Ginkgo has been studied extensively in diverse medical conditions. Findings from large trials have been pivotal in evaluating the efficacy of G. biloba extracts; however, there is not enough quality evidence to support the use of ginkgo for any indication. Evidence is lacking to support a protective role in cardiovascular conditions and stroke. Ginkgo's place in therapy for dementia seems limited, and a role in schizophrenia has not been established. Additionally, data do not support enhanced cognitive function resulting from G. biloba use in healthy individuals. Although interest exists in chemotherapeutic applications, safety concerns persist.
Standardized ginkgo leaf extracts have been used in clinical trials for cognitive and cardiovascular disorders at daily doses of 120 to 240 mg.
Contraindications have not been established.
Information regarding safety and efficacy in pregnancy and lactation is lacking. Ginkgo should be used with caution during pregnancy, particularly around labor due to risk of prolonged bleeding time, and should be avoided during lactation.
At recommended doses, standardized preparations of ginkgo leaf extract are unlikely to exhibit any clinically important interactions.
Severe adverse reactions are rare; possible reactions include headache, dizziness, heart palpitations, and GI and dermatologic reactions. Ginkgo pollen can be strongly allergenic. Contact with the fleshy fruit pulp may cause allergic dermatitis similar to that caused by poison ivy.
Concerns persist regarding the safety of ginkgo leaf extract, based on studies in rodents that suggested increased mitosis and proliferation of tumor cells, as well as the large Ginkgo Evaluation of Memory (GEM) study in which the potential for an increased risk of certain cancers was noted. Consumption of the seeds may induce a toxic syndrome.
The dioecious ginkgo is the world's oldest living tree species. It has been traced back more than 200 million years to fossils of the Permian geologic period and is the sole survivor of the family Ginkgoaceae. Individual trees may live as long as 1,000 years and grow to a height of approximately 38 m. Ginkgo has characteristic fan-shaped leaves. Male trees older than 20 years blossom in the spring, and adult female trees produce plum-like, yellow-brown drupe that fall in late autumn. The fleshy layer and pulp have a foul, offensive odor and can cause contact dermatitis. The edible inner seed resembles an almond and is sold in Asian markets.USDA 2018, WHO 1999
The ginkgo species almost became extinct during the last ice age that began approximately 2 million years ago. The species survived in China, where it was cultivated as a sacred tree, and it still decorates Buddhist temples throughout Asia. Ginkgo preparations have been used for medicinal purposes for more than 1,000 years. Traditional Chinese physicians used ginkgo leaves to treat asthma and chilblains. Roasted ginkgo seeds were consumed in ancient China and Japan and were considered a digestive aid and preventive agent for drunkenness. In the Western world, ginkgo has been used since the 1960s, when technology made it possible to isolate its active compounds. The flavonoids act as free radical scavengers, and the terpenes (ginkgolides) inhibit platelet-activating factor. Ginkgo is one of the most commonly prescribed medications in Europe, but it is not approved for medical use in the United States, where it is sold only as a nutritional supplement.Mohanta 2014, WHO 1999
Reviews of the chemical constituents of ginkgo have been published. Analytical methods, biological standardization, and fingerprinting of ginkgo extracts have been reported.Liu 2015, Ude 2013, van Beek 2009
