Ginkgo biloba

Ginkgo biloba is the world's oldest living tree species, having been traced back more than 200 million years. The medicinal use of gingko has its roots in antiquity being mentioned in the oldest Chinese materia medica, dated around 2800 B.C. The leaf is the part of the ginkgo tree from which medicinal extracts are made.

The Ginkgo biloba extract (GBE) marketed in Europe is a well-defined product prepared from the green leaves, containing at least 26 identified components, and standardized to contain 24% flavonoid glycosides (ginkgo flavone glycosides) and 6% terpenoids (ginkgolides and bilobadlide). Extracts identical to this European GBE are available in the United States as food supplements. GBE can be incorporated into liquid or tablet preparations.

More than 400 clinical and experimental studies utilizing Ginkgo biloba extract demonstrate its wide range of beneficial physiological effects. GBE is a powerful antioxidant that prevents free radicals from damaging cellular membranes, an effect that has been found to be especially beneficial in brain and nerve cells. GBE also increase blood flow to the brain, helps normalize circulation by improving the tone of the vascular system, inhibits platelet aggregation, increases the amount of blood flowing to the heart, and improves the hearts ability to contract.

These varied physiological effects support the role of GBE for a variety of conditions, including: inadequate peripheral and cerebral blood flow, memory enhancement, Azheimer's disease, vertigo and equilibrium disorders, tinnitus, cochlear deafness, senile macular degeneration, diabetic retinopathy, intermittent claudication, impotence, premenstrual syndrome, idiopathic cyclic edema, mood elevation, depression, allergies and altitude sickness.

Animal research suggests that GBE is non-mutagenic, non-teratogenic, and that it does not illicit organ damage or impairment of renal or hepatic function. Although gingko seeds, stems and leaves contain 4'-O-methylpyridoxine, which can cause vitamin B6 deficiency symptoms including convulsions, the highest concentration of this toxin found in medical preparations is much lower than the acute oral toxic dose found in animals.

GBE is extremely safe and side-effects are uncommon. In contrast to the lack of side effects from GBE, which is extracted from the leaf, contact with or ingestion of the fruit pulp has produced severe allergic reactions similar to an allergic reaction to the poison ivy-oak-sumac group suggesting cross-reactivity between Ginkgo biloba fruit and this family.

Individuals taking anticoagulant or antiplatelet medication are advised to use caution using gingko. Due to GBE's inhibition of platelet aggregation, patients should discontinue GBE at least 2 weeks before elective surgical procedures. As there is concern that GBE might be associated with seizures in some patients, individuals with seizure disorder and those taking drugs that lower the seizure threshold should avoid ginkgo products until more evidence has been reported. Ginkgo and GBE may be involved in drug/nutrient/herb interactions with the following: aspirin, anticoagulant drugs, insulin, seizure threshold lowering drugs thiazide diuretics, trazodone (Desyrel), and drugs metabolized by CYP450 Enzymes 1A2, 2D6, 3A4.

Typical dosage varies depending upon the form being used and the health care application for which it is being used.

The Ginkgo biloba extract (GBE) marketed in Europe (trade names include Tanakan, Rokan, Ginkgobil, Kaveri, and Tebonin) is a well-defined product prepared from the green leaves, containing at least 26 identified components, and standardized to contain 24% flavonoid glycosides (Ginkgo flavone glycosides) and 6% terpenoids (ginkgolides and bilobadlide). The culturing, harvesting, and extracting techniques are all standardized and necessitate careful control. Extracts identical to this European GBE are available in the United States as food supplements.

The leaf of the ginkgo, from which GBE is produced, contains the following active components:

• ginkgo-flavone glycosides or ginkgo heterosides (flavonoid molecules with sugars attached which are unique to the ginkgo) including quercetin, kaempferol, and isorhamnetine (ginkgo's primary flavonoids), and proanthocyanidins, ginkgo extract is standardized to contain 24% flavonoid glycosides.
• several unique terpene lactone molecules found only in ginkgo (ginkgolides A, C and J, and bilobalide). GBE contains 6% terpenes.
• organic acids, which make ginkgo's otherwise water-insoluble flavonoid and terpene molecules water-soluble.

