GINKGOACEAE

The Ginkgoaceae family belongs to the Gymnosperms and consists of 1 genus and 1 species extinct in the wild but preserved as temple trees in China and Japan.

Ginkgo biloba

Ginkgo, maidenhair tree

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Family Ginkgoaceae

Description

A deciduous, resinous, dioecious tree to 40 × 7 m. Branches stiff with both elongate and spur shoots. Leaves alternate or clustered, fan-shaped, cut or divided in the middle, dichotomously veined, long-petioled, 5–7 cm long, soft green in spring, turning rich gold in autumn. Reproductive structures on spur shoots in axils of leaves or bracts; male catkin-like, female consisting of 2 ovules on a long peduncle, usually only 1 maturing but sometimes both. Fruit plum-like, yellow, fleshy to 2.5 cm long, seed a kernel, ripening in late autumn.

Odour—weak and characteristic.

Habitat and cultivation

Originally from S-E China the Ginkgo is grown as a street or ornamental tree throughout temperate regions of the world. It may be grown from seed, layers and cuttings and several cultivars are grown from buds or grafts. Male trees are most common because the smell of the ripe fallen fruits of female trees is unpleasant. Frost resistant, drought tender.

Parts used

The leaves gathered from mid summer to just prior to their turning yellow in mid autumn, this is when the content of the main active constituents is highest.

Active constituents1–4

1) Flavonoids (0.5–1.16%)5–7

a) flavones—mainly derivatives of kaempferol, quercetin and isorhamnetin, also derivatives of myricetin and rutin

b) biflavones—amentoflavone, bilobetin and ginkgetin8

The flavonoid levels which are influenced by geographical location,9 are highest in early summer, decrease till the end of summer and then are stable to the end of autumn before rising again just before leaf fall.10,11

2) Terpene lactones including diterpene lactones known as ginkgolides (up to 0.23%), mainly A, B and C with much smaller amounts of J, K and L12—these are unique chemical entities. Leaves from young trees of either sex are richer in terpenes than those from mature trees.13

3) Sesquiterpene lactone—bilobalide (up to 0.26%)

Also contains proanthocyanidins, phenolic acids (mainly protocatechuic acid, also vanillic and caffeic),14,15 ginkgolic acids (up to 1.5%),16,17 amino acids (around 9%) including some that are essential,18 polyprenols and phytosterols.19 Male leaves have a higher phenolic content than those of the female tree,10 although the latter have a more beneficial metal ion profile.20

Nutritional constituents

Vitamins: A, B6, C and E18

Actions

1) Vasodilator

2) Antispasmodic

3) Anti-inflammatory

4) Anti-oxidant

Scientific information

Ginkgo is one of the most consumed herbs, possibly because of the scientific information available and conversely because of its high usage, there continues to be a significant amount of research into it at all levels. Standardised extracts are registered in a number of countries for the treatment of neurological and vascular problems. Although there is a long history of Ginkgo use in Asia it was the seeds (called “nuts”) that were used, the first mention of the medicinal use of the leaves occurring in the 15th Century.21 Ginkgo was not part of the European materia medica until recent decades. Its modern application is being established by research into its constituents and their unique pharmacological actions. German Commission E has approved leaf extracts for use in the treatment of dementia, with symptoms of impaired memory, altered concentration and mood, dizziness, tinnitus and headaches. Also for use in peripheral arterial occlusive disease and vertigo. Research has been conducted on standardised extracts which have a variety of commercial names depending on the particular manufacturer.

Anti-oxidant

The flavonoids, terpenes,22 proanthocyanidins and organic acids all contribute to this activity15,23–26 which is comparable to that of vitamin E.27 The flavonoids are considered the most powerful anti-oxidants6 being significantly stronger than ascorbic acid.28

In vitro—Ginkgo has a variety of anti-oxidant mechanisms which include increases in oxygen scavenging, superoxide dismutase activity29 and cellular glutathione levels.30

It protects metabolites31–34 and cells35–39 against oxidative stress and using Ginkgo in topical preparations helps to stabilise them and may also offer protection to skin from free radical damage.40

Ex vivo—Gingko improved the anti-oxidant status of erythrocytes from healthy people as well as those with glucose-6 dehydrogenase deficiency,41 type 2 diabetes42 and patients with Behçets disease (in which this mechanism is impaired).43

In vivo—Oral doses were strongly anti-oxidant as seen in platelets from normal people and those with hypercholesterolaemia,44 reduced damaging free radicals in serum and erythrocyte membranes of insulin-dependent diabetics45 and in the serum of ultra-violet exposed sunbathers.46

However commercial preparations vary considerably in anti-oxidant potential depending on their method of preparation.47,48

Antiplatelet activating factor

Platelet activating factor (PAF) is released from various cells where it mediates reactions which include platelet aggregation, vasodilation, inflammation, vascular permeability, bronchoconstriction and anaphylaxis.

