary research comparing ginkgo to pentoxifylline (Trental®) has not provided clear answers. Most studies have used 120 milligrams of ginkgo per day, divided into two to three doses, for up to six months. Additional evidence is needed from well-designed studies comparing or combining ginkgo with drug and exercise therapies. Grade A

DEMENTIA (MULTI-INFARCT AND ALZHEIMER'S TYPE)
Many human and laboratory studies have examined the use of ginkgo for dementia. Most research has not been well designed. Despite these deficiencies, the scientific literature overall does suggest that ginkgo (120 to 240 milligrams daily) benefits people with early stage Alzheimer's disease and multi-infarct dementia, and may be as helpful as acetylcholinesterase inhibitor drugs such as donepezil (Aricept®). Well-designed research comparing ginkgo to prescription drug therapies is needed.       A

CEREBRAL INSUFFICIENCY
Multiple clinical trials have evaluated ginkgo for a syndrome called "cerebral insufficiency." This condition, more commonly diagnosed in Europe than the United States, may include poor concentration, confusion, absent-mindedness, decreased physical performance, fatigue, headache, dizziness, depression, and anxiety. It is believed that cerebral insufficiency is caused by decreased blood flow to the brain due to clogged blood vessels. Some research reports benefits of ginkgo in patients with these symptoms, but most have been poorly designed without reliable results. Better studies are needed before a strong recommendation can be made.        B

ACUTE HEMORRHOIDAL ATTACKS
In early study ginkgo was shown to be effective in the treatment of patients with acute hemorrhoidal attacks. Further research is needed to confirm these results.            C

AGE-ASSOCIATED MEMORY IMPAIRMENT (AAMI)
Age-associated memory impairment (AAMI) is a non-specific syndrome, which may be caused by early Alzheimer's disease or multi-infarct dementia (conditions for which ginkgo has been shown to have benefit). There is preliminary research showing small improvements in memory and other brain functions in patients with AAMI, although some studies disagree. Overall, there is currently not enough clear evidence to recommend for or against ginkgo for this condition.     Grade C

ALTITUDE (MOUNTAIN) SICKNESS
A small amount of poorly designed research reports benefits of ginkgo for the treatment of altitude (mountain) sickness. A definite benefit over a prescription drug has not been demonstrated. Additional study is needed before a recommendation can be made.   C

CHEMOTHERAPY SIDE EFFECTS REDUCTION
In limited human study, ginkgo has been examined in addition to 5-fluorouracil (5-FU) in the treatment of pancreatic and colorectal cancer, to measure possible benefits on side effects. At this time, there is not conclusive evidence in this area.     C

DEAFNESS (COCHLEAR)
Preliminary clinical study has been conducted on the effect of ginkgo in chronic cochleovestibular disorders. Further research is needed before a recommendation can be made.            C

DEPRESSION AND SEASONAL AFFECTIVE DISORDER (SAD)
Preliminary study of seasonal affective disorder (SAD) suggests that ginkgo is not effective in preventing the development of winter depression. Other research in elderly patients with depression shows possible minor benefits. Overall, there is not enough evidence to form a clear conclusion.     C

GASTRIC CANCER
Ginkgo biloba exocarp polysaccharides (GBEP) capsule preparation has been studied for upper digestive tract malignant tumors of middle and late stage with positive results. However, further research is needed before a recommendation can be made.        C

GLAUCOMA
Several small human studies report ginkgo may be associated with mild increases in blood flow to the eyes, vision and intraocular pressure. However, these studies are poorly designed and small in size. Additional well-designed research is needed before a recommendation can be made.          C

MACULAR DEGENERATION
Preliminary research suggests that ginkgo may improve eye blood flow, although it remains unclear if macular degeneration is significantly affected by ginkgo. More research is needed in this area before a conclusion can be drawn.         C