The total extract has been shown to be more active than single isolated components, suggesting synergistic activity occurs among the various active constituents of GBE.

The world's oldest living tree species and the sole surviving member of the family Ginkgoaceae, the ginkgo tree has been traced back more than 200 million years to fossils of the Permian period, and is often referred to as "the living fossil".

Once common in North America and Europe, the ginkgo was almost destroyed during the Ice Age in all regions of the world except China, where it is has long been cultivated as a sacred tree. The medicinal use of ginkgo can be traced back to the oldest Chinese materia medica (2800 BC) in which ginkgo use for asthma and bronchitis was described. Ginkgo leaves continue to be used in Traditional Chinese Medicine for their ability to "benefit the brain", for symptom relief of asthma and coughs, and to help the body eliminate filaria.

In the late 17th century, Engelbert Kaempfer, a German physician and botanist for whom ginkgo's flavonoid maempferol is named, became the first European to discover and catalog the ginkgo tree.

In 1771, Linnaeus named the tree Ginkgo biloba.

In 1784, the ginkgo tree was brought to America to the garden of William Hamilton near Philadelphia, and today, the ginkgo is planted throughout the US as an ornamental tree. Because of its hardiness and resistance to insects, disease and pollution, the ginkgo is frequently planted along city streets.

In 1989, over 100,000 physicians worldwide wrote over 10,000,000 prescriptions for GBE. Ginkgo leaf extracts are among the leading prescription medicines in both Germany and France, where they account for 1 and 1.5%, respectively, of total prescription sales. In Germany, ginkgo is the most frequently prescribed herbal medicine and the preferred treatment for dementia. Currently in the U.S., The National Center for Complementary and Alternative Medicine (NCCAM) is beginning studies evaluating the effects of GBE on asthma, intermittent claudication, peripheral vascular disease, multiple sclerosis, memory disorders, dementia and Alzheimer's disease. The dementia and Alzheimer's disease trial (the largest study to date on dementia) will be a 5-year study of 3,000 people aged 75 and older to determine if GBE (240mg per day) can help prevent dementia or Alzheimer's disease.

More than 400 clinical and experimental studies utilizing GBE extract demonstrate its wide range of beneficial physiological effects. GBE exerts significant membrane-stabilizing, antioxidant, and free radical-scavenging effects; plus, ginkgo enhances cellular utilization of oxygen and glucose.

Cell Membrane Protection and Stabilization

The cell's membranes are its gatekeepers, providing the first line of defense in maintaining cellular integrity and also serving as fluid barriers, exchange sites, and electrical capacitors. Because they are largely composed of fatty acids (phospholipids), cellular membranes are vulnerable to damage, especially the lipid peroxidation caused by reactive oxygen species. GBEs antioxidant action very effectively prevents lipid peroxidation of cellular membranes.

In addition to directly stabilizing membrane structures and scavenging free radicals, GBE also activates the sodium pump, thus enhancing membrane transport of potassium into and sodium out of the cell, which improves membrane polarization. GBE's effects on membrane polarization are particularly beneficial in excitable tissues like nerve cells.

Nerve cell effects

GBE's membrane-stabilizing and free radical-scavenging effects are perhaps most beneficial in brain and nerve cells. Brain cells contain the highest percentage of unsaturated fatty acids in their membranes of any cells in the body and are therefore at high risk of free radical damage. The brain cell is also highly susceptible to damage from hypoxia since, unlike most tissues, the brain has very little energy reserve, yet constantly requires large amounts of energy. Diminished circulation to the brain compromises the continual supply of glucose and oxygen upon which the brain relies, setting off a chain of reactions that disrupt membrane function and energy production and, if not halted, ultimately lead to cellular death.

