Ginkgo

• How It Works

  Ginkgo does not improve memory or brain function, and does not prevent or decrease the occurrence of dementia or Alzheimer’s disease in elderly individuals.

  Ginkgo biloba, one of the oldest living tree species, is used in traditional Chinese medicine and is also a popular supplement marketed to improve memory and circulation. Although some scientific studies have observed these properties, large clinical trials do not support the use of ginkgo to improve memory or prevent memory loss. In addition, one study suggests ginkgo supplementation may increase stroke risk, while other studies suggest it may have protective effects or did not see a significant increase in strokes. Therefore, more studies are needed to determine risks and any benefits with ginkgo supplementation.

  Ginkgo inhibits platelet-activating factor, which is important for blood clotting, and therefore has blood-thinning qualities.

• Purported Uses
  • o prevent memory loss or decline
    In several large studies among elderly patients, ginkgo did not improve memory. It also did not prevent Alzheimer’s disease or dementia, and did not prevent what is commonly known as “brain fog” among cancer patients.
  • To manage cardiovascular disease
    A large analysis did not find any benefit with ginkgo for heart disease.
  • To treat tinnitus
    Several studies indicate that ginkgo is not beneficial for tinnitus.
• 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 warfarin or other blood thinners: Ginkgo may have additive effects, increasing the risk of spontaneous bleeding.
  • You are taking antipsychotic medications or prochlorperazine: Ginkgo may cause seizures when combined with these medications.
  • You are taking insulin: Ginkgo can alter insulin secretion and affect 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 an antiretroviral such as efavirenz: Ginkgo may reduce its effectiveness.
  • You are taking nonsteroidal anti-inflammatory drugs (NSAIDs): Ginkgo can increase adverse effects.
  • You are taking amlodipine: Ginkgo may increase the risk of side effects of this drug.
  • You are taking a cytochrome P450 3A4 substrate drug: Ginkgo may increase the risk of side effects of these drugs.
  • You are taking a P-glycoprotein substrate drug: Ginkgo may increase the risk of side effects of these drugs.
  • You are taking a UGT substrate drug: Ginkgo may increase the risk of side effects of these drugs.
• Side Effects

  Case reports

  Spontaneous bleeding: In a few cases, including in the eye and brain, related to ginkgo supplementation.

  Prolonged bleeding: Among some healthy volunteers in a study that evaluated the interaction of gingko with antiplatelet drugs.

  Seizures: In a few patients who were prone to seizures or on medications that lower the seizure threshold (e.g. prochlorperazine, chlorpromazine, perphenazine, etc.), ginkgo may have induced seizures.

  Rash and itching: In a man after repeatedly ingesting a natural product containing ginkgo and vinpocetine.

  Acute hemolytic anemia: In a patient after receiving an injection of G. biloba for dementia. Her symptoms resolved following intravenous fluid infusion and discontinuation of G. biloba.

• Scientific Name

  Ginkgo biloba

• 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 leaves have been used in traditional Chinese medicine to treat respiratory diseases, circulatory disorders, sexual dysfunction, and hearing loss. In vitro, ginkgo extracts exhibit chemopreventive ⁽¹⁾, anticancer ⁽²⁾, and cytotoxic ⁽³⁾ effects.

  Although marketed for memory improvement, clinical studies including the large Gingko Evaluation of Memory (GEM) study generally show supplementation with ginkgo does not improve cognitive performance or prevent Alzheimer’s disease or dementia ^{(4) (5) (6) (7) (8)} . In addition, positive effects from earlier studies were not confirmed in more recent trials and some systematic reviews determined there was insufficient evidence on any benefits in adults with either normal cognition or mild cognitive impairment ^(9) (10).

  Although two trials suggest potential benefit with gingko in patients who had an acute ischemic stroke ^(11) (12), a study in older adults noted increased stroke incidence in the ginkgo group versus placebo ⁽⁴⁾. In addition, the large GEM study did not find benefit with ginkgo for cardiovascular disease incidence or mortality ⁽¹³⁾. Several studies indicate that ginkgo is not beneficial for tinnitus ^(14) (15).

  Studies on using ginkgo for ADHD in children ^(16) (17) and for mountain sickness ^(18) (19) yielded mixed results.

