One of the most popular herbal supplements, extracts of the ginkgo leaf are recommended for the treatment of a variety of conditions. In particular, they are thought to be of benefit for enhancing memory and cognition. The popularity of this product is demonstrated by the fact that annual sales of ginkgo exceed $1 billion worldwide, with more than $100 million of this spent in the United States alone.
Ginkgo has been widely available in the Western hemisphere for the past 40 years, first in Europe and then in the United States. The relatively recent interest in this leaf extract is notable because ginkgo, also known as maidenhair or kew, is one of the oldest living species of tree. Fossil evidence suggests that ginkgos were present throughout the world up to 200 million years ago, but were rendered nearly extinct during the last ice age, surviving only in Asia. Reintroduced to the West in the sixteenth century, modern ginkgo is the sole survivor of the Ginkgophyla division of the Ginkgoaceae family. A dioecious species, the female ginkgo produces a plum-like fruit that emits an offensive odor due to the presence of butanoic and hexanoic acids. The male ginkgo is preferred for ornamental planting in part because of the unpleasant odor of the rotting fruit.
Although the ginkgo was present throughout human evolution, the possible medicinal value of its fruit, seeds, and leaves was not recorded until some 800 years ago. One of the earliest extant publications on its therapeutic potential is Lan Mao’s Dian Nan Ben Cao where it is suggested that the leaves be used as a topical treatment for freckles, head sores, chilblains, and wounds. The first known mention of systemic use, for the treatment of diarrhea, appeared in the fourteenth century with the publication of Liu Wen-Tai’s Ben Cao Pin Hui Jing Yao. At about the same time, Li Shih-Chen in Pen Ts’ao Kang Mu proposed ginkgo seeds as a remedy for a host of conditions, including cough, asthma, and worm infections. It was not until the 1960s, however, that ginkgo leaf extract was introduced as an herbal remedy in Western Europe. Its popularity in the United States dates from the 1980s.
It is possible the delay in documenting the possible medicinal value of ginkgo was because of its limited geographical distribution and the unpleasant aroma of its fruit. The former seems unlikely as the Chinese were publishing descriptions of herbal remedies, such as in the Shen Nong Ben Cao Jing, as early as 2800 BC. As for the possibility that the foul odor lessened enthusiasm for consumption of the fruit, seeds, and leaves, there is written evidence suggesting ginkgo seeds were a food source in China from at least 200 BC. This indicates these plant products have been ingested for more than 2000 years. It seems more likely that the ancients were slow to appreciate the possible medical value of the ginkgo because responses to the application or consumption of its seeds, leaves, fruit, or their extracts, are subtle and unpredictable. This differentiates the ginkgo from other natural products, such as opium, which display a rapid, dramatic, and consistent effect on central nervous system function. Even with the most modern tools available for assessing cognition and memory, there is still debate about whether gingko extract improves brain function. A careful analysis of the literature on the chemical composition of gingko extract, and on what is known of its pharmacokinetics and pharmacodynamics, provides some insights into this ongoing controversy.
Today, leaf extracts of ginkgo are the most commonly used herbal remedies, although the seeds are consumed for this purpose in some countries. Following the last ice age, the ginkgo and related species continued to grow wild in what is now China. With the arrival of humans, ginkgo survived under cultivation while all other species of Ginkgoaceae became extinct. The Chinese ginkgo was subsequently exported to other countries as an ornamental tree, reestablishing its presence throughout the world.
The name ginkgo comes from the Japanese term ginkyo, meaning silver apricot, an apt description of the fruit produced by the female of the species. Biloba refers to the shape of the leaf, which resembles a small fan having two lobes. The tree can grow to over 100 feet, with individual specimens living for 1,000 years or more. The seeds are contained in cherry-like seed heads. Botanically, ginkgo is a Gymnosperm. Like pines and other members of this group, its mature seeds are not enclosed in an ovary. Yews are considered the most closely related living relative of the gingko. A very hardy plant with a significant resistance to disease, ginkgos are found in temperate regions throughout the world. The appearance in the West of the cultured variety was recorded in Europe in the seventeenth and in North America the nineteenth centuries.