In experimental models of cerebral ischemia, GBE enhances oxygen utilization and increases cellular uptake of glucose, thus restoring energy production and preventing metabolic and neuronal disturbances. In addition to the above beneficial metabolic effects, GBE re-establishes effective tissue perfusion, normalizing circulation in the areas most affected by microembolization: the hippocampus (the area of the brain most affected by Alzheimer's disease) and striatum. GBE also promotes increased nerve transmission rate, improves synthesis and turnover of brain neurotransmitters, and normalizes acetylcholine receptors in the hippocampus.

Improved Blood Flow to the Brain

GBE has been shown to increase blood flow to the brain in more than 40 double-blind studies. GBE has demonstrated effectiveness comparable to FDA-approved drugs used in the treatment of cerebral vascular insufficiency and Alzheimers disease. In addition to increasing blood flow to the brain, and therefore oxygen and glucose utilization by brain cells, GBE has also been shown to reduce blood viscosity, thus offering additional protection against stroke. These beneficial effects of GBE have been demonstrated even in post-stroke patients.

Vascular effects

GBE exerts its vascular effects primarily via its actions on the vascular endothelium and the system that regulates blood vessel tone. GBE directly stimulates the release of endothelium-derived relaxing factor (EDRF) and prostacyclin (a beneficial prostaglandin), thus causing vasodilation. In addition, GBE inhibits an enzyme that triggers vascular constriction, thus further promoting relaxation of the blood vessel. GBE also stimulates greater venous tone, promoting the clearance of toxic metabolites that accumulate during ischemia.

GBE normalizes circulation by producing tonic effects on vascular components, many of which are still largely unexplained. What is evident, however, is that GBE can combat the sequelae resulting from vascular spasm, while simultaneously restoring circulation to areas subject to vasomotor paralysis. GBE's multiple actions are particularly relevant in cerebral insufficiency, as single direction drugs, e.g., vasodilators, often aggravate this condition by preferentially dilating the healthy areas, which deflects blood and oxygen away from the ischemic area.

Platelet effects

GBE and isolated ginkgolides have been shown to inhibit platelet aggregation, adhesion, and degranulation and to improve cardiac contractility and coronary blood flow. These actions appear to be due to ginkgo's direct membrane and antioxidant effects, increased synthesis of prostacyclin, and inhibition of platelet activating factor (PAF). PAF is a potent stimulator of platelet degranulation that is involved in many inflammatory and allergic processes, including neutrophil activation, increasing vascular permeability, smooth muscle contraction including bronchoconstriction, and reduction in coronary blood flow. GBE and the ginkgolides compete with PAF for binding sites, thus inhibiting PAF-induced events including platelet aggregation, phagocyte chemotaxis, smooth muscle contraction, degranulation of neutrophils, free radical production, damaging glycine production after brain injury, excitatory amino acid receptor activity. Despite its inhibition of PAF, GBE does not inhibit beneficial platelet aggregation in humans.

Peripheral and Cerebral Vascular Insufficiency

GBE has primarily been used in the treatment of vascular insufficiency. Patients with peripheral arterial insufficiency and chronic cerebral arterial insufficiency have responded favorably to GBE in more than 50 clinical trials.

GBE improves blood flow to the arms, legs, fingers and toes, and has been of significant benefit in peripheral vascular disease due to diabetes. GBE appears to improve blood flow to capillaries throughout the body including the CNS, eyes, ears, and extremities, most likely by both decreasing blood viscosity and balancing vascular smooth muscle tone. GBE improves vasoregulation by restoring the balance between prostacyclin and thromboxane A2. In addition, GBE inhibits type 4 phosphodiesterase, resulting in increased cAMP levels and release of catecholamines. The adaptogenic result is a relaxation of spasmodic contracting vasculature along with a contraction of abnormally dilated vessels.

Cerebral vascular insufficiency is extremely common in the elderly of developed countries (most likely because of the high incidence of atherosclerosis) and may be a major causative factor in a variety of so-called "age-related cerebral disorders" including: short-term memory loss, vertigo, headache, ringing in the ears, lack of vigilance, and depression. In well-designed studies, GBE has produced a statistically significant regression of all of these symptoms.

