By Clement O. Egharevba

Ginkgo biloba L. is a popular medicinal plant which is commonly used for the treatment of problems associated with peripheral circulation and to improve memory and cognitive function especially in the elderly. It has a high economic value and is arguable one of the top selling herbal medicine in the world.

Ginkgo biloba L. (Ginkgoaceae), commonly called maidenhair tree, It is the oldest living tree on earth with no relative, it is believed to have been around from the middle of the Jurassic period for over 180 million years and has rightly been described (Cranes 2013) as the tree that time forgets. They are reputed to be the only trees that survived a nuclear explosion and it is undoubtedly one of the most loved trees of the world (Zhou and Zhang 1989).

It is one of the oldest documented Chinese herbs; the leaves are used to enhance memory and concentration in the elderly while the nuts are used as a popular delicacy in Eastern Asian countries even today. It was nearly extinct at a time, but was rescued from Buddhist monasteries in China, where it is treated as a sacred plant. It was introduced to Europe in the 1700s and was initially cultivated solely for its beauty (as ornamental trees in gardens). Ginkgo is one of the trees found in Brunswick Square Gardens, a few minutes walking distance from Mecklenburgh Square Garden. The trees are capable of reaching an age of a thousand years. Occurring as either male (staminate) or female (carpelate) plants, the male form is planted throughout the temperate regions of the world for ornamental purposes. The female trees are rarely planted for such purpose because the seeds emit a pungent unpleasant odour after exposure to frost (Santamour et al., 1983b).

Just as the human population is estimated to occur in an approximate ratio of 1 : 1 of males to females, natural Ginkgo populations are also estimated to occur in a similar ratio. Occasionally, individual trees with both male and female flowers are seen (Santamour et al., 1983b). Young growing Ginkgo trees are distinctly pyramidal in shape with a prominent central leader and widely spaced whorls of lateral branches that grow out diagonally to the main trunk, but this shape is changes to a broad – spreading crown at around 25 years of age when the plant starts maturing sexually, grows slows down and the tree fills its sparsely branched structure (Del Tredici, 1991c). Ginkgo trees usually grow to a height of 20 – 40 metres at maturity depending on the growing conditions. (Del Tredici, 1991b).

It has unique attractive fan-shaped leaves with long stalks which emerge from the sheath on the stem. The tree is sometimes commonly called ‘maidenhair tree’ due to the resemblance of its leaves to maidenhair fern leaves, and they usually turn from green to yellow in autumn. Ginkgo longevity may be partly due to its resistance to diseases caused by germs, as well as sulphur dioxide and ozone pollution, thus making them suitable horticultural plants for urban areas (Sinclair et al., 1987).

The female plant bears ovules which are fertilized by pollen from the male plants between April and May to yield fruits, the developing ovules are green, and turn yellow in autumn in response to cold temperatures as they mature. The mature fruits have a foul odour and fall off from the tree one month after fertilization (Parliament, 1995).

Historical and modern uses

Ginkgo has a remarkable healing virtue which was recorded as far back as 2800 BCE in the oldest Chinese materia medica (Del Tredici, 1991). The leaves were used in China to strengthen cerebral function, improves memory and blood circulation, while the seeds were traditionally served to guests with alcoholic drinks in Japan. It has been demonstrated pharmacologically that there is an enzyme in the seed which speeds up alcohol metabolism in the body, thus underscoring the folkloric ancient wisdom. In addition, raw Ginkgo nuts cleaned of their fresh pulp have long been used in traditional Chinese medicine to treat a variety of lung-related ailments such as bronchitis and asthma, as well as for the treatment of kidney and bladder disorders (Bensky et al. 1986).

The general medical benefits of Ginkgo are related to its ability to improve circulation of blood in the small blood vessels of the body/ brain, and thus, the conditions for which Ginkgo are recommended are those in which these capillaries are either damaged or not working maximally. Generally, Ginkgo

is used to treat conditions of cerebral insufficiency related to aging, when caused by poor circulation and subsequent poor oxygen supply to the cells of the brain and body, for instance: it is registered in the UK for the treatment of Raynaud’s disease, a condition where there is impaired circulation of blood to the extremities of hands and feets in response to cold or emotional stress.