In vitro—The ginkgolides are PAF antagonists, ginkgolide B being the most effective49,50 and this, combined with their antioxidant capacity, may account for the anti-inflammatory action.51–54 In addition ginkgolide B enhances white blood cell function via its effect on their PAF receptors.55 Whole leaf extracts also inhibit platelet aggregation through a variety of mechanisms.56

In vivo—Ginkgolide B used in patients prior to kidney transplantation significantly improved their post-operative renal function, due to the anti-PAF activity inhibiting organ ischaemic-reperfusion injury.57

Circulatory system

Ginkgo's prime benefit is that it improves blood flow and much research has focussed on how this is achieved.

In vitro—Apart from the anti-PAF effect, the herb and/or some fractions of it:-

Excessive amounts of nitric oxide in macrophages leads to tissue damage and an exacerbation of atherosclerosis. Ginkgo reduces levels of nitric oxide produced by stimulated macrophages69,70 including that caused by homocysteine.71

Ex vivo—It reduces factors in blood indicative of active atherosclerotic plaque formation, in patients with coronary disease.72

In vivo—Ginkgo improves peripheral and cerebral blood flow,73 without increasing blood pressure74 and with a decrease in erythrocyte aggregation.75 In older adults it not only increased cerebral perfusion and cognitive function but also decreased blood viscosity.76 Indeed in a variety of vascular-related diseases the extract reduced blood-associated risk factors.77

In healthy adults Ginkgo protected against hypoxia-induced neurological dysfunction,78 reduced both systolic and diastolic blood pressure,79 had a vasoregulatory effect, being capable of either increasing or decreasing blood flow80 and reduced platelet hyperactivity.81

Clinical tests have found Ginkgo an aid in the treatment of:-

The majority of trials of Ginkgo treatment for cerebrovascular insufficiency have concluded it was an effective treatment for this condition.114,115 Benefits of Ginkgo to help in recovery from acute ischaemic strokes has been questioned, for although trials have reported improvement in neurological deficits in these patients, the methodology has been criticised and one scientifically acceptable study failed to demonstrate any advantage.116,117

Given Ginkgo's biological actions it was tested as a potential medication to prevent acute mountain sickness. Results have been mixed with several positive trials,118 two negative trials119,120 and one trial where it significantly reduced the severity of the symptoms.121 It may be beneficial in low oxygen environments by reducing nitric oxide-related cerebral vasodilation.122

Nervous system

This is the other main system in which Ginkgo's use has been extensively examined. Age-related dementia cases are increasing and as yet there is no medical “cure” for them. Oxidative stress is again considered one of the primary factors involved in neurodegenerative diseases causing neuronal loss and dysfunction. Patients with Alzheimer's disease for example have been found to have higher levels of oxidative damage in their frontal cortex.123

The aetiology and progression of neurodegenerative diseases like Alzheimer's dementia and Parkinson's disease have been associated with increased levels of particular proteins in brain tissue that accumulate, aggregate and become neurotoxic. In the case of Alzheimer's disease this protein is β-amyloid.124

In vitro—Ginkgo protects neurons from oxidative damage123,125–130 decreasing their apoptosis, reducing both the production of β-amyloid protein, via reduced cholesterol levels,131 and its aggregation.132 In addition ginkolides protect neurons directly from the toxic effects of β-amyloid protein and also from PAF.124,133

Ginkgo has other actions that may affect the nervous system. It inhibits the breakdown of neuropeptides that aid mental function134 and the ginkgolides and bilobalide are antagonists of inhibitory neurotransmitters, including GABAA, leading to increased neuronal excitability (used therapeutically in some antidepressants).135–137 It does not however seem to have any effect on monoamine oxidase activity.138,139

In vivo—Many clinical trials have demonstrated Ginkgo's efficacy in treating dementia due to multiple infarcts and Alzheimer-type dementia.140–144 Although the exact mechanisms by which the herb exerts these benefits are still not well understood actions such as protection for nerve cells, including from free radical damage, and increased blood flow no doubt contribute and it is probable that all the constituents of the herb are important in achieving the effect.