A comprehensive review on the quality of research in over 40 clinical studies of GBE in the treatment of cerebral insufficiency found that GBE is effective in reducing all symptoms of cerebral insufficiency, including impaired mental function (senility), and that the quality of research was comparable to that done on Hydergine (dihydroergotamine), an FDA-approved drug used in the treatment of cerebral vascular insufficiency and Alzheimer's disease.

By increasing cerebral blood flow, and therefore oxygen and glucose utilization, GBE may not only provide relief of the impaired mental function that is presumed to be a "side-effect" of aging, but may offer significant protection against its development. GBE's inhibition of PAF offers additional protection against stroke by preventing excessive platelet aggregation. Even in post-stroke patients, GBE has been shown to improve cerebral blood flow and viscosity.

Memory Enhancement

In addition to improving blood flow to the brain, GBE increases the rate at which information is transmitted at the nerve cell level and has been shown to enhance memory in young as well as elderly subjects. In one double-blind study, after GBE administration, the reaction time of healthy young women performing a memory test improved significantly.

Alzheimer's Disease

In addition to GBE's ability to increase the functional capacity of the brain, it has been shown to normalize the acetylcholine receptor in the hippocampus of aged animals, increase cholinergic transmission, and to combat other major elements of Alzheimer's disease. It has been suggested that GBE inhibits catechol-O-methyl-transferase (COMT, an enzyme that breaks down adrenergic transmitters) and increases the number of alpha-adrenoreceptors in the brain, which would help reverse the decline in brain alpha-adrenoreceptor activity that occurs with aging. A recent in vitro study found that GBE protects hippocampal neurons against cell death induced by beta-amyloid (an abnormal protein thought to be toxic to neurons and found in the plaques that form in the brains of individuals with Alzheimer's).

Currently, studies show that GBE helps to reverse or delay mental deterioration in the early stages of Alzheimer's disease. In a double-blind clinical study of patients given GBE, results on standard tests including the SKT, Sandoz Clinical Assessment Geriatric Scale, and EEG, all improved, usually in the first month, compared with the placebo. Not only was GBE well tolerated (no side effects were noted), but the longer GBE was used, the more obvious its benefits became.

In addition, to offering benefit in early-stage Alzheimer's disease, if the mental deficit is due, not to Alzheimer's disease, but to vascular insufficiency or depression, GBE is typically effective in reversing the deficit.

Vertigo and Equilibrium Disorders

GBE has been shown to be significantly more effective than placebo and possible as effective as the drug, betahistine, in the treatment of vertigo and dizziness caused by vascular disorders. Some evidence suggests that a higher dose (240mg per day) may be more beneficial than the typical (120mg per day) dose.

Tinnitus

GBE has been found to be quite effective in improving the condition of patients with recent onset tinnitus, regardless of prognostic factor, but less effective in patients with long term (3 years or more) severe tinnitus. However, in recent studies in which GBE was not found effective, its lack of benefit may have been due to flaws in study design. In the most recent study, the dosage (14.6mg twice daily or 29.2mg per day) was insufficient; the standard dosage of GBE is 40mg three times daily or roughly four times the dosage used in the study. Secondly, studies of patients with cerebral vascular insufficiency have firmly established that GBE typically takes a minimum of 2 weeks before benefit begins to manifest, and the longer that GBE is used, the more obvious its benefit. Particularly given the severity of permanent severe tinnitus, the amount of time GBE was administered in the study (24 weeks) is not an adequate amount of time to evaluate potential benefit. Combined with the fact that the dosage given was way too low, all this study shows is that GBE's potential benefit in permanent severe tinnitus remains to be determined. GBE's excellent safety profile and known beneficial effects, its use should certainly be considered in this condition.

Cochlear Deafness

GBE has been shown to improve recovery in cases of acute cochlear deafness due to unknown factors or due to sound trauma or pressure (barotrauma). Since ischemia is usually the underlying factor in acute cochlear deafness, GBEs effectiveness is most likely due to its beneficial effects on blood flow and cellular utilization of oxygen and glucose.