MEMORY ENHANCEMENT (IN HEALTHY PEOPLE)
A recent well-designed study reports that ginkgo at a dose of 120 milligrams daily for six weeks did not improve memory or concentration in people older than 60 years. However, prior evidence from smaller, less rigorous studies suggests that ginkgo in doses greater than or equal to 240 milligrams daily may enhance memory in healthy individuals. Therefore, although it remains unclear if higher doses of ginkgo are effective, it seems unlikely that 120 milligrams has significant benefits.           C

MULTIPLE SCLEROSIS
Based on laboratory study, it has been suggested that ginkgo may provide benefit in multiple sclerosis (MS). Human research is limited to several small studies, which have not found consistent benefit. Additional research is needed before a recommendation can be made.    Grade  C

PREMENSTRUAL SYNDROME (PMS)
Initial study in women with premenstrual syndrome or breast discomfort suggests that ginkgo may relieve symptoms including emotional upset. Further well-designed research is needed before a recommendation can be made.             C

PULMONARY INTERSTITIAL FIBROSIS
Based on early study, ginkgo may be effective in treating pulmonary interstitial fibrosis. Further research is needed to confirm these results.           C

QUALITY OF LIFE
Two studies have suggested that ginkgo may aid in quality of life. More randomized controlled trials are needed before a conclusion can be made.     C

RAYNAUD'S DISEASE
Results from one clinical trial suggest that Ginkgo biloba may be effective in reducing the number of Raynaud's attacks in patients suffering from Raynaud's disease. In order to confirm these results, further clinical trials are required. C

RETINOPATHY (DIABETES MELLITUS TYPE II)
Evidence from one non-placebo controlled study suggests Ginkgo biloba extract may offer benefit to individuals with retinopathy. Further clinical trials are required to determine efficacy .   Grade C

RINGING IN THE EARS (TINNITUS)
There is conflicting research regarding the use of ginkgo for tinnitus. Traditional use and multiple small, poorly designed studies from the 1980s and 1990s report benefits. However, a well-designed recent study found no benefit. Additional well-designed research is needed in order to resolve this controversy. C

SEXUAL DYSFUNCTION
Ginkgo has been used and studied for the treatment of sexual dysfunction in men and women. Ginkgo may be effective in the treatment of erectile dysfunction, based on human and animal studies that show blood vessel relaxant properties, which may improve blood flow in the penis to achieve an erection. Ginkgo has also been reported in limited human study to treat sexual dysfunction in men and women caused by antidepressant drugs, such as fluoxetine (Prozac®), although other study results disagree. In general, studies are small and not well designed. Additional research is needed before a recommendation can be made.             C

STROKE
Laboratory studies suggest that ginkgo may be helpful immediately following strokes because of possible antioxidant or blood vessel effects. However, initial study of ginkgo in people having strokes found no benefits. Further research is needed in this area.    C

VERTIGO
A small amount of poorly designed research reports benefits of ginkgo for the treatment of vertigo. Additional study is needed before a recommendation can be made.       C

VITILIGO
One small study using oral ginkgo biloba extract 40 milligrams three times daily reports that ginkgo appears to arrest the progression of this disease. Better-designed studies are needed to confirm these results.            C

KEY TO GRADES
A Strong scientific evidence for this use
B Good scientific evidence for this use
C Unclear scientific evidence for this use
D Fair scientific evidence against this use (it may not work)
F Strong scientific evidence against this use (it likely does not work)

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References:

Blumenthal M. German Federal Institute for Drugs and Medical Devices. Commission E. The complete German Commission E monographs: therapeutic guide to herbal medicines. Austin, Tex.: American Botanical Council, 1998:11-12.

Blumenthal M. German Federal Institute for Drugs and Medical Devices. Commission E. Herbal medicine: expanded Commission E monographs. Newton, Mass.: Integrative Medicine Communications, 2000:160-9, 479-80.

Oberpichler H, Sauer D, Rossberg C, Mennel HD, Krieglstein J. PAF antagonist ginkgolide B reduces postischemic neuronal damage in rat brain hippocampus. J Cereb Blood Flow Metab 1990;10:133-5.