  Preliminary epidemiological and biological data suggest ginkgo may reduce ovarian cancer risk ⁽²⁰⁾. Orally administered capsules of ginkgo exocarp polysaccharides reduced the tumor area in a small study of patients with gastric cancer ⁽³⁾. An injectable form of ginkgo extract and 5-flurouracil administered to advanced colorectal cancer patients demonstrated benefit with the combination therapy ⁽²¹⁾. However, secondary outcome data from the aforementioned GEM study does not support the use of gingko to reduce cancer risk ⁽²²⁾. It is also ineffective in preventing chemotherapy-associated cognitive dysfunction in breast cancer patients ⁽²³⁾.

  Interestingly, high doses of a ginkgo extract showed hepatocarcinogenic effects in a murine model ^(24) (25). More studies are needed to determine the significance of these findings.

• Purported Uses
  • Cardiovascular disease
  • Memory loss
  • Tinnitus
• Mechanism of Action

  Ginkgo interacts with several cytochrome P450 enzymes. Pretreatment with G. biloba extract induces expression of CYP3A proteins and mRNA and increases CYP3A activity ⁽²⁶⁾. It also inhibits CYP2B6 catalytic activity and bupropion hydroxylation ⁽²⁷⁾. Ginkgo may play a role in decreasing high-glucose-induced endothelial inflammation via inhibition of interleukin-6 activation ⁽²⁸⁾, and repeated intake of ginkgo enhanced cell proliferation and neuroblast differentiation ⁽²⁹⁾. Flavonoids present in ginkgo extracts inhibited estrogen biosynthesis via aromatase inhibition, decreased CYP19 mRNA, and induced transcriptional suppression ⁽³⁰⁾.

  Chemopreventive properties of bilobalide, a terpene trilactone, may occur via alterations in cryptal cell proliferation and drug-metabolizing enzyme activities ⁽¹⁾. The exocarp polysaccharides from ginkgo affected expression of c-myc, bcl-2 and c-fos genes, which can inhibit proliferation and induce apoptosis and differentiation of human gastric tumor cells ⁽³⁾.

• Adverse Reactions

  Case reports
  Spontaneous bleeding: Including hematomas ^(31) (32), hyphema ⁽³³⁾, and cerebral and intracerebral bleeding ^(34) (35).
  Prolonged bleeding time: Among some healthy volunteers in a pharmacodynamic study that evaluated the interaction of gingko with antiplatelet drugs ⁽³⁶⁾.
  Seizures: In predisposed patients or those on medications that lowered the seizure threshold ⁽³⁷⁾.
  Cutaneous reaction: Pruritus and macular erythema in a man after repeatedly ingesting a natural product containing ginkgo and vinpocetine ⁽³⁸⁾.
  Acute hemolytic anemia (with injected ginkgo): In a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency receiving a G. biloba injection for dementia prophylaxis. Symptoms resolved following intravenous fluid infusion and discontinuation of G. biloba  ⁽³⁹⁾.