The main medicinal constituents of ginkgo are found in the leaf. These include flavonoids and several terpene trilactones unique to ginkgo (ginkgolides and bilobalide). The 3 major flavonoids of ginkgo are quercetin, kaempferol, and isorhamnetin. Approximately 40 minor flavonoids have also been identified, including catechins, dehydrocatechins (proanthocyanidins), and flavones (eg, ginkgetin, amentoflavone, bilobetin, sciadopitysin). The major terpene molecules unique to ginkgo are ginkgolides A, B, C, J, and M and bilobalide. Other medicinal constituents of ginkgo include shikimic, vanillic, ascorbic, and p-coumaric acids. Other leaf components include the steroids sitosterol and stigmasterol, polyprenols, benzoic acid derivatives, carbohydrates, straight chain hydrocarbons, alcohol, ketones, and 2-hexenol. There is seasonal variation in active compound content of the leaves, with the highest amounts present in autumn.Liu 2015, Ude 2013, van Beek 2009
The seed portion of ginkgo contains carbohydrate (38%), protein (4%), and less than 2% fat. Ginkgotoxin, amino acids, cyanogenetic glycosides, and long-chain phenols, including anacaric acid, bilobol, and cardanol, are also present. Ginkgolic acid and related alkylphenols from the lipid fraction of the fruit pods have been reviewed. The foul-smelling odor of the fleshy portion of the seedcoat is caused by high concentrations of butanoic and hexanoic acids. 4-O-methylpyridoxine has been isolated from the seeds.Liu 2015, Ude 2013, USDA 2018, van Beek 2009
A standardized extract of G. biloba leaves has been examined in several forms of cancer, and numerous mechanisms of action have been proposed based on in vitro studies.(Cao 2017, Eli 2006, Li 2002, Liu 2017, Lou 2017, Park 2017, Pretner 2006) Some animal experiments suggest that ginkgo leaf extract reduces the risk of oral cavity, stomach, and colorectal cancer.(Ahmed 2017, Chen 2005, Kim 2005, Wang 2000) The deleterious effects of electromagnetic radiation on hippocampal cells were reduced by ginkgo extract given to rats for 1 month,(Gevrek 2018) and a protective effect was reported in bleomycin-induced lung fibrosis in rats.(Iraz 2006)
Conversely, in a mouse colon cancer model, ginkgo exacerbated metastasis to the liver and decreased necrosis and apoptosis of tumor cells.(Wang 2017) This is potentially explained by observed carcinogenicity of quercetin in rodents.(Wang 2017)
Limited clinical studies evaluating use of ginkgo in cancer have produced equivocal findings. Smaller clinical studies have generally reported positive findings,(Bonassi 2018, Hauns 2001, Xu 2003) and one epidemiologic study claimed that ginkgolide A and B may be associated with chemoprevention of certain forms of ovarian cancer.(Ye 2007) However, in an analysis of cancer as a secondary end point in the 3,069 participants of the GEM study, no protective effect of ginkgo was observed. For site-specific cancers, there were nonsignificant trends towards an increased risk of breast (hazard ratio [HR], 2.15; 95% CI, 0.97 to 4.8; P=0.06) and colorectal (HR, 1.62; 95% CI, 0.92 to 2.87; P=0.1) cancers, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43 to 1.17; P=0.18).(Biggs 2010)
Antioxidant effects of G. biloba extract were studied in Chernobyl nuclear accident recovery workers with clastogenic factors evidenced as DNA fragmentation and damage. G. biloba extract was tested on the plasma of salvage personnel; after 2 months of treatment at 120 mg per day, plasma clastogenic factors regressed or completely disappeared.(Eli 2006, Emerit 1995) An anticlastogenic effect was demonstrated for ginkgo versus placebo in patients with Graves disease who were receiving radioiodine therapy.(Dardano 2007)
Animal studies report efficacy in preventing cardiovascular conditions, and researchers have attempted to explain the mechanisms by which the extract may act.(Abdel-Zaher 2017, Jiang 2017, Li 2009, Tang 2017, Wu 2008) Antiplatelet activity has been described, although evidence from controlled studies consistently indicates that ginkgo does not significantly impact hemostasis.(Bone 2008)
Evidence is lacking to support a protective role in cardiovascular conditions and stroke.
