GINKGO BILOBA

The ginkgo biloba tree is the world’s oldest living tree – its species can be dated back to over 250 million years. The medicinal use of the leaves was recorded in China in 2800 BC and a monograph still exists in the modern Chinese Pharmacopoeia. Ginkgo biloba leaf extract is the most widely sold phytomedicine in Europe, where it is used to treat the symptoms of early-stage Alzheimer’s disease, vascular dementia, peripheral claudication, and tinnitus of vascular origin. There are over 400 published clinical studies on ginkgo, primarily from Europe. Standardized preparations contain 24 percent ginkgo flavonoid glyco- sides,6 percent terpene lactones,and no more than 5 parts per million ginkgolic acids (1,2). The mechanism of action of ginkgo is believed to be produced by its functions as a neuroprotective agent, an antioxidant, a free-radical scavenger, a membrane stabilizer, and an inhibitor of platelet-activating factor via the terpene ginkgolide B.(3-6). Other pharmacologic effects include the following: endothelium relaxation, (7,8) ;inhibition of age-related loss of muscarinergic cholinoceptors and adrenoceptors; and stimulation of choline uptake in the hippocampus (1,9) Ginkgo extract also has been shown to inhibit beta-amyloid deposition (10).

 

Neuroprotection

A systematic review of eight randomized, double-blind, placebo-controlled studies concluded that ginkgo had modest effects on improving the symptoms of dementia and cerebral insufficiency equivalent to pharmacologic therapy with ergoloid mesylates (Hydergine) (11). A later meta- analysis surveyed 50 articles to examine the effect of ginkgo on objective measures of cognitive function in patients with Alzheimer’s disease (12). Four of these studies met inclusion criteria for adequate clinical trial design (13-16).In the 212 subjects in the placebo and ginkgo groups, a significant overall effect size was found that was comparable with the benefits of donepezil (Aricept) (17). Efficacy was measured using the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other standardized measures of cognition.

A review of studies of at least six months in duration demonstrated that ginkgo extract and second-generation cholinesterase inhibitors were equally effective in treating mild to moderate Alzheimer’s dementia (18). A systematic review of nine studies on ginkgo use showed a safe and positive effect beyond placebo (19). A Cochrane meta-analysis of 33 trials concluded that ginkgo appears to be safe, and showed promising evidence of improvement of cognition and function among patients who received the herb (20).

 

Cognitive effects

The main active constituents are generally considered to belong to two distinct chemical groups: the biflavone glycosides such as ginkgetin, isoginkgetin, bilobetin and related compounds and the terpene lactones known as ginkgolides A, B, C, etc. and a sesquiterpene trilactone bilobalide (21,22). Most of the pharmacological and clinical work carried out on ginkgo has used an extract containing both these classes of compounds. Extracts also possess neuroprotective potential, thought to be mediated via inhibition of nitric oxide synthesis (23). It is not yet clear which individual classes of compounds are responsible for those effects relevant to memory enhancement; although each class has some differing effects, they also have others in common, in particular free radical scavenging and antioxidant effects (22). The ginkgolides are anti-inflammatory due to their specific platelet-activating factor antagonist properties (24) and also have complex effects on neurotransmitter uptake and certain neurotransmitter receptors in cerebral ischaemia and neuronal injury (21). Bilobalide has a protective effect against reactive oxygen species-induced apoptosis in PC12 cells (25) and, more importantly, is now known to act as an antagonist at recombinant GABA A receptors (26). There is now a body of literature pertaining to the cognitive enhancing properties of ginkgo in clinical populations suffering from vascular dementia (27,28) or Alzheimer’s disease (12,15, 27).

 

Memory

There is also some evidence of improved cognition in healthy ageing populations. Rigney et al. (28) investigated the effects of ginkgo in healthy volunteers (30–59 years) over a 1- to 2-day treatment period. They reported an improvement on the Sternberg memory scanning test after both 1 and 2 days of treatment, which was more pronounced for the 50- to 59-years age group. Hartley et al. (29) found improvements on tests of short-term memory, mental flexibility and sustained attention after 1 week of ginkgo treatment in postmenopausal women (aged 53–65 years). Since the participants in this study were not tested after an acute dose, it is not possible to determine whether the effects after 1 week differ from those after an acute dose. However, in a small cross-over study, Nathan et al. (30) found no effects of a single dose of ginkgo in older participants (aged 50–70 years) on tests of working memory, attention, visual or auditory episodic memory. The lack of effects in this study may be due to the small sample size or the time of testing after the dose (90 min).

 

Recall and attention

Mix and Crews (31) reported that ginkgo (180 mg/day) administered for 6 weeks improved performance on the selective reminding test and the Weschler Memory Scale in participants aged 60 years and older. In a similar study, ginkgo administered for 6 weeks improved performance on the colour-naming component of the Stroop task and showed a trend towards an improvement on the visual reproduction component of the Weschler Memory Scale in participants aged 55–86 (32). Four studies have investigated the effects of acute/subchronic doses of ginkgo in university students. Kennedy et al. (33) reported improvement in a factor of ‘quality of memory’ with an acute dose of ginkgo and improvement in a factor of ‘speed of attention’. Furthermore, ginkgo was found to improve performance on serial subtraction tasks (34), and improve performance on a factor of ‘secondary memory’ and, to a lesser extent, on a factor of attention (35). Moulton et al. (36) investigated the effects of short-term treatment with ginkgo in male college students. The ginkgo group performed better than the placebo group at the easiest stage of the Sternberg memory test the task. Stough et al. (37) is the only study to investigate chronic effects in a younger population. They reported improvement in working memory and memory consolidation in participants (aged 18–40 years) after 30 days of treatment with ginkgo.