Senile Macular Degeneration and Diabetic Retinopathy

In double-blind studies, GBE has demonstrated a statistically significant improvement in long-distance visual acuity in both macular degeneration and diabetic retinopathy. In human experimental studies, GBE has demonstrated significant protective effects against free radical damage to the retina. In diabetic rats, GBE been shown to prevent diabetic retinopathy, suggesting it may exert protective effects in human diabetics as well.

Peripheral Arterial Insufficiency

In peripheral arterial disease, cholesterol-containing plaque is a primary contributing factor as it is in other conditions associated with atherosclerosis, e.g., coronary artery disease and cerebral vascular insufficiency. The plaque obstructs and narrows the artery, causing a reduction in blood flow. Clinical symptoms are the result of the consequent ischemia.

Intermittent claudication-pain upon exertion-is the most common symptom of peripheral arterial disease. Pain typically occurs bilaterally in the calves and is described as a cramp or tightness or severe fatigue. Pain is caused not only by reduced oxygen delivery, but also by increased production and accumulation of toxic metabolites and cellular free radicals. These free radicals accumulate and react with the lipid constituents of the cell membrane. Pain at rest indicates significant reduction in resting blood flow and signals severe disease.

The standard medical approach to peripheral vascular disease and intermittent claudication includes avoidance of tobacco (which causes vasoconstriction), a regular exercise program consisting of walking, and/or a prescription for pentoxifylline (Trental).

Seventeen placebo-controlled trials have shown that Trental will prolong the total and pain-free walking distance in patients with intermittent claudication; however, the level of improvement (approximately 65% for pain-free walking distance) is less than that achieved with exercise or with GBE.

In nine double-blind randomized clinical trials of GBE versus placebo in two matched groups of patients with peripheral arterial insufficiency of the leg, not only were measurements of pain-free walking distance (75-110%) and maximum walking distance (52.6-119%) dramatically increased, but plethysmographic and Doppler ultrasound measurements also demonstrated increased blood flow through the affected limb, and blood lactate levels also dropped. The demonstration that Ginkgo biloba extract improves limb blood flow as well as improved walking tolerance indicates that GBE is far superior to pentoxifylline and standard medical therapy in peripheral arterial insufficiency, including other peripheral vascular disorders such as diabetic peripheral vascular disease, Raynauds syndrome, acrocyanosis, and post-phlebitis syndrome.

The longer the period over which GBE is used, the greater is the benefit. In a 2 year trial of GBE (160mg/day) in the treatment of peripheral arterial disease (Fontaine's stage IIb), pain-free walking distance increased by 300%.

Impotence

GBE may be extremely beneficial in the treatment of erectile dysfunction due to lack of blood flow, the cause of most cases of impotence (erectile dysfunction). GBE is also used to treat sexual dysfunction caused by SSRI antidepressants. GBE's beneficial effects are likely due to GBE's enhancement of blood flow through both arteries and veins without any change in systemic blood pressure.

In a study of 60 patients with proven erectile dysfunction who had not reacted to papaverine injections up to 50mg, GBE (60mg/day) was given and penile blood flow was re-evaluated by duplex sonography every 4 weeks. Signs of improved blood supply were seen after 6-8 weeks. After 6 months' therapy, 50% of the patients had regained potency. In the remaining 30 patients, a new trial of papaverine injection was then successful in 20%; 25% of the patients showed an improved blood flow, but papaverine was still not successful; and the remaining 5% were unchanged. In these patients, better results might have been obtained with a 120mg/day dose.

Premenstrual Syndrome and Idiopathic Cyclic Edema

In a recent double-blind placebo controlled study, 165 women between the ages of 18 and 45 years who had suffered from congestive symptoms (fluid retention, vascular congestion, increased capillary permeability and breast tenderness), for at least three cycles were given either the GBE (80mg twice daily) or placebo from the 16th day of the period to 5th day of the next. GBE was found to be effective not only against the congestive symptoms of PMS, particularly breast pain or tenderness, but also resulted in improvements in neuropsychological assessments.