The GEM study (N=3,069 elderly men and women) preplanned an evaluation of cardiovascular outcomes and found no evidence that ginkgo 240 mg/day reduced total or cardiovascular mortality or cardiovascular events.(Kuller 2010) A statistically significant positive finding was obtained for ginkgo in peripheral vascular disease; however, the number of events was too small to make any generalizations.(Kuller 2010) Similarly, ginkgo did not reduce blood pressure in hypertensive or normotensive participants in the GEM study.(Brinkley 2010) A 2009 Cochrane meta-analysis of 14 clinical trials evaluating the role of ginkgo in intermittent claudication found no evidence of a clinically important benefit in patients with peripheral arterial disease; the 2013 update reinforced this conclusion.(Nicolaï 2009, Nicolai 2013) The American College of Cardiology Foundation/American Heart Association guidelines for the management of peripheral artery disease (2005/2011) state that the effectiveness of ginkgo in improving walking distance for patients with intermittent claudication is marginal and not well established (level B evidence).(Anderson 2013)
A Cochrane systematic review of studies to 2005, including 10 trials (N=792) assessing the efficacy of ginkgo, found no convincing evidence to support the use of ginkgo for recovery after stroke or for improvement in neurological deficit at the end of treatment.(Zeng 2005) In 2020, a systematic review and meta-analysis of data from 13 randomized controlled studies (N=1,466) all conducted in Asia reported significant improvement in neurological function with ginkgo compared to controls (P<0.001) in patients admitted to the hospital with acute ischemic stroke or cerebral vascular accident. However, heterogeneity was high among the 5 studies that reported on neurological function with all but 1 study administering ginkgo as an IV infusion. Activities of daily living were also improved with ginkgo (3 studies, n=535; P<0.001; high heterogeneity); only 1 study administered ginkgo orally. Additionally, adverse event rates were similar between groups and no increase was found in risk of intracranial bleeding with the use of ginkgo compared to controls (5 studies, n=547; no heterogeneity). Doses of standardized ginkgo extract ranged from 120 to 160 mg/day; however, most of the studies administered treatment as an IV infusion (for 2 to 3 weeks), whereas only 5 studies used a tablet dose form (for 1 to 6 months). Overall, the strength of evidence was very low for each outcome.(Chong 2020)
In a double-blind, randomized, placebo-controlled trial (N=102), significantly more patients in the ginkgo group achieved a 50% reduction in 4-month poststroke follow-up National Institutes of Health Stroke Scale (NIHSS) score compared with baseline than those in the placebo group (58.6% vs 18.5%, respectively; P<0.05).(Oskouei 2013) In contrast, multivariate regression analysis of the trend of NIHSS scores from admission to follow-up revealed a significant decline in scores for G. biloba when adjusted for age and gender (P<0.05).(Oskouei 2013)
The widespread use of G. biloba extracts in clinical trials makes data from animal studies largely redundant.
It remains unclear whether ginkgo has a role in reducing the incidence of dementia in elderly patients or protecting against decline in cognitive function.
In a retrospective study, outcomes were compared in 189 patients 80 years or older with Alzheimer disease who had used either donepezil or standardized G. biloba extract (EGb 761) for 12 months. No differences were noted in cognitive decline, as measured by MMSE. Rates of discontinuation because of lack of effect were similar between groups; however, more donepezil patients discontinued because of adverse effects.(Rapp 2018) Secondary analysis of data from a randomized controlled trial that enrolled 150 patients with Alzheimer's disease or mild cognitive impairment found no significant difference in 6 neuropsychological outcome measures between ginkgo biloba extract and donepezil when administered alone or in combination for 6 months. Similar improvement was seen across all 3 groups. Only Mini Mental State Examination (MMSE) at month 1 was significantly lower with donepezil alone (P=0.019); otherwise, between-group comparisons were similar at months 1, 3, and 6 for MMSE, cognition, activities of daily living, geriatric depression, neuropsychiatric inventory, and quality of life. Additionally, changes in significant discriminative brain regions were observed according to treatment group that were found to correlate to specific functional magnetic resonance imaging metrics. For example, changes in 2 specific metrics were positively correlated in the right gyrus rectus in gingko patients (P=0.03) and negatively correlated in the left superior cerebellum gyrus in donepezil patients (P=0.01).