Ginkgo biloba (DB01381): A Comprehensive Pharmacological and Clinical Review

Executive Summary

Ginkgo biloba (DrugBank ID: DB01381; CAS Number: 90045-36-6) is a phytopharmaceutical agent with a unique standing in both traditional and modern medicine. Derived from one of the world's oldest living tree species, its leaf extract has been investigated for a wide range of therapeutic applications, primarily centered on cognitive and circulatory disorders. The extract's pharmacological activity is attributed to a complex mixture of bioactive compounds, principally flavonoid glycosides and terpene lactones, which confer a multifaceted mechanism of action. These mechanisms include potent antioxidant effects, vasodilation and improvement of blood rheology, modulation of key neurotransmitter systems, and antagonism of Platelet-Activating Factor (PAF).

This comprehensive review synthesizes the current body of scientific evidence on Ginkgo biloba, critically examining its botanical origins, pharmacology, clinical efficacy, safety profile, and regulatory status. A central theme emerging from the analysis is the significant discrepancy between the highly standardized, pharmaceutical-grade extract used in credible clinical research (EGb 761) and the often-adulterated, unregulated products sold as dietary supplements, which complicates the translation of research findings into clinical practice.

The clinical evidence for Ginkgo biloba is marked by a significant paradox. While a large body of evidence from systematic reviews and meta-analyses suggests that the standardized extract EGb 761 at a dose of 240 mg/day may offer modest symptomatic benefit in stabilizing or slowing the decline in cognition and function in patients with established dementia or mild cognitive impairment, the most definitive large-scale trial to date—the Ginkgo Evaluation of Memory (GEM) Study—found it to be unequivocally ineffective for the primary prevention of dementia in older adults.

The safety profile of the standardized leaf extract is generally favorable, with most adverse effects being mild and transient. However, a clinically significant risk of increased bleeding, stemming from its antiplatelet activity, necessitates caution, particularly in patients on anticoagulant or antiplatelet therapy, those with bleeding disorders, or individuals scheduled for surgery. Furthermore, Ginkgo biloba exhibits a broad and clinically relevant drug interaction profile, affecting medications commonly used by the elderly, including anticoagulants, antidepressants, anti-seizure drugs, and statins. This underscores the need for professional medical oversight.

Globally, Ginkgo biloba exists in a state of regulatory dichotomy. In the United States, it is classified as a dietary supplement by the Food and Drug Administration (FDA), with no approved therapeutic claims and significant concerns regarding product quality and adulteration. Conversely, in the European Union, the European Medicines Agency (EMA) has recognized the standardized extract as a herbal medicinal product with a "well-established use" for improving age-related cognitive impairment and quality of life in mild dementia. This report provides a detailed analysis of these complex issues to inform clinical decision-making and future research.

Section 1: Botanical Origin and Phytochemical Profile

1.1. The "Living Fossil": Historical Context and Botanical Description

Ginkgo biloba L., commonly known as the maidenhair tree, holds a unique position in the botanical world as the sole surviving species of the order Ginkgoales, which first appeared over 290 million years ago.[1] Its resilience, having survived mass extinctions and glaciation periods, has earned it the designation of a "living fossil".[2] The tree is native to China, where it is considered a national symbol of hope and peace, but due to its ornamental value and high resistance to environmental stressors, it is now cultivated globally in parks, gardens, and urban landscapes.[3]

The use of Ginkgo biloba as a medicinal plant dates back centuries in Traditional Chinese Medicine (TCM), where its leaves and seeds were employed to treat a variety of ailments, including circulatory disorders, asthma, cough, diarrhea, tinnitus, and vertigo.[2] The transition to modern pharmaceutical use began in Germany in 1965 with the development of a purified and standardized leaf extract, which has since become the basis for the vast majority of scientific research.[8]

1.2. Active Constituents: Flavonoids and Terpene Lactones

The therapeutic properties of Ginkgo biloba are not attributed to a single molecule but to a complex synergy of bioactive compounds extracted from its fan-shaped leaves. These constituents are broadly categorized into two principal classes that are responsible for its diverse pharmacological effects.