An acute dose of ginkgo significantly improved performance on the sustained-attention task and pattern recognition memory task; however, there were no effects on working memory, planning, mental flexibility or mood (38). In line with the literature, after acute administration ginkgo improved performance in tests of attention and memory.

The European Medicines Agency have reviewed ginkgo biloba and published a monograph and concluded it to have a well established use for the improvement of (age-associated) cognitive impairment and of quality of life in mild dementia (39-41).

 

References

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2. Blumenthal M. Commission E. Herbal medicine: expanded Commission E monographs. Newton, Mass.: Integrative Medicine Communications, 2000:160-9, 479-80.

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6. Ahlemeyer B, Kriegelstein J. In: Lawson LD, Bauer R. Phytomedicines of Europe: Washington, D.C.: American Chemical Society, 1998:210-20.

7. World Health Organization. WHO monographs on selected medicinal plants. Vol. 1, Ch. 16. Folium Gingko. Geneva: World Health Organization, 1999:154-67.

8. DeFeudis FV. Ginkgo biloba extract (EGb 761): pharmacological activities and clinical applications. Amsterdam: Elsevier, 1991:1187.

9. DeFeudis FV. Ginkgo biloba extract (EGb 761): from chemistry to the clinic. Wesbaden: Ullstein Medical, 1998.

10. Watanabe CM, Wolffram S, Ader P, Rimbach G, Packer L, Maquire JJ, et al. Proc Natl Acad Sci U S A 2001;98:6577-80.

11. Kleijnen J, Knipschild P. Br J Clin Pharmacol 1992;34:352-8.

12. Oken BS, Storzbach DM, Kaye JA. Arch Neurol 1998; 55:1409-15.

13. Hofferberth B. Hum Psychopharmacol 1994;9:215-22.

14. Kanowski S, Herrmann WM, Stephan K, Wierich W, Horr R. Pharmacopsychiatry 1996;29:47-56.

15. Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. JAMA 1997;278:1327-32.

16. Wesnes K, Simmons D, Rook M, Simpson P. Hum Psychopharmacol. 1987; 2:159-69.

17. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. Neurology 1998;50:136-45.

18. Wettstein A. Phytomedicine 2000;6:393-401.

19. Ernst E, Pittler MH. Clin Drug Invest 1999;17:301-8.

20. Birks J, Grimley E, Van Dongen M. Cochrane Database Syst Rev 2002; 4:CD003120.

21 DeFeudis FV (1998) Ginkgo biloba: from chemistry to clinic. Ullstein Medical, Wiesbaden, Germany

22 Joyeux M, Lobstein A, Anton R, Mortier F (1995) Comparative antilipoperoxidant, antinecrotic and scavenging properties of terpenes and biflavones from Ginkgo, and some flavonoids. Planta Med 62:126–129

23 Calapai G, Crupi A, Firenzuoli F, Marciano MC, Squadrito F, Inferrera G, Parisi A, Rizzo A, Crisafulli C, Fiore A, Caputi AP (2000) Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis. Life Sci 67:2673–2683

24 Braquet P (1987) The Ginkgolides: potent platelet activating factor antagonists isolated from Ginkgo biloba L.: chemistry, pharmacology and clinical applications. Drugs Future 12:634–699

25 Zhou L-J, Zhu X-Z (2000) Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide. J Pharmacol Exp Ther 293:982–988

26 Huang SH, Duke RK, Chebib M, Sasaki K, Wada K, Johnston G (2003) Bilobalide, a sesquiterpene trilactone from Ginkgo biloba is an antagonist at recombinant α1β2γ2L GABAA receptors. Eur J Pharmacol 464:1–8

27 Kanowski S, Herrmann WM, Stephan K, Wierich W, Horr R (1996) Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 29:47–56

28 Rigney U, Kimber S, Hindmarch I (1999) The effects of acute doses of standardized Ginkgo biloba extract on memory and psychomotor performance in volunteers. Phytother Res 13:408–415

29 Hartley DE, Heinze L, Elsabagh S, File SE (2003) Effects on cognition and mood in postmenopausal women of 1-week treatment with Ginkgo biloba. Pharmacol Biochem Behav 75:711–720

30 Nathan PJ, Ricketts E, Wesnes K, Mrazek L, Greville W, Stough C (2002) The acute nootropic effects of Ginkgo biloba in healthy older human subjects: a preliminary investigation. Hum Psychopharmacol 17:45–49

31 Mix JA, Crews WD Jr (2000) An examination of the efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults. J Altern Complement Med 6:219–229

32 Mix JA, Crews WD Jr (2002) A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: neuropsychological findings. Hum Psychopharmacol 17:267–277

33 Kennedy DO, Scholey AB, Wesnes KA (2000) The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology 151:416–423

34 Scholey AB, Kennedy DO (2002) Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: differential interactions with cognitive demand. Hum Psychopharmacol 17:35–44

35 Kennedy DO, Scholey AB, Wesnes KA (2002) Modulation of cognition and mood following administration of single doses of Ginkgo biloba, ginseng, and a ginkgo/ginseng combination to healthy young adults. Physiol Behav 75:739–751

36 Moulton PL, Boyko LN, Fitzpatrick JL, Petros TV (2001) The effect of Ginkgo biloba on memory in healthy male volunteers. Physiol Behav 73:659–665

37 Stough C, Clarke J, Lloyd J, Nathan PJ (2001) Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol 4:131–134

38 Elsabagh S . Hartley D. Ali O. Williamson E. File S Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers Psychopharmacology (2005) 179; 437-446

39 Adopted monograph http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_herbal_monograph/2015/04/WC500185243.pdf 40 Assessment report http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2015/04/WC500185241.pdf 41 References http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_List_of_references_supporting_the_assessment_report/2015/04/WC500185242.pdf