(Zheng 2021) In Alzheimer patients, a meta-analysis that included data from 6 double-blind, randomized, placebo-controlled and 1 donepezil comparator trial (N=939) reported significant improvements in cognitive function (relative risk [RR],1.983; 95% confidence interval [CI], 1.521 to 2.585; P<0.001; low heterogeneity) and global clinical assessment (odds ratio=3.119; 95% CI, 2.206 to 4.410; P<0.001; low heterogeneity) with ginkgo, but an uncertain effect on activities of daily living (no heterogeneity). All studies were of high quality and used EGb 761 for a duration of therapy that ranged from 3 to approximately 7 months at doses of 120, 160, and 240 mg/day.(Liao 2020)
Results of 2 large clinical trials have been published: the GEM study (N=3,069) and the GuidAge study (N=2,854). The GEM study found no effect of ginkgo in reducing the incidence of dementia or in preventing decline in cognitive impairment among enrolled older adult participants with normal to mild cognitive impairment.(DeKosky 2008, Snitz 2009) Similarly, in the GuidAge study, long-term use of standardized ginkgo extract had no effect on the risk of progression to Alzheimer disease compared with placebo.(Vellas 2012)
In the Impact of Cholinergic Treatment Use (ICTUS) study (N=828), 96.5% of patients received cholinesterase inhibitor therapy alone and 3.5% received ginkgo in combination with cholinesterase inhibitors. Improvements in MMSE score were observed in the combination therapy group; however, changes in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score and the Activities of Daily Living score were not significantly different. Patients receiving combination therapy were found to have a significantly higher education level (P=0.01) and lower baseline ADAS-Cog score (P<0.01) compared to those receiving cholinesterase inhibitor therapy alone.(Canevelli 2014)
A Cochrane meta-analysis (published in 2009 and including 36 trials) found that results lacked consistent evidence of clinically important effects on dementia or cognitive impairment. Some trials included in the meta-analysis were of small sample size, and treatment duration was less than 3 months in each of the studies.(Birks 2009)
The effect of G. biloba on cognitive function in healthy individuals was examined in a systematic review and meta-analysis published in 2012, which concluded that no positive effect was evident for memory, executive function, or attention in 13 studies involving more than 2,500 participants.(Laws 2012)
In a single-blind, randomized, controlled trial that enrolled patients who suffered an acute ischemic stroke within the previous 7 days, administration of ginkgo biloba extract 150 mg 3 times daily for 6 months plus 100 mg aspirin significantly improved cognitive and executive function at days 30 (P=0.0116), 90 (P=0.0165), and 180 (P=0.0004) compared to aspirin alone. Patients receiving ginkgo demonstrated less of a decline in mean MMSE scores than controls (day 180; P=0.0110). Additionally, neurological and global function were significantly better in the ginkgo group than controls at days 12 (P=0.123) and 30 (P=0.0037). However, no significant difference was noted in the incidence of vascular events between groups at the 2-year follow-up.(Li 2017)
A number of guidelines have been published on the use of ginkgo in Alzheimer disease and dementia. The European Federation of Neurological Sciences guidelines on the management of Alzheimer disease (2010) state that there is insufficient evidence to support the use of ginkgo for primary prevention of dementia, and that ginkgo should not be used in the treatment of patients with mild cognitive impairment. Additionally, the guidelines state that there is inconsistent evidence supporting the use of ginkgo in the treatment or prevention of Alzheimer disease.(Hort 2010) According to a British Association for Psychopharmacology revised (third) consensus statement (2017), until further evidence is available, ginkgo cannot be recommended for either treatment or prevention of Alzheimer disease.(O'Brien 2017)
