Health Care Professional Information

Scientific Name
Ginkgo biloba
Common Name

Fossil tree, maidenhair tree, kew tree, bai guo ye, yinhsing

Brand Name

Ginkoba®

Clinical Summary

Ginkgo biloba is one of the oldest living tree species. It is cultivated around the world for its medicinal properties and aesthetic value. The seeds and the leaves have been used in traditional Chinese medicine to treat respiratory diseases, circulatory disorders, sexual dysfunction, and loss of hearing.

Ginkgo biloba extract exhibits anti-infective (1), chemopreventive (2), anticancer (3), and cytotoxic (4) effects in vitro.
Supplementation with Ginkgo improved cognitive performance in healthy adults (5), and in patients with dementia(6) although data are conflicting (7) (8) (9) (10) (11). In a study of older adults with normal cognition or with mild cognitive impairment (32), gingko did not slow down cognitive decline. And findings from the Gingko Evaluation of Memory (GEM) study, the largest trial of Ginkgo for dementia so far, indicate that ginkgo is ineffective in decreasing the incidence of dementia or Alzheimer's disease in elderly individuals (30); another randomized trial reported similar findings (43). However, ginkgo may be effective as a short-term treatment to improve memory in Alzheimer’s patients, although taking ginkgo supplements regularly does not prevent dementia (55).

It was less effective than the standard treatment for ADHD in children (37).
Ginkgo biloba may also reduce the severity of acute mountain sickness, but the evidence is mixed (25) (26) (27) (28). More studies are warranted.

A few studies have also explored Ginkgo's anticancer potential.
Ginkgo has also been implicated in reducing the risk of ovarian cancer but this is based only on epidemiological and biological data (12). Orally administered capsules of Ginkgo biloba exocarp polysaccharides reduced tumor area in patients with gastric cancer (4). In another study, an injectable form of Ginkgo extract and 5-flurouracil were administered to patients with advanced colorectal cancer. Data suggests benefits of the combination therapy (13). But data from the GEM study, in which cancer was the secondary outcome, do not support Gingko's effectiveness in reducing cancer risk (38).
Ginkgo supplementation was also reported ineffective in preventing chemotherapy-associated cognitive dysfunction in a randomized controlled trial of breast cancer patients (45).

High doses of a Ginkgo biloba extract showed carcinogenic effects in mice (44). However, dietary supplements in use today have much smaller concentrations.

Purported Uses
  • Asthma
  • Bronchitis
  • Cardiovascular disease
  • Circulatory disorders
  • Hearing loss
  • Memory loss
  • Raynaud's disease
  • Sexual dysfunction
  • Stress
  • Tinnitus
Constituents

Leaves:

Polyphenol flavonoids
Terpene trilactones: Ginkgolides A, B, C, J, M, Bilobalide
Proanthocyanidins

Seeds: Ginkgotoxin, cyanogenic glycosides
(2) (46) (47) (48)

Mechanism of Action

Ginkgo interacts with several cytochrome P450 enzymes. Pretreatment with G. biloba extract was shown to induce the expression of CYP3A protein and mRNA, and increased CYP3A activity (34). It also inhibits CYP2B6 catalytic activity and bupropion hydroxylation (36).
In other studies, Ginkgo was shown to play a role in decreasing high-glucose-induced endothelial inflammation via inhibition of interleukin-6 activation (49), and repeated intake of Ginkgo enhanced cell proliferation and neuroblast differentiation (50).

The chemopreventive ability of bilobalide, a terpene trilactone, is thought to be via alterations in cryptal cell proliferation and drug-metabolizing enzyme activities (2). The exocarp polysaccharides from G. biloba were shown to affect the expression of c-myc, bcl-2 and c-fos genes, which can inhibit proliferation and induce apoptosis and differentiation of human gastric tumor cells (4).