Sastre J, Millan A, Garcia de la Asuncion J, Pla R, Juan G, Pallardo, et al. A Ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress. Free Radic Biol Med 1998;24:298-304.

Van Beek T, Bombardelli E, Peterlongo G. Ginkgo biloba L. Fitoterapia 1998;69:195-244.

Ahlemeyer B, Kriegelstein J. Neuroprotective effects of Ginkgo biloba extract. In: Lawson LD, Bauer R. Phytomedicines of Europe: chemistry and biological activity. Washington, D.C.: American Chemical Society, 1998:210-20.

World Health Organization. WHO monographs on selected medicinal plants. Vol. 1, Ch. 16. Folium Gingko. Geneva: World Health Organization, 1999:154-67.

DeFeudis FV. Ginkgo biloba extract (EGb 761): pharmacological activities and clinical applications. Amsterdam: Elsevier, 1991:1187.

DeFeudis FV. Ginkgo biloba extract (EGb 761): from chemistry to the clinic. Wesbaden: Ullstein Medical, 1998.

Watanabe CM, Wolffram S, Ader P, Rimbach G, Packer L, Maquire JJ, et al. The in vivo neuromodulatory effects of the herbal medicine gingko biloba. Proc Natl Acad Sci U S A 2001;98:6577-80.

Kleijnen J, Knipschild P. Ginkgo biloba for cerebral insufficiency. Br J Clin Pharmacol 1992;34:352-8.

Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 1998; 55:1409-15.

Hofferberth B. The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type, a double-blind, placebo-controlled study on different levels of investigation. Hum Psychopharmacol 1994;9:215-22.

Kanowski S, Herrmann WM, Stephan K, Wierich W, Horr R. Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 1996;29:47-56.

Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA 1997;278:1327-32.

Wesnes K, Simmons D, Rook M, Simpson P. A double-blind placebo-controlled trial of Tanakan in the treatment of idiopathic cognitive impairment in the elderly. Hum Psychopharmacol. 1987; 2:159-69.

Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology 1998; 50:136-45.

Wettstein A. Cholinesterase inhibitors and Ginkgo extracts -- are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months' duration. Phytomedicine 2000;6:393-401.

Ernst E, Pittler MH. Ginkgo biloba for dementia. A systematic review of double-blind, placebo-controlled trials. Clin Drug Invest 1999;17:301-8.

Birks J, Grimley E, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2002; 4:CD003120.

van Dongen MC, van Rossum E, Kessels AG, Sielhorst HJ, Knipschild PG. 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;48:1183-94.

Weber W. Ginkgo not effective for memory loss in elderly. Lancet 2000;356:1333.
Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial. JAMA 2002;288:835-40.

Mix JA, Crews WD Jr. A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: neuropsychological findings. Hum Psychopharmacol 2002;17:267-77.

Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med 2000;108:276-81.

Schweizer J, Hautmann C. Comparison of two dosages of ginkgo biloba extract EGb 761 in patients with peripheral arterial occlusive disease Fontaine's stage IIb. A randomised, double-blind, multicentric clinical trial. Arzneimittelforschung 1999;49:900-4.

Peters H, Kieser M, Holscher U. Demonstration of the efficacy of ginkgo biloba special extract EGb 761 on intermittent claudication--a placebo-controlled, double-blind multicenter trial. Vasa 1998;27:106-10.

Bauer U. 6-Month double-blind randomised clinical trial of Ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency. Arzneimittelforschung 1984;34:716-20.

Drew S, Davies E. Effectiveness of Ginkgo biloba in treating tinnitus: double blind, placebo controlled trial. BMJ 2001;332:73.

Meyer B. Multicenter randomized double-blind drug vs. placebo study of the treatment of tinnitus with Ginkgo biloba extract [in French]. Presse Med 1986;15:1562-4.

Ernst E, Stevinson C. Ginkgo biloba for tinnitus: a review. Clin Otolaryngol 1999;24:164-7.

Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther 1998;24:139-43.

Roncin JP, Schwartz F, D'Arbigny P. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure. Aviat Space Environ Med 1996;67:445-52.

Evans JR. Ginkgo biloba extract for age-related macular degeneration. Cochrane Database Syst Rev 2003;(2):CD001775.

Li M, Yange B, Yu H, Zhang H. Clinical observation of the therapeutic effect of ginkgo leaf concentrated oral liquor on bronchial asthma. Chinese Journal of Integrative Medicine 1997;3:264-7.

Schaffler K, Reeh PW. Double blind study of the hypoxia protective effect of a standardized Ginkgo biloba preparation after repeated administration in healthy subjects [in German]. Arzneimittelforschung 1985;35:1283-6.

Engelsen J, Dalsgaard N, Winther K. The health care products Coenzyme Q10 and Ginkgo biloba do not interact with warfarin. Thromb Haemost 2001;(Supp)(Abstract No. P796).
Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA 2001;286:208-16.

Leak JA. Herbal medicines: what do we need to know? ASA Newsletter February 2000. Retrieved June 10, 2003, from www. asahq.org/Newsletters/2000/02_00/herbal0200.html.
Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology 1996; 46:1775-6.

Gilbert GJ. Ginkgo biloba. Neurology 1997;48:1137.

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

Matthews MK JR. Association of Ginkgo biloba with intracerebral hemorrhage. Neurology 1998;50:1933-4.

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

Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements. A 5-year toxicological study (1991-1995). Drug Saf 1997;17:342-56.

Murray MT, Pizzorno JE. Encyclopedia of natural medicine. 2d ed. Rocklin, Calif.: Prima Pub., 1998.

Mills S, Bone K. Principles and practice of phytotherapy: modern herbal medicine. Edinburgh: Churchill Livingstone, 2000.

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University of Maryland Medical Center:

Based on studies conducted in laboratories, animals, and humans, professional herbalists may recommend ginkgo for the following health problems:

DEMENTIA AND ALZHEIMER'S DISEASE
Ginkgo is widely used in Europe for treating dementia. The reason that ginkgo is thought to be helpful for preventing or treating these brain disorders is because it improves blood flow in the brain and because of its antioxidant properties. Although many of the clinical trials have been scientifically flawed, the evidence that ginkgo may improve thinking, learning, and memory in people with Alzheimer's disease (AD) has been highly promising.

Clinical studies suggest that ginkgo provides the following benefits for people with AD:
•          Improvement in thinking, learning, and memory
•          Improvement in activities of daily living
•          Improvement in social behavior
•          Fewer feelings of depression

One recent study also found that ginkgo may be as effective as leading AD medications in delaying the symptoms of dementia in people with this debilitating condition. In addition, ginkgo is sometimes used preventively because it may delay the onset of AD in someone who is at risk for this type of dementia (for example, family history).

EYE PROBLEMS
The flavonoids found in ginkgo may help halt or lessen some retinal problems (that is, problems to the back part of the eye). Retinal damage has a number of potential causes, including diabetes and macular degeneration. Macular degeneration (often called age-related macular degeneration or ARMD) is a progressive, degenerative eye disease that tends to affect older adults and is the number one cause of blindness in the United States. Studies suggest that gingko may help preserve vision in those with ARMD.

INTERMITTENT CLAUDICATION
Because ginkgo is reputed to improve blood flow, this herb has been studied in people with intermittent claudication (pain caused by inadequate blood flow [atherosclerosis] to the legs). People with intermittent claudication have difficulty walking without suffering extreme pain. An analysis of eight published studies revealed that people taking ginkgo tend to walk roughly 34 meters farther than those taking placebo. In fact, ginkgo has been shown to be as effective as a leading medication in improving pain-free walking distance. However, regular walking exercises are more beneficial than ginkgo in improving walking distance.