• Flavonoid Glycosides: This group constitutes a significant portion of the standardized extract and includes compounds such as quercetin, kaempferol, isorhamnetin, ginkgetin, and bilobetin.[4] These polyphenolic compounds are primarily credited with the extract's potent antioxidant and free-radical scavenging activities. They protect cells from oxidative damage, a key pathological process in aging and neurodegenerative diseases.[11]
• Terpene Lactones (Terpenoids): This class contains unique diterpenes and a sesquiterpene that are exclusive to Ginkgo biloba. The diterpenes are known as ginkgolides (e.g., Ginkgolide A, B, C, J, M), and the sesquiterpene is bilobalide.[4] These molecules are primarily associated with the extract's vasoactive and neuroprotective effects. Notably, Ginkgolide B is a powerful antagonist of Platelet-Activating Factor (PAF), a key mediator in inflammatory and thrombotic processes, which contributes significantly to the extract's effects on blood circulation.[6]

In addition to these primary compounds, the leaves also contain other substances, including alkylphenols like ginkgolic acid. These compounds are known to be toxic and allergenic, and their concentration is strictly limited to very low levels (typically less than 5 ppm) in high-quality, pharmaceutical-grade extracts to ensure safety.[3]

1.3. The Standard for Research: Understanding the EGb 761 Extract

It is crucial to recognize that the body of credible clinical evidence pertaining to Ginkgo biloba is overwhelmingly based on studies of a specific, proprietary extract known as EGb 761.[10] This extract, first developed by Dr. Willmar Schwabe Pharmaceuticals in Germany, is highly purified and standardized to ensure a consistent concentration of active compounds.[8]

The standardization of EGb 761 is defined by its composition: a 50:1 concentrate containing 24% flavonoid glycosides and 6% terpene lactones.[5] This precise formulation is the "drug" that has been tested in major clinical trials, including the Ginkgo Evaluation of Memory (GEM) Study. Consequently, the clinical findings, whether positive or negative, associated with EGb 761 cannot be reliably extrapolated to other

Ginkgo products on the market that do not adhere to this rigorous standard of quality and composition.

1.4. The Problem of Adulteration and Quality in Commercial Products

A significant challenge in the field of Ginkgo biloba is the chasm between the pharmaceutical-grade extract used in research and the products widely available to consumers, particularly in markets where it is sold as a dietary supplement. There is well-documented, widespread, and economically motivated adulteration within the industry.[8]

Unscrupulous manufacturers have been found to use cheaper plant materials, such as buckwheat extract or sophora japonica, to augment or entirely replace authentic Ginkgo leaf extract. These adulterants contain compounds like rutin (a flavonoid) that can deceive simple analytical tests designed to quantify total flavonoid content, thus appearing to meet quality standards while containing little to no actual Ginkgo or its unique terpene lactones.[20]

Independent analyses have repeatedly shown that a substantial percentage of commercial Ginkgo supplements fail quality testing. These products either contain significantly less active ingredient than stated on the label or do not meet the required 24%/6% standardization for flavonoid glycosides and terpene lactones, respectively.[21] This crisis in quality control fundamentally undermines the ability of consumers to achieve the potential benefits observed in clinical trials and introduces a major confounding variable when evaluating the overall effectiveness of

Ginkgo biloba in the general population. The experience of a consumer taking an off-the-shelf supplement may have no bearing on the results obtained from studies using pure, standardized EGb 761.

Section 2: Multifaceted Pharmacology and Mechanisms of Action

Ginkgo biloba extract does not function as a single-target agent but rather as a pleiotropic substance, exerting its effects through multiple, synergistic pharmacological pathways. This "pharmacological shotgun" approach provides a strong preclinical rationale for its investigation in complex, multifactorial diseases like Alzheimer's, which are characterized by oxidative stress, vascular compromise, and neurotransmitter deficits.

2.1. Antioxidant and Neuroprotective Properties

A cornerstone of Ginkgo biloba's mechanism of action is its capacity as a potent antioxidant and free radical scavenger.[9] The flavonoid glycosides within the extract are adept at neutralizing a wide range of reactive oxygen species (ROS) and reactive nitrogen species.[10] This activity protects vulnerable cellular structures, particularly neuronal membranes, from oxidative damage, a key contributor to the pathophysiology of aging and neurodegenerative disorders.[6] By inhibiting lipid peroxidation, the extract helps maintain the integrity and fluidity of cell membranes, which is crucial for normal cellular function and signaling.[11] This neuroprotective effect, demonstrated by reducing apoptosis (programmed cell death) in neurons under oxidative stress, forms a primary basis for its use in conditions of cognitive decline.[10]

2.2. Vasoactive Effects and Hemorheology

Ginkgo biloba exerts significant effects on the vascular system, improving both cerebral and peripheral circulation.[9] Its vasoactive properties are multifaceted. The extract promotes vasodilation by stimulating the release of endogenous relaxing factors from the arterial endothelium, most notably nitric oxide (NO) and prostacyclin.[10] This leads to an increase in blood flow, which may help alleviate conditions associated with ischemia or poor microcirculation.[25] Furthermore, the extract has been shown to improve hemorheology by reducing blood viscosity and enhancing the flexibility of red blood cells, which further facilitates passage through narrow capillaries.[15] This combination of vasodilation and improved blood flow properties underpins its traditional and modern use for circulatory disorders, from peripheral artery disease to cerebrovascular insufficiency.