The American Academy of Neurology (AAN) practice parameter for the management of dementia (published in 2001, reaffirmed in 2003) states that some patients with unspecified dementia may benefit from G. biloba; however, evidence-based efficacy data are lacking (practice option recommendation).(Doody 2001) The American Association for Geriatric Psychiatry position statement for patients with dementia resulting from Alzheimer disease (2006) does not recommend the general use of ginkgo for Alzheimer disease.(Lyketsos 2006) The American Psychiatric Association practice guideline for the treatment of patients with Alzheimer disease and other dementias (2007) does not recommend ginkgo for routine use in treating cognitive and functional loss due to uncertainty regarding safety and efficacy.(Rabins 2007)
As an antioxidant, ginkgo is of interest in schizophrenia. Meta-analyses of quality clinical trials evaluating ginkgo as add-on therapy in chronic schizophrenia have been conducted; G. biloba extract performed better than placebo in the management of total and negative symptoms.(Chen 2015, Magalhães 2016, Singh 2010) However, data from a systematic review of herbal and nutritional products for treatment of ADHD in 50 children suggested that ginkgo 80 to 120 mg/day for 6 weeks provided no benefit compared with methylphenidate.(Sarris 2011)
Guidelines have been published regarding ginkgo's use in major depressive disorder and tardive dyskinesia. AAN guidelines for the treatment of tardive syndromes, including tardive dyskinesia syndrome (2013), conclude that G. biloba extract is probably useful in treatment of tardive dyskinesia syndrome; however, data are limited to inpatients with schizophrenia.(Bhidayasiri 2013) For major depressive disorder, the Canadian Network for Mood and Anxiety Treatments clinical guidelines for the management of major depressive disorder in adults (2009) state there is insufficient evidence to provide recommendations regarding use of gingko.(Ravindran 2009)
The AAN guideline on complementary and alternative medicine in multiple sclerosis (2014) advises that ginkgo is possibly effective for reducing short-term fatigue (low-quality evidence) and is ineffective for improving cognition (high-quality evidence).(Yadav 2014)
A limited number of small trials evaluating use of ginkgo in diabetes have been conducted. After 3-month ingestion of G. biloba extract in one study (N=20), significant (P<0.001) increases in fasting plasma levels of insulin and C-peptide, and in insulin and C-peptide area under the curve (AUC) were observed after a 2-hour 75 g oral glucose tolerance test. No changes in glucose tolerance were observed.(Kudolo 2000) In a follow-up study of type 2 diabetes patients taking oral hypoglycemic agents, ginkgo increased pancreatic beta cell function in response to glucose loading.(Kudolo 2001) Over a 3-month period, the pharmacokinetic properties of metformin 500 mg once daily were not affected by coadministration of 120 mg of ginkgo.(Kudolo 2006) Ingestion of 120 mg/day of standardized ginkgo extract for 3 months did not produce insulin resistance in nondiabetic and prediabetic populations, nor did it exacerbate the disease in type 2 diabetic subjects.(Aziz 2018, Kudolo 2006)
Evidence is lacking regarding the role of gingko in the management of menopausal symptoms or sexual function in women.(Reid 2014, Wheatley 2004) Clinical trials with small sample sizes have produced varying and equivocal results regarding effects of ginkgo on sexual function.(Ashton 2000, Boone 2005, Oh 2006, Ozgoli 2009, Wheatley 2004) In one study (N=99), G. biloba extract had a small but significant facilitatory effect on physiological, but not subjective, sexual arousal compared to placebo. The long-term effects of G. biloba extract on sexual function were then assessed in 68 sexually dysfunctional women randomly assigned to 8 weeks of treatment with G. biloba extract 300 mg/day, placebo, sex therapy alone, or sex therapy in combination with G. biloba extract. G. biloba extract was determined to be no more effective than placebo.(Meston 2008) Canadian Society of Obstetricians and Gynaecologists revised clinical practice guidelines on managing menopause (2014) do not recommend ginkgo for reducing menopausal symptoms, based on a lack of evidence supporting clinical benefit.(Reid 2014)
Small studies suggest efficacy in treating migraine; however, methodological limitations (eg, open-label design, multi-ingredient preparations tested) do not allow for extrapolation of the findings.(Allais 2013)