MEMORY IMPAIRMENT
Ginkgo is widely touted as a "brain herb" and is commonly added to nutrition bars and fruit smoothies to boost memory and enhance cognitive performance. Researchers recently reviewed all of the high-quality published studies on ginkgo and mild memory impairment (in other words, people without Alzheimer's or other form of dementia), and concluded that ginkgo was significantly more effective than placebo in enhancing memory and cognitive function. Despite the encouraging findings, some researchers speculate that more high-quality research, involving larger numbers of people, is needed before ginkgo can be recommended as a memory enhancer to otherwise healthy adults.

TINNITUS
Given that nerve damage and certain blood vessel disorders can lead to tinnitus (the perception of ringing, hissing, or other sound in the ears or head when no external sound is present), some researchers have investigated whether ginkgo relieves symptoms of this hearing disorder. Although the quality of most studies was poor, the reviewers concluded that ginkgo moderately relieves the loudness of the tinnitus sound. However, a recent well-designed study including 1,121 people with tinnitus found that ginkgo (given 3 times daily for 3 months) was no more effective than placebo in relieving symptoms of tinnitus. Given these conflicting findings, the therapeutic value of ginkgo for tinnitus remains uncertain. In general, tinnitus is a very difficult problem to treat. Talk to your doctor about whether a trial of ginkgo to alleviate this frustrating symptom may be safe and worthwhile for you.

OTHER
In addition to these health problems, professional herbalists may also recommend ginkgo for a variety of other ailments including altitude sickness, asthma, depression, disorientation, headaches, high blood pressure, erectile dysfunction, and vertigo.

Precautions:

Pregnant and breastfeeding women should avoid using ginkgo preparations. In addition, ginkgo use should be discontinued at least 36 hours prior to surgery due to the risk of bleeding complications.

The use of herbs is a time-honored approach to strengthening the body and treating disease. Herbs, however, contain active substances that can trigger side effects and interact with other herbs, supplements, or medications. For these reasons, herbs should be taken with care, under the supervision of a practitioner knowledgeable in the field of botanical medicine.

GBE is considered to be safe and side effects are rare. In a few cases, gastrointestinal upset, headaches, skin reactions, and dizziness were reported.

Because gingko decreases platelet aggregation (stickiness), there is some concern that it may increase risk of intracranial (brain) hemorrhage. In fact, there have been several reports of bleeding complications associated with ginkgo use. However, it is not clear whether ginkgo or another factor (such as the combination of ginkgo and blood-thinning medications including aspirin) caused the bleeding complications.

Do not ingest Ginkgo biloba fruit.

Possible Interactions:

If you are currently being treated with any of the following medications, you should not use ginkgo without first talking to your healthcare provider:

ANTICONVULSANT MEDICATIONS
High doses of Ginkgo biloba could decrease the effectiveness of anticonvulsant therapy in patients taking carbamazepine or valproic acid to control seizures.

BLOOD-THINNING MEDICATIONS
Ginkgo has blood-thinning properties and therefore should not be used if you are taking anticoagulant (blood-thinning) medications, such as aspirin, clopidogrel, dipyridamole, heparin, ticlopidine, or warfarin.

CYLOSPORINE
Ginkgo biloba may be beneficial during treatment with cyclosporine because of its ability to protect cell membranes from damage.

MONOAMINE OXIDASE INHIBITORS (MAOIS)
Ginkgo may enhance the effects (both good and bad) of antidepressant medications known as MAOIs, such as phenelzine and tranylcypromine.

PAPAVERINE
The combination of papaverine and ginkgo may be effective for the treatment of erectile dysfunction in patients who do not respond to papaverine alone.

THIAZIDE DIURETICS
Although there has been one literature report of increased blood pressure associated with the use of ginkgo during treatment with thiazide diuretics, this interaction has not been verified by clinical trials. Nevertheless, you should consult with your healthcare provider before using ginkgo if you are taking thiazide diuretics.