Ginkgo extracts are also used for the symptomatic treatment of cerebral insufficiency, mild to moderate dementia syndromes, enhancement of cognitive performance, and symptomatic treatment of peripheral arterial occlusive disease. Furthermore, it is useful in the management of Alzheimer’s disease. (Weitbrecht W-U and Jansen W. 1986, Vesper J. Hansgen K-D. 1994, Rigney et al 1999, Bauer U. 1984)

Ginkgo botanicals has become one of the top selling herbal medicines in the world, possibly because people are living longer and encountering more frequently those conditions for which Ginkgo is useful.

Phytochemistry

Several studies have shown that the leaves contains numerous chemical constituents such as terpenes, flavonoids, alkyl phenols, tannins, lipids, calcium oxalate, cytokinins, but the terpenes and flavonoids are the predominant constituents. Standardized Ginkgo extract is made from the dried leaves of Ginkgo biloba and should not contain less than 0.5 per cent of flavonoids, expressed as flavone glycosides. The principal terpenes are called ginkgolides while the flavonoids are majorly Quercetin and kaemferol derivatives. These flavonoids contribute to the free radical scavenging activities of Ginkgo (DeFeudis, 1991)

Scientific evidence

There is substantial published scientific evidence that demonstrates the beneficial effects of the use of Ginkgo. Firstly, effects of chemically well-defined extracts on the blood flow in the brain have been demonstrated in many studies. For example, Szabo et al. 1997 also demonstrated the ability of Ginkgo to improve the circulation of blood flow in the body. This effect is not unique to the brain, but it is particularly important to the brain where it contributes to the relaxation of the brain capillaries, allowing more blood as well as more oxygen into the brain, therefore helping to improve one’s cognitive ability. In addition, it also inhibits the release of nitric oxide, a naturally occurring ROS, which acts as a vasodilator. This mechanism is hypothesized to reduce oxidative cellular damage in Alzheimer’s disease.

Braquet et al. (1991), demonstrated that ginkgolide B inhibited the generation of inflammatory mediators and prevent blood platelets from sticking to endothelial cells, thereby preventing blood-clotting within the blood vessels which usually results in complete blockage (stroke) if it blocks supply to (part of) brain when unchecked.

Furthermore, Augustin et al. 2009 found that consumption of Ginkgo by mice increases the expression of certain types of genes in parts of the mouse brain such as hippocampus, which is the centre of learning and memory, and the cerebral cortex, which serves to control speech, memory, and a variety of other functions. These genes play important roles in reducing symptoms of Alzheimer’s disease and were greatly increased as a result of Ginkgo consumption.

Also, flavonoids have long been known to act as free radical scavengers and Pietri et al. in 1997 demonstrated that the flavonoids in Ginkgo serve as free radical scavengers and helps to combat oxidative stress by mopping up reactive oxygen species (ROS). ROS can damage DNA, lipids, and proteins, and as these damaged molecules accumulate in the body, they bring about the unfortunate aspects of ageing. ROS are always present in the body because they are part of the consequences of normal metabolic process. However, their actual amount is a balance between the natural processes that create them, lifestyle choices (smoking, diet) and the efficiency of the mopping-up mechanism. Therefore, consumption of Ginkgo extract would contribute to a person’s general health just as an antioxidant-rich diet of vegetables would do. The antioxidant properties and/or free radical-scavenging properties are said to help prevent transient ischemic attacks and strokes.

CLINICAL EVIDENCE

The clinical efficacy of Ginkgo has been demonstrated by clinical studies which suggests that Ginkgo exerts a neuroprotective effect over the brain by increasing blood flow to the degenerating brain cells. As a result, it exerts a positive effect in the treatment of dementia due to Alzheimer’s disease and normal cognitive decline in the elderly (Hofferberth, 1994). Ginkgo extracts are also known to strengthen a number of neurotransmitter receptors, including serotonin and noradrenaline. Furthermore, it also potentiates the effect of neurotransmitters such as dopamine and serotonin by inhibiting their neuronal uptake (Ramassamy et al., 1992a). However, Cochrane review (2009) concludes ‘There is no convincing evidence that Ginkgo biloba is efficacious for dementia and cognitive impairment’.

