Ginkgo

Plant Part Used

Leaf

Active Constituents

Terpene lactones (ginkgolides A, B, and C; bilobalide); flavonoids (including myricetin, quercetin, proanthocyanidins, catechins).(1),(2)

[span class=alert]This section is a list of chemical entities identified in this dietary supplement to possess pharmacological activity. This list does not imply that other, yet unidentified, constituents do not influence the pharmacological activity of this dietary supplement nor does it imply that any one constituent possesses greater influence on the overall pharmacological effect of this dietary supplement.[/span]

Introduction

Ginkgo is among the oldest living species on earth and has been used extensively as a medicinal agent worldwide for centuries. The chemical constituents that have helped ginkgo resist potentially damaging pests during the millennia most certainly contribute to its positive effects on health.(3) Ginkgo is the most frequently prescribed medicinal herb in Europe, with hundreds of studies reporting positive effects from taking ginkgo for both the prevention and treatment of various health complaints. The most dramatic benefits are reported in improving circulation in the elderly.(4),(5) This can lead to enhanced memory, possibly delaying the onset of Alzheimer's disease,(6) reducing senile dementia,(7) tinnitus,(8) and vertigo.(9) Ginkgo’s memory-enhancing effects are reported in younger populations as well.

Interactions and Depletions

Interactions

Dosage Info

Dosage Range

120-240mg (standardized extract) daily in divided doses.

Most Common Dosage

160mg (standardized extract daily in divided doses.

Standardization

[span class=doc]Standardization represents the complete body of information and controls that serve to enhance the batch to batch consistency of a botanical product, including but not limited to the presence of a marker compound at a defined level or within a defined range.[/span]

The most current available medical and scientific literature indicates that this dietary supplement should be standardized to 24-32% ginkgo flavoglycosides and 6-12% triterpenes.

Uses

Frequently Reported Uses

  • Antioxidant
  • Peripheral Vascular Disease
  • Raynaud's Disease
  • Cerebral Vascular Insufficiency
  • Tinnitus
  • Dementia
  • Memory Enhancement
  • Depression
  • Vertigo
  • Alzheimer's Disease/senile dementia
  • Cognitive Enhancement
  • Improves Microcirculation To The Brain, Heart, Periphery
  • Increases Peripheral Circulation; Cardiovascular Tonic
  • Cardiovascular Support (Angioplasty, Angina, Bypass)

Other Reported Uses

  • Allergies
  • Asthma
  • Hypoxia
  • Impotence
  • Macular Degeneration
  • Arterial Or Venous Insufficiency, Intermittent Claudication
  • Decreases Platelet Aggregation, Improves Blood Flow
  • Increases Cellular Oxygenation
  • Radioprotective
  • Sexual dysfunction
  • Vascular Spasm (Raynaud's)

Toxicities & Precautions

General

Ginkgo is safe and side effects are extremely rare, but fresh seeds of the ginkgo tree should not be eaten because they may be toxic.

Allergy

An extremely rare allergic skin reaction has occurred with Ginkgo. (10)

Health Conditions

Based on pharmacology, use with caution in individuals with bleeding disorders. (11)

Side Effects

The most typical side effects are GI distress and headache. These are present in fewer than 0.5 percent of the people in studies.(9)

Cases of subdural hematoma have been reported due to ginkgo use.(12)

Pregnancy/ Breast Feeding

If pregnant or nursing, consult a physician before use.(13),(94)

Age Limitations

Do not use in children under 2 years of age unless recommended by a physician.

Pharmacology

Antioxidant Effects

The main active components of ginkgo include the flavoglycosides, and terpene lactones. These compounds act as strong free radical scavengers or antioxidants which can be attributed to many of ginkgo’s positive effect on body systems.(14),(15),(16) Ginkgo’s ability to decrease the loss of cell viability due to oxidative stress in many areas of the body is the main pharmacological property of the therapeutic efficacy of this dietary supplement.(17) Studies have reported that constituents in ginkgo may actually protect the brain neurons from oxidation and subsequent damaging free radicals, decreasing post-ischemic effects, and diseases such as Alzheimer’s disease.(18),(19),(20) It is also postulated that ginkgo’s positive effects against cardiac ischemia-reperfusion injury depend on its antioxidant properties.(21),(22),(23) Also, due to the potent antioxidant activity of ginkgo, a clinical study reported statistically significant improvements in visual function in patients having macular degeneration, glaucoma cataracts, and retinal impairments.(24),(25),(26),(27) Among the many clinical applications of ginkgo as an antioxidant are spinal cord injury,(28) lipid peroxidation pertaining to cholesterol metabolism including protection of HDL,(29),(30) cardiovascular protection including limiting oxidative stress in cardiovascular surgery,(31),(32) hepatoprotective effects,(33),(34) and in general to decrease the mitochondrial oxidative stresses that cause normal aging.(35)