Given its long absence from Europe, the ginkgo is not included in Western writings up through the Renaissance. In Chinese medicine, both the seeds and the dried leaves were used to treat numerous conditions. In the Pen Ts’ao, Li Shih-Chen recommends the ripe seed be taken orally to reduce cough and dyspnea, and for the treatment of asthmatic bronchitis.In addition, these seeds were used in traditional Chinese medicine for managing leukorrhea, a vaginal condition, and enuresis, or bedwetting. Recorded side effects and toxicities for the seeds include muscle spasm, seizures, skin irritation, and kidney inflammation.
The use of ginkgo leaves and their extracts for therapeutic purposes is a more recent development. A modern compilation of Chinese herbals includes ingestion of the ginkgo leaf or extract for the treatment of Parkinson’s disease, migraine, atherosclerosis, hypercholesterolemia, and chronic bronchitis.
In the West, leaf extracts are taken primarily to improve memory and cognition, especially in the elderly. Several of the more popular recommended uses as a treatment for central nervous system disorders include memory loss in general, the memory deficits associated with Alzheimer’s disease, and a condition referred to as mental fatigue (see Table below). Ginkgo is also reported to improve the mental health of those afflicted with multiple sclerosis, and to have some positive benefit in the treatment of glaucoma, macular degeneration, and tinnitus, or ringing in the ears. Other advertised indications are allergic inflammation, asthma, hardening of the arteries, Reynaud’s disease, psoriasis, vitiligo, male infertility, and generalized aging (see Table below). While this list is not exhaustive, it illustrates the wide range of purported beneficial effects of this extract.
Table Some Recommended Indications for Ginkgo Biloba Extract
|Alzheimer’s Disease||Memory Loss|
|Allergic Inflammation||Mental Fatigue|
|Hardening of the Arteries||Psoriasis|
|Intermittent Claudication||Raynaud’s Disease|
It is difficult for a pharmacologist to assess the effectiveness of ginkgo as a treatment for conditions such as mental fatigue for which the pathology is unknown and the symptoms purely subjective. It is also not possible to assess effects on aging without identifying the specific aspect of the aging process to be studied. In contrast, the efficacy of ginkgo extract as a treatment for defined clinical conditions, such as Alzheimer’s or Reynaud’s diseases, and as a means for lessening symptoms, such as memory loss, can be examined critically.
It is notable that the earliest written reports on the therapeutic uses of ginkgo do not generally include mention of effects on central nervous system function. Rather, emphasis was placed on its possible value as a treatment for respiratory conditions, such as asthma, and vascular disorders, such as intermittent claudication, which is hardening of the arteries in the legs. This suggests that early ginkgo preparations displayed no obvious effects on brain function.
Interest in ginkgo leaf extract as a palliative, if not a remedy, for memory loss was stimulated in the latter half of the twentieth century by the belief that it induces vasodilation, and therefore may increase blood flow to the brain. Interest in this use was fostered by the production and sale of a ginkgo extract, EGb 761, by Dr. Willmar Schwabe GmbH & Company in Germany. Research was performed, some underwritten by the company, to examine its effects in humans and to assess its mechanism of action. While positive results were published on the clinical effectiveness of EGb 761 in enhancing memory and cognition, these conclusions were often based on data from uncontrolled trials, anecdotal reports, case studies, or small statistically underpowered studies. The popularity of ginkgo extract grew considerably, especially in the United States, when Dr. Elias James Corey mentioned his work on the total chemical synthesis of ginkgolide B, a constituent of the extract, when accepting the 1990 Nobel Prize in Chemistry. While Dr. Corey made no mention of the possible therapeutic benefits of ginkgolide B, nor endorsed its use as an herbal product, his chemical interest in the compound was taken as a validation of its clinical potential.4 Sales of ginkgo extract increased substantially in the 1990s as it became a popular herbal supplement for enhancing memory in the elderly and in those experiencing cognitive decline, regardless of the cause.