Lastly, several other studies have also demonstrated that Ginkgo improves cognition and memory, In one study (Stough et al. 2001), 61 healthy participants (18-40 years) showed improved memory process (particularly working memory process), working memory speed, memory consolidation and executive functioning when given 120 mg of Ginkgo extract daily for 30 days, study was compared to placebo.

It must be noted that the vast majority of these studies have been conducted with one propitiatory extract (EGb761), which had been developed specifically for the above indications

Caution, risks and interactions.

There have been no serious adverse events reported with the use of Ginkgo. However, there are rare cases of mild gastrointestinal disturbances, headaches and allergic skin reactions reported (Kleijnen and Knipschild 1992). There have also been reports of possibility of Ginkgo increasing the bleeding time in patients on concomitant warfarin, but there have been no evidence of inhibition of blood coagulation by the extract (Kohler 2003).

Raw Ginkgo nuts contain a toxin (4-O-methylpyridoxine), whose primary mode of action is to antagonise the activity of vitamin B6 and also causes contact dermatitis (Wada and Haga, 1997, Kochibe 1997). Children are typically more susceptible to poisoning from raw ginkgo nuts than adults.

Conclusion

The use of Ginkgo leaf extract has increased tremendously in the world over the past decades due to its numerous beneficial effects which have been supported by several scientific and clinical studies. It has become one of the top selling herbal medicines / botanicals in the world. While it is a prescription medicine (licensed drug) in some countries e.g. Germany, it is simply a food supplement or traditional herbal medicine in others like the UK. The increased demand for Ginkgo may not be unconnected with the fact that people are living longer these days and are more likely to experience ageing conditions such as memory loss, Alzheimer’s disease or other symptoms associated with decreased blood flow for which Ginkgo is predominantly used.

It is however not practical to use the leaves from the tree directly because the active ingredients are in minute concentrations, not sufficient to give a reasonable beneficial health effects, it is for this reason that commercial Ginkgo leaf extracts are available. Sadly as of 2015 / 2016 a large number of unregulated products were available through shops on highstreets and the internet, which often do not even contain a relevant amount of a Ginkgo extract (Booker et al 2016). Registered products with the Traditional Herbal Registration (THR) number and logo as well as patient information leaflet are of guaranteed quality and only these can recommended..

Disclaimer

In this essay, we do not intend to advise or recommend herbs for medicinal or health use. This information is for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products). The information provided should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

© Clement Osaigbokan Egharevba

MSc student (2015-2016),
Research Cluster Biodiversity and Medicines / Centre for Pharmacognosy and Phytotherapy,
UCL School of Pharmacy, Univ. London,
29-39 Brunswick Sq.,
London. WC1N 1AX.