Ginkgo has been considered as effective as the current cholinesterase inhibitors used in the treatment of mild to moderate Alzheimer's disease145–148—(not corroborated149) with the added advantage that loss of improvement did not occur to the same extent on cessation of treatment.150 Ginkgo has in fact been shown to have the same effect on the brain's electrical activity as the cholinesterase inhibitors and drugs called cognitive activators or “nootropics”,151 normalising disturbed electrical activity in the cognitively impaired.152 It has also been shown to:-

Measurements of amyloid protein in plasma, which increases with age as well as with Alzheimer's disease, were lowered in healthy elderly people on Ginkgo supplements157 so that it may also help prevent the development of the disease.158 A large prospective trial has begun to evaluate this aspect.159

Some clinical trials found Ginkgo did not improve Alzheimer's disease,160 and/or age-related memory impairment161,162 or showed only slight benefit.163,164 Overall however the conclusion appears to be it has promise for the treatment of cognitive function in dementia or cognitive decline,165–167 is apparently as effective as current pharmaceuticals but with a better safety record.168 Ginkgo is regularly prescribed in Germany for the treatment of dementia.169

It has also helped in the treatment of other conditions of the nervous system. These include:-

Cancer protective

In vitro—Ginkgo has a biphasic effect on oestrogen and its receptors. It is oestrogenic when low levels of oestrogen are present, which would help in hormone depletion e.g. menopause, but is anti-oestrogenic when oestrogen levels are high and therefore may protect against hormone-dependent cancer.250,251 It has antiproliferative effects on a number of cancer cell lines252–256 and is anti-angiogenic.257 In addition the flavonoids can act as anticancer agents as they are anti-oxidant, alter genetic expression of factors associated with cancer formation and increase detoxification of chemical carcinogens.258,259

In vivo—Extracts have inhibited chromosomal damage from radiation and oxidative stress, both being potential cancer-inducers.257 Chromosomal radiation damage was significantly reduced in workers from the Chernobyl reactor accident after 2 months treatment260 and benefits persisted for months after cessation of Ginkgo therapy.261

Intra-venous Ginkgo improved the effect of conventional chemotherapy treatment in progressive colorectal cancer, so it may have an adjunctive role too.262,263

Endocrine

In vitro—Ginkgo inhibits fatty acid synthase which is a new target treatment for obesity.264

Fractions of the leaf were good relaxants of penile corpus cavernosum tissue and may have significance for treating impotence.265

In vivo—studies have indicated Ginkgo could also help in the following:-

Gingko increased the production of insulin from pancreatic cells in non-diabetics79 and also in type 2 diabetics (including those with pancreatic exhaustion), although this may not necessarily mean improved glucose tolerance as it may increase insulin catabolism too.278 The increase in insulin level was not accompanied by increased resistance to the hormone.279 In addition type 2 diabetics on Ginkgo supplements showed a reduced risk of developing vascular problems.279

Antimicrobial

Gingko inhibits the growth of Streptococcus pyogenes280 and the cytotoxic enzyme produced by Porphyromonas gingivalis.281 Constituents inhibit Clostridium perfringens, Escherichia coli,282 Enterococcus faecalis283 and Pneumocystis carinii284 and a peptide also has antifungal activity.285

Other

In vitro—Gingko stimulates production of collagen and fibronectin and enhances growth of skin fibroblasts,286 reduces platelet aggregation and thromboxane levels suggesting inhibition of COX-1287 and inhibits T-cell lymphocyte stimulation by inflammatory cytokines.288

In vivo—The herb was effective in the treatment of interstitial pulmonary fibrosis289 and helped in the treatment of moderate chronic asthma,290 reducing airway inflammation.291 It also arrested the progress of vitiligo292 and liver fibrosis due to chronic hepatitis293 and with co-enzyme Q was reported to benefit fibromyalgia syndrome.294 Applied topically the flavones inhibited skin inflammation.295

Ginkgo has been subject to more research than most other herbs. The inconsistencies in the results of clinical trials above highlight general flaws associated with research into agents as complex as herbal medicines. Reviewers of the trials found large inconsistencies in methodology296 and often the extracts used were not characterised.297 Furthermore by using standardised extracts it may be assumed that the test “drug” is consistent but standardised commercial extracts still vary chemically1,298–301 and some may have been synthetically fortified.301,302 Standardisation of one or two constituents also ignores the contribution of other constituents which could still have variable levels and/or variable bioavailability.303,304

Medicinal uses

Cardiovascular system

Respiratory tract

Nervous system

Reproductive tract

Endocrine system

Pharmacy

Three times daily  
Infusion of dried herb –   2–3 g
Standardised extract –   40 mg

It may take at least 12 weeks to see improvements.

Standardised extracts used in clinical trials contained a flavone glycoside content in the range of 22–27% and terpene lactone content of 5–7% of which 2.8–3.4% are ginkgolides and 2.6–3.2% is bilobalide.2 These extracts were not all identical and some may not have contained all the constituents present in the raw leaf e.g. some lacked biflavones.