A hallmark of conventional pharmaceuticals, whether prescription or over-the-counter, is that the precise amounts of all chemical components and their pharmacological properties are known. This includes not only the active component, but also any biologically inert materials included in the product as preservatives or to enhance solubility, taste, or absorption of the drug. This is not the case with preparations of gingko. There are scores, if not hundreds, of chemicals in gingko products, with the exact number and type depending on the extraction and purification procedure. Typically, commercial ginkgo products contain an extract resulting from several different purification steps to enhance the concentration of some constituents, and to lower that of others.5 After the extraction procedure, the solvent is removed and the dried powder sold to the consumer. As these processing steps may vary among manufacturers, the chemical composition differs among producers. Indeed, as with wines, variations in constituents among batches would be anticipated even with the same extraction process because the relative quantities of the various chemicals in the leaves are affected by many factors, such as the growing conditions, the time of year the leaves are harvested, and the age of the tree.
The aim in preparing most ginkgo leaf extracts is to have a powder composed of 6% terpene trilactones and 24% flavonol glycosides, with only a trace of ginkgolic acids.5 This mixture of terpenes and flavonols is referred to as the standardized extract. The remaining constituents of this preparation, composing roughly 70% of the total, are generally unidentified in individual preparations. This large, uncharacterized, component is known to include various classes of organic compounds, such as proanthocyanidins, carboxylic acid derivatives, polyphenols, catechins, carbohydrates, alcohols, ketones, alkylphenols, and non-flavonol glycosides. The standardized extract also contains a host of undefined, high molecular weight compounds and inorganic molecules. It is estimated that approximately 13% of the standardized powder has never been identified. Besides its commercial use, the standardized extract is often employed for preclinical and clinical studies.
As the list above includes only chemical classes, the actual number of individual agents in ginkgo powder is unknown. It is believed that any therapeutic benefit derived from the consumption of the standardized extract is due to the actions of certain flavonoids and terpenes, some of which have been chemically characterized. While the ginkgo leaf flavonoids receiving the most attention are kaempferol, quercetin, and isorhamnetin, at least 40 others in the preparation are present in smaller quantities. Chief among the ginkgo terpenes are ginkgolides A, B, C, J, and M, and bilobalide. Of these, ginkgolide B has been examined most thoroughly as it is believed to be one of the most active ingredients in the preparation. Some other individual compounds identified in the ginkgo extract are shikimic, vanillic, ascorbic and p-coumaric acids, as well as sitosterol and stigmasterol.
Thus, only a small fraction of the individual chemical compounds present in the standardized ginkgo product are known. This fact, plus the variations that occur in the concentrations of these constituents among the commercial preparations, poses a significant challenge in precisely defining the pharmacological properties of this product.
Studies on the absorption, distribution, and metabolism of ginkgo constituents have employed the standardized extract and some individual components thought to be responsible for biological activity. In general, the bioavailability of orally administered flavonoids is limited because of their low lipid solubility. Flavonoid metabolites have been identified in rats after oral administration of leaf extract. These include 4-hydroxybenzoic acid conjugate, 3-methoxy-4-hydroxybenzoic acid, hippuric acid, and 4-hydroxyhippuric acid. While some investigators report that no intact flavonoids appear in rat or human blood after oral administration of the standardized ginkgo extract, others have detected quercetin, kaempferol, and isorhamnetin/tamarixetin in rat blood and brain following ingestion. These flavonoids have also been reported to be present in the hippocampus following administration of the extract. Continued oral administration to rats is reported to increase the brain accumulation of these substances.
The different findings with regard to flavonoid bioavailability in rats could be attributable to differences in the administered doses or to the sensitivity of the analytical procedures employed to identify these substances in blood. In general, however, it appears that the ginkgo flavonoids are extensively metabolized in the gastrointestinal tract following ingestion, primarily to phenolic acids. As the extent of this metabolism appears to be greater in humans than rats, the types of flavonoid metabolites detected in the blood and urine following oral administration differ between the two species. Intravenous administration to rats of the standardized extract reveals that when the ginkgo flavonoids are placed directly into the bloodstream the half-lives of kaempferol and isorahamnetin are less than two hours, and for quercetin, slightly less than four hours.