TRAZODONE
Additionally, there has been a report of an adverse interaction between ginkgo and trazodone, an antidepressant medication, that resulted in an elderly patient going into a coma.

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From American Academy of Family Physicians:

“GINKGO BILOBA”
VICTOR S. SIERPINA, M.D., University of Texas Medical Branch, Galveston, Texas
BERND WOLLSCHLAEGER, M.D., North Miami Beach, Florida
MARK BLUMENTHAL, American Botanical Council, Austin, Texas

Ginkgo biloba is commonly used in the treatment of early-stage Alzheimer's disease, vascular dementia, peripheral claudication, and tinnitus of vascular origin. Multiple trials investigating the efficacy of ginkgo for treating cerebrovascular disease and dementia have been performed, and systematic reviews suggest the herb can improve the symptoms of dementia. Ginkgo is generally well tolerated, but it can increase the risk of bleeding if used in combination with warfarin, antiplatelet agents, and certain other herbal medications. Clinical issues of safety, dosing, use in the perioperative period, and pharmacology are addressed in this review. (Am Fam Physician 2003;68:923-6. Copyright© 2003 American Academy of Family Physicians)

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. It also is one of the 10 best-selling herbal medications in the United States.1 There are over 120 published clinical studies on ginkgo, primarily from Europe. The standardized preparation of Ginkgo biloba extract is EGb 761. In the United States, ginkgo is classified as a dietary supplement; the American brands that are comparable with EGb 761 that have been subjected to clinical studies are Ginkgold, Ginkoba, and Ginkai.2 Standardized preparations contain 24 percent ginkgo flavonoid glycosides, 6 percent terpene lactones, and no more than 5 parts per million ginkgolic acids.

Pharmacology
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) phosphodiesterase7,8; inhibition of age-related loss of muscarinergic cholinoceptors and a-adrenoceptors; and stimulation of choline uptake in the hippocampus. Ginkgo extract also has been shown to inhibit beta-amyloid deposition.10

Uses and Efficacy

Cerebrovascular disease, dementia, and memory enhancement
A systematic review11 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). 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. [Evidence level A, meta-analysis] 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). Efficacy was measured using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other standardized measures of cognition.

A review18 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. A systematic review 19 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. 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. However, the three modern trials showed inconsistent results, suggesting that a large trial with modern methodology is needed to answer questions about treatment effects.20 [Evidence level A, meta-analysis]

One of the studies analyzed in the Cochrane review was a Dutch study 21 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. This study failed to show improvement in age-associated memory impairment or mild or moderate dementia in several neuro-psychologic and behavior outcome measures.2 However, this study 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.

A randomized, placebo-controlled trial of the effects of ginkgo in healthy, noninstitutionalized adults without dementia or other known mental deficit found no benefit from six weeks of ginkgo therapy (120 mg per day) on several standardized neuropsychologic measures of memory and learning. 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.

The National Institutes of Health and the National Center for Complementary and Alternative Medicine have sponsored a multi-center, 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 underway at the Oregon Health Sciences Center, 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. [Evidence level A, meta-analysis] A trial26 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. Two placebo-controlled trials with a total of 190 patients, showed improved walking distance and decreased pain in patients with peripheral vascular disease.

Tinnitus
Another common indication for ginkgo is tinnitus. A recent study 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. Another randomized, placebo-controlled trial30 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. A review31 of five heterogenous randomized controlled trials concluded that extracts of ginkgo biloba are moderately effective in treating tinnitus.

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 vasoactivity in response to cold, macular degeneration, asthma, and hypoxia. The World Health Organization has recommended the use of ginkgo in Raynaud's disease, acrocyanosis, and post-phlebitic syndrome.

Warnings, Interactions, Adverse Effects
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 (Coumadin), 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.

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. Several case reports of bleeding complications associated with ginkgo use include subdural hematoma, subarachnoid hemorrhage, intracerebral hemorrhage, and hyphema; the causality of these events has not been established. One case report discussed an elderly patient who developed elevated blood pressure while taking a thiazide diuretic and ginkgo. The patient's blood pressure returned to normal when both substances were discontinued. This reaction is paradoxical in light of the known pharmacologic actions of these agents.

