By Georges Ramalanjaona MD, DSc, MBA, FACEP
Ginkgo biloba (GB) is one of the most studied and commonly used herbal remedies, with U.S. sales reaching $240 million annually.
Since our last publication on this topic in 1998, recent reports in peer-reviewed journals have shown conflicting results on GB’s ability to enhance memory.1-3
We present an update on the findings of these recent trials and recommend the cautious use of GB in selected patients based on these studies.
Because Ginkgo biloba extracts (GBE) are composed of many active ingredients, it is difficult to define the pharmacokinetics of each component. Many studies have utilized the extract called EGb 761, containing 24% flavone glycosides and 6% terpenoids.
More than 60% of the extract is absorbed in the stomach and small intestines; the rest is absorbed in neuronal and glandular tissues and the eyes. Elimination occurs mainly in the feces (29%) and urine (22%) and the remaining through exhaled air.4
Mechanism of Action
The acute chemical compounds found in ginkgo leaf are too diluted to have any pharmacological effect. Thus, standardized extracts concentrate them by processing 50 pounds of leaves into one pound of extract (50:1 ratio).
GB’s pharmacological effects are due to two main groups of active constituents that are present in various concentrates in the leaf of GB.5 These two groups include flavonoids and terpenes: Forty different flavonoid and three main terpene groups have been isolated, including ginkgolides A, B, and C.
GBE has known bioactive properties. Flavone glycosides display antioxidant properties, inhibit platelet aggregation, and act as scavengers for free radicals that are mediators of the lipid peroxidation and cell destruction found in Alzheimer’s disease.6 Terpene lactones inhibit the binding of platelet-activating factor (PAF) to its membrane receptor in animal studies. Biological activities of PAF include induction of platelet aggregation and oxygen free radical production leading to increased microvascular permeability.
Few well controlled studies exist of the effect of GB on memory. The most recent and significant trials that provide level of evidence I on a scale of I to III are summarized in Table 1.
Rigney et al investigated the effects of GBE in a randomized, double-blind, placebo-controlled, five-way crossover design.7 The study’s goal was to determine the optimum dose required for significant effects on memory and psychomotor performance. The investigators administered tests every hour for 12 hours. Thirty-one healthy volunteers ages 30-59 years received either GBE 150 mg (50 mg PO tid), GBE 300 mg (100 mg PO tid), GBE 120 mg PO once daily, GBE 240 mg PO once daily, or placebo for two days.
A battery of nine memory tests was used including: Stroop task (test of selective attention), digit symbol substitution task (measures both a simple information process and psychomotor performance), wrist actigraphy (assesses both psychometric and subjective state of sedation and arousal), the line analogue rating scale (measures state of mental alertness on a 10 cm line scale), the Leeds sleep evaluation questionnaire (assesses effects of psychoactive compounds on sleep), the short-term memory test (STM, uses a reaction time method), the immediate and delayed recall of supraspan word lists (measures central executive component and explicit memory), the choice reaction time task (indicator of sensorimotor performance based on ability to respond to a critical stimulus), and critical flicker fusion test (CFFT, assesses the integrity of the CNS).
Results showed that the most effective acute dose for cognitive enhancement (as assessed by CFFT) was 120 mg in the morning compared to the other doses and placebo, and that enhancing effects on working memory (as assessed by STM) were more pronounced than they were on selective attention or arousal. The best results were observed in subjects ages 50-59 years.
Van Dongen et al conducted a 24-week, placebo-controlled, double-blind multicenter study to evaluate the efficacy, dose dependence, and durability of the effect of GBE in older people with dementia or age-associated memory impairment (AAMI).8 Two hundred fourteen participants (34 men, 180 women, mean age 82.6 years) diagnosed with AAMI or mild-to-moderate dementia randomly received either 240 mg/d of GBE (high-dose group), 160 mg/d of GBE (usual dose group), or placebo for 24 weeks. Outcome measures were assessed after 12 and 24 weeks and included neuropsychological testing (trial making speech), digit memory span, verbal learning, severity and presence of geriatric symptoms, depressive mood, self-perceived health and memory status, and self-reported behavioral assessment.