Taken together, these findings suggest that very little, if any, of the ginkgo extract flavonoids reach the bloodstream unchanged following oral administration in humans and that, even if they did, their biological half-lives are relatively short. These pharmacokinetic data indicate it may be inappropriate to extrapolate ginkgo extract results from in vivo rodent studies to the clinical situation. Moreover, these findings suggest that any therapeutic response to the flavonoid components of ginkgo extract is due to actions of their metabolites rather than to the parent compound in the leaf. This is important when interpreting the results of experiments aimed at defining the pharmacodynamics of ginkgo constituents, as it would appear to be more appropriate to study responses to the relevant flavonoid metabolites rather than to extract constituents themselves.
The absorption characteristics of ginkgo terpene trilactones are quite different from the flavonoids. Rat and human studies indicate that the vast majority of the ingested ginkgolides A, B, and bilobalide are readily absorbed from the gastrointestinal system following oral administration of the standardized ginkgo extract. In a study with human volunteers, the time to reach the maximum plasma concentration of ginkgolides following administration of dried ginkgo leaf extract was two hours for all of these ingredients, with the elimination half-lives being approximately 2.5 hours for each. Very little ginkgolide C appears in blood following its oral administration. In addition, measurable quantities of ginkgolides A, B, and bilobalide are detectable in a rat brain after a single oral administration of the standardized extract. Thus, unlike the flavonoids, it appears that the ginkgo terpene trilactones may penetrate into the human brain following oral administration.
A number of studies were undertaken to determine the effect of ginkgo on the metabolism of other drugs. Because ginkgo may be taken for extended periods by individuals also consuming prescription or over-the-counter medications, it is important to know whether the extract might modify the breakdown of these other agents and thereby increase or decrease their blood levels and therefore their effectiveness. The most common studies of such interactions involve in vitro examinations of the ginkgo extract, or some of its known chemical constituents, on enzyme activity in human or laboratory animal tissue, or in cell systems containing a particular drug metabolizing enzyme. In general, depending on its concentration, ginkgo extract may increase or decrease the activities of various drug metabolizing enzymes. It is reported that a particular human liver enzyme is inhibited by the ginkgo extract and that this effect is probably not mediated by either the terpene trilactones or flavone glycosides. While the flavone aglycones resulting from metabolism of the parent compound in the extract inhibit this enzyme activity, it was suggested the concentrations needed for this may be higher than those achieved following oral administration of the extract to humans. The metabolizing enzyme inhibition might therefore be due to the presence of some other, perhaps as yet unidentified, substance in the ginkgo powder.
It has also been reported that the activity of other drug metabolizing enzymes are enhanced or inhibited by certain concentrations of ginkgo extract. The possible clinical significance of such findings is illustrated by the report that ginkgo administration significantly enhances the metabolism of omeprazole, an ulcer medication, in humans. This suggests that ginkgo ingestion could reduce or enhance the clinical potency of some prescription medications.
While it appears ginkgo extract has the potential to influence the metabolism, and therefore the response, to a number of drugs, the degree of risk for such interactions is unknown as most of the studies addressing this question were conducted in vitro. Because such experiments seldom reveal the extract constituent responsible for any observed effect, it is impossible to know whether a sufficient amount of the relevant component is absorbed from the orally ingested product to have such an effect on drug metabolism in vivo. Nonetheless, caution should be exercised when consuming ginkgo extract with conventional medications, as the former might affect the response to the latter.
Over the past three decades scores of in vitro and in vivo animal studies have been performed to determine the mechanism of any therapeutic action attributed to ginkgo extract.7 The results suggest that the extract itself, or selected individual chemical constituents, can influence virtually all brain neurotransmitter systems, depending on the concentration or dose examined. Given the variety of tests employed, possible differences in the chemical composition of the extracts, and variations in experimental conditions, it is not surprising that these results are often conflicting. For example, while some show that the standardized ginkgo extract inhibits norepinephrine, dopamine, and serotonin uptake into rat brain neurons, others report the extract enhances the accumulation of these neurotransmitters. Work has also suggested the extract, or certain constituents, are capable of modifying neurotransmitter metabolism, the accumulation of neurotransmitter precursors, and the number of neurotransmitter receptors in the brain. Again, it has not been possible to determine whether such effects occur in humans following consumption of the standard quantity of ginkgo extract.
