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  Vol. V, No. V
  September/October 2002

  Andreea Popa, Pharm.D.

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Ginkgo Biloba and Memory

Memory Disorders:

Complaints of declining memory are common with advancing age. Memory disorders are associated with difficulty in learning and retaining new information. Dementia is defined as an insidious decline in a number of mental functions resulting in the loss of personal and social independence in a previously competent individual. Even though the most common component of dementia is memory loss, isolated defects in memory or in language do not qualify as dementia, which is usually associated with defective reasoning, decision making and judgment.

Dementia occurs when several of the cerebral systems that support learning, memory, language, emotion and reason are dysfunctional. Dementia can be self-limited (e.g., damage from head trauma or cardiac arrest) or progressive (e.g., dementia associated with Alzheimer's Disease).

Epidemiological studies indicate that approximately 15% of patients greater than 65 years old suffer from some form of dementia, while the incidence increases to 23% in patients 75 to 84 years old and 48% in patients greater than 85 years old. Objective assessment of memory loss and cognitive impairment is done by using neuropsychological testing (See Table 1).

Interventions to Improve Memory:

For Alzheimer's Disease associated memory loss cholinesterase inhibitors, such as tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®) and galantamine (Reminyl®), have been beneficial. Vitamin E, estrogen, non-steroidal anti-inflammatory drugs (NSAIDs) and Ginkgo biloba are also used to slow down the progression of memory loss in these patients. Supportive measures, such as orientation reinforcement to areas where memory loss is observed, and treatment of associated depression, anxiety, sleep disorders or other related conditions is also recommended.

This article will describe the chemical composition, active ingredients, pharmacological properties, adverse reactions, drug interactions, and dosing of Ginkgo biloba leaf extract. Additionally, this article will review some of the trials evaluating the use of Ginkgo biloba specifically for memory impairment or improvement.

Ginkgo Biloba
Background: Ginkgo biloba is obtained from the Ginkgo biloba Linne tree. Threatened with extinction during the ice age, the ginkgo tree survived in China, and it is believed to be the oldest living tree species. The ginkgo tree has been introduced in Europe and North America as an ornamental tree, and it can be found along city streets and in parks. Ginkgo biloba is one of the most widely used and studied herbal products, and in Germany and China, it is the most commonly prescribed herbal medication. Because of the Dietary Supplement Health and Education Act of 1994, the United States Food and Drug Administration (FDA) does not regulate dietary supplements, including herbs, for safety or efficacy. Therefore, unlike prescription and non-prescription drugs approved by the FDA, there is no guarantee of strength, purity or safety of dietary supplements that contain Ginkgo biloba.

Chemical Composition: Ginkgo biloba leaf extract contains flavonol and flavone glycosides, lactone derivatives (ginkgolides), bilobalide, ascorbic acid, catechin, iron-based superoxide, 6-hydroxykinuretic acid, protocatechuic acid, shikimic acid, sterols and vanilic acid. The major classes of active ingredients are the ginkgolides and bilobalides (also known as terpenes) and the flavonoids. The ginkgo seeds contain a potentially toxic substance, ginkgotoxin (4-O-methoxypyridoxine), which has anti-vitamin B6 activity and inhibits GABA formation, which can potentially lead to convulsions and loss of consciousness. The ginkgo tree roots have a greater concentration of the active ingredients. Commercial manufacturers use the Ginkgo biloba leaves to extract the active ingredients. The standardization of Ginkgo biloba leaf extract products is done by the active ingredients: flavones, ginkgolides and bilobalides.

Pharmacology: Even though the chemical components of the ginkgo leaf have distinctive intrinsic pharmacological properties, they work synergistically to produce more potent pharmacological effects (See Table 2). For example, the ginkgo leaf extract protects the neurons from oxidative damage potentially preventing the progression of tissue degeneration in patients with dementia. Additionally, Ginkgo biloba leaf extract improves blood flow throughout the body, and it restores the balance between prostacyclin and thromboxane A2 resulting in improved vasoregulation. Vascular contraction and improvement in the venous tone are thought to be the result of phosphodiesterase inhibition and release of catecholamines. The beneficial effects of Ginkgo biloba leaf extract in Alzheimer's Disease might also be due to the inhibition of toxicity and cell death induced by beta-amyloid peptides. It has been proposed that Ginkgo biloba leaf extract 1) inhibits monoamine oxidase A and B, 2) inhibits catechol-O-methyl transferase (an enzyme that breaks down adrenergic transmitters), and 3) increases the number of alpha-adrenoreceptors in the brain as there is a decline in alpha-adrenoreceptors with age.

Other proposed mechanisms of action for the Ginkgo biloba leaf extract include possible effects on the benzodiazepine receptors, a possible decrease in glucocorticoid biosynthesis, and a possible increase in pancreatic beta-cell function in response to glucose loading. The pharmacological properties of the Ginkgo biloba seeds are the result of cyanogenic glycosides and ginkgotoxins. The cyanogenic glycosides have antibacterial and antifungal effects, while the ginkgotoxins can cause seizures, loss of consciousness and even death.