Pharmacokinetics

In vitro—Studies show that membrane transport may limit cellular levels of the main flavonoids.305

In vivo—The flavonoids, quercetin and kaempferol are absorbed at about the same rate and are excreted as glucuronides in urine.306 The main ginkgolides and bilobalide appear to be well absorbed, ginkgolide A having a half-life of 4.5 hours, ginkgolide B 10.6 hours and bilobalide 3.2 hours.307 Gingkolide B reaches maximum plasma concentration 2.3 hours after administration of the extract308 and total ginkgolides peak 2 hours after ingestion.309 About 70% of ginkgolide A, 50% ginkgolide B and 30% of bilobalide were excreted unchanged in urine following oral doses.49

Precautions and/or safety

Ginkgolic acids are potentially toxic and allergenic and German Commission E has set maximum allowable level of 5 ppm (5 mg/kg) in standardised extracts.310,311 Ginkgolic acids have been found in commercial ginkgo products at levels a great deal higher than this.302,312 Colchicine, as a contaminant, has also been reported.313 Possible side-effects are gastric disturbance, vomiting and diarrhoea; restlessness and headache all of which have been reported after using standardised preparations. Their occurrence is rare and the trials above consistently reported good safety and tolerance for Ginkgo, adverse events being no different from that reported for placebo.204,314

There are more serious anecdotal reports implicating Ginkgo in the development of acute generalised exanthematous pustulosis,315 toxic epidermal necrolysis,316 ventricular arrhythmia,317 spontaneous haemorrhage,318–320 post-operative bleeding,321–326 sub-dural haematoma327 and seizures in epileptics.328,329 The nuts inside the fruit are considered neurotoxic and cytotoxic330 and have been associated with vomiting and convulsions.331 Contamination of leaf extracts with ginkgolic acid is cited as a possible contribution to epileptic seizures, particularly in the elderly.332

In healthy volunteers, including some who were elderly, Ginkgo did not alter bleeding or coagulation times.333–335 Furthermore the levels of ginkgolides required to produce anti-PAF activity are estimated to be 100 times higher than that found at peak plasma levels when recommended doses of standardised extracts are used suggesting that it is unlikely to cause haemorrhaging.336 Reviews of data on patients using Ginkgo have concluded there is a low but increased risk of bleeding.337,338

Extracts have been found to be free of type I allergens.339

Interactions

In vitro—Ginkgo affected the organic anion-transporting polypeptide B which is involved in intestinal absorption of some drugs,340 although no related in vivo problems have been reported.

In vivo—Studies are not consistent regarding the effects of the extract or its fractions on the various P450 isozymes.341–345 Where inhibition of P450 has occurred e.g. CYP2C9 indicating a potential interaction between warfarin and Ginkgo,346 which was demonstrated using rats as a model,347 it did not occur in vivo in humans. Specifically, at recommended doses, it did not affect clotting time, pharmacokinetics or pharmacodynamics of warfarin in healthy volunteers.346–348 Data from either in vitro or animal studies are therefore not necessarily predictive of what is likely to occur in humans in vivo. Cytochrome-P450 levels are believed to decline with age possibly changing drug metabolism in the elderly in a more marked manner and as this is a subset of the population more likely to use Ginkgo this could be a concern. The herb's effect on elderly healthy subjects was tested with a variety of drugs metabolised by different P450 isozymes, no significant interactions occurred.349

Another possible area for interaction arises from Ginkgo's anti-PAF activity where it has been predicted it would increase bleeding if used with aspirin or other antithrombotic medications.350 Co-administering Ginkgo with antithrombotic pharmaceuticals, including aspirin and warfarin (as above), did not enhance antiplatelet activity.351–355

Specific tests failed to produce an interaction with metformin (diabetes),356 donepezil (Alzheimer's disease),357 digoxin358 and antipyrine (anti-inflammatory).359

Caution: Ginkgo was shown to potentiate the effect on bleeding time of cilostazol without enhancing antiplatelet activity.351 It may interact with omeprazole360 and nifedipine.361

Anecdotal cases have been reported of interactions with the concomitant use of a standardised extract and ibuprofen (fatal intracerebral bleed)362 and low-dose trazodone (coma).363

Further studies are needed to clarify these potential interactions but to-date no human studies have found a proven interaction between ginkgo and any pharmaceuticals in vivo.364,365

Historical uses

Chinese use has been long term (4000 years!) to “benefit the brain, coughs, asthma and heart. Also for filariasis, enuresis; leucorrhoea and longevity. Leaves for diarrhoea.