In vitro studies also suggest that ginkgo extract can slow apoptosis, or cell death, presumably because flavonoids are thought to scavenge free radicals and other reactive oxygen species. However, studies indicate that flavonoid antioxidant activity is unlikely to occur in vivo given the concentrations of these substances absorbed after oral administration, and their rapid and extensive metabolism in the body. Although some have suggested that the terpenoid constituents of the extract also inhibit cell death, others report no effect in this regard.
Because the in vitro laboratory studies suggest that the flavonoid components of ginkgo may reduce the levels of reactive oxygen species, it was reasoned these compounds might be of benefit in treating neurodegenerative and cardiovascular disorders, as well as age-associated neuronal cell loss. It is unknown, however, whether in vitro rodent brain studies supporting this notion are of relevance with regard to any clinical response given the aforementioned differences in the extent of metabolism of ginko extract between humans and rats, and the fact that it is unlikely these flavonoids are absorbed intact. Accordingly, for a pharmacologist it is difficult to know which, if any, of the effects found with these in vitro studies could be anticipated in humans. There is also uncertainty as to whether the amount of extract used for the in vitro work, or the doses employed for in vivo laboratory animal studies, approximate the concentrations of these extract constituents or metabolites present in the human brain following oral administration of the commercial product.
It has been known for some time that the terpene trilactones are platelet-activating factor (PAF) receptor antagonists. As PAF is a potent, endogenous mediator of bronchoconstriction and platelet aggregation, blockade of its action could explain the purported beneficial effects of ginkgo extract in the treatment of asthma, other inflammatory conditions, and clotting disorders. However, the ginkgolides appear to have only modest affinity for the PAF receptor, suggesting they are weak in this regard. Nonetheless, it has been shown that administration of ginkgo extract to humans decreases erythrocyte aggregation and increases blood flow in the nail fold capillaries. It has also been reported that the duration of the PAF blockade of an inflammatory response in human skin is brief following oral administration of a ginkgolide preparation. This is consistent with the pharmacokinetic studies indicating the elimination half-lives for the ginkgolides in humans is quite short. It is unknown what direct effect PAF receptor antagonism has on central nervous system activity.
The effects of ginkgo extract, and in particular the terpene trilactones, on animal behavior have been examined. These substances are reported to both enhance and reduce anxiety, to display an antidepressant effect, and to show promise as a possible treatment for drug abuse. The ginkgolides are also reported to enhance vigilance and alertness, suggesting an activating effect on the central nervous system.7 Again, determining the possible clinical relevance of these data is problematic because of the differences in doses and in the metabolism of extract constituents between humans and laboratory animals. Nonetheless, such laboratory findings stimulated a host of studies aimed at defining the effect of ginkgo extract on a number of clinical parameters, including cerebral blood flow and alertness, and on conditions such as age-related cognitive decline and Alzheimer’s disease.7 Included among these are several double-blind, placebo-controlled studies aimed at determining whether ginkgo extract is of benefit in enhancing memory and cognition, especially in those with neurodegenerative disorders. Such studies are particularly challenging because of the difficulty in objectively measuring changes in these mental attributes over time. To this end, rating scales are used to quantify alterations in various parameters as described by the subjects, their caretakers, or clinical personnel.
A meta-analysis is a retrospective study combining and analyzing the results of a large number of previously published experiments. By combining such data from many clinical studies, the number of observations is increased, as is the likelihood of detecting a small, but clinically significant, effect. In conducting a meta-analysis it is important that all studies included be well-controlled and involved a similar patient population. The results of a meta-analysis covering 36 clinical trials of ginkgo extract have been reported. All the studies chosen for this analysis were randomized, double-blind, placebo-controlled trials. Trials with Alzheimer’s patients were included as well. The results indicate no consistent clinical benefit associated with the consumption of ginkgo leaf extract.
Recently completed prospective clinical studies include one involving 118 cognitively intact subjects, 85 years of age or older, who took ginkgo leaf extract for 42 months. The aim of this trial was to determine whether ginkgo improves cognition in the elderly. No significant difference in the rate of cognitive decline was noted between those taking ginkgo and the control subjects.