Ginkgo has been evaluated for the prevention of acute mountain sickness with equivocal results with most finding no benefit.(Chow 2005, Gertsh 2004, Leadbetter 2009, Moraga 2007, Tsai 2018) Results from a systematic review and meta-analysis of 7 studies that enrolled 451 healthy nonacclimated adults were also equivocal regarding use of ginkgo biloba extract compared to placebo for the prevention of acute mountain sickness. However, when the difference in observed risks between the 2 groups was assessed, the pooled risk difference (RD=25%; 95% CI, 6% to 45%) revealed a significant risk reduction with the use of ginkgo biloba extract (P<0.001).(Tsai 2018) A network meta-analysis of pharmacological interventions for prevention of acute mountain sickness found no significant benefit for ginkgo compared to placebo, and the addition of ginkgo to acetazolamide provided no benefit over acetazolamide alone.(Sridharan 2018)
Studies in rodents suggest that antioxidant and vascular effects of ginkgo may have a role in glaucoma(Hirooka 2004, Wimpissinger 2007) and cataractogenesis prevention.(Khedr 2018)
Limited clinical studies have reported positive findings with G. biloba use in patients with glaucoma.(Harris 2018, Kang 2018, Ritch 2005)
In rats with induced osteoporosis given ginkgo for 30 days, bone mineral density was improved.(Lucinda 2017)
Protective effects were observed in a study of rats with induced periodontitis administered G. biloba extract.(Freires 2018)
The updated American Academy of Neurology practice guideline summary for oral and topical treatment of painful diabetic polyneuropathy (2021) concluded that ginkgo biloba is possibly more likely than placebo to improve pain (large effect; low). They recommend that clinicians assess patient preferences for effective oral, topical, nontraditional, and nonpharmacological interventions and offer ginkgo biloba to those who prefer nontraditional interventions (Level C).(Price 2022)
An early double-blind, randomized, placebo-controlled pilot study (N=19) in 2002 observed a significant reduction in number of attacks when Raynaud patients were treated with 360 mg/day of a standardized ginkgo supplement (Seredrin) for 10 weeks compared to placebo (P=0.000).(Muir 2002) In contrast, no significant reduction was seen in frequency or duration of vasospastic attacks in adults with Raynaud disease after 10 weeks of the proprietary ginkgo product EGb 761 (240 mg/day). Per-protocol data were collected from 24 predominantly female patients in this double-blind, randomized placebo-controlled trial.(Bredie 2012)
Publication of clinical trial data makes available animal studies of tinnitus less relevant, except to establish a mechanism of action.(Dogan 2018, Esen 2018)
A Cochrane meta-analysis of 4 clinical trials (N=1,543) conducted up to March 2012 in adults with tinnitus, either as the primary complaint or as a component of cerebral insufﬁciency, showed no evidence that supplemental ginkgo was effective. In patients with vascular dementia or Alzheimer disease and tinnitus, a small but statistically significant reduction in tinnitus was observed.(Hilton 2013) Similar results were reported in another systematic review and meta-analysis of 4 randomized placebo-controlled clinical trials (N=1,246). No significant benefit was found for ginkgo on the severity or intensity of tinnitus or quality of life.(Kramer 2018) A literature review reports equivocal results,(Mahmoudian-Sani 2017) and a small (N=56) clinical study found no effect of ginkgo supplementation on idiopathic sudden sensorineural hearing loss for most outcomes measured, except for speech discrimination.(Koo 2016)
In 33 adults with tinnitus and hearing loss, the effect of Ginkgo biloba extract (EGb 761) with and without a digital hearing aid was assessed in a double-blind, randomized, controlled trial. Patients were allocated to 1 of 3 groups: Ginkgo 240 mg/day, hearing aid, or ginkgo plus a hearing aid. After 90 days, all groups experienced significant improvements in quality of life scores (P<0.0001 each). The improvement with ginkgo was independent of tinnitus duration, whereas improvement with the hearing aid was correlated to shorter tinnitus duration. The improvements reported in discomfort scores among all groups were statistically significant only in those fitted with a hearing aid (P=0.0002).(Radunz 2020)
The American Association of Otolaryngology – Head and Neck Surgery clinical practice guidelines for tinnitus (2014) recommend against the use of ginkgo or other dietary supplements for treating patients with persistent tinnitus (moderate-quality aggregate evidence).(Tunkel 2014)
Standardized ginkgo leaf extracts such as EGb 761 have been used in clinical trials for cognitive and cardiovascular disorders at daily doses of 120 to 240 mg.DeKosky 2008, Kuller 2010, Snitz 2009 Extracts are usually standardized to 24% flavones and 6% terpene lactones.DeKosky 2008, Snitz 2009 Ginkgo is commercially available in several doseforms, including teas, liquids, colas, capsules, extracts, tablets, sprays, and bars.