The unprocessed ginkgo leaf contains ginkgolic acids that are toxic. Hypersensitivity to ginkgo preparations is a contraindication to use. Ginkgo is generally well tolerated, with side effects being rare, usually mild, and including nausea, vomiting, diarrhea, 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.

Dosage
For patients who have memory problems and dementia, the dosage of ginkgo is 120 to 240 mg daily, taken in two to three doses. The dosage for patients who have tinnitus and peripheral vascular disease is no more than 160 mg per day, taken in two or three doses. An initial period of six to 12 weeks is recommended to assess the effectiveness of ginkgo, although results have been seen as early as four weeks.

Final Comment
With an aging population seeking solutions to troubling problems such as dementia and vasculopathy, ginkgo offers some benefit as a mild vasoactive and neuroprotective phytomedicine. It offers a relatively safe, inexpensive, and modestly effective treatment option when selected by patients or prescribing physicians for multi-infarct or Alzheimer's dementia. Evidence indicates that it is effective in slowing disease progression and ameliorating symptoms.

While some studies show no benefit in Alzheimer's disease, others show that it is comparable in its efficacy with the second-generation cholinesterase inhibitors. Ginkgo should be discontinued before surgery, but the time period has not been determined conclusively. Ginkgo also has demonstrated benefits in patients with peripheral vascular disease and tinnitus. Name brands using the same extract as those used in clinical research studies are to be recommended as the most reliable in the current herbal market in the United States.
The authors indicate that they do not have any conflicts of interests. Sources of funding: This manuscript was made possible in part by grant no. R25AT00586-01 from the National Center for Complementary and Alternative Medicine.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the National Center for Complementary and Alternative Medicine or the National Institutes of Health.

The Authors
VICTOR S. SIERPINA, M.D., is associate professor of family medicine at the University of Texas Medical Branch at Galveston. Dr. Sierpina received his medical degree from the University of Illinois, Abraham Lincoln School of Medicine, Chicago. He completed a residency in family practice at MacNeal Memorial Hospital, Chicago. He is board-certified by the American Board of Family Practice and the American Board of Holistic Medicine.

BERND WOLLSCHLAEGER, M.D., is in private practice in North Miami Beach, Fla. He also is an assistant professor of medicine and family medicine at the University of Miami School of Medicine. Dr. Wollschlaeger received his medical training in Germany and Israel, including special education in botanical medicine and homeopathy. He completed a residency at Jackson Memorial Hospital, Miami.

MARK BLUMENTHAL is founder and executive director of the American Botanical Council, Austin, Tex., and adjunct professor of medicinal chemistry at the University of Texas, College of Pharmacy, Austin. He is the senior editor of The Complete Commission E Monographs and the journal HerbalGram.


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Studies & Citations:

“Peroxyl radical scavenging activity of Ginkgo biloba extract EGb 761.”
Maitra, I : Marcocci, L : Droy Lefaix, M T : Packer, L
Biochem-Pharmacol. 1995 May 26; 49(11): 1649-55