Another clinical trial was the Ginkgo Evaluation of Memory (GEM) study. This undertaking, funded by the United States National Institutes of Health, involved five academic medical centers and 3,069 individuals aged 72 to 96 years. Over a six year period these individuals participated in a double-blind, randomized study of ginkgo to assess its effects on memory and on the incidence of Alzheimer’s disease. The subjects received either placebo or 120 mg of leaf extract twice daily. Several different rating scales were used for evaluation of mental state, memory function, and development of symptoms associated with Alzheimer’s disease. No significant differences were noted for any of these measures between the treated and control groups, suggesting that ginkgo leaf extract is ineffective for delaying memory decline in the elderly and for slowing or preventing the onset of Alzheimer’s disease.
Attempts have been made to assess the effect of ginkgo leaf extract in combination with standard medications used to treat psychiatric disorders. In one study, the extract was taken by treatment-resistant schizophrenic patients along with clozapine, an antipsychotic agent. For this trial, 42 patients received, in combination with clozapine, either ginkgo extract or placebo for 17 weeks. While the addition of the ginkgo extract may have enhanced the effectiveness of clozapine in reducing the negative symptoms of this disorder, there was no significant improvement in overall symptomatology.
While there have been dozens of published reports suggesting ginkgo extract has positive effects in enhancing cognition and memory in humans, and there have been laboratory animal studies suggesting it may delay the progression of neurodegenerative disorders, well-controlled, large-scale clinical trials have failed to confirm these findings. Accordingly, from a pharmacological perspective, the utility of ginkgo extract in treating central nervous system disorders remains unproven. This conclusion supports the hypothesis that any effects of ginkgo extract on the central nervous system are minor, subtle, or evident only in certain types of individuals.
Side effects to the recommended doses of ginkgo extract appear minimal and are quantitatively and qualitatively similar to complaints reported after consumption of a placebo. This safety profile explains, in part, the popularity of this product. Side effects include gastrointestinal discomfort, nausea, diarrhea, and headaches. Some may experience allergic reactions as ginkgo leaves contain allergens related to those found in poison ivy. Because constituents of the extract may inhibit clotting, it is possible that consumption of the powder could lead to bleeding, especially in those taking anticoagulant drugs. While clinical studies on this question are inconclusive, caution should be exercised by those taking drugs known to slow blood coagulation, such as aspirin and warfarin. Because there are reports suggesting the constituents of ginkgo extract might inhibit or activate drug metabolizing enzymes, consumers should be alert to possible changes in the responsiveness to prescription or over-the-counter medications when taking ginkgo products.
As the precise mechanism of action of any central nervous system effects of ginkgo is unknown, it is difficult to speculate about the possibility of adverse consequences due to pharmacodynamic interactions with known psychotherapeutics. Nonetheless, it is recommended that ginkgo extract should not routinely be taken by those on antidepressant medications unless under the close supervision of a physician.
Given the popularity of ginkgo extract, many obviously feel they benefit from the consumption of this herbal product. While its lack of side effects is a positive characteristic, it might also be interpreted as indicating the product has little, if any, biological activity. Indeed, from a pharmacodynamic standpoint, it is difficult to take seriously the number of neurochemical responses that have been attributed to ginkgo extract and extract constituents from laboratory animal studies as such generalized actions would be expected to result in a number of serious side effects, none of which are observed in clinical trials.
The pharmacological data do, however, suggest the possibility that ginkgo leaf extract might diminish the inflammatory and clotting responses to PAF, and therefore symptoms of some clinical conditions. Its value as an agent for treating central nervous system conditions remains unproven, at least with respect to enhancing cognition, slowing cognitive decline, or delaying the onset of Alzheimer’s disease. In the absence of large scale, placebo-controlled clinical trials for the treatment of other central nervous system disorders, it is impossible to draw any conclusions about the overall effectiveness of this product. Inasmuch as ginkgo leaf extract has been widely available for years, and taken by millions of people for a variety of reasons, it would be anticipated that any obvious and consistent effect on central nervous system activity would be known by now. The possibility remains that ginkgo constituents may influence brain function in a select group of individuals experiencing certain types of central nervous system dysfunction. However, until it is possible to identify which, if any, components of the ginkgo extract, or their metabolites, penetrate into the human brain at concentrations sufficient to influence neuronal activity, the pharmacological properties, and therefore the therapeutic potential, of this product will remain undefined.