2.3. Modulation of Neurotransmitter Systems

Beyond its vascular and antioxidant effects, Ginkgo biloba directly interacts with the central nervous system by modulating various neurotransmitter pathways. This complex activity is thought to contribute to its nootropic, or cognitive-enhancing, properties. The extract has been shown to inhibit the sodium-dependent noradrenaline transporter and the reuptake of other key monoamines, including dopamine and serotonin, which can increase their availability in the synaptic cleft.[6]

Furthermore, chronic administration of the extract can alter the density of postsynaptic receptors. Studies have demonstrated an increase in muscarinic acetylcholine and 5-HT1A (serotonin) receptors, alongside a decrease in beta-adrenoceptors.[10] The upregulation of cholinergic receptors is particularly relevant for Alzheimer's disease, which is characterized by a significant cholinergic deficit. The extract also exhibits antagonist activity at glycine receptors and acts as a negative modulator at gamma-aminobutyric acid (GABA) receptors, further highlighting its broad impact on central nervous system signaling.[27]

2.4. Anti-inflammatory and Platelet-Activating Factor (PAF) Antagonism

A unique and highly significant mechanism of Ginkgo biloba is the antagonism of Platelet-Activating Factor (PAF) by its terpene lactone constituents, particularly ginkgolide B.[6] PAF is a potent phospholipid mediator involved in a wide array of pathological processes, including platelet aggregation, inflammation, allergic reactions, and bronchoconstriction. By specifically inhibiting the binding of PAF to its receptor, ginkgolides can attenuate these processes.[17] This PAF antagonism contributes to the extract's anti-inflammatory properties, its ability to reduce platelet aggregation (contributing to the bleeding risk discussed in Section 4), and its effects on blood flow. This mechanism also provides the rationale for its investigation in conditions like asthma and other inflammatory disorders.[6]

Section 3: Clinical Evidence for Therapeutic Applications: A Critical Analysis

The clinical evidence for Ginkgo biloba is extensive but fraught with contradictions, leading to significant debate regarding its therapeutic utility. A critical analysis reveals a clear divergence in outcomes depending on the population studied and the clinical endpoint measured. The evidence strongly suggests a failure as a primary preventative agent in healthy aging, while simultaneously indicating a potential role as a modest palliative agent once dementia is established.

3.1. Dementia and Mild Cognitive Impairment (MCI): A Tale of Contradictory Evidence

The most intensely studied and controversial application of Ginkgo biloba is for the management of age-related cognitive decline. The body of evidence can be best understood by separating the findings related to the treatment of existing dementia from those related to its prevention.

3.1.1. Analysis of Evidence Suggesting Modest Efficacy for Treatment

Multiple systematic reviews and meta-analyses of randomized controlled trials have concluded that the standardized Ginkgo biloba extract, EGb 761, at a dose of 240 mg per day, may offer a small but statistically significant benefit for patients already diagnosed with dementia (including Alzheimer's disease and vascular dementia) or mild cognitive impairment (MCI).[15] These analyses, which pool data from numerous smaller trials, consistently show that EGb 761 is superior to placebo in stabilizing or slowing the decline across three key domains:

• Cognition: Improvements are noted on standardized cognitive tests such as the Mini-Mental State Examination (MMSE) and the Short Cognitive Performance Test (SKT).[13]
• Function: Benefits are observed in Activities of Daily Living (ADLs), indicating a potential to help patients maintain independence for longer.[15]
• Behavior: The extract has been shown to reduce neuropsychiatric symptoms (e.g., depression, anxiety) that are common in dementia.[13]

Some head-to-head trials have even suggested that the efficacy of EGb 761 in mild to moderate dementia is comparable to that of standard pharmaceutical treatments like the cholinesterase inhibitor donepezil.[6] However, it is important to contextualize these findings: the observed effects are modest, and not all studies have been positive. The most consistent benefits are seen at the 240 mg/day dosage over a period of at least 22-26 weeks.[15]