Depression

GBE's ability to improve general mood in patients suffering from cerebral vascular insufficiency has led to a study investigating the antidepressive effects of GBE. A recent double blind study suggests that GBE can be used with standard antidepressants and may enhance their effectiveness, particularly in patients over 50 years of age.

In this study of 40 elderly patients (age range, 51-78 years) with depression who had not benefited fully from standard antidepressant drugs, patients were given either 80mg of GBE three times daily ( a dosage twice as high as the standard dosage of 40mg, three times daily) or a placebo. After 8 weeks, the total score of the Hamilton Rating Scale for Depression in the Ginkgo biloba extract group dropped from 14 to 4.5. In comparison, the placebo group score dropped only one point, from 14 to 13.

Allergies

Due to their inhibition of platelet activating factor (PAF) - a key chemical mediator in asthma, inflammation, and allergies-mixtures of ginkgolides as well as GBE (standardized to contain 24% ginkgoflavonglycosides) have shown beneficial clinical effects in allergic conditions.

One double-blind placebo-controlled study investigated the ability of a mixture of ginkolides to block the effects of PAF injected into the skin. Normally, when injected, PAF causes immediate formation of a hive (classic wheal and flare reaction). When the ginkgolide mixture (120 mg) was given prior to PAF injection, the flare (reddened) area was reduced by a mean of 62.4% and the wheal (hive) volume by a mean of 60%.

Altitude Sickness

GBE (80mg, twice daily) has been shown to significantly reduce symptoms of altitude sickness including headache, fatigue, nausea, dyspnea, and vomiting. GBE also appears to improve cold tolerance.

Ginkgo biloba extract (GBE) prepared from the green leaves, containing at least 26 identified components, and standardized to contain 24% flavonoid glycosides (ginkgo flavone glycosides) and 6% terpenoids (ginkgolides and bilobadlide). GBE can be incorporated into liquids or tablets.