Reported Uses: Since ancient times, Ginkgo biloba has been used for medicinal purposes. In the oldest Chinese Materia Medica (2800 B.C.), Ginkgo biloba was recommended for asthma, swelling of the hands and feet, coughs, vascular disorders, aging and for the brain. Since 1965, Gingko biloba has been used in Europe for the treatment of cerebral insufficiency and peripheral vascular disease. See Table 3 for the reported uses of Ginkgo biloba.

Clinical Efficacy: Ginkgo biloba has been clinically studied for the following conditions: peripheral vascular disease, claudication, dementia, cerebral insufficiency, ischemic stroke, tinnitus, memory impairment, asthma, and vertigo.

Ginkgo biloba leaf extract is possibly effective when used for Alzheimer's vascular or mixed dementia. Studies report that Ginkgo biloba leaf extract can stabilize or improve several measures of cognitive function and social functioning. Outcome studies have not yet verified Ginkgo's effect on disease progression, and it has not been directly compared to conventional dementia treatment. Clinical improvements in patients treated with Ginkgo biloba leaf extract appear to be similar to clinical improvement in patients treated with donepezil and tacrine. German practitioners consider Ginkgo biloba leaf extract to be the treatment of choice for dementia and for age-related memory dysfunction.

The role of Ginkgo biloba leaf extract in memory impairment will be discussed later in the article.

Ginkgo biloba leaf extract increases pain-free walking in patients with intermittent claudication and in patients with Fontaine's IIb peripheral arterial occlusive disease. Ginkgo biloba leaf extract was also found to be more effective than placebo when used for vertigo and equilibrium disorders. Some evidence suggests that Ginkgo biloba leaf extract can help breast tenderness and neuropsychological symptoms associated with pre-menstrual syndrome. Limited evidence suggests that treatment with Ginkgo biloba leaf extract can improve color vision in patients with diabetic retinopathy. Finally, clinical studies suggest that Ginkgo biloba leaf extract is possibly ineffective when used for tinnitus and prevention of winter depression in patients with seasonal affective disorder.

Adverse Effects: Orally at typical doses Ginkgo biloba leaf extract can cause mild gastrointestinal upset, headache, dizziness, palpitations, constipation and allergic skin reactions. Larger doses can cause restlessness, diarrhea, nausea, vomiting, and weakness. Other adverse effects are listed in Table 4. Spontaneous bleeding is a serious, potential adverse effect.

Contraindications: Ginkgo biloba is contraindicated in patients with a history of hypersensitivity to Ginkgo preparations. Due to insufficient information, the use of Ginkgo biloba leaf extract in pregnancy and lactation is not recommended. Even though there are not enough data to support that a Ginkgo biloba leaf product was the main cause of seizures in several anecdotal reports, it is recommended to avoid these products in patients with a history of seizures. Ginkgo biloba leaf products should be discontinued at least two weeks prior to elective surgery procedures due to the potential for an increased risk of bleeding.

Drug Interactions: In vitro evidence suggests that Ginkgo biloba leaf extract can inhibit the cytochrome P450 1A2 activity by 13% and 2D6 activity by 9%. Anecdotal evidence suggests that Ginkgo biloba leaf extract might also be an inhibitor and an inducer of 3A4 activity. However, based on current reports, the effects on the cytochrome P450 enzymes are not likely to lead to clinically significant drug interactions. It is important to note that there is the potential for an increased risk of bleeding when Ginkgo biloba is used concurrently with antiplatelet agents [e.g., aspirin, clopidogrel (Plavix®)], anticoagulants [e.g., warfarin (Coumadin®), enoxaparin (Lovenox®), heparin] or herbs with coumarin constituents (e.g., angelica, anise, capsicum, celery, chamomile, clove, danshen, garlic, ginger, horseradish, licorice, onion, papain, red clover).

Hypomania has been reported in patients with depression when Ginkgo leaf extract was used in combination with fluoxetine (Prozac®)/buspirone (BuSpar®), St. John's wort, and melatonin. It is not known whether Ginkgo leaf extract in combination with either fluoxetine alone or buspirone alone can cause hypomania. Ginkgo leaf extract also has the potential to amplify the activity of monoamine oxidase inhibitors, however this effect has not been confirmed in humans.

Due to the fact that Ginkgo leaf extract can alter insulin secretion, patients taking insulin should monitor glucose levels closely. Additionally, due to the anecdotal reports of seizures associated with Ginkgo biloba leaf extract use, patients taking medications known to lower the seizure threshold should avoid the use of Ginkgo leaf products. Some medications known to lower seizure threshold include: propofol (Diprivan®), mexiletine (Mexitil®), amphotericin B (Fungizone®), penicillins, cephalosporins, imipenem/cilastatin (Primaxin®), bupropion (Wellbutrin®), cyclosporine (Neoral®), fentanyl (Sublimaze®), methylphenidate, and theophylline.