3.1.2. The Ginkgo Evaluation of Memory (GEM) Study: A Definitive Finding of Inefficacy for Prevention

In stark contrast to the treatment data stands the Ginkgo Evaluation of Memory (GEM) Study, the largest and most rigorous clinical trial ever conducted on the substance.[32] This landmark, multi-center, randomized, double-blind, placebo-controlled trial was specifically designed to answer the question of prevention. It enrolled 3,069 adults aged 75 and older with either normal cognition or MCI at baseline and followed them for an average of 6.1 years.[32]

The primary finding of the GEM study was unequivocal: a daily dose of 240 mg of EGb 761 was completely ineffective in reducing the incidence of all-cause dementia or the specific incidence of Alzheimer's disease compared to placebo.[2] During the study, 277 participants in the

Ginkgo group developed dementia, compared to 246 in the placebo group, a statistically non-significant difference.[35]

Further analyses of the GEM study data reinforced this negative conclusion, finding no benefit of Ginkgo biloba in slowing the rate of cognitive decline in any domain, reducing the incidence of hypertension, or preventing major cardiovascular events like heart attack and stroke.[29] This robust negative finding for prevention is supported by Cochrane reviews, which have consistently described the overall evidence for

Ginkgo's cognitive benefits as "inconsistent and unreliable".[25]

3.1.3. Reconciling the Discrepancies: The Treatment vs. Prevention Paradox

The apparent contradiction between the positive meta-analyses and the negative GEM study can be logically reconciled by examining the fundamental differences in their study designs and objectives. The positive findings emerge from studies testing Ginkgo biloba as a treatment in patients who already have established dementia pathophysiology. Their goal was to measure changes in existing symptoms. In contrast, the GEM study tested Ginkgo biloba as a preventative agent in a population that was largely cognitively healthy at the outset. Its goal was to see if the supplement could stop the disease from developing in the first place.

This distinction is critical. Failing to prevent the onset of a complex neurodegenerative disease is a different pharmacological outcome than modestly mitigating its symptoms once the pathological cascade is already underway. This suggests that Ginkgo's mechanisms—such as improving cerebral blood flow and reducing oxidative stress—may be insufficient to halt the primary upstream pathological events of dementia (e.g., amyloid plaque formation) but may provide some downstream palliative or stabilizing effect on brain function in an already compromised system.

Study/Review	Population	Dosage	Duration	Key Outcomes	Conclusion
GEM Study 32	Prevention in 3,069 adults >75 with normal cognition or MCI	240 mg/day EGb 761	Avg. 6.1 years	Incidence of dementia, rate of cognitive decline	Ineffective for preventing dementia or slowing cognitive decline.
Cochrane Review (2009) 25	Treatment of cognitive impairment and dementia (36 trials)	Varied	Varied	Cognition, ADLs, mood	Evidence is inconsistent and unreliable for predictable, clinically significant benefit.
Gauthier & Schlaefke (2015) Meta-Analysis 15	Treatment of cognitive impairment and dementia (9 trials, 2,561 patients)	Primarily 240 mg/day EGb 761	22-26 weeks	Cognition (SKT), ADLs, CGIC	EGb 761 at 240 mg/day stabilizes or slows decline in cognition, function, and behavior.
Yang et al. (2016) Meta-Analysis 29	Treatment of MCI or AD (21 trials, 2,608 patients)	Varied	Varied	Cognition (MMSE), ADLs	Potentially beneficial for improving cognitive function and ADLs.

3.2. Peripheral Circulatory Disorders and Cardiovascular Health

Based on its vasoactive and hemorheological properties, Ginkgo biloba has long been used for peripheral circulatory disorders, most notably intermittent claudication (pain on walking due to poor blood flow).[6] The clinical evidence, however, is mixed. While some small, early studies reported that

Ginkgo could improve pain-free walking distance, larger, more rigorous studies and a Cochrane review have failed to find convincing evidence of a clinically significant benefit.[17] The comprehensive data from the GEM study further dampened enthusiasm, showing no reduction in the incidence of major cardiovascular events, although it did note a smaller number of peripheral vascular disease events in the

Ginkgo arm.[28]

3.3. Neurosensory Disorders: Tinnitus and Vertigo

Tinnitus (ringing in the ears) and vertigo are common and distressing neurosensory symptoms in the elderly, often occurring as comorbidities in patients with dementia.[37] The rationale for using

Ginkgo stems from its ability to improve inner ear microcirculation and its neuroprotective effects.[38] A meta-analysis of five trials focusing on patients with dementia found that EGb 761 at 240 mg/day was statistically superior to placebo in reducing the severity of both tinnitus and dizziness.[38]

An interesting aspect of this effect is the potential role of psychological mediation. A detailed analysis found that while Ginkgo has a direct effect on tinnitus severity, approximately 40% of the total therapeutic benefit was indirect, mediated by its concurrent improvement of comorbid symptoms of anxiety and depression.[37] This suggests that part of its efficacy in tinnitus may stem from its anxiolytic and antidepressant properties, helping patients cope better with the distress caused by the condition.