Pharmacokinetics

The pharmacokinetics of EGb 761, a 14C radiolabelled Ginkgo leaf extract, were studied in rats. Absorption was at least 60% and specific activity in blood peaked after 1–5 h.The highest values for specific radioactivity were measured in the stomach and small intestine at 3 h, indicating that this may be the site of absorption. Glandular and neuronal tissues and eyes showed a high affinity for the labelled substance. Seventy-two hours after oral administration, exhaled 14CO2 accounted for about 38 % of the administered dose; 22 % was excreted in urine and 29 % in feces.
Human data on the bioavailability of Ginkgo are limited. Studies conducted thus far show that the pharmacologically active compounds are available in human and animal plasma following oral and intravenous administration. The triterpene trilactones and flavonoids were shown to cross the blood-brain barrier in adequate concentrations and were detected in the CNS. (52)

Warnings

Ginkgo biloba extracts should not contain ginkgolic acid.
Discontinue use of Ginkgo at least 36 hours before surgery.

Adverse Reactions

Case reports:
Seizures were reported in patients predisposed to seizures or on medications that lower the seizure threshold (e.g. prochlorperazine, chlorpromazine, perphenazine, etc.) (17).
Spontaneous bleeding (18), including hematomas (15) (19), hyphema (20), and cerebral bleeding (41) have also been reported.
A patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency developed acute hemolytic anemia after receiving an injection of Ginkgo biloba for dementia prophylaxis. Her symptoms resolved following intravenous fluid infusion and discontinuation of G. biloba (53).

Herb-Drug Interactions
  • Monoamine oxidase inhibitors (MAO-I): Ginkgo may potentiate the effects of MAO-Is.
  • Anticoagulants / Antiplatelets: Ginkgo may induce spontaneous bleeding possibly associated with reduced platelet aggregation resulting from inhibition of platelet activating factor by ginkgolide components (21).
  • Antipsychotics / Prochlorperazine: Ginkgo may cause seizures when combined with medications that lower the seizure threshold (17).
    Insulin: Ginkgo can alter insulin secretion and affect blood glucose levels (22) (23).
  • Cytochrome P450 substrates: Studies show that ginkgo can inhibit and induce the CYP450 1A2, 2D6, and 3A4 enzymes but data are conflicting (24) (34) (35) (36) (39) (40).
  • P-Glycoprotein substrates: Ginkgo inhibits P-glycoprotein and can therefore interfere with drugs that are transported by P-glycoprotein (33).
  • Trazodone: Ginkgo extract was associated with coma in a patient with Alzheimer's disease who was also taking trazodone (21).
  • Nonsteroidal Anti-inflammatory drugs (NSAIDS): Ginkgo can have additive anticoagulant/antiplatelet effects (31).
  • Efavirenz: Ginkgo may inhibit its effects (40) (51)
  • UGT (Uridine 5'-diphospho-glucuronosyltransferase) substrates: Ginkgo modulates UGT enzymes in vitro and can increase the side effects of drugs metabolized by them (42).

    Isorhamnetin, a compound present in ginkgo was shown to be a strong inhibitor of the human multidrug and toxic compounds extrusion transporter 1 (hMATE1), which is responsible for the final step of excretion of various xenobiotics in the kidney and liver (54).
Literature Summary and Critique

Vellas B, Coley N, Ousset P-J, et al. Long-term use of standardised ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol. 2012 Oct;11(10):851-9.
This study was conducted to determine the effectiveness of Gingko biloba in decreasing the incidence of Alzheimer’s disease in elderly adults with memory complaints. It involved 2,854 participants (age 70 and older) who were randomized to receive 120 mg of a standardized gingko extract, twice a day, or a placebo. At the 5-year follow-up point, all subjects received at least one dose of the ginkgo extract or the placebo. Sixty-one participants in the ginkgo group and 73 in the placebo group were diagnosed with probable Alzheimer’s disease (95% CI 0·60–1·18; p=0·306). There was no difference in the incidence of adverse effects between the two groups.Researchers concluded that long-term supplementation with a ginkgo extract did not prevent the onset of Alzheimer’s disease in the elderly.
However, data analysis shows that at >5 years, the protective effects of ginkgo extract are greater than the placebo.
Also, the study has limitations: A high dropout rate at the beginning of the trial, and a selection bias toward individuals with higher levels of education.
Further studies are needed to clarify the role of ginkgo in preventing memory loss.

DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of Dementia. A randomized controlled trial. JAMA. 2008;300(19):2253-2262.
In this study, 3,069 community volunteers aged 75 years or older with normal cognition (n = 2587) or mild cognitive impairment (MCI) (n = 482) were randomized to receive a twice-daily dose of 120 mg extract of G. biloba (n = 1545) or placebo (n = 1524). This trial was conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years.
Participants were assessed every 6 months for incident dementia. Five hundred twenty-three individuals developed dementia (246 from the placebo group and 277 who took G. biloba). And 92% of the dementia cases were classified as possible or probable Alzheimer's disease (AD), or AD with evidence of vascular disease of the brain. Adverse effects were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in the G. biloba group and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G. biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94-1.33; P = .21) and for AD, 1.16 (95% CI, 0.97-1.39; P = .11). There was no effect of G. biloba on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85-1.50; P = .39).
G. biloba was not beneficial in reducing the overall incidence rate of dementia or incidence of AD in elderly subjects with normal cognition or those with MCI.
The researchers do cite a potential limitation of this study: Because the delay from initial brain changes to clinical dementia involves a long period of time, it is possible it may take several years before the effects of G. biloba are observed.

Dosage (Inside MSKCC Only)
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References
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  13. Hauns B, Haring B, Kohler S, et al. Phase II study of combined 5-fluorouracial/Ginkgo biloba extract (GBE 761 ONC) therapy in 5-fluorouracil pretreated patients with advanced colorectal cancer. Phytother Res 2001;15(1):34-8.
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  19. Gilbert GJ. Ginkgo biloba. Neurology 1997;48:1137.
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  21. Brinker F. Herb Contraindications and Drug Interactions, 2nd ed. Sandy (OR): Eclectic Med Pub; 1998.
  22. Kudolo GB. The effect of 3-month ingestion of Ginkgo biloba extract on pancreatic beta-cell function in response to glucose loading in normal glucose tolerant individuals. J Clin Pharmacol 2000;40:647.
  23. Budzinski JW, et al. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial extracts and tinctures. Phytomedicine 2000;7:273-82.
  24. Scott GN, Elmer GW. Update on natural product-drug interactions. Am J Health-Syst Pharm 2002;59:339-47.
  25. Gertsch JH, Seto TB, Mor J, Onopa J. Ginkgo biloba for the prevention of severe acute mountain sickness (AMS) starting one day before rapid ascent. High Alt Med Biol. 2002;3(1):29-37.
  26. Moraga FA, Flores A, Serra J, et al. Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollagüe (3696 m) in northern Chile. Wilderness Environ Med 2007;18(4):251-7.
  27. Chow T, Browne V, Heileson HL, et al. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial. Arch Intern Med. 2005;165(3):296-301.
  28. Gertsch JH, Basnyat B, Johnson WE, et al. Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT).BMJ 2004;328(7443):797.
  29. Dodge HH, Zitzelberger T, Oken BS, et al. A randomized placebo-controlled trial of ginkgo biloba for the prevention of cognitive decline. Neurology 2008.
  30. DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of Dementia. A randomized controlled trial. JAMA. 2008;300(19):2253-2262.