Antioxidant mechanisms have been proposed to underlie the beneficial pharmacological effects of EGb 761, an extract from Ginkgo biloba leaves used for treating peripheral vascular diseases and cerebrovascular insufficiency in the elderly. In vitro evidence has been reported that EGb 761 scavenges various reactive oxygen species, i.e. nitric oxide, and the superoxide, hydroxyl, and oxoferryl radicals. However, the ability of EGb 761 to scavenge peroxyl radicals (reactive species mainly involved in the propagation step of lipid peroxidation) has not been investigated. To characterize further the antioxidant action of EGb 761, we measured the protective effects of EGb 761 during: (1) the oxidation of B-phycoerythrin by peroxyl radicals generated in aqueous solution by 2,2'-azobis (2-amidinopropane) hydrochloride (AAPH); and (2) the reaction of luminol or cis-parinaric acid with peroxyl radicals generated from 2,2'-azobis (2,4-dimethylvaleronitrile) (AMVN) in liposomes or in human low density lipoprotein (LDL), respectively. To evaluate the peroxyl radical scavenging activity of EGb 761 in a more physiologically relevant model of damage to lipid-containing systems, we also analyzed the effect of the extract on the oxidation of human LDL exposed to the azo-initiators in terms of: (1) accumulation of cholesterol linoleate ester hydroperoxides, (2) depletion of alpha-tocopherol and beta-carotene, and (3) changes in intrinsic tryptophan fluorescence. EGb 761 afforded protection against oxidative damage in all the systems we analyzed; thus, it is an efficient scavenger of peroxyl radicals. This result extends the oxygen radical scavenging properties of the extract and supports the hypothesis of an antioxidant therapeutic action of EGb 761.

“Antioxidant effect of a Ginkgo biloba extract (EGb 761) on the retina.”
Droy Lefaix, M T : Cluzel, J : Menerath, J M : Bonhomme, B : Doly, M
Int-J-Tissue-React. 1995; 17(3): 93-100

Several investigations have recently shown that the retina is very sensitive to oxygenated free radicals (O2-, OH.) at the origin of the membrane phospholipids peroxidation. Peroxy radical (ROO.) release is responsible for the induction of electrophysiological disturbances leading to retinopathy development. As Ginkgo biloba extract (EGb 761, IPSEN, France) was reported to scavenge primary (O2-, OH.) and secondary (ROO.) free radicals, we evaluated its antioxidant effect on retinas of albino rats submitted to different types of aggressors. On isolated rat retina, EGb 761 given orally significantly protected against lipoperoxidation induced by a mixture of ferrous sulfate and sodium ascorbate added to the perfusion solution. With EGb 761, the decrease of the b-wave ERG amplitude was less pronounced and the retina survival was increased. EGb 761 was also effective against ischaemia-reperfusion disorders due to occlusion of the central retinal artery or by intraocular hypertony. Like other antioxidants such as superoxide dismutase tested on these models, EGb 761 significantly attenuated, according to a dose-response effect, the free-radical injury. EGb 761 reduces the decrease of the b-wave amplitude, the oedema, necrosis and ion homeostasis disturbances. Xenobiotics are also responsible for the retinotoxicity partly due to free radicals and PAF release. We noted an EGb 761 dose-dependent protective effect against acute and chronic chloroquine toxicity to the retina. The deleterious effect of chloroquine was characterized by a delayed b-wave and an asymmetry of the signal with slow declining b-wave. After EGb 761 treatment, the ERG aspect was partially normal. In conclusion, EGb 761, by its general free-radical scavenger properties, is an antioxidant that inhibits or reduces the functional and morphological retina impairments observed after lipoperoxide release.

“The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF).”
 Smith, P F : Maclennan, K : Darlington, C L
 J-Ethnopharmacol. 1996 Mar; 50(3): 131-9

Ginkgo biloba (Ginkgoaceae) is an ancient Chinese tree which has been cultivated and held sacred for its health-promoting properties. There is substantial experimental evidence to support the view that Ginkgo biloba extracts have neuroprotective properties under conditions such as hypoxia/ischemia, seizure activity and peripheral nerve damage. Research on the biochemical effects of Ginkgo biloba extracts is still at a very early stage. One of the components of Ginkgo biloba, ginkgolide B, is a potent platelet-activating factor (PAF) antagonist. Although the terpene fraction of Ginkgo biloba, which contains the ginkgolides, may contribute to the neuroprotective properties of the Ginkgo biloba leaf, it is also likely that the flavonoid fraction, containing free radical scavengers, is important in this respect. Taken together, the evidence suggests that Ginkgo biloba extracts are worthy of further investigation as potential neuroprotectant agents.


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