An intent-to-treat analysis showed no significant effects on each of the outcome measures for all treatment groups compared with placebo for the entire 24-week period. No beneficial effects of a higher dose or a prolonged duration of GBE were found. The authors concluded that GBE is not as effective as placebo treatment for older people with mild-to-moderate dementia or AAMI.
The longest (52 weeks) randomized, placebo-controlled, double-blind trial was conducted by Le Bars et al.9 This study evaluated the efficacy of GBE on 309 patients diagnosed with uncomplicated Alzheimer’s disease or dementia according to ICD-10 and DSM-IIIR criteria. Patients were randomized to receive either 120 mg (40 mg PO tid) daily of GBE or placebo for 52 weeks. The primary outcome tests included the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative’s Rating Instrument (GERRI), and Cognitive Global Impression of Change (CGIC). Compared to the placebo group, the treatment group scored 1.4 points significantly higher on the ADAS-Cog (P = 0.04) and 0.12 point higher on the GERRI (P = 0.007). There was, however, no clinically significant change in the CGIC in either group. Cognitive performances and social behavior did slightly improve in the treatment group for six months to a year. Whether this suggests a delay in progression of the disease within that period, as the author believes, is uncertain.
The most significant of all the negative studies was published by Solomon et al in the Journal of the American Medical Association.1 This six-week, double-blind, placebo-controlled study randomized 230 healthy older adults (age range 60-82 years) to receive either GBE 40 mg PO tid (as specified by manipulation) (n = 115) or matching placebo (n = 115). Participants were required to have baseline Mini-Mental State Examination scores greater than 26 of 30, to be independent in daily living activities, and to be free of neuropsychiatric disorders.
Outcome measures included the digit symbol subscale of the Wechsler adult intelligence scale revised (WAIS-R, test attention and memory); the Stroop test; mental control and digit span; subscales of Wechsler memory scale revised (WMS-R); measurement of verbal and non-verbal learning and memory composed of logical memory (I and II); visual reproduction (I and II); subscales of WMS-R and the California verbal learning test; expressive language test including controlled category fluency test; and the Boston naming test.
Results showed that at six weeks, mean scores on 14 standardized neuropsychological tests of verbal and visual learning and memory, attention and concentration, and expressive language did not significantly differ between GB and placebo groups. Also, mean scores on self-reported memory function or global rating by spouses, relatives, or friends did not differ between the two groups. The author concluded that when taking GB according to the manufacturer’s instructions, GB provided no measurable benefit in memory (or function) to elderly adults with healthy cognitive function.
Lastly, to validate the efficacy of GB in healthy older adults, Mix et al used a six-week randomized, placebo-controlled, double-blind study.2 Forty-eight cognitively intact adults ages 55-86 years were assigned to either a fixed dose of GBE (180 mg/d) or placebo control group. A series of neuropsychological tests were administered to evaluate subjects’ cognitive and behavioral function prior to therapy (baseline) and after six weeks.
Results showed that the treatment group displayed a significant improvement (P < 0.03) on tasks assessing simple speed of processing abilities (Stroop color and word test color naming task) compared to the placebo group. Also, participants rated their overall memories as assessed by follow-up and self-report questionnaire by the end of treatment as significantly improved (P < 0.03) compared to placebo group. Furthermore, trends favoring improved performance in the GB group were seen in the timed cognitive processing speed, visual-motor scanning (trial making test, part A), complex cognitive processing speed (trial making test, part B), and cognitive flexibility. In contrast, no significant differences were found on any of the four objective memory tests.
Notwithstanding the high methodological quality of these clinical trials (evidence-based value grade I) with the ensuing validity of the results, their current limitations, including small sample size, short duration of trials, and lack of uniform memory tests, preclude meaningful comparison.
The National Institute of Health (NIH) recently sponsored a five-year $15 million randomized double-blind placebo-controlled multicenter study to examine whether GB can prevent Alzheimer’s disease. Participants include 3,000 men and women age 75 years and older with normal mental function. People with Parkinson’s disease, Alzheimer’s disease, or other disorders leading to dementia or on medications that interfere with performance on memory tests are excluded. Primary outcomes include rate and incidence of development of AD and cognitive and memory function changes.