  31. Haller C, Kearney T, Bent S, et al. Dietary supplement adverse events: report of a one-year poison center surveillance project. J Med Toxicol. 2008 Jun;4(2):84-92.
  32. Snitz BE, O'Meara ES, Carlson MC, et al. Ginkgo biloba for Preventing Cognitive Decline in Older Adults. A Randomized Trial. JAMA. 2009;302(24):2663-2670.
  33. Fan L, Mao XQ, Tao GY, et al. Effect of Schisandra chinensis extract and Ginkgo biloba extract on the pharmacokinetics of talinolol in healthy volunteers. Xenobiotica. 2009 Mar;39(3):249-54.
  34. Deng Y, Bi HC, Zhao LZ, et al. Induction of cytochrome P450 3A by the Ginkgo biloba extract and bilobalides in human and rat primary hepatocytes. Drug Metab Lett. 2008 Jan;2(1):60-6.
  35. Hellum BH, Hu Z, Nilsen OG. Trade herbal products and induction of CYP2C19 and CYP2E1 in cultured human hepatocytes. Basic Clin Pharmacol Toxicol. 2009 Jul;105(1):58-63.
  36. Lau AJ, Chang TK. Inhibition of human CYP2B6-catalyzed bupropion hydroxylation by Ginkgo biloba extract: effect of terpene trilactones and flavonols. Drug Metab Dispos. 2009 Sep;37(9):1931-7.
  37. Salehi B, Imani R, Mohammadi MR, et al. Ginkgo biloba for attention-deficit/hyperactivity disorder in children and adolescents: a double blind, randomized controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Feb 1;34(1):76-80.
  38. Biggs ML, Sorkin BC, Nahin RL, Kuller LH, Fitzpatrick AL. Ginkgo biloba and risk of cancer: secondary analysis of the Ginkgo Evaluation of Memory (GEM) Study. Pharmacoepidemiol Drug Saf. 2010 Jul;19(7):694-8.
  39. Lin YY, Chu SJ, Tsai SH. Association between priapism and concurrent use of risperidone and Ginkgo biloba. Mayo Clin Proc. 2007 Oct;82(10):1289-90.
  40. Wiegman DJ, Brinkman K, Franssen EJ. Interaction of Ginkgo biloba with efavirenz. AIDS. 2009 Jun 1;23(9):1184-5.
  41. Pedroso JL, Henriques Aquino CC, Escórcio Bezerra ML, et al. Ginkgo biloba and cerebral bleeding: a case report and critical review. Neurologist. 2011 Mar;17(2):89-90.
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  44. Hoenerhoff MJ, Pandiri AR, Snyder SA, et al. Hepatocellular Carcinomas in B6C3F1 Mice Treated with Ginkgo biloba Extract for Two Years Differ from Spontaneous Liver Tumors in Cancer Gene Mutations and Genomic Pathways. Toxicol Pathol. 2012 Dec 21. [Epub ahead of print]
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Consumer Information

How It Works

Bottom Line: Ginkgo does not improve memory or cognitive functioning in healthy people. It was also found ineffective in decreasing the occurrence of dementia or Alzheimer's disease in elderly individuals.

Scientists have found that ginkgo dilates blood vessels in the brain in animals and humans, thereby increasing blood flow to the brain. This enables the body to handle ischemic (low oxygen) conditions, which can help prevent tissue damage. In animal studies, ginkgo showed a beneficial effect on smooth muscle tone found in arteries, maintaining their appropriate dilation and constriction. Experiments have also revealed that ginkgo can reduce inflammation and calm muscle spasms. As an antioxidant, it can also neutralize free radicals in the body, which cause cellular and DNA damage. Laboratory and animal experiments suggest that ginkgo can help prevent infections. Ginkgo also inhibits platelet-activating factor, which is important for blood clotting, and therefore has blood thinning qualities. Ginkgo supplementation may increase risk of stroke.