• Herb-Drug Interactions
  • Cytochrome P450 substrates: Studies show that ginkgo can inhibit and induce the CYP450 1A2, 2D6, and 3A4 enzymes but data are conflicting ^{(26) (27) (40) (41) (42) (43)}.
  • P-glycoprotein substrates: Ginkgo inhibits P-glycoprotein and can therefore interfere with drugs that are transported by P-glycoprotein ⁽⁴⁴⁾.
  • UGT (Uridine 5’-diphospho-glucuronosyltransferase) substrates: Ginkgo modulates UGT enzymes in vitro and can increase the side effects of drugs metabolized by them ⁽⁴⁵⁾.
  • MATE1 substrates: Isorhamnetin, a compound present in ginkgo was shown to be a strong inhibitor of the human multidrug and toxic compounds extrusion transporter 1 (hMATE1), responsible for the excretion of various drugs in the kidney and liver ⁽⁴⁶⁾.
  • Anticoagulants / Antiplatelets: Ginkgo may induce or prolong bleeding time ^(36) (47).
  • Nonsteroidal anti-inflammatory drugs (NSAIDS): Ginkgo can have additive anticoagulant/antiplatelet effects ⁽⁴⁸⁾.
  • Antipsychotics / Prochlorperazine: Ginkgo may cause seizures when combined with medications that lower the seizure threshold ⁽³⁷⁾.
  • Insulin: Ginkgo can alter insulin secretion and affect blood glucose levels ^(49) (50).
  • Trazodone: Ginkgo extract was associated with coma in a patient with Alzheimer’s disease who was also taking trazodone ⁽⁴⁷⁾ .
  • Efavirenz: Ginkgo may inhibit its effects ^(43) (51).
  • Midazolam: Ginkgo may decrease serum concentrations ⁽⁵²⁾.
  • Amlodipine: Ginkgo leaf tablet, a multiherbal formula containing ginkgo, was shown to inhibit the metabolism of amlodipine in a rat model ⁽⁵³⁾.
• References
  1. Suzuki R, Kohno H, Sugie S, et al. Preventive effects of extract of leaves of ginkgo (Ginkgo biloba) and its component bilobalide on azoxymethane-induced colonic aberrant crypt foci in rats. Cancer Lett. Jul 16 2004;210(2):159-169.
  2. Pretner E, Amri H, Li W, et al. Cancer-related overexpression of the peripheral-type benzodiazepine receptor and cytostatic anticancer effects of Ginkgo biloba extract (EGb 761). Anticancer Res. Jan-Feb 2006;26(1a):9-22.
  3. Xu AH, Chen HS, Sun BC, et al. Therapeutic mechanism of Ginkgo biloba exocarp polysaccharides on gastric cancer. World J Gastroenterol. Nov 2003;9(11):2424-2427.
  4. Dodge HH, Zitzelberger T, Oken BS, et al. A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline. Neurology. May 6 2008;70(19 Pt 2):1809-1817.
  5. DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. Nov 19 2008;300(19):2253-2262.
  6. Snitz BE, O’Meara ES, Carlson MC, et al. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA. Dec 23 2009;302(24):2663-2670.
  7. Vellas B, Coley N, Ousset PJ, 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. Oct 2012;11(10):851-859.
  8. Solomon PR, Adams F, Silver A, et al. Ginkgo for memory enhancement: a randomized controlled trial. JAMA. Aug 21 2002;288(7):835-840.
  9. Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. Jan 21 2009(1):Cd003120.
  10. Butler M, Nelson VA, Davila H, et al. Over-the-Counter Supplement Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review. Ann Intern Med. Jan 2 2018;168(1):52-62.
  11. Li S, Zhang X, Fang Q, et al. Ginkgo biloba extract improved cognitive and neurological functions of acute ischaemic stroke: a randomised controlled trial. Stroke Vasc Neurol. Dec 2017;2(4):189-197.
  12. Oskouei DS, Rikhtegar R, Hashemilar M, et al. The effect of Ginkgo biloba on functional outcome of patients with acute ischemic stroke: a double-blind, placebo-controlled, randomized clinical trial. J Stroke Cerebrovasc Dis. Nov 2013;22(8):e557-563.
  13. Kuller LH, Ives DG, Fitzpatrick AL, et al. Does Ginkgo biloba reduce the risk of cardiovascular events? Circ Cardiovasc Qual Outcomes. Jan 2010;3(1):41-47.
  14. Han SS, Nam EC, Won JY, et al. Clonazepam quiets tinnitus: a randomised crossover study with Ginkgo biloba. J Neurol Neurosurg Psychiatry. Aug 2012;83(8):821-827.
  15. Rejali D, Sivakumar A, Balaji N. Ginkgo biloba does not benefit patients with tinnitus: a randomized placebo-controlled double-blind trial and meta-analysis of randomized trials. Clin Otolaryngol Allied Sci. Jun 2004;29(3):226-231.
  16. Shakibaei F, Radmanesh M, Salari E, et al. Ginkgo biloba in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. A randomized, placebo-controlled, trial. Complement Ther Clin Pract. May 2015;21(2):61-67.
  17. 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. Feb 1 2010;34(1):76-80.
