Ginkgo biloba: What Good Is It? Mature Medicine Canada (Jan/Feb 1999) 2:34-7. Marc Lemay, Ph.D.

;1,2 Marie-Jeanne Kergoat, MD, CSPQ;1,3 Sonia Lupien, Ph.D.4,1 1 Centre de recherche, Institut universitaire de gériatrie de Montréal 2 Département de psychologie, Université de Montréal 3 Faculté de médecine, Université de Montréal 4 McGill University--Douglas Hospital Research Centre, Montreal. Correspondence to: Marc Lemay, 35 La Linda Drive, Long Beach, CA USA 90807

Ginkgo biloba: What Good Is It?

More of us are already older than the average age in the population than ever before in history. This, combined with a rising number of Alzheimer's Disease (AD) cases,1 and growing lay,2 medical,3-4 and pharmaceutical company5-6 interest in herbal drugs, has made Ginkgo biloba a hot topic of late. Ginkgo biloba is first a tree, a relict species which first emerged in the Paleozoic age, before the dinosaurs but along with the earliest forms of highly organized life. Some 200 million years later, Ginkgo was nearing extinction when, in 13th century China, it began to be cultivated, as it has been ever since, for shade, ornament, and medicinal use.7 Today Ginkgo can be found growing along streets, where rather spindly specimens attract little attention among the cell phones and exhaust fumes of busy urban centers; in front of houses and in parks, where Ginkgo can reach its full and splendid stature and live 2000 years or more; and in plantations such as the one, 10-million tree strong, in South Carolina, where fresh Ginkgo leaves are harvested, dried and then shipped to Ireland and Germany to be processed into standardized extracts. 8 One of the most prescribed products in Europe,6 Ginkgo biloba only came to serious attention
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in North America with the publication in the Journal of the American Medical Association of a report on the first U.S.-based trial of a Ginkgo extract for AD.9 The findings, suggestive of Ginkgo's utility as an AD stabilizer, were trumpeted in the mass media—in part due to JAMA's prestige10—and picked up as well by the research review literature, where tentatively positive recommendations11-12 as to the pharmacologic use of Ginkgo for AD were offered based on that one study.9 Such disregard of European or non-English language research has rightly been criticized as unscientific.13 However, Ginkgo's status as an herbal drug, free of regulatory oversight, does invite caution,14 as do the unfamiliar entry criteria and outcome measures used in Europe.9 Much of the Ginkgo literature concerns its effects in "cerebral (or cerebrovascular) insufficiency," a nebulous condition characterized by cognitive and mood disturbances with associated symptoms, such as tinnitus and vertigo, and believed to be caused by impaired cerebral circulation, neurodegeneration, or both.15 In a 1992 review of 40 randomized studies of Ginkgo for this indication, 8, all positive, were considered methodologically sound. 16 Research conducted since then on Ginkgo for AD proper produced results which can be summarized as modest improvement17-19 or maintenance9 of cognitive function, along with improvement of self-20 or informant- rated9 quality of life.

WHICH GINKGO? The basic difference between herbal and chemically-defined drugs is that the former almost always contain a mixture of putative active substances22 and can be of widely varying quality and potency.5 Two types of Ginkgo products are best avoided: The raw, dried leaf form, often packaged in gelatin capsules, is of doubtful potency23 and may contain allergenic substances24 which are removed in the making of purified extracts.25 Homeopathic Ginkgo products are also best avoided, for lack of memory-relevant data. The most widely studied extract, EGb 761 (in the U.S. and Canada marketed under the names Ginkgold and Ginkoba), contains 40, 60, 80 or 120 mg of a purified, concentrated (on average, 50:1) Ginkgo extract free of ginkgolic acids and standardized to 24% ginkgo-flavone glycosides and 6% terpene lactones.26 If the goal is to

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produce effects similar to those described in the literature, a Ginkgo extract should contain those two constituents in the same proportions. A pilot bioequivalency study 27 with three brands in 12 healthy male subjects showed that EGb 761 produced dynamic EEG profiles (decreasing slow wave and increasing alpha wave activity) that were more pervasive, homogenous (affecting a greater proportion of subjects), and similar to those associated with known or suspected cognitive activators, than the other extracts. The manufacturer of EGb 761 has made some standardization data available.14,26 Although EGb 761 is not necessarily the most efficacious, it is probably the best characterized and certainly the most studied Ginkgo extract.