References
Augustin S., Rimbach G., Augustin K., Cermak R., and Wolffram S (2009). Gene Regulatory Effects of Ginkgo biloba Extract and Its Flavonol and Terpene lactone Fractions in Mouse Brain. Journal of Clinical Biochemistry and Nutrition; 45(3): 315–321
Bensky D., Gamble A., Kaptchuk T. (1986) Chinese Herbal Medicine: Materia Medica .
Birks J, Grimley E. J. (2009). Dementia and Cognitive Improvement Group. Cochrane reviews.
Booker, A., Frommenwiler D., Reich E., Horsfield S, Heinrich M. (2016) Adulteration and Poor Quality of Ginkgo biloba Supplements. Journal of Herbal Medicines 6, 79–87
Braquet P., Hosford D., Koltz P., guilbaud J., Paubert-Braquet M. (1991). Effect of platelet –activating factor on tumour necrosis factor-induced superoxide generation from human neutrophils. Possible involvement of G proteins. Lipids 1991; 26: 1071-5.
Crane, P. and Von Knorring, P. (2013) Ginkgo: The tree that time forgot. Yale University Press.
DeFeudis, F. V. (1991) Ginkgo biloba extract (EGb 761): Pharmacological Activities and Clinical Applications. Editions Scientifiques Elsevier, Paris.
Del Tredici, P. (1991). The architecture of Ginkgo biloba L. L’ Arbre. Biologie et developpement. C. Edelin ewd., Naturalia Monspeliensia, 155-167.
Del Tredici, P. (1991b) Ginkgos and People: A thousand years of interaction. Arnoldia, 51, 2-15.
Del Tredici, P. (1991c) The architecture of Ginkgo biloba L. In C. Edelin (ed.), L’ Arbre, Biologie et Developpement. Naturalia Monspeliansia n. h. s., pp. 155-168.
Hofferberth, B. (1994). The efficacy of EGb 761 in patients with senile dementia of the Alzhemer type, a double-blind, placebo-controlled study on different levels of investigation. Human Psychopharmacology, 9, 215-222.
Hoffmann F., Beck C., Schutz A., Offermann P. (1994) Ginkgo –extrakt EGb 761 (Tebonin)/ HAES versus Naftidrofuryl (Desodril) / HAES. Eine randomisierter Studie zur 73: 149-52.
Kleijnen J. and Knipschild P. (1992). Ginkgo biloba for cerebral insufficiency. British Journal of Clinical Pharmacology; 34:352-8.
Kochibe, N. (1997). Allergic substances of Ginkgo biloba. In T. Hori, R. W. ridge, W. Tulecke, P. del Tredici, J. Tremouillaux-Guiller, and H. Tobe (eds0, Ginkgo biloba – A Global Treasure. Springer- Verlag, Tokyo, pp. 301-307.
Kohler S. (2003) Influence of Ginkgo biloba extract versus placebo on coagulation. Clinical Research Department, Dr. Willmar Schwabe Pharmaceuticals, 76227 in a controlled study. Clinical Laboratory Haematology; 25:251-3.
Parliament, T. (1995) Characterization of the putrid aroma compounds in Ginkgo biloba fruits. In R. Rouseff and M. Leahy (eds.) Fruit Flavour: Biogenesis, Characterization, and Authentication, American Chemical Society. Symposium Series, 596, pp. 276-279.
Pietri S., Seguin J. R., D’Arbigny P, Drieu K, Culcasi M. (1997). Ginkgo biloba extract (EGb 761) pretreatment limits free radical-induced oxidative stress in patients undergoing coronary bypass surgery. Cardiovascular Drugs Therapy; 11(2):121-131.
Pietri S., Maurelli E., Drieu K., Culcasi M. (1997) Journal of Molecular Cell Cardiology. 29:733–742.
Ramassamy, C., Christen, Y. and Costentin, J. (1992a) The Ginkgo biloba extract, EGb 761, increases synaptosomal uptake of 5-hydroxytryptamine: in-vitro and ex-vitro studies. J. Pharmacol., 44, 943-945
Rigney U., Kimber S., Hindmarch I. (1999). The effects of acute doses of standardized Ginkgo biloba extract on memory and psychomotor performance in volunteers. Phytotherapy Res; 13:408-15.
Santamour, F. S., He, S. A., Ewert, T. E. (1983b) Growth, Survival and Sex expression in Ginkgo. J. Arboriculture 9: 170-171.
Sinclair, W. A., Lyon, H. H., Johnson, W. T. (1987) Diseases of Tress and Shrubs, Comstock Publishing Associates, Ithaca.
Szabo, M. E., Droy-Lefaix, M. T., and Doly, M. (1997). Direct measurement of free radicals in ischemic/reperfused diabetic rat retina. Clinical Neurosciences 1997; 4(5): 240-245..
Wada K. and Haga M., (1997) Food poisoning by Ginkgo biloba seeds in Hori et al. 373-383.
Zhou, Z. and Zhand, B. (1989) A middle – Jurassic Ginkgo with ovule-bearing organs from Henan, China. Palaeontographica, b 211, 113-133.