  18. Gertsch JH, Basnyat B, Johnson EW, 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. Apr 3 2004;328(7443):797.
  19. Moraga FA, Flores A, Serra J, et al. Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollague (3696 m) in northern Chile. Wilderness Environ Med. Winter 2007;18(4):251-257.
  20. Ye B, Aponte M, Dai Y, et al. Ginkgo biloba and ovarian cancer prevention: epidemiological and biological evidence. Cancer Lett. Jun 18 2007;251(1):43-52.
  21. Hauns B, Haring B, Kohler S, et al. Phase II study of combined 5-fluorouracil/Ginkgo biloba extract (GBE 761 ONC) therapy in 5-fluorouracil pretreated patients with advanced colorectal cancer. Phytother Res. Feb 2001;15(1):34-38.
  22. Biggs ML, Sorkin BC, Nahin RL, et al. Ginkgo biloba and risk of cancer: secondary analysis of the Ginkgo Evaluation of Memory (GEM) Study. Pharmacoepidemiol Drug Saf. Jul 2010;19(7):694-698.
  23. Barton DL, Burger K, Novotny PJ, et al. The use of Ginkgo biloba for the prevention of chemotherapy-related cognitive dysfunction in women receiving adjuvant treatment for breast cancer, N00C9. Support Care Cancer. Apr 2013;21(4):1185-1192.
  24. 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. Aug 2013;41(6):826-841.
  25. Mei N, Guo X, Ren Z, et al. Review of Ginkgo biloba-induced toxicity, from experimental studies to human case reports. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. Jan 2 2017;35(1):1-28.
  26. 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. Jan 2008;2(1):60-66.
  27. Lau AJ, Chang TK. Inhibition of human CYP2B6-catalyzed bupropion hydroxylation by Ginkgo biloba extract: effect of terpene trilactones and flavonols. Drug Metab Dispos. Sep 2009;37(9):1931-1937.
  28. Chen JS, Chen YH, Huang PH, et al. Ginkgo biloba extract reduces high-glucose-induced endothelial adhesion by inhibiting the redox-dependent interleukin-6 pathways. Cardiovasc Diabetol. May 3 2012;11:49.
  29. Yoo DY, Nam Y, Kim W, et al. Effects of Ginkgo biloba extract on promotion of neurogenesis in the hippocampal dentate gyrus in C57BL/6 mice. J Vet Med Sci. Jan 2011;73(1):71-76.
  30. Park YJ, Choo WH, Kim HR, et al. Inhibitory Aromatase Effects of Flavonoids from Ginkgo biloba Extracts on Estrogen Biosynthesis. Asian Pac J Cancer Prev. 2015;16(15):6317-6325.
  31. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology. Jun 1996;46(6):1775-1776.
  32. Gilbert GJ. Ginkgo biloba. Neurology. Apr 1997;48(4):1137.
  33. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med. Apr 10 1997;336(15):1108.
  34. Matthews MK, Jr. Association of Ginkgo biloba with intracerebral hemorrhage. Neurology. Jun 1998;50(6):1933-1934.
  35. Pedroso JL, Henriques Aquino CC, Escorcio Bezerra ML, et al. Ginkgo biloba and cerebral bleeding: a case report and critical review. Neurologist. Mar 2011;17(2):89-90.
  36. Aruna D, Naidu MU. Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects. Br J Clin Pharmacol. Mar 2007;63(3):333-338.
  37. Gregory PJ. Seizure associated with Ginkgo biloba? Ann Intern Med. Feb 20 2001;134(4):344.
  38. Cohen PR. Fixed Drug Eruption to Supplement Containing Ginkgo biloba and Vinpocetine: A Case Report and Review of Related Cutaneous Side Effects. J Clin Aesthet Dermatol. Oct 2017;10(10):44-47.
  39. Lai SW, Chen JH, Kao WY. Acute hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency complicated by Ginkgo biloba. Acta Haematol. 2013;130(4):288-290.
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  42. Lin YY, Chu SJ, Tsai SH. Association between priapism and concurrent use of risperidone and Ginkgo biloba. Mayo Clin Proc. Oct 2007;82(10):1289-1290.
  43. Wiegman DJ, Brinkman K, Franssen EJ. Interaction of Ginkgo biloba with efavirenz. AIDS Jun 1 2009;23(9):1184-1185.
  44. 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. Mar 2009;39(3):249-254.
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  49. 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. Jun 2000;40(6):647-654.
  50. Budzinski JW, Foster BC, Vandenhoek S, et al. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine. Jul 2000;7(4):273-282.
  51. Naccarato M, Yoong D, Gough K. A potential drug-herbal interaction between Ginkgo biloba and efavirenz. J Int Assoc Physicians AIDS Care (Chic). Mar-Apr 2012;11(2):98-100.
  52. Robertson SM, Davey RT, Voell J, et al. Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin. Feb 2008;24(2):591-599.
  53. Wang R, Zhang H, Sun S, et al. Effect of Ginkgo Leaf Tablets on the Pharmacokinetics of Amlodipine in Rats. Eur J Drug Metab Pharmacokinet. Dec 2016;41(6):825-833.