Purported Uses
  • To reduce stress and anxiety
    No scientific evidence supports this use.
  • To treat asthma and bronchitis
    A single study conducted in China supports this use.
  • To manage heart disease
    There are no data to support this claim.
  • To treat circulatory problems
    Studies in animals and humans have shown that ginkgo can increase blood flow, but clinical trials do not support this use.
  • To treat sudden hearing loss
    Several clinical trials support this use.
  • To treat tinnitus
    There are no data to support this use.
  • To prevent memory loss
    Although several clinical trials support this use in patients with dementia, recent studies suggest that healthy adults do not seem to benefit from ginkgo.
  • To treat dementia and Alzheimer's disease
    Results from clinical studies are inconclusive.
  • To treat Raynaud's disease
    Laboratory studies show that ginkgo can calm muscle spasms and maintain the tone of arteries, but these effects were not observed in human clinical trials.
  • To treat sexual dysfunction
    An herbal mixture containing ginkgo was found effective in treating sexual dysfunction in one clinical trial.
  • To treat acute mountain sickness
    Data are conflicting on Ginkgo's ability in treating acute mountain sickness.
Research Evidence

Prevention of Alzheimer's Disease:
This study included 2,854 participants (age 70 and older) who were randomized to receive 120 mg of a standardized gingko biloba extract, twice a day, or a placebo. At the 5-year follow-up point, all subjects received at least one dose of the ginkgo extract or the placebo. Sixty-one participants in the ginkgo group and 73 in the placebo group were diagnosed with probable Alzheimer’s disease. There was no difference in the incidence of adverse effects between the two groups. Long-term supplementation with a ginkgo extract may not prevent the onset of Alzheimer’s disease in the elderly.
However, due to limitations of the study, which include a high dropout rate at the beginning of the trial, and a selection bias toward individuals with higher levels of education, more studies are needed.

Patient Warnings
  • Ginkgo biloba extracts should be checked to make sure they do not contain ginkgolic acid, which can increase the risk of allergic reactions.
  • Ginkgo biloba should be discontinued at least 36 hours before surgery due to the risk of increased bleeding.
Do Not Take If
  • You have a blood clotting disorder.
  • You have a history of seizures.
  • You are at risk for stroke. Ginkgo may increase this risk.
  • You are taking monoamine oxidase inhibitors (MAO-Is) (Ginkgo may have additive effects).
  • You are taking warfarin or any other blood thinner (Ginkgo may have additive effects, increasing the risk of spontaneous bleeding).
  • You are taking antipsychotic medication or prochlorperazine (Ginkgo may cause seizures when combined with these medications).
  • You are taking insulin (Ginkgo can alter insulin secretion and effect blood glucose levels).
  • You are taking trazodone (In one case, ginkgo extract was associated with coma in a woman with Alzheimer's disease who was also taking trazodone. Use with caution and ask your doctor).
  • You are taking Nonsteroidal Anti-inflammatory drugs (NSAIDS) (Ginkgo can have additive anticoagulant/antiplatelet effects).
  • You are taking drugs that are substrates of Cytochrome P450 3A4 (Ginkgo may increase the risk of side effects of these drugs).
  • You are taking drugs that are substrates of P-Glycoprotein (Ginkgo may increase the risk of side effects of these drugs).
  • You are taking Efavirenz (a antiretroviral drug): Ginkgo may reduce its effectiveness.
  • You are taking drugs that are substrates of UGT (Uridine 5'-diphospho-glucuronosyltransferase) enzymes (Ginkgo may increase the risk of side effects of these drugs).
Side Effects

Case reports:
In a few patients who were predisposed to seizures or on medications that lower the seizure threshold (e.g. prochlorperazine, chlorpromazine, perphenazine, etc.), ginkgo may have induced seizures.
A few cases of spontaneous bleeding, including hematomas (collections of blood in organs or tissues due to a broken blood vessel) and hyphema (hemorrhage within the eye), have been reported.
A patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency developed acute hemolytic anemia after receiving an injection of Ginkgo biloba for dementia. Her symptoms resolved following intravenous fluid infusion and discontinuation of G. biloba.

 

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