Ginkgo’s antioxidant effects are also reported to decrease the damaging effects of radiation and chemotherapy.(36) The antioxidant activity of ginkgo was reported to decrease the negative effects of clastogenic factors created by radiation exposure.(37) Clastogenic factors are bio-markers of oxidative stress found in the plasma of irradiated persons, either accidentally or therapeutically, and cause the development of latent effects associated with damaging radiation. The negative effects of cyclosporin A on lipid peroxidation in human liver microsomes was decreased with the administration of a standardized ginkgo preparation during in vitro testing, suggesting that ginkgo might be able to prevent radical mediated damage to human membranes caused by this agent.(38) It should be noted that also in this study, vitamin E almost completely inhibited the lipid peroxidation caused by cyclosporin A.

PAF Antagonism

Ginkgo is also reported to inhibit platelet activating factor (PAF), reducing the adhesive nature of platelets possibly through competitive binding.(39) One of the components of ginkgo, ginkgolide B, is a potent platelet-activating factor (PAF) antagonist.(40) This action has been reported to contribute to ginkgo’s influence on increased cerebral and peripheral blood flow, improvement of delivery of nutrients to the brain, oxygenation of the tissues, and its positive effects in asthma and cardiovascular protection.(5),(41),(42) Free radicals and platelet activating factor (PAF) have been implicated as important mediators in neuronal injury after cerebral ischemia-reperfusion and, particularly, in postischemic hypoperfusion.(43) The PAF and antioxidant properties of ginkgo have also been reported useful in acute pancreatitis.(44) Ginkgo may foster vasodilation by stimulating endothelium releasing factor and prostacyclin.(45) It may also stimulate venous tone and improve the clearance of hemotoxins during ischemic episodes.(46)

Senile Dementia and Alzheimer’s Disease  

The efficacy of standardized ginkgo preparations in dementia of the Alzheimer type and multi-infarct dementia has been confirmed by many scientific studies in human subjects (6),(7),(95) although there are conflicting studies.(96),(97),(98),(99) In 1994, a standardized dry extract of ginkgo leaves was approved by German health authorities for the treatment of primary degenerative dementia and vascular dementia.(47) Modern research has helped to provide a better understanding of biochemical events that occur with the disease process of Alzheimer’s, including theories of the accumulation of beta-amyloid (Abeta)-derived peptides and free radical damage in the involvement of the destruction of neuronal cells. (19),(48) Ginkgo has been reported effective in decreasing the toxicity induced by (Abeta)-derived peptides (Abeta25-35, Abeta1-40 and Abeta1-42) on hippocampal primary cultured cells in vitro and also, as stated above, in reducing the damaging oxidative stress to neuronal cells, both of which have been reported to increase the probability of developing senile dementia and Alzheimer’s disease.(49),(50)

A randomized, double-blind, placebo-controlled, parallel-group, multicenter study of 309 patients with mild to severe dementia including Alzheimer disease or multi-infarct dementia were placed on a standardized ginkgo preparation or placebo for 52 weeks.(51) From the initial 309 patients included in the study, 202 of these individuals provided data for statistical analysis. Although not as significant as expected, the standardized ginkgo preparation (40mg three times a day) was reported safe and capable of stabilizing and improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. However, a recent 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of 214 subjects with dementia (either Alzheimer’s or vascular dementia) reported that treatment with the same standardized ginkgo preparation as above (either 2 tablets per day, total dosage either 240 or 160mg/day or placebo for a total of 24 weeks) reported no advantage of using the ginkgo extract over placebo.(52)

A study involving healthier individuals also questions the benefit of ginkgo for memory enhancement. This six-week randomized, double-blind, placebo-controlled, parallel-group trial involving 230 individuals older than 60 was designed to evaluate whether ginkgo could improve memory in this patient population. These individuals had to be in good health and needed a baseline Mini-Mental State Examination (MMSE) score greater than 26. They were then randomized to receive ginkgo, 40 mg, 3 times per day or matching placebo, 115 people in each group. Prior to beginning treatment and three days before completion of the six-week treatment program, each patient was evaluated by fifteen standard neuropsychological tests evaluating verbal and nonverbal learning and memory, attention and concentration, and naming and expressive language. Each participant completed a subjective self-report on memory and a companion completed a caregiver clinical global impression of change. The results of this study showed no improvement in the standard neuropsychological tests utilized and there was no difference between the groups in the self-reported memory function or in the global rating completed by their companion.(53)

The efficacy of four commonly used cholinesterase inhibitors (tacrine, donepezil, rivastigmine, metrifonate) and a standardized ginkgo extract were compared for their use in Alzheimer's disease versus placebo.(54) There were no major differences in the four medications and the ginkgo preparation in delaying the symptoms of the progression of dementia. However, tacrine exhibited adverse drug reactions and subsequently a higher drop-out rate. The authors concluded that second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) and the standardized ginkgo extract should be considered equally effective in the treatment of mild to moderate Alzheimer's dementia.