EGb 761: ACTION The most important active agents in EGb 761 are three major flavonoid groups whose chemical structure resemble those of nucleosides, isoalloxazine and folic acid; and two terpene groups: a sesquiterpene, bilobalide; and diterpenes, the ginkgolides. These terpenoids have three lactone functions and a tertiary butyl group that to date is unique in nature. 25,27 EGb 761 has at least 4 modes of action relevant to the aging brain: (1) oxidative damage to mitochondrial (MT) proteins, lipids, and DNA contributes to several age- related dysfunctions;28-29 in rats, EGb 761 partly prevents the age-related increase in MT peroxide generation, MT glutathione oxidation, and MT DNA oxidative damage.30 (2) Platelet activating factor (PAF), which normally has little effect on cerebral metabolism, amplifies excitatoxic glutamate receptor function after neuronal injury;31 one of the components of EGb 761 is a potent PAF antagonist.32 (3) Neuroprotective effects of EGb 761 or its isolated constituents have been demonstrated in mice, with EGb 761 increasing the projection field of mossy fibers in the CA3 hippocampal regions, which are important for learning and sensitive to aging.33 In rats or mice, EGb 761 decreases cortical and total infarct volume after occlusion of the middle cerebral artery.34 EGb 761 also increases the binding of [3H]quinuclidinyl benzilate to muscarinic cholinergic receptors of the hippocampus in old rats,35 and may be an indirect cholinergic agonist by activating presynaptic M2

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autoreceptors.36 (4) High or rising basal glucocorticoid levels are associated with impaired cognition in rats37-39 and humans.40-41 In rats EGb 761 reduces the ligand- binding capacity, protein and mRNA expression of the adrenocortical mitochondrial peripheral-type benzodiazepine receptor, a key element in the transport of the steroid substrate cholesterol, thereby causing a drop in glucocorticoid levels; no other steroid hormone is affected. 42-43 EGb 761 lowers cortisol and promotes behavioural adaptation in stressed rodents. 44 In rat models, EGb 761 has anti-depressant- and anxyolitic-like action, without being directly comparable to any known anti- depressant or anxyolitic.45 Short of a cure, AD can only be treated symptomatically or stabilized.46 In one study Ginkgo stabilized about twice as many AD patients as did a placebo (29:13%).9 But stabilization should ideally be initiated before frank AD, in order to slow or arrest neuronal loss.21 In this light, we are currently setting up a trial of EGb 761 for circumscribed memory impairment,21 with memory, stress, and cortisol measures over six months.

SAFETY EGb 761 is thought to be free of serious adverse effects.23,47-48 Mild gastrointestinal complaints, headaches and allergic skin reactions occur infrequently; very large doses may induce restlessness, diarrhea, nausea and vomiting.48 The long-term use side effect profile of Ginkgo (beyond 1 year) has not been investigated. There is one report of intracerebral hemorrhage,49 one of subarachnoid haemorrhage,50 two of a spontaneous subdural hematoma,51-52 and one of hyphema,53 associated with use of Ginkgo. It is difficult to determine the relative likelihood of causality versus coincidence in such cases.54 In the U.S.-based EGb 761 trial,9 among 327 randomized patients, serious adverse events comprised 3 deaths, 1 in the placebo group and 2 in the treatment group, due to acute conditions unrelated to the study medication; as well as 1 stroke and 1 subdural hematoma, both in the placebo group, related to aggravation of preexisting conditions. EGb 761 is postulated to exert some of its clinical effect via Platelet Aggregating Factor (PAF) antagonism,32 which in theory may affect blood clotting. The

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intracranial hemorrhage patient had been on warfarin,49 and the hyphema patient had been taking aspirin 325 mg daily for three years.53 Until this issue is clarified, patients on anticoagulant therapy should be cautioned against concurrent Ginkgo use. Physicians and pharmacists should encourage Ginkgo users to consult a physician in case of dizziness, persistent headaches, double- or blurred vision, nausea, vomiting, or unusual bleeding.55-56

CONCLUSIONS Physicians with a non-judgmental attitude could discover whether their patients are using or considering any "alternative" therapy,57 and also, if both agree, supervise its use.58 In some patients, EGb 761 may be useful as a stabilizing agent. The usual dose is 40-80 mg before the three principal daily meals. A trial should last at least 6-8 weeks;16 treatment effects could be evaluated using clinical judgment informed by results from suitable instruments, e.g. Goal Attainment Scaling,59-60 the standardized61 ADAS-cog,62 or the 3MS.63 Participants in the active treatment group of our multi-site six-month study will be taking EGb 761 80 mg t.i.d., which at Canadian retail would cost about $3 a day. EGb 761 therapy combined with other AD-stabilizing agents (such as vitamin E) or symptomatic agents (such as donepezil), might provide additive or synergistic benefits, though this has yet to be systematically evaluated.46,64

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