Pharmacokinetic testing of ginkgo doseforms, including capsules, drops, and tablets, has been conducted. When ginkgo is administered orally during fasting, bioavailability is high; food did not change the AUC quantitatively but did increase the time to maximum plasma concentration.Ude 2013, Woelkart 2010
The availability of unregulated or nonstandardized products needs to be considered when using ginkgo.Yadav 2014
Although a systematic review reports that traditional and common use has not indicated substantive risks in pregnancy or lactation, very weak scientific evidence from animal and in vitro studies shows ginkgo leaf has antiplatelet activity, and low-level evidence based on expert opinion shows ginkgo leaf may be an emmenagogue. Ginkgo should be used with caution during pregnancy, particularly around labor due to risk of prolonged bleeding time, and should be avoided during lactation.Dugoua 2006 An animal study of pregnant rats treated with ginkgo 7 to 14 mg/kg/day reported reduced fetal body weights,Pinto 2007 while another study found no evidence of embryotoxicity.Fernandes 2010
At recommended doses, standardized preparations of ginkgo leaf extract are unlikely to exhibit any clinically important interactions.(Bone 2008, Unger 2013) Caution may be required with use of raw extracts of the leaf with anticoagulants, although evidence from controlled studies consistently indicates that ginkgo does not impact hemostasis.(Bone 2008)
At higher than recommended dose levels, weak induction of cytochrome P450 (CYP-450) 2C19- and weak inhibition of CYP3A4-mediated metabolism has been observed, as well as a limited effect on drug transporters.(Unger 2013) Case reports of treatment failure implicate ginkgo, including in a 41-year-old man receiving antiretroviral therapy with efavirenz and taking a G. biloba 300 mg/day supplement(Naccarato 2012); other studies suggest no interaction with raltegravir.(Blonk 2012)
The availability of unregulated or nonstandardized products, as well as potential interactions of supplements with pharmaceutical medications, must be considered when using ginkgo.(Yadav 2014)
Agents with antiplatelet properties: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of agents with antiplatelet properties. Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)
Anticoagulants: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of anticoagulants. Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)
Digoxin: G. biloba does not appear to affect serum concentration of digoxin. No known interaction.(Mauro 2003)
Fosphenytoin-phenytoin: Ginkgo biloba may decrease the serum concentration of fosphenytoin-phenytoin. No action needed.(Kupiec 2005)
Herbs (anticoagulant/antiplatelet properties): Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of other herbs (anticoagulant/antiplatelet properties). Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)
Nimodipine: CYP3A4 inducers (weak) may decrease the serum concentration of nimodipine. Monitor therapy.(Nimodipine 2015, Tartara 1991)
Nonsteroidal anti-inflammatory agents: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of nonsteroidal anti-inflammatory drugs (NSAIDs). Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)
Selpercatinib: CYP3A4 inducers (weak) may decrease the serum concentration of selpercatinib. Monitor therapy.(Retevmo May 2020)
Simvastatin: Ginkgo biloba may decrease the serum concentration of simvastatin. No action needed.(Dai 2013)
Thiazide and thiazide-like diuretics: The concomitant use of thiazide and thiazide-like diuretics and G. biloba may result in hypertension. No action needed.(Shaw 1997)
Thrombolytic agents: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of thrombolytic agents. Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)
Triazolam: CYP3A4 inducers (weak) may decrease the serum concentration of triazolam. No action needed.(Banzel November 2019, Villikka 1998)
Ubrogepant: CYP3A4 inducers (weak) may decrease the serum concentration of ubrogepant. Consider therapy modification.(Ubrelvy December 2019)
Valproate products: Ginkgo biloba may decrease the serum concentration of valproate products. Monitor therapy.(Granger 2001, Kupiec 2005)