A randomized, double-blind, placebo-controlled trial sponsored by the National Center for Complementary and Alternative Medicine (NCCAM) also is under way and will assess the effect of GBE on preventing or delaying cognitive decline in people age 85 years and older. Participants include 200 elderly cognitively healthy subjects, who will be followed for conversion to mild cognitive impairment. The magnitude of GB effect will be assessed with volumetric quantitative MRI (measured by a decrease in brain volume loss with treatment) and peripheral markers of oxidation status.
There were no significant side effects reported during recent clinical trials with standardized GBE.1,2,9 The most common adverse reactions are mild gastrointestinal complaints (nausea), and allergic skin reactions from contact or ingestion of the fruit pulp of ginkgo.
Doses greater than 600 mg daily may cause diarrhea, nausea, and vomiting.
Contraindications and Precautions
GBE should not be combined with nonsteroidal anti-inflammatory drugs, heparin, or coumadin due to increased risk of spontaneous bleeding.10 A recent literature review recommended GBE discontinuation at least 36 hours prior to surgery.11
GBE theoretically may potentiate the effects of monoamine oxidase inhibitors. Although the actual risk is unknown, patients should be informed about these drug interactions.
The safety of GBE in women who are pregnant or lactating and in children is unknown.
Also, GB products are contraindicated in subjects with hypersensitivity to the plant or its extracts (i.e., alkylphenols found in the seeds).
Formulation and Dosage
In Europe, GBE is sold as a prescription drug; in the United States and Canada, it is marketed and sold as a dietary supplement. GBE commonly is sold as capsules or tablets containing 40 mg, 60 mg, or 120 mg of concentrated leaf extract.
Four preparations are used in the reported clinical trials: Tebonin®, Tanakan®, Rokan®, and Kaveri®. The first three are composed of the extract EGb 761, containing 24% of flavone glycosides and 6% of terpenoids. Kaveri, known as EGb 1370, has a slightly different formula at 25% flavone glycosides and 6% terpenoids. During storage, GB should be protected from light and moisture to increase shelf life.
The majority of clinical trials used the standardized GB extract EGB 761 in a dosage of 40 mg PO tid or 80 mg PO bid for six weeks to three months.
Based on these short-term data, GBE appears to be relatively safe. However, trial results on its effectiveness are mixed and inconsistent, ranging from probably effective to ineffective. These studies differ in duration of intervention, dosage used, subject age, and status of cognitive function of the population tested.
GBE appears to be probably effective in enhancing memory acutely and in a dose-dependent manner (120 mg daily) in healthy, middle-aged adults without memory impairment (ages 50-59 years). Chronic administration of GBE at a dose of 120 mg daily in healthy adults (ages 18-41 years) and in elderly subjects (ages 45-90 years) with dementia may be effective in improving neurocognitive functions for up to 52 weeks.
In contrast, a daily dose of 120 mg GBE is likely to be ineffective in healthy elderly adults age 65 years and older, and in subjects with dementia, at a dose of more than 160 mg daily, for enhancing neurocognitive function for up to 24 weeks.
Although the low cost, easy accessibility, and apparent overall safety of GBE make its use attractive in enhancing memory, broad recommendation should await the results of large, long-term, controlled clinical trials that are currently well-funded and under way. GBE’s role in preventing or delaying neurocognitive impairment associated with age or Alzheimer’s disease should be identified upon completion of ongoing NIH and NCCAM trials in five years.
In the meantime, upon a patient’s request, physicians can recommend a trial of GBE at a dose of 120 mg daily for up to four weeks in young healthy adults ages 18-41 years to improve memory, or in patients ages 45-90 years with dementia for up to 52 weeks to improve neurocognitive functions. Caution should be exercised in the latter group due to polypharmacy. v
Dr. Ramalanjaona is Associate Chairman for Acad- emic Affairs, Department of Emergency Medicine, Seton Hall University, School of Graduate Medical Educa- tion, South Orange, NJ; and Director of Research, Division of Emergency Medicine, St. Michael’s Hospital, Newark, NJ.
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