Ginkgo Biloba for Attention and Memory Disorders

December 1998; Volume 1: 137-139

By Mady Hornig, MD

Ginkgo biloba extracts have emerged recently as part of the "herbal armamentarium." This broad group of natural remedies has enticed people who never before would have entered a health food store to flock in for putative, antiaging miracles.

Ginkgo has been touted as an effective antioxidant, with presumed ability to provide protection against damage induced by free radicals. In addition, it is thought to improve many disorders related to circulatory problems, including peripheral and cerebral vascular disease. There is increasing interest in the efficacy of ginkgo extracts for the treatment of even mild, age-related deficits in memory, vigilance, and attention.1

The German Commission E notes that ginkgo is approved for symptomatic treatment of deficits in memory impairment, concentration difficulties, and depression from organic brain disease. My own clinical experience with adult attention deficit/hyperactivity disorder (AD/HD) patients who have taken ginkgo formulations, either as monotherapy or in conjunction with psychostimulants, indicates modest to marked improvement in vigilance capacity in this population.

History

Since 2800 B.C. extracts of the fan-shaped, bilobed leaves, the fruits, and the seeds of the ancient Ginkgo biloba tree have been used as part of Chinese herbal therapies to combat age-related symptoms and asthma. A remnant of the prehistoric era that is believed to be more than 200 million years old, the ginkgo tree is used to produce EGb 761, the most widely prescribed botanical extract in Germany, where it is used for cognitive and circulatory disorders.

Culture

The expansion of the aged population in the United States and concerns about memory loss and preventing dementia have led to an increased interest in memory-boosting, antiaging agents. Heightened desire to im-prove performance in a wide variety of arenas, ranging from the workplace to the bedroom, has paralleled the consumer’s increased interest in natural remedies to enhance everything from cognitive to social to sexual functioning. Ginkgo extracts are now included in a number of popular "memory boosting" preparations that are easily available at local supermarkets.

Pharmacokinetics

Ginkgo biloba extracts contain a variety of flavo-noids, terpenoids, and phenolic acids. The pharmacokinetic profile is dependent upon the relative concentrations of the different components in the specific preparation. Bioavailability of EGb 761 appears to be high. The German Commission E notes that only extracts with an herb-to-extract ratio in the range of 35:1 to 67:1 are acceptable.

Mechanism of Action

Ginkgo extracts have a wide range of potential effects that relate to the large number of active components. Actual effects vary according to the relative concentrations of each of these components. Proposed mechanisms of action similarly cover a broad spectrum, ranging from prevention of oxidative stress from free radicals or hypoxia to alterations in peripheral and central neurotransmitter systems.

The antioxidant potential of ginkgo constituents is demonstrated by their ability to down-regulate mediators of free radical-induced damage, such as superoxide dismutase, lipid peroxide products, and phospholipids;2 inhibit products of hypoxia-induced membrane breakdown, including choline-containing phospholipids;3 antagonize the anticoagulant effects of platelet activating factor;4 and improve vascular relaxation, through inhibition of nitric oxide.5,6 Together, these effects work to improve cerebral blood flow.

Ginkgo’s capacity to alter neurotransmission and provide neuroprotection derives from at least four animal-model mechanisms. One, ginkgo induces significant decreases in glucose utilization in brain areas mediating somatosensory processing and vigilance as well as vestibular mechanisms. These mechanisms (frontoparietal somatosensory cortex, nucleus accumbens, cerebellar cortex, and pons of the rat)7 are consistent both with ginkgo’s ability to improve attention and its efficacy in tinnitus and vertigo. Two, ginkgo reduces the number of adrenal peripheral benzodiazepine receptors, thereby altering cholesterol transport-inhibiting, stress-related corticosteroid secretion.8 Three, EGb 761 ginkgo extract protects against age-related changes in hippocampus.9 And four, ginkgo extracts are reversible inhibitors of monoamine oxidase A and B subspecies.10

Clinical Studies

Few controlled studies on the cognitive-enhancing effects of ginkgo have been performed in humans, despite its popularity. A randomized, double-blind, placebo-controlled study in mildly to severely demented patients with Alzheimer’s disease or multi-infarct dementia showed stabilization or improvement of cognitive performance and social functioning after six to 12 months of treatment with EGb 761 ginkgo extract (120 mg/d).11 For a detailed review, see Alt Med Alert 1998;1:23-24.

In subjects with age-associated memory impairment, automatic information processing was improved after both acute and chronic (57 days) ginkgo biloba extract administration.12 Assessment of memory processing was based on reaction time in electrophysiologic testing (P300 evoked potential).

Much of the extensive German literature on ginkgo, most done over 8-12 weeks with 120-160 mg/d is not statistically rigorous. There have been no controlled studies in AD/HD or depression.

Table
Sample Ginkgo Biloba Prices 
Brand Formulation Price/Count
Nature’s Resource 40 mg (24% leaf extract) $9.79/50 capsules
Kroger 40 mg (50:1) $5.99/36 tablets
Pharmaton Ginkoba 40 mg (50:1) $14.99/36 tablets
Sundown Herbals 400 mg (leaf extract) $4.95/100 capsules
One-A-Day Memory* 60 mg (leaf extract) $8.99/30 tablets
Lichtwer Pharma Ginkai 50 mg (50:1) $7.99/30 tablets
*also contains vitamins B6, B12, and choline
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Animal Studies

Studies in animal models provide encouraging results with respect to cognitive and neuroprotective effects of ginkgo extracts. Improvements in learning are seen in both adult and aged mice, correlated with improved histologic appearance of the hippocampus.13 Chronic administration of EGb 761 is also associated with improved learning and memory in rats (and with greater longevity).14

Adverse Effects

In general, toxicity is very low. In a large, placebo-controlled dementia study, there was no significant difference in the placebo and the EGb 761 group with respect to reports of adverse effects, although gastrointestinal complaints occurred twice as often in the treated group as compared to the control group.11 In combination with other platelet inhibitors, such as aspirin, spontaneous bleeding into the anterior chamber of the eye has been reported.15 Spontaneous subdural hematomas have also been reported.16 Until further studies are per-formed, patients on aspirin or anticoagulants should avoid ginkgo.