In large clinical trials using maximum dosages of standardized ginkgo extract 240 mg/day for durations of up to 6 years, reported adverse reactions did not differ from those in placebo groups.Birks 2009, Dekosky 2008, Snitz 2009, Weinmann 2010 A trial evaluating the safety and effectiveness of ginkgo at dosages of 240 mg/day over 22 weeks found no difference in adverse events for ginkgo compared with placebo.Napryeyenko 2009
The effect of ginkgo on platelets is unclear, but evidence from controlled studies consistently indicates that ginkgo does not impact hemostasis.Bone 2008 Case reports of increased bleeding risk exist, but clinical trials have found no effect on platelet function.Bebbington 2005, Rosenblatt 1997, Wolf 2006 Ginkgo should be used with caution in populations with bleeding risks.Page 2016
Severe adverse reactions are rare. Case reports describe headache, dizziness, and heart palpitations, as well as GI and dermatologic reactions. Injectable forms of ginkgo may cause circulatory disturbances, skin allergy, or phlebitis; parenteral ginkgo was withdrawn from the market because of the potential for severe adverse reactions.De Smet 1997
Data collected between 2004 and 2013 from 8 US centers in the Drug-induced Liver Injury Network revealed that 15.5% (130) of hepatotoxicity cases were caused by herbals and dietary supplements, whereas 85% (709) of cases were related to prescription medications. Of the 130 cases of liver injury related to supplements, 65% were from non-bodybuilding supplements and occurred most often in Hispanics/Latinos compared with non-Hispanic whites and non-Hispanic blacks. Liver transplant was also more frequent with toxicity from non-bodybuilding supplements (13%) than with conventional medications (3%) (P<0.001). Overall, the proportion of severe liver injury cases was significantly higher for supplements than for conventional medications (P=0.02). Of the 217 supplement products implicated in liver injury, 175 had identifiable ingredients, of which ginkgo biloba was among the 32 (18%) single-ingredient products.Navarro 2014
Ginkgo pollen can be strongly allergenic. Contact with the fleshy drupe pulp can cause allergic dermatitis similar to that caused by poison ivy.De Smet 1997 Case reports of seizures associated with ginkgo supplementation existGranger 2001; however, ginkgo extracts have been shown to exhibit both anti- and proconvulsant activity in animal experiments.Jahanshahi 2012, Lee 2012
Data have been reported regarding the carcinogenic potential of G. biloba extract, with increased mitosis and cell proliferation observed in some,Wang 2017 but not all, rodent studies.Fernandes 2010, Grollino 2017
Limited clinical studies have also produced equivocal findings. One study (N=47) reported no increase in liver injury markers or genomic measures (micronucleus frequency, comet assay, c-myc, p53, and ctnnb1 expression profile in lymphocytes).Bonassi 2018 In an analysis of cancer as a secondary end point in the 3,069 participants of the GEM study, no protective effect of ginkgo was observed. For site-specific cancers, there were nonsignificant trends towards an increased risk of breast (HR, 2.15; 95% CI, 0.97 to 4.8; P=0.06) and colorectal (HR, 1.62; 95% CI, 0.92 to 2.87; P=0.1) cancers, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43 to 1.17; P=0.18).Biggs 2010
Ginkgo seeds have been reported to induce a toxic syndrome ("Gin-nan" food poisoning). Consumption of approximately 50 ginkgo seeds has produced convulsions in a 21-month-old child, and consumption of 70 to 80 seeds induced tonic-clonic seizures and loss of consciousness in a 36-year-old woman.Benjamin 2001, Hasegawa 2006, Miwa 2001 In a similar case, a 64-year-old woman with a 40-year history of daily alcohol intake and signs of fatty liver presented with generalized tonic-clonic seizures within 9.5 hours of consuming 50 roasted ginkgo seeds. Ginkgo biloba intoxication was confirmed by a methylpyridoxine level in excess of 3,000 nM, which was normalized within an hour of IV pyridoxal phosphate replacement. She was discharged after 3 days of hospitalization.Azuma 2020 Between 1930 and 1960, 70 reports of poisoning related to ginkgo ingestion revealed a 27% mortality rate, with infants being the most vulnerable. Ginkgotoxin (4-O-methylpyridoxine), found only in the seeds, was considered responsible for this toxicity.De Smet 1997, Newall 1996
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