• Aspirin: GBE may induce spontaneous bleeding when combined with chronic use of aspirin. Increased bleeding potential reported after Ginkgo biloba usage in a chronic user (2-years) of aspirin. The GBE constituent, ginkgolide B, displaces platelet-activating factor from its binding sites, decreasing blood coagulation.
• Anticoagulant drugs: Theoretically, other chronically used anticoagulant drugs might induce spontaneous bleeding when combined with GBE. Anticoagulant drugs include dalteparin (Fragmin), enoxaparin (Lovenox), heparin, indomethacoin (Indocin), ticlopidine (Ticlid), and warfarin (Coumadin).
• Insulin: GBE enhances cellular utlilzation of oxygen and glucose and has been reported to increase pancreatic beta-cell function in response to glucose. GBE may also increase metabolic clearance of insulin. In diet-controlled NIDDM patients, GBE produced no significant effect on insulin levels, whereas in hyperinsulinemic NIDDM patients taking oral hypoglycemic medications, GBE ingestion increased the hepatic metabolic clearance rate of not only insulin but also the hypoglycemic agents, resulting in reduced insulin-mediated glucose metabolism and elevated blood glucose. People taking insulin should therefore monitor glucose levels closely if using GBE since insulin dose adjustments may be necessary.
• Seizure Threshold Lowering Drugs: Anecdotal reports of seizure after use of ginkgo leaf in patients with previously well-controlled epilepsy and in patients with no prior history of seizure suggest a theoretical risk to patients taking drugs that lower seizure threshold including anesthetics (e.g., propofol), antiarrhythmics (e.g., mexiletine), antibiotics (e.g., amphotericin, penicillin, cepahlosporins, mimpenem), antidepressants (e.g., bupropion), antihistamines (e.g., cypropheptadine), immunosuppressants (e.g., cyclosporine), narcotics (e.g., fentanyl), stimulants (e.g., methyphenidate), theophylline, and others.
• Thiazide Diuretics: GBE can increase blood pressure when used with thiazide diuretics.
• Trazodone (Desyrel): In one patient with Alzheimers, coma was induced after taking trazodone (20mg twice daily) and GBE (80mg twice daily). Coma was reversed by administration of flumazenil (Romazicon). Ginkgo flavonoids stimulate GABA and directly act on benzodiazepine receptors, thus supplementation with GBE might induce excessive GABA-ergic activity. GBE might also increase metabolism of trazodone to active GABA-ergic metabolites by inducing cytochrome P450 3A4 metabolism.
• Possible Slight Increase of Levels of Drugs Metabolized by CYP450 Enzymes 1A2, 2D6, 3A4: GBE mildly inhibits CYP1A2 and CYP2D6 and might therefore slightly increase levels of drugs metabolized by these enzymes. Evidence is conflicting as to whether GBE induces or inhibits CYP3A4. Drugs metabolized by CYP1A2 include acetaminophen (Tylenol), amitriptyline (Elavil), clopidogrel (Plavix), clozapine (Clozaril), diazepam (Valium), estradiol, olanzapine (Zyprexa), ondansetron (Zofran), propranolol (Inderal), ropinirole (Requip), tacrine (Cognex), theophylline, verapamil (Calan, Covera-HS, Isoptin, Verelan), warfarin (Coumadin). Drugs metabolized by CYP2D6 include amitriptyline (Elavil), clozapine (Clorazil), codeine, desipramine (Norpramin), donepezil (Aricept), fentanyl (Duragesic), flecainide (Tambocor), fluoxetine (Prozac), meperidine (Demerol), methadone (Dolophine), metoprolol (Lopressor, Toprol XL), olanzapine (Zyprexa), ondansetron (Zofran), tramadol (Ultram), trazodone (Deseryl). Drugs metabolized by CYP450 3A4 include lovastatin (Mevacor), ketoconazole (Nizoral), itraconazole (Sporanox), fexofenadine (Allegra), triazolam (Halcion).

• Chronic toxicity studies in mice (27 weeks at an initial dose of 20 and 100mg/kg/day and gradually increasing to 400 and 500mg/kg/day) found no evidence of organ damage and no impairment of hepatic or renal function.
• Oral administration of 900 and 1600mg/kg/day to rabbits and rats, respectively, did not elicit teratogenic effects or affect reproduction.Assays (in vitro and in vivo)found GBE posessed no mutagenic activity.
• The seeds, stems and leaves of ginkgo contain 4'-O-methylpyroxidine, which can cause symptoms of vitamin B6 deficiency, including convulsions. This toxic compound has been measured at levels of 42mcg per gram of fresh weight ginkgo stem. Prior to 1960 in China and Japan, where the stems are eaten as a luxury food or in times of food shortage, poisoning has occured. A daily dose of the medicinal preparations tested showed a maximum concentration of 4'-O-methylpyroxidine of 60mcg, a small amount in contrast to the acute oral toxic dose in guinea pigs, which was measured at 11g/kg. In addition, the presence in ginkgo of bilobalide decreases the severity of convulsions.Ingestion of ginkgo extracts and seeds is unlikely to cause adverse effects; however, ingestion of ginkgo seed should be limited, especially in children.

• Bleeding disorders: Ginkgo inhibits platelet-activating factor, thus decreasing platelet aggregation, and could exacerbate bleeding disorders. Use with caution in individuals with bleeding disorders.
• Anticoagulant or antiplatelet medication: Persons taking blood-thining medications such as warfarin or aspirin should use ginkgo with caution due to its blood-thinning effects.
• Surgery: Ginkgo biloba extract's anticoagulant effects could result in excessive bleeding. Ginkgo should be discontinued at least 2 weeks prior to any elective surgical procedure.
• Diabetes: Ginkgo has been shown to increase pancreatic beta-cell function in response to glucose and may increase metabolic clearance of insulin. Blood levels should be monitored closely since diabetes medications may require adjustment.