3.4. Psychiatric Conditions: Anxiety, Depression, and Schizophrenia

The evidence base for Ginkgo biloba in primary psychiatric disorders is less extensive but suggests a potential role as an adjunctive therapy.

• Schizophrenia: A meta-analysis of three randomized controlled trials concluded that when added to standard antipsychotic medication, Ginkgo biloba produced a modest but significant reduction in positive symptoms (e.g., hallucinations, delusions). However, it had no effect on negative symptoms (e.g., apathy, social withdrawal).[6]
• Depression: One small trial found that adding EGb 761 to the SSRI antidepressant citalopram improved depressive symptoms and cognitive function more than citalopram alone in elderly patients with depression.[5]
• Anxiety: Evidence is more limited, but a study focusing on Generalized Anxiety Disorder reported that EGb 761 was significantly more effective than placebo in reducing anxiety symptoms.[6]

Section 4: Comprehensive Safety and Toxicology Profile

While Ginkgo biloba has a long history of use, its safety profile is not without concerns. A clear distinction must be made between the standardized leaf extract used in supplements and other parts of the plant, particularly the seeds, which are toxic. For the leaf extract, the primary clinical concern revolves around its antiplatelet activity and the associated risk of bleeding.

4.1. Adverse Effects of Standardized Leaf Extract

When taken at recommended doses (up to 240 mg/day), the standardized leaf extract is generally considered safe and is well-tolerated by most healthy adults.[2] The majority of reported side effects are mild and transient. The most common adverse events include:

• Gastrointestinal issues: Upset stomach, nausea, diarrhea, or constipation.[29]
• Central nervous system effects: Headache and dizziness.[2]
• Cardiovascular effects: Palpitations or the feeling of a racing heart.[36]
• Dermatological reactions: Allergic skin reactions or rash.[29]

4.2. The Bleeding Risk: A Primary Clinical Concern

The most clinically significant safety issue associated with Ginkgo biloba leaf extract is an increased risk of bleeding.[29] This effect is a direct consequence of its pharmacological action, specifically the antagonism of Platelet-Activating Factor (PAF) and other antiplatelet properties, which inhibit normal blood clotting.[6] Case reports have described spontaneous bleeding events, including intracranial and ocular hemorrhages, in individuals taking the supplement.

While the large-scale GEM study did not find a statistically significant increase in major hemorrhagic events or stroke in the Ginkgo group compared to placebo [34], the mechanistic basis for the risk is sound. This potential for increased bleeding remains the primary driver behind most of the clinical warnings, contraindications, and drug interaction alerts associated with its use.

4.3. Contraindications and High-Risk Populations

Given the bleeding risk and other potential effects, Ginkgo biloba is contraindicated or should be used with extreme caution in several specific populations:

• Patients with Bleeding Disorders: Individuals with conditions like hemophilia or von Willebrand disease should avoid Ginkgo as it may exacerbate their condition.[39]
• Patients Undergoing Surgery: Use of Ginkgo biloba should be discontinued at least two weeks prior to any scheduled surgical or dental procedure to minimize the risk of excessive intraoperative and postoperative bleeding.[36]
• Pregnancy and Lactation: Ginkgo is considered unsafe during pregnancy as it may induce premature labor or cause excessive bleeding during delivery. Its safety during breastfeeding has not been established and its use is not recommended.[2]
• Patients with Epilepsy or a History of Seizures: There is evidence that Ginkgo may lower the seizure threshold and could potentially induce seizures, particularly at high doses. Individuals with a history of seizure disorders should avoid its use.[36]
• Patients with Diabetes: Ginkgo may interfere with blood glucose regulation and the management of diabetes. Patients with diabetes who choose to use it should monitor their blood sugar levels closely.[36]

4.4. Toxicity of Non-Extract Plant Parts (Seeds)

It is imperative to distinguish the safety profile of the purified leaf extract from that of other parts of the Ginkgo tree. The raw or roasted seeds of the Ginkgo biloba tree are toxic and should never be consumed.[2] The seeds contain high levels of ginkgotoxin (4'-O-methylpyridoxine), a neurotoxin that can interfere with vitamin B6 metabolism and induce serious adverse effects, including convulsions, loss of consciousness, and, in severe cases, death. Children are particularly vulnerable to ginkgo seed poisoning.[5]