A 2009 randomized, double-blind exploratory study found that there was no significant difference in the efficiency of Alzheimer’s treatment between a standardized ginkgo supplement and donepezil, with a combination therapy being superior to a mono-therapy with one of both substances.(100) The authors also reported less side effects under a combination therapy of ginkgo and donepezil than under mono-therapy with donepezil.

Using appropriate dosages (240-480mg daily or greater) and standardized supplements are imperative when using ginkgo in AD and senile dementia therapy. It is also important for researchers to follow a more intensive follow-up rather than minimal follow-up of individuals in clinical trials using ginkgo in treating mild-moderate dementia.(101)

General Memory and Learning Impairment

Ginkgo has been reported in laboratory animals to increase learning and other cognitive behaviors.(55),(56),(57) Also, studies in humans have reported positive effects on age-associated memory impairment and learning along with an increase in attention. (52),(58),(59) Although the terpene fraction of ginkgo, which contains the ginkgolides, may contribute to the neuroprotective properties of the leaf, it is also likely that the flavonoid fraction, containing free radical scavengers, is also important in this respect. Taken together, the evidence suggests that Ginkgo biloba extracts are worthy of further investigation as potential neuroprotective agents. Ginkgo may also normalize acetylcholine receptors and, therefore, improve cholinergic function.(60)

A recent 6-week, double-blind, fixed-dose, placebo-controlled, parallel-group experimental study design was conducted to evaluate the effectiveness of ginkgo on cognitive and behavioral functioning.(61) The individuals were given 180 mg of a standardized ginkgo extract or placebo daily for 6 weeks. This group exhibited significantly more improvement on a task assessing speed of processing abilities and memory as compared to participants who received placebo.

Another double blind, placebo controlled, 14 week, parallel group, repeated assessment, multi-center trial of 256 healthy individuals was conducted to evaluate the effectiveness of ginkgo in combination with Panax ginseng (containing 60mg standardized ginkgo and 100mg standardized panax, either 1 capsule twice daily or 2 capsules in the am) on cognitive function.(62) The ginkgo/panax combination was found to significantly improve several different aspects of memory, including working and long-term memory. The memory enhancement was reported throughout the 12-week dosing period and also after a 2-week washout. A small multiple dose, placebo-controlled, double-blind, balanced-crossover study in young healthy subjects found that ginkgo modestly improved memory performance, but acute administration may have a negative effect on the speed of attention task performance, which is opposite to that seen previously following higher doses (greater than 120mg daily standardized).(102)

A 2009 selective review of 29 randomized controlled trials found that here is consistent evidence that chronic administration of ginkgo supplements improves selective attention, some executive processes and long-term memory for verbal and non-verbal material.(103) Also complexation of ginkgo with phosphatidylserine appears to potentiate the cognitive effects.(104)

Intermittent Claudication/ Cardiovascular Effects

 

Ginkgo has been reported useful in the treatment of peripheral occlusive arterial diseases (PAD).(63) Studies have reported that ginkgo products produce a statistically significant and clinically relevant improvement of the walking performance in patients suffering from intermittent claudication.(64),(65),(66) Ginkgo has been studied and compared to trental, which is used for intermittent claudication and peripheral vascular disturbances.(67) In treadmill walking studies, ginkgo significantly increased pain-free walking distance.(68),(69) Exercising regularly, stopping smoking, and limiting caffeine intake are also important in treating these conditions. Because of its ability to improve blood flow, ginkgo has been used for diabetic neuropathy, circulatory disorders, Raynaud’s Disease (70) or cyanotic, or post-phlebitis pathologies.

A double-blind, placebo-controlled, parallel design trial with a 4-month duration found that in older adults with PAD, ginkgo produced a modest but insignificant increase in maximal treadmill walking time and flow-mediated vasodilation.(105) However, a 2009 Cochrane Database review looked at randomized controlled trials of ginkgo extract, irrespective of dosage, versus placebo in people with intermittent claudication.(106) The authors concluded there is no evidence that ginkgo has a clinically significant benefit for patients with peripheral arterial disease. Further research needs to be performed in this area.