Dose and Administration: The Gingko leaf product is produced from green, picked leaves grown on plantaDose and Administration: The Gingko leaf product is produced from green, picked leaves grown on plantations specifically developed for pharmaceutical purposes. Gingko biloba leaf extract is available in various formulations (e.g., capsules, tablets, concentrated liquids, sublingual sprays, bars and cola drinks), as well as many combination products. Standardized products can contain 24% of flavone glycosides and 6% terpenes (ginkgolides and bilobalides). The products most commonly used in clinical trials are Ginkgo biloba standardized leaf extracts EGb 761 (Tanakan) and LI 1370 (Lichewer Pharma) and are available in the United States. Products with similar ingredients include Ginkai® (Lichtwer Pharma), Ginkgo 5®(Pharmline), Ginkgold® and Ginkgo® (Nature's Way), and Quanterra Mental Sharpness (Warner-Lambert).

The recommended dose of Ginkgo biloba is 40 mg three times a day administered orally, but the daily dose can range from 120 to 600 mg depending on the disorder being treated. The majority of Ginkgo biloba products claim that a minimum of four weeks is required to achieve enhancement of mental focus and improvement of memory and concentration in patients with or without clinically significant cognitive impairments. There are a variety of examples of marketed products specifically for memory enhancement including, Quanterra Mental Status Sharpness®, One-A-Day Memory and Concentration®, AIM GinkgoSense®, and the Ultimate Memory Formula®. The average price of these products is $30.00 for 30 tablets.

Ginkgo biloba for Memory Impairment: In the German Commission E Monograph, Ginkgo biloba is approved for symptomatic treatment of deficits in memory impairment, concentration difficulties and depression from organic brain disease.

Numerous trials have been conducted using standardized Ginkgo biloba extract (GBE) for treatment of dementia syndromes and memory impairment (See Table 5). Several Ginkgo biloba single-dose trials have been conducted to assess its effect on short-term memory. These trials were small, used various doses of Ginkgo biloba, and involved healthy volunteers or elderly patients with mild memory impairment. The studies that reported beneficial effects associated with Ginkgo biloba leaf extract were small uncontrolled studies and have found benefit in one of many cognitive tests administered. The trials that compare Ginkgo biloba to placebo use an array of doses (120 to 240 mg daily), lengths of therapy (6 to 52 weeks), age groups, and disease severity (healthy adults to Alzheimer's Disease patients). The neuropsychological outcome measured varied between studies, and there was no clear pattern of benefit for Ginkgo biloba-treated patients. Additionally, a recent trial by Solomon and colleagues, assessing the use of Ginkgo biloba for memory impairment in a healthy elderly population failed to show any benefit. Clinical trials evaluating the efficacy of Ginkgo biloba in Alzheimer's Disease patients report some benefits. A recent trial that assessed the effectiveness of Ginkgo biloba leaf extract in patients with Alzheimer's Disease or multi-infarct dementia reported a 1.4-point decline on the ADAS-Cog scale (Alzheimer's Disease Assessment Scale-Cognitive) in the placebo group, compared to a slight improvement in the Ginkgo group. Currently, a multicenter, clinical trial is assessing elderly patients (median age of 80 years) comparing Ginkgo biloba 240 mg administered orally once daily and placebo for six years. The primary endpoint is incidence of dementia and secondary endpoints include incidence of Alzheimer's Disease, incidence of vascular dementia, changes in cognitive function scores over time, and changes in functional status.

Summary: Despite the lack of well-controlled studies to support the use of Ginkgo biloba leaf extract for prevention and treatment of memory impairment, ginkgo products continue to be heavily marketed and widely used. In 1997, sales of Ginkgo leaf extract products reached $240 million in the United States. In Germany, more than 5 million Ginkgo prescriptions are written for the treatment of dementia, cerebral decline and peripheral arterial insufficiency. A recent summary on the patterns of medication use in the ambulatory adult population in the United States reports that Ginkgo biloba leaf extract was the second most used herbal/dietary supplement. The age group with the highest Ginkgo usage was 45 to 65 year old men and women. The use of Ginkgo biloba leaf extract for memory impairment is marketed and targeted at the healthy adult that experiences forgetfulness. Currently, the claims that Ginkgo biloba has beneficial effects on learning and memory are not supported by the literature. Ginkgo biloba extract was found to stabilize or improve several measures of cognitive function and social functioning in Alzheimer's Disease, vascular or mixed dementia patients. Ginkgo biloba standardized leaf extract products that have been used in clinical trials varied and not all studies tested the product quality. The use of Ginkgo biloba leaf extract should be monitored for drug interactions, and it should not be used in patients with a history of seizures or during pregnancy and breast-feeding. Spontaneous bleeding is a serious adverse effect, therefore, Ginkgo biloba leaf extract products should not be used in patients with a high risk for bleeding.

References available upon request