Section 5: Clinically Significant Drug and Herb Interactions

The extensive pharmacological activity of Ginkgo biloba gives rise to a significant potential for interactions with prescription medications, over-the-counter drugs, and other herbal supplements. The number of known interactions exceeds 300, many of which are moderately clinically significant.[45] These interactions position

Ginkgo biloba as an agent that requires careful medical oversight, particularly in polymedicated elderly patients—the very demographic most likely to use it for cognitive concerns. The classification as a "dietary supplement" in some regions can be misleading, as it belies the high potential for serious adverse drug events.

5.1. Interactions with Anticoagulant and Antiplatelet Agents

This is the most critical and well-documented class of interactions. Due to its inherent antiplatelet effects, co-administration of Ginkgo biloba with any substance that thins the blood can synergistically increase the risk of serious bleeding. This includes:

• Prescription Anticoagulants: Warfarin.[42]
• Prescription Antiplatelet Drugs: Clopidogrel.
• Over-the-Counter (OTC) Drugs: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen.[36]
• Other Herbal Supplements: Garlic, ginseng, and saw palmetto, which also possess blood-thinning properties.[42]

This combination should generally be avoided, and if used, requires vigilant monitoring for signs of bleeding or bruising.

5.2. Interactions with Antidepressants and Anxiolytics

Ginkgo biloba can interfere with the metabolism and efficacy of several psychiatric medications. It may reduce the effectiveness of certain selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and anxiolytics like alprazolam.[36] While less well-documented, there is a theoretical risk of serotonin syndrome—a potentially life-threatening condition—when

Ginkgo is combined with SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) due to its modulatory effects on serotonin pathways.[19]

5.3. Impact on Anti-seizure and Diabetes Medications

The potential for Ginkgo biloba to lower the seizure threshold creates a dangerous interaction with anticonvulsant medications. By opposing the action of these drugs, Ginkgo can reduce their effectiveness and increase the risk of breakthrough seizures.[36] This combination is strongly discouraged. Additionally,

Ginkgo can alter blood glucose levels, potentially disrupting glycemic control in patients with diabetes and interfering with the efficacy of oral hypoglycemic agents or insulin.[39]

5.4. Cytochrome P450-Mediated and Other Interactions

Ginkgo biloba has been identified as an inhibitor of the Cytochrome P450 2C9 (CYP2C9) enzyme system in the liver.[27] This can slow the metabolism of numerous drugs that are substrates for this enzyme, potentially leading to increased drug levels and toxicity. Other notable interactions include:

• Statins: May reduce the efficacy of cholesterol-lowering drugs like simvastatin and atorvastatin.[36]
• Proton Pump Inhibitors (PPIs): Can decrease the levels and effectiveness of acid-reducers like omeprazole and esomeprazole.[42]
• Calcium Channel Blockers: Has been shown to significantly increase blood levels of nifedipine, leading to exaggerated side effects such as headache, dizziness, and hot flashes.[17]

Drug/Drug Class	Specific Examples	Nature of Interaction	Clinical Management Recommendation
Anticoagulants/Antiplatelets	Warfarin, Clopidogrel, Aspirin, Ibuprofen, Garlic, Ginseng	Additive antiplatelet effect increases risk of serious bleeding.	Avoid combination. Counsel patient on signs of bleeding (bruising, hematuria).
Anti-seizure Medications	Phenytoin, Carbamazepine, Valproic Acid	Lowers seizure threshold, reducing anticonvulsant efficacy.	Avoid combination. Poses a significant risk of breakthrough seizures.
Antidepressants (SSRIs/SNRIs)	Fluoxetine, Sertraline, Duloxetine	May decrease antidepressant efficacy. Theoretical risk of serotonin syndrome.	Use with caution. Monitor for changes in mood and symptoms of serotonin syndrome.
Anxiolytics	Alprazolam (Xanax)	May decrease alprazolam levels and reduce its anxiolytic effect.	Use with caution. Monitor for loss of efficacy.
Statins	Simvastatin, Atorvastatin	May reduce the efficacy of the statin in lowering cholesterol.	Monitor lipid panels. Consider alternative or dose adjustment if necessary.
Proton Pump Inhibitors	Omeprazole, Esomeprazole	Decreases levels of the PPI, reducing its acid-suppressing effect.	Avoid combination if possible. Monitor for symptoms of GERD or ulcers.
Diabetes Medications	Metformin, Glyburide, Insulin	May alter blood glucose levels and interfere with glycemic control.	Monitor blood sugar closely. Dose adjustments of diabetes medication may be required.
Calcium Channel Blockers	Nifedipine	Can significantly increase nifedipine levels, leading to severe side effects.	Avoid combination. The risk of adverse effects outweighs potential benefits.