A small randomized trial found that ginkgo was effective in improving vascular endothelial function in early stage diabetic patients through decreasing the plasma level of von Willebrand Factor (vWF), raising the plasma nitric oxide (NO) levels and improving the endothelium dependent vascular dilating function.(107)

Tinnitus

Ginkgo has traditionally been used in the treatment of tinnitus with positive results in both human and animal studies.(71),(72) One multicenter, double-blind placebo controlled study of 103 patients with tinnitus reported positive benefits in the condition when using a ginkgo extract.(8) However, some studies have shown contradictory results of ginkgo in the treatment of tinnitus, with no reported value in the condition versus placebo.(73),(74) In these negative studies, three parameters should be taken into consideration that may have prognostic significance: chronicity, periodicity and uni- or bilateral nature of symptoms.(75)

Depression

Ginkgo’s use in depression may be in part due to its increase in cerebral blood flow.(76) Ginkgo has been reported in laboratory studies to have monoamine oxidase inhibiting (MAOI) effects (both MAO-A and -B types were inhibited to a similar extent).(77) The authors have postulated that ginkgo’s MAOI ability may be one mechanism for its reported anti-stress and antidepressant uses. Recent studies (both in humans and laboratory animals), however, have reported that ginkgo administration does not produce significant changes in brain MAO A or MAO B, suggesting that mechanisms other than MAO inhibition need to be considered as mediating some of its antidepressant effects.(78),(79) Another study evaluated the effectiveness of ginkgo in forty depressed patients above the age of fifty who showed incomplete response to tricyclic or tetracyclic antidepressants.(80) Patients in the treated group demonstrated significantly improved outcomes in depressive symptoms when compared to the placebo group.

Of interest, is that ginkgo products may be effective in reducing antidepressant-induced sexual dysfunction in humans.(81),(82),(83) It was reported to be 84% effective in treating antidepressant-induced sexual dysfunction predominately caused by selective serotonin reuptake inhibitors.(81) The authors presumed the effectiveness was due to such pharmacological mechanisms as effects on platelet activating factor, prostaglandin inhibition, peripheral vasodilatation, and central serotonin and norepinephrine receptor factor modulation.

Asthma

Ginkgo has been used in China for thousands of years in the treatment of asthma. Ginkgo, a PAF inhibitor, can inhibit inflammatory pathways that are implicated in asthmatic conditions, and has been reported beneficial in reducing antigen-induced lung anaphylaxis in laboratory animals.(84),(85) In one study, clinical symptoms and pulmonary functions of asthma patients were improved in contrast to placebo, where the ginkgo product significantly reduced airway hyper-reactivity.(86) Another in vitro study reported that ginkgolide B may have anti-inflammatory effects that are helpful in addition to other conventional therapies in controlling asthmatic patients.(87) A clinical study found that ginkgo may decrease the activation of PKCalpha in inflammatory cells and thereby decrease the IL-5 level in induced sputum, allowing ginkgo to be used in conjunction with glucocorticosteroid therapy for asthma.(108)

PMS

Ginkgo has also been reported in clinical studies to help decrease the symptoms of PMS. A standardized extract of gingko was reported useful in a placebo controlled, multicenter, double blind study in treating congestive symptoms of PMS.(88) The authors reported that the ginkgo preparation was effective against the congestive symptoms of PMS, particularly breast symptoms and emotional disturbances. Another randomized, placebo-controlled study in 85 women with PMS found that ginkgo was efficient effective at reducing the severity of symptoms.(109)

Other Uses

Ginkgo is used in a variety of clinical conditions that require an increase in blood flow, including altitude sickness,(89),(110) vertigo and other symptoms of vestibulocochlear disorders,(90),(91),(111) and sexual dysfunction.(83),(92) A small randomized trial found that the addition of ginkgo to glucocorticoid therapy for olfactory loss improved symptoms greater than drug monotherapy alone.(112)

A small placebo-controlled study found that the use of ginkgo as an adjunct to clozapine was found useful for enhancing the effect of clozapine on negative symptoms in patients with treatment-resistant schizophrenia.(113)

A small clinical study in China found that administration of ginkgo supplement to doxorubicin (Adriamycin) treatment reduced the acute cardiotoxic effects of doxorubicin.(114)

Studies using ginkgo in combination with other supplements (including L-arginine, ginseng, damiana and vitamins/minerals, ArginMax) has reported to be beneficial in treating sexual dysfunction, although a study using ginkgo alone reported no benefit over placebo.(115),(116)

A small double-blind, placebo-controlled, parallel group trial found that ginkgo improved fatigue in patients with multiple sclerosis.(117)

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