Drug Interactions

Because of ginkgo’s reversible monoamine oxidase inhibitory capacity, the potential for interactions with other agents that affect monoamine neurotransmitters (e.g., antidepressants) is not known. Given the potential for serotonin syndrome, caution should be used when coadministering these agents. There is also the remote possibility of hypertensive crisis if ginkgo is used in very high dosage or if the extract preparation has a particularly high concentration of the monoamine oxidase inhibiting component and if the patient also ingests food with a high concentration of tyramine (cheeses, red wine) or sympathomimetic agents. Interactions with other platelet inhibitors have been reported. (See Adverse Effects.)

Formulation

The EGb 761 formulation of ginkgo biloba extract is the most popular, and contains flavonoids, terpenoids (including the ginkgolides and bilobalide), and organic acids. It is standardized to 24% flavone glycosides and 6% terpenelactones. Currently, it is not clear whether specific preparations of ginkgo have greater overall efficacy or if they might be more effective for specific conditions. Differential efficacy of the various components of different ginkgo extracts is only now being explored. There are also no data regarding differential efficacy or toxicity of formulations containing other "memory boosters," such as phosphatidyl serine or B complex vitamins.

Dosage

Dosage of the EGb 761 preparation is typically 120 mg/d, although studies with Alzheimer’s patients, such as the one by Le Bars and colleagues, suggest that 240 mg/d is a more effective dosage. It is sometimes divided into three daily doses, but based on the most popular extract formulation, EGb 761, once-daily dosing appears to be adequate for many conditions, including cognitive disorders such as Alzheimer’s disease.

Conclusion

Ginkgo biloba extracts appear to be effective in mod-ulating reactions to inflammatory and oxidative stress and in regulating neurotransmission, with preliminary evidence of beneficial effects in disorders of attention, learning and memory, including age-associated memory impairment, AD/HD, and Alzheimer’s disease. The precise mechanism of action is unclear, but evidence suggests a capacity to avert free radical-induced damage through inhibition of membrane breakdown, protection against age-related hippocampal degeneration, and effects on monoamine transmission. Side effects such as bleeding are uncommon and appear to be associated with platelet inhibitory effects of ginkgo extracts.

Recommendation

Given the absence of alternatives and the relatively low toxicity, therapeutic trials are clearly warranted in Alzheimer’s disease. The data from the Le Bars group indicate that long-term therapy is likely to be helpful in either preventing further deterioration or in inducing improvement. For younger patients with AD/HD, traditional therapies should be pursued first, with continued patient surveillance at least every three months. Ginkgo should not be coadministered with anticoagulants.

References

1. Lin JH. Evaluating the alternatives. JAMA 1998;279:706.

2. Seif-El-Nasr M, El-Fattah AA. Lipid peroxide, phospholipids, glutathione levels and superoxide dismutase activity in rat brain after ischaemia: effect of ginkgo biloba extract. Pharmacol Res 1995;32:273-278.

3. Klein J, et al. Phospholipid breakdown and choline release under hypoxic conditions: inhibition by bilobalide, a constituent of Ginkgo biloba. Brain Res 1997;755:347-350.

4. Smith PF, et al. The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF). J Ethnopharmacol 1996;50:131-139.

5. Chen X, et al. Extracts of Ginkgo biloba and ginsenosides exert cerebral vasorelaxation via a nitric oxide pathway. Clin Exp Pharmacol Physiol 1997;24: 958-959.

6. Kobuchi H, et al. Ginkgo biloba extract (EGb 761): inhibitory effect on nitric oxide production in the macrophage cell line RAW 264.7. Biochem Pharmacol 1997;53:897-903.

7. Duverger D, et al. Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761) on cerebral glucose utilization in the rat: an autoradiographic study. Gen Pharmacol 1995;26:1375-1383.

8. Marcilhac A, et al. Effect of chronic administration of Ginkgo biloba extract or ginkgolide on the hypothalamic-pituitary-adrenal axis in the rat. Life Sci 1998;62:2329-2340.

9. Barkats M, et al. Effect of long-term treatment with EGb 761 on age-dependent structural changes in the hippocampi of three inbred mouse strains. Life Sci 1995;56:213-222.

10. White HL, et al. Extracts of Ginkgo biloba leaves inhibit monoamine oxidase. Life Sci 1996;58: 1315-1321.

11. Le Bars PL, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 1997;278:1327-1332.

12. Semlitsch HV, et al. Cognitive psychophysiology in nootropic drug research: effects of Ginkgo biloba on event-related potentials (P300) in age-associated memory impairment. Pharmacopsychiatry 1995;28:134-142.

13. Cohen-Salmon C, et al. Effects of Ginkgo biloba extract (EGb 761) on learning and possible actions on aging. J Physiol Paris 1997;91:291-300.

14. Winter JC. The effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat. Physiol Behav 1998;63:425-433.

15. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med 1997;336:1108.

16. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology 1996;46:1775-1776.