Section 6: Administration, Dosage, and Formulations

6.1. Dosing Regimens in Clinical Trials and Practice

There is no universally standardized or FDA-approved dosage for Ginkgo biloba.[19] However, a consensus dosage has emerged from the body of clinical research, particularly from trials investigating its effects on dementia and cognitive impairment.

The most common evidence-based dosage regimen for adults is 120 mg to 240 mg of standardized extract per day.[5] This total daily dose is typically administered in two or three divided doses to maintain stable blood levels, such as 40 mg three times daily, 80 mg twice daily, or 120 mg twice daily.[19] Daily doses exceeding 240 mg are not recommended, as they are associated with an increased risk of adverse effects without evidence of greater therapeutic benefit.[19]

6.2. Available Formulations and Bioavailability

Ginkgo biloba is commercially available in a variety of formulations, catering to consumer preference. These include:

• Capsules
• Tablets
• Liquid extracts or tinctures
• Dried leaves for teas
• Powders [5]

While multiple forms exist, it is important to note that the vast majority of rigorous clinical trials have utilized oral capsules or tablets containing the standardized EGb 761 extract.[19] The bioavailability and efficacy of other formulations, such as teas or non-standardized powders, have not been well-established.

6.3. Guidelines for Product Selection and Administration

For clinicians counseling patients who choose to use Ginkgo biloba, providing guidance on product selection is crucial due to the aforementioned issues of quality and adulteration.

• Look for Standardization: Advise patients to select products that explicitly state on the label that they contain a standardized extract, ideally matching the research standard of 24% flavonoid (or flavone) glycosides and 6% terpene lactones.[19] The term "EGb 761" on the label is a strong indicator of a product adhering to this standard.
• Seek Third-Party Certification: Recommend products that have been verified by a third-party organization, such as the United States Pharmacopeia (USP) or NSF International. While not a guarantee of efficacy, this certification provides some assurance that the product contains the ingredients listed on the label in the stated amounts and is free from harmful contaminants.[19]
• Administration: To minimize the risk of gastrointestinal upset, it is often recommended that Ginkgo biloba be taken with meals.[48]

Section 7: The Global Regulatory Divide: A Comparative Analysis

The legal and medical status of Ginkgo biloba differs dramatically across the globe, creating a confusing landscape for clinicians and consumers. This divergence is not driven by access to different scientific evidence but by fundamentally different regulatory philosophies and legal frameworks, most notably between the United States and the European Union.

7.1. United States (FDA): Status as a Dietary Supplement

In the United States, Ginkgo biloba is regulated by the Food and Drug Administration (FDA) under the Dietary Supplement Health and Education Act of 1994 (DSHEA).[2] Under this framework, it is classified and marketed as a

dietary supplement, not a drug. This classification has several critical implications:

• No Pre-market Approval: Unlike pharmaceutical drugs, dietary supplements do not require FDA approval for safety or efficacy before they are sold to the public.[2] The responsibility for ensuring safety and truthful labeling lies with the manufacturer.
• Restricted Health Claims: Manufacturers are prohibited from making claims that their product can diagnose, treat, cure, or prevent any disease. They are limited to making vague "structure/function" claims, such as "supports brain health".[28]
• Post-market Enforcement: The FDA's role is primarily reactive. It can take action—such as issuing warning letters or ordering recalls—only after a product is on the market and found to be unsafe, adulterated, or misbranded.[20] The FDA has issued numerous warnings against unregistered or adulterated Ginkgo products.[50]
• Not GRAS: The FDA has explicitly determined that Ginkgo biloba is not Generally Recognized as Safe (GRAS) for use as an ingredient in conventional foods.[49]

This regulatory environment contributes to the problems of inconsistent product quality and adulteration, as there are no mandated manufacturing standards for herbal supplements equivalent to those for pharmaceuticals.[41]

7.2. European Union (EMA): Status as a Herbal Medicinal Product

In sharp contrast, the European Medicines Agency (EMA), through its Committee on Herbal Medicinal Products (HMPC), has established a formal European Union herbal monograph for Ginkgo folium (ginkgo leaf), classifying it as a herbal medicinal product.[43] This framework provides a pathway for official recognition based on scientific evidence and historical use. The EMA monograph defines two distinct levels of use:

• "Well-established use": This designation applies to the standardized dry extract (equivalent to EGb 761). It is indicated for the "improvement of (age-related) cognitive impairment and of quality of life in adults with mild dementia." This status is granted based on sufficient scientific and bibliographic data demonstrating safety and efficacy from at least 10 years of use within the EU.[18]
• "Traditional use": This designation applies to the powdered leaf preparation. It is indicated for the "relief of heaviness in the legs and the sensation of cold hands and feet associated with minor circulatory disorders." This status is based on evidence of safe use for at least 30 years and does not require the same level of clinical trial evidence as the "well-established use" category.[43]

7.3. Implications of Regulatory Differences for Clinicians and Consumers

This regulatory chasm creates a paradoxical global situation. In Germany or France, a physician can prescribe a pharmacy-grade, quality-controlled Ginkgo biloba product for a recognized medical indication, and it is treated as a medicine. In the United States, the same substance is available over-the-counter in a largely unregulated market, where a consumer self-selects a product of uncertain quality and potency for a self-perceived need. This discrepancy highlights how a substance's legal and medical status can be highly dependent on geography, leading to major international differences in clinical practice, product reliability, and public health guidance.

Section 8: Synthesis and Concluding Remarks

8.1. Summary of Evidence: Distinguishing Preclinical Promise from Clinical Reality

Ginkgo biloba presents a compelling case study in the complexities of phytopharmaceutical research. Its multifaceted pharmacological profile, encompassing antioxidant, vasoactive, neuro-modulatory, and anti-inflammatory actions, provides a robust preclinical rationale for its therapeutic potential in complex, age-related disorders. This promise, however, has not been consistently translated into definitive clinical benefit.

The clinical evidence is sharply divided. The largest and most methodologically sound trial, the GEM study, provides conclusive evidence that Ginkgo biloba does not prevent the onset of dementia or cognitive decline in older adults. Conversely, a body of evidence from meta-analyses of smaller trials suggests that the standardized extract EGb 761, at a dose of 240 mg/day, may offer a modest palliative or stabilizing effect on cognitive, functional, and behavioral symptoms in patients already diagnosed with dementia. For other conditions, such as tinnitus comorbid with dementia and as an adjunctive therapy in schizophrenia, the evidence is suggestive but not definitive.

Crucially, any discussion of efficacy is predicated on the use of a high-quality, standardized extract. The pervasive issue of adulteration and poor quality control in the dietary supplement market means that the products available to many consumers may lack the necessary composition and potency to confer any of the benefits observed in clinical trials.

8.2. Key Considerations for Clinical Practice and Patient Counseling

For healthcare providers, the evidence supports a cautious and nuanced approach to counseling patients about Ginkgo biloba.

1. Manage Expectations: Patients should be informed that there is strong evidence that Ginkgo biloba is ineffective for preventing dementia. The evidence for treating existing symptoms is inconsistent and the benefits, if any, are modest.
2. Prioritize Safety Assessment: The primary role of the clinician is to conduct a thorough risk assessment. This must begin with a detailed review of the patient's medical history for contraindications, particularly bleeding disorders, seizure history, and planned surgeries.
3. Conduct Medication Reconciliation: Given the extensive and clinically significant potential for drug interactions, a comprehensive medication and supplement review is mandatory. The combination of Ginkgo biloba with anticoagulants, antiplatelet agents, or anti-seizure medications should be strongly discouraged.
4. Guide Product Selection: If a patient makes an informed decision to use Ginkgo biloba, the provider should guide them toward selecting a high-quality product that specifies standardization (24% flavonoid glycosides, 6% terpene lactones) and, if possible, has third-party certification.
5. Warn Against Seed Consumption: Patients must be explicitly warned that Ginkgo seeds are toxic and must never be eaten.

8.3. Future Research Directions

While further large-scale dementia prevention trials with Ginkgo biloba are unlikely given the definitive results of the GEM study, several areas may warrant future investigation. Research could focus on identifying specific patient subgroups who might derive greater benefit, such as those with a prominent vascular component to their cognitive impairment, who may be more responsive to the extract's vasoactive effects. Further well-designed trials are needed to clarify its role as an adjunctive therapy in psychiatric disorders like schizophrenia and depression. Finally, and perhaps most importantly from a public health perspective, greater regulatory oversight and the development of more reliable, accessible methods for ensuring quality control in the dietary supplement industry are urgently needed to protect consumers from